Effects of Physical Training on Physical and Psychological Parameters in Individuals with Patella Tendinopathy: A Systematic Review and Meta-Analysis.
The effectiveness of physical training on physical and psychological parameters in individuals with patella tendon myopathy has not been investigated in a systematic review and meta-analysis. The aim of the present study was to determine the effects of physical exercise interventions for measures of physical and psychological performance in subjects with patella tendon myopathy. A computerised systematic literature search was conducted in the electronic databases PubMed, Medline, and Web of Science from January 1960 to July 2020. Initially, 506 articles were identified for review of which eleven articles met the inclusion criteria. Our results revealed a small effect (weighted mean standardized mean difference (SMD) = 0.12; nine studies) of physical training on the psychological measure Victorian Institute of Sport Assessment-Patellar tendon scale and a medium effect (weighted mean SMD = 0.61; five studies) on the psychological measure visual analogue scale-both in favour of the intervention group. In contrast, a small effect (weighted mean SMD = -0.05; two studies) in favour of the control group was detected for the physical measure muscle power. Compared to the control condition, physical training seems to be an effective means to improve psychological but not physical parameters in individuals with patella tendon myopathy; although conclusions on the latter could have been biased by the small amount of eligible studies (n = 2). In addition, the predetermined cut-off value of ≥6 for the Physiotherapy Evidence Database scale score (i.e., assessment of methodological quality) was only achieved by six out of eleven studies. Thus, further research of high methodological quality is needed to verify whether there is or is not an effect of physical training on physical parameters in persons with patella tendon myopathy.


Rapid infrared mapping for highly accurate automated histology in Barrett's oesophagus.
Barrett's oesophagus (BE) is a premalignant condition that can progress to oesophageal adenocarcinoma. Endoscopic surveillance aims to identify potential progression at an early, treatable stage, but generates large numbers of tissue biopsies. Fourier transform infrared (FTIR) mapping was used to develop an automated histology tool for detection of BE and Barrett's neoplasia in tissue biopsies. 22 oesophageal tissue samples were collected from 19 patients. Contiguous frozen tissue sections were taken for pathology review and FTIR imaging. 45 mid-IR images were measured on an Agilent 620 FTIR microscope with an Agilent 670 spectrometer. Each image covering a 140 μm × 140 μm region was measured in 5 minutes, using a 1.1 μm2 pixel size and 64 scans per pixel. Principal component fed linear discriminant analysis was used to build classification models based on spectral differences, which were then tested using leave-one-sample-out cross validation. Key biochemical differences were identified by their spectral signatures: high glycogen content was seen in normal squamous (NSQ) tissue, high glycoprotein content was observed in glandular BE tissue, and high DNA content in dysplasia/adenocarcinoma samples. Classification of normal squamous samples versus 'abnormal' samples (any stage of Barrett's) was performed with 100% sensitivity and specificity. Neoplastic Barrett's (dysplasia or adenocarcinoma) was identified with 95.6% sensitivity and 86.4% specificity. Highly accurate pathology classification can be achieved with FTIR measurement of frozen tissue sections in a clinically applicable timeframe.


Successively thresholded domain boundary roughening driven by pinning centers and missing bonds: Hard-spin mean-field theory applied to d=3 Ising magnets.
Hard-spin mean-field theory has recently been applied to Ising magnets, correctly yielding the absence and presence of an interface roughening transition respectively in d=2 and d=3 dimensions and producing the ordering-roughening phase diagram for isotropic and anisotropic systems. The approach has now been extended to the effects of quenched random pinning centers and missing bonds on the interface of isotropic and anisotropic Ising models in d=3. We find that these frozen impurities cause domain boundary roughening that exhibits consecutive thresholding transitions as a function of interaction anisotropy. For both missing-bond and pinning-center impurities, for moderately large values of the anisotropy, the systems saturate to the "solid-on-solid" limit, exhibiting a single universal curve for the domain boundary width as a function of impurity concentration.


NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1α.
Transcription factor NRF2 is an important modifier of cellular responses to oxidative stress. Although its cytoprotective effects are firmly established, recent evidence suggesting important roles in cancer pathobiology has yet to be mechanistically developed. In the current study, we investigated the role of NRF2 in colon tumor angiogenesis. Stable RNAi-mediated knockdown of NRF2 in human colon cancer cells suppressed tumor growth in mouse xenograft settings with a concomitant reduction in blood vessel formation and VEGF expression. Similar antiangiogenic effects of NRF2 knockdown were documented in chick chorioallantoic membrane assays and endothelial tube formation assays. Notably, NRF2-inhibited cancer cells failed to accumulate HIF-1α protein under hypoxic conditions, limiting expression of VEGF and other HIF-1α target genes. In these cells, HIF-1α was hydroxylated but pharmacological inhibition of PHD domain-containing prolyl hydroxylases was sufficient to restore hypoxia-induced accumulation of HIF-1α. Mechanistic investigations demonstrated that reduced mitochondrial O(2) consumption in NRF2-inhibited cells was probably responsible for HIF-1α degradation during hypoxia; cellular O(2) consumption and ATP production were lower in NRF2 knockdown cells than in control cells. Our findings offer novel insights into how cellular responses to O(2) and oxidative stress are integrated in cancer cells, and they highlight NRF2 as a candidate molecular target to control tumor angiogenesis by imposing a blockade to HIF-1α signaling.


Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein-protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X). Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.


Seasonal dynamics of arboreal spider diversity in a temperate forest.
Measuring and estimating biodiversity patterns is a fundamental task of the scientist working to support conservation and inform management decisions. Most biodiversity studies in temperate regions were often carried out over a very short period of time (e.g., a single season) and it is often-at least tacitly-assumed that these short-term findings are representative of long-term general patterns. However, should the studied biodiversity pattern in fact contain significant temporal dynamics, perhaps leading to contradictory conclusions. Here, we studied the seasonal diversity dynamics of arboreal spider communities dwelling in 216 European beeches (Fagus sylvatica L.) to assess the spider community composition in the following seasons: two cold seasons (I: November 2005-January 2006; II: February-April) and two warm seasons (III: May-July; IV: August-October). We show that the usually measured diversity of the warm season community (IV: 58 estimated species) alone did not deliver a reliable image of the overall diversity present in these trees, and therefore, we recommend it should not be used for sampling protocols aimed at providing a full picture of a forest's biodiversity in the temperate zones. In particular, when the additional samplings of other seasons (I, II, III) were included, the estimated species richness nearly doubled (108). Community I possessed the lowest diversity and evenness due to the harsh winter conditions: this community was comprised of one dominant species together with several species low in abundance. Similarity was lowest (38.6%) between seasonal communities I and III, indicating a significant species turnover due to recolonization, so that community III had the highest diversity. Finally, using nonparametric estimators, we found that further sampling in late winter (February-April) is most needed to complete our inventory. Our study clearly demonstrates that seasonal dynamics of communities should be taken into account when studying biodiversity patterns of spiders, and probably forest arthropods in general.


Text Entry in Virtual Environments using Speech and a Midair Keyboard.
Entering text in virtual environments can be challenging, especially without auxiliary input devices. We investigate text input in virtual reality using hand-tracking and speech. Our system visualizes users' hands in the virtual environment, allowing typing on an auto-correcting midair keyboard. It also supports speaking a sentence and then correcting errors by selecting alternative words proposed by a speech recognizer. We conducted a user study in which participants wrote sentences with and without speech. Using only the keyboard, users wrote at 11 words-per-minute at a 1.2% error rate. Speaking and correcting sentences was faster and more accurate at 28 words-per-minute and a 0.5% error rate. Participants achieved this performance despite half of sentences containing an uncommon out-of-vocabulary word (e.g. proper name). For sentences with only in-vocabulary words, performance using speech and midair keyboard corrections was faster at 36 words-per-minute with a low 0.3% error rate.


Mechanism of glucocorticoid effect on renal transport of phosphate.
We explored whether glucocorticoid administration, a known stimulus of renal gluconeogenesis (GNG), could decrease avid inorganic phosphate (Pi) reabsorption in rats stabilized on low-phosphorus diet (LPD). Rats adapted to LPD were injected with the glucocorticoid (GCD) triamcinolone acetonide (1.25 or 2.5 mg.100 g body wt-1.day-1 ip) for 2 days; they showed a profound increase in urinary excretion of Pi during the injection period. In clearance studies GCD increased the clearance and fractional excretion of Pi but did not change the filtered load of Pi. Initial "uphill" Na+-gradient (Nao+ greater than Nai+)-dependent uptake of 32Pi by luminal brush-border membrane (BBM) vesicles prepared from renal cortex of rats treated with GCD was markedly (greater than 40%) decreased compared with control rats; Na+-gradient-dependent uptake of D-[3H]glucose was not diminished. At the "equilibrium" time interval, measured at 120 min, BBM vesicles from control and GCD-treated rats did not differ in the uptake of 32Pi or D-[3H]glucose. With kinetic analysis, BBM from GCD-treated rats showed a marked decrease (-40%) in the maximum velocity (Vmax) of initial Na+-dependent 32Pi uptake, but the apparent affinity of the BBM transport system for Pi (apparent Km = 0.078 mM Pi) was not different from that of controls. Alkaline phosphatase specific activity was much lower (-40%) in BBM from GCD-treated rats compared with controls, but the activities of three other BBM enzymes (maltase, leucine aminopeptidase, and gamma-glutamyl transferase) were not different. The addition of triamcinolone to BBM in vitro had no effect on either Na+-dependent uptake of 32Pi or alkaline phosphatase activity. The rate of GNG from alpha-ketoglutarate was significantly increased in cortical slices from GCD-treated rats adapted to LPD. Also, the NAD+-to-NADH ratio was higher in the renal cortex of GCD-treated rats, although the total content of NAD [NAD+ + NADH] was not different from controls. Renal excretory, BBM, and metabolic changes elicited controls. Renal excretory, BBM, and metabolic changes elicited by GCD treatment were similar in intact and thyroparathyroidectomized rats. Phosphaturia elicited in rats fed LPD by GCD administration in vivo appears to be at least in part due to a decreased capacity of luminal BBM of proximal tubules for decreased capacity of luminal BBM of proximal tubules for Na+-dependent uptake of Pi. Although the causal relationship between observed parameters is not established, our results are compatible with the interpretation that an increase in the rate of renal GNG, perhaps via action of NAD+ on BBM (J. Clin. Invest. 67: 1347-1360, 1981), decreases luminal uptake and reabsorption of Pi in proximal tubules.


A randomly selected population sample undergoing colonoscopy: prevalence of the irritable bowel syndrome and the impact of selection factors.
To analyse the epidemiology of irritable bowel syndrome (IBS) symptoms in a random sample of the general population and in a subsample consenting to a colonoscopy, and to what extent this introduces symptom selection bias. Overall, 3347 randomly selected Swedish adults aged 18-70 years were mailed the validated Abdominal Symptom Questionnaire (ASQ). Responders (n=2293; 68.5%) were contacted by phone, and 745 consented to a colonoscopy. All nonresponders were contacted by phone; 265 were reached and asked seven key ASQ questions. Colonoscopy participants also completed the Rome II Modular Questionnaire. The prevalence of IBS on the basis of the mailed ASQ (troublesome abdominal pain and bowel disturbance in the past 3 months) was 26.2% [95% confidence interval (CI): 24.4-28.0] among the ASQ responders and 36.6% (95% CI: 33.2-40.1) among the colonoscopy participants (P<0.001). Nonresponders had a lower prevalence of IBS (15.8%; 95% CI: 11.4-20.3, P<0.001) than ASQ responders. Colonoscopy participants were slightly older than noncolonoscoped participants completing the ASQ (P<0.001), but men and women were equally represented and no significant socioeconomic differences were identified. The prevalence of IBS was 14.8% (95% CI: 12.2-17.5) on the basis of the Rome II Modular Questionnaire in colonoscopy participants and 14.5% (95% CI: 11.9-17.2) when visible inflammatory disease was excluded. Of the colonoscopy participants, 31.9% (95% CI: 28.5-35.3) were symptom free. IBS symptoms are common and rarely explained by visible inflammatory disease or cancer. There was a modest selection bias by IBS in participants accepting a screening colonoscopy, but still, one-third were symptom free. Thus, conclusions for the general population can be made from findings in the study cohort.


Artificial Intelligence for COVID-19: Rapid Review.
COVID-19 was first discovered in December 2019 and has since evolved into a pandemic. To address this global health crisis, artificial intelligence (AI) has been deployed at various levels of the health care system. However, AI has both potential benefits and limitations. We therefore conducted a review of AI applications for COVID-19. We performed an extensive search of the PubMed and EMBASE databases for COVID-19-related English-language studies published between December 1, 2019, and March 31, 2020. We supplemented the database search with reference list checks. A thematic analysis and narrative review of AI applications for COVID-19 was conducted. In total, 11 papers were included for review. AI was applied to COVID-19 in four areas: diagnosis, public health, clinical decision making, and therapeutics. We identified several limitations including insufficient data, omission of multimodal methods of AI-based assessment, delay in realization of benefits, poor internal/external validation, inability to be used by laypersons, inability to be used in resource-poor settings, presence of ethical pitfalls, and presence of legal barriers. AI could potentially be explored in four other areas: surveillance, combination with big data, operation of other core clinical services, and management of patients with COVID-19. In view of the continuing increase in the number of cases, and given that multiple waves of infections may occur, there is a need for effective methods to help control the COVID-19 pandemic. Despite its shortcomings, AI holds the potential to greatly augment existing human efforts, which may otherwise be overwhelmed by high patient numbers.


Short-term effect of acute and repeated urinary bladder inflammation on thigmotactic behaviour in the laboratory rat.
Understanding the non-sensory components of the pain experience is crucial to developing effective treatments for pain conditions. Chronic pain is associated with increased incidence of anxio-depressive disorders, and patients often report feelings of vulnerability which can decrease quality of life. In animal models of pain, observation of behaviours such as thigmotaxis can be used to detect such affective disturbances by exploiting the influence of nociceptive stimuli on the innate behavioural conflict between exploration of a novel space and predator avoidance behaviour. This study investigates whether acute and repeated bladder inflammation in adult female Wistar rats increases thigmotactic behaviour in the open field paradigm, and aims to determine whether this correlates with activation in the central amygdala, as measured by c-Fos immunoreactivity. Additionally, up-regulation of inflammatory mediators in the urinary bladder was measured using RT-qPCR array featuring 92 transcripts to examine how local mediators change under experimental conditions. We found acute but not repeated turpentine inflammation of the bladder increased thigmotactic behaviour (decreased frequency of entry to the inner zone) in the open field paradigm, a result that was also observed in the catheter-only instrumentation group. Decreases in locomotor activity were also observed in both models in turpentine and instrumentation groups. No differences were observed in c-Fos activation, although a general increased in activation along the rostro-caudal axis was seen. Inflammatory mediator up-regulation was greatest following acute inflammation, with CCL12, CCL7, and IL-1β significantly up-regulated in both conditions when compared to naïve tissue. These results suggest that acute catheterisation, with or without turpentine inflammation, induces affective alterations detectable in the open field paradigm accompanied by up-regulation of multiple inflammatory mediators.


Inherent electrochemistry and charge transfer properties of few-layered two-dimensional Ti3C2Tx MXene.
We report the effect of the Ti3C2Tx MXene flake thickness on its inherent electrochemistry and heterogeneous charge transfer characteristics. It is shown that Ti3C2Tx undergoes irreversible oxidation in a positive potential window, which strongly depends on the flake thickness and pH of the electrolyte. Few-layered Ti3C2Tx exhibits faster electron transfer kinetics (k0 = 0.09533 cm s-1) with a [Fe(CN)6]4-/3- redox mediator compared to multi-layered Ti3C2Tx (k0 = 0.00503 cm s-1). In addition, the few-layered free standing Ti3C2Tx film electrode remains intact after enduring irreversible oxidation.


Novel usage of fresh frozen plasma in hereditary angioedema.
Hereditary angioedema (HAE) is a rare and potentially life threatening autosomal dominant disease characterized by recurrent episodes of cutaneous and mucosal oedema. It results from reduced expression or loss of function of CI-esterase inhibitors (C1-INH). As opposed to the more common histamine-mediated angioedema, HAE does not respond well to conventional treatments with anti-histamines, steroids and adrenaline. Early recognition and timely intervention with the correct treatment are crucial particularly preventing airway obstruction. New disease specific treatment including plasma derived or recombinant C1-INH, ecallantide and icatibant have recently emerged and its appropriate use can reduce HAE-associated mortality and morbidity. However due to its costs, these disease specific treatments have yet to reach Malaysia. Despite that no randomized clinical trial on FFP has been performed, its efficacy in treating acute attacks of HAE is only demonstrated in case studies. This case report illustrates the successful treatment of acute HAE episode with FFP in a Malaysian government hospital setting.


Social network models predict movement and connectivity in ecological landscapes.
Network analysis is on the rise across scientific disciplines because of its ability to reveal complex, and often emergent, patterns and dynamics. Nonetheless, a growing concern in network analysis is the use of limited data for constructing networks. This concern is strikingly relevant to ecology and conservation biology, where network analysis is used to infer connectivity across landscapes. In this context, movement among patches is the crucial parameter for interpreting connectivity but because of the difficulty of collecting reliable movement data, most network analysis proceeds with only indirect information on movement across landscapes rather than using observed movement to construct networks. Statistical models developed for social networks provide promising alternatives for landscape network construction because they can leverage limited movement information to predict linkages. Using two mark-recapture datasets on individual movement and connectivity across landscapes, we test whether commonly used network constructions for interpreting connectivity can predict actual linkages and network structure, and we contrast these approaches to social network models. We find that currently applied network constructions for assessing connectivity consistently, and substantially, overpredict actual connectivity, resulting in considerable overestimation of metapopulation lifetime. Furthermore, social network models provide accurate predictions of network structure, and can do so with remarkably limited data on movement. Social network models offer a flexible and powerful way for not only understanding the factors influencing connectivity but also for providing more reliable estimates of connectivity and metapopulation persistence in the face of limited data.


Population pharmacokinetics of mefloquine, piperaquine and artemether-lumefantrine in Cambodian and Tanzanian malaria patients.
Inter-individual variability in plasma concentration-time profiles might contribute to differences in anti-malarial treatment response. This study investigated the pharmacokinetics of three different forms of artemisinin combination therapy (ACT) in Tanzania and Cambodia to quantify and identify potential sources of variability. Drug concentrations were measured in 143 patients in Tanzania (artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine), and in 63 (artesunate, dihydroartemisinin and mefloquine) and 60 (dihydroartemisinin and piperaquine) patients in Cambodia. Inter- and intra-individual variabilities in the pharmacokinetic parameters were assessed and the contribution of demographic and other covariates was quantified using a nonlinear mixed-effects modelling approach (NONMEM®). A one-compartment model with first-order absorption from the gastrointestinal tract fitted the data for all drugs except piperaquine (two-compartment). Inter-individual variability in concentration exposure was about 40% and 12% for mefloquine. From all the covariates tested, only body weight (for all antimalarials) and concomitant treatment (for artemether only) showed a significant influence on these drugs' pharmacokinetic profiles. Artesunate and dihydroartemisinin could not be studied in the Cambodian patients due to insufficient data-points. Modeled lumefantrine kinetics showed that the target day 7 concentrations may not be achieved in a substantial proportion of patients. The marked variability in the disposition of different forms of ACT remained largely unexplained by the available covariates. Dosing on body weight appears justified. The concomitance of unregulated drug use (residual levels found on admission) and sub-optimal exposure (variability) could generate low plasma levels that contribute to selecting for drug-resistant parasites.


Efficacy of Plant Growth-Promoting Rhizobacteria, Acibenzolar-S-Methyl, and Soil Amendment for Integrated Management of Bacterial Wilt on Tomato.
Greenhouse experiments were conducted to study the effect of plant growth promoting rhizobacteria (PGPR; Bacillus pumilus SE 34, Pseudomonas putida 89B61, BioYield, and Equity), acibenzolar-S-methyl (Actigard), and a soil amendment with S-H mixture (contains agricultural and industrial wastes such as bagasse, rice husk, oyster shell powder, urea, potassium nitrate, calcium super phosphate, and mineral ash) on bacterial wilt incidence caused by Ralstonia solanacearum (race 1, biovar 1) in susceptible tomato (Lycopersicon esculentum cv. Solar Set). In experiments with PGPR, Pseudomonas putida 89B61 significantly reduced bacterial wilt incidence when applied to the transplants at the time of seeding and 1 week prior to inoculation with Ralstonia solanacearum. BioYield, a formulated PGPR that contained two Bacillus strains, decreased disease significantly in three experiments. Equity, a formulation containing more than 40 different microbial strains, did not reduced wilt incidence compared with the untreated control. With inoculum at low pathogen densities of 1 × 105 and 1 × 106 CFU/ml, disease incidence of Actigard-treated plants was significantly less than with nontreated plants. This is the first report of Actigard-mediated reduction of bacterial wilt incidence in a susceptible tomato cultivar. When PGPR and Actigard applications were combined, Actigard plus P. putida 89B61 or BioYield reduced bacterial wilt incidence compared with the untreated control. Incorporation of S-H mixture into infested soil 2 weeks before transplanting reduced bacterial wilt incidence in one experiment. Combination of Actigard with the S-H mixture significantly reduced bacterial wilt incidence in tomato in two experiments.


The evolution of family-centered care: From supporting parent-delivered interventions to a model of family integrated care.
There is increasing recognition that parents play a critical role in promoting the health outcomes of low birthweight and preterm infants. Despite a large body of literature on interventions and models to support family engagement in infant care, parent involvement in the delivery of care for such infants is still restricted in many neonatal intensive care units (NICUs). In this article, we propose a taxonomy for classifying parent-focused NICU interventions and parent-partnered care models to aid researchers, clinical teams, and health systems to evaluate existing and future approaches to care. The proposed framework has three levels: interventions to support parents, parent-delivered interventions, and multidimensional models of NICU care that explicitly incorporate parents and partners in the care of their preterm or low birthweight infant. We briefly review the available evidence for interventions at each level and highlight the strong level of research evidence to support the parent-delivered intervention of skin-to-skin contact (also known as the Kangaroo Care position) and for the Kangaroo mother care and family integrated care models of NICU care. We suggest directions for future research and model implementation to improve and scale-up parent partnership in the care of NICU infants.


Respiratory control in the treatment of panic attacks: replication and extension with concurrent measurement of behaviour and pCO2.
A case series is reported in which nine patients who experienced phobic and/or nonphobic panic attacks were given a cognitive-behavioural treatment based on the supposition that catastrophic interpretations of sensations produced by hyperventilation played an important role in their attacks. Large and rapid reductions in panic attack frequency and questionnaire report of fear were observed. Patients' resting pCO2 was significantly lower than controls and rose to normal levels during treatment.


Epidemic dynamics, interactions and predictability of enteroviruses associated with hand, foot and mouth disease in Japan.
Outbreaks of hand, foot and mouth disease have been documented in Japan since 1963. This disease is primarily caused by the two closely related serotypes of Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16). Here, we analyse Japanese virologic and syndromic surveillance time-series data from 1982 to 2015. As in some other countries in the Asia Pacific region, EV-A71 in Japan has a 3 year cyclical component, whereas CV-A16 is predominantly annual. We observe empirical signatures of an inhibitory interaction between the serotypes; virologic lines of evidence suggest they may indeed interact immunologically. We fit the time series to mechanistic epidemiological models: as a first-order effect, we find the data consistent with single-serotype susceptible-infected-recovered dynamics. We then extend the modelling to incorporate an inhibitory interaction between serotypes. Our results suggest the existence of a transient cross-protection and possible asymmetry in its strength such that CV-A16 serves as a stronger forcing on EV-A71. Allowing for asymmetry yields accurate out-of-sample predictions and the directionality of this effect is consistent with the virologic literature. Confirmation of these hypothesized interactions would have important implications for understanding enterovirus epidemiology and informing vaccine development. Our results highlight the general implication that even subtle interactions could have qualitative impacts on epidemic dynamics and predictability.


Aspen pectate lyase PtxtPL1-27 mobilizes matrix polysaccharides from woody tissues and improves saccharification yield.
Wood cell walls are rich in cellulose, hemicellulose and lignin. Hence, they are important sources of renewable biomass for producing energy and green chemicals. However, extracting desired constituents from wood efficiently poses significant challenges because these polymers are highly cross-linked in cell walls and are not easily accessible to enzymes and chemicals. We show that aspen pectate lyase PL1-27, which degrades homogalacturonan and is expressed at the onset of secondary wall formation, can increase the solubility of wood matrix polysaccharides. Overexpression of this enzyme in aspen increased solubility of not only pectins but also xylans and other hemicelluloses, indicating that homogalacturonan limits the solubility of major wood cell wall components. Enzymatic saccharification of wood obtained from PL1-27-overexpressing trees gave higher yields of pentoses and hexoses than similar treatment of wood from wild-type trees, even after acid pretreatment. Thus, the modification of pectins may constitute an important biotechnological target for improved wood processing despite their low abundance in woody biomass.


Designing and using computer simulations in medical education and training: an introduction.
Computer-based technologies informed by the science of learning are becoming increasingly prevalent in education and training. For the Department of Defense (DoD), this presents a great potential advantage to the effective preparation of a new generation of technologically enabled service members. Military medicine has broad education and training challenges ranging from first aid and personal protective skills for every service member to specialized combat medic training; many of these challenges can be met with gaming and simulation technologies that this new generation has embraced. However, comprehensive use of medical games and simulation to augment expert mentorship is still limited to elite medical provider training programs, but can be expected to become broadly used in the training of first responders and allied health care providers. The purpose of this supplement is to review the use of computer games and simulation to teach and assess medical knowledge and skills. This review and other DoD research policy sources will form the basis for development of a research and development road map and guidelines for use of this technology in military medicine.


Does neuroticism make you old? Prospective associations between neuroticism and leukocyte telomere length.
Telomere attrition, causing accelerated aging, might be one of the mechanisms through which neuroticism leads to somatic disease and increased all-cause mortality. In the current study we investigated whether neuroticism is prospectively associated with shorter telomere length (TL), a biological marker of aging. Participants were 3432 adults (mean age 52.9 years, range 32-79). Data were collected at baseline (T1) and at two follow-up visits after 4 years (T2) and 6 years (T3). Neuroticism was assessed using the 12-item neuroticism scale of the Revised Eysenck Personality Questionnaire (EPQ-R) at T2 and T3. TL was measured by a monochrome multiplex quantitative polymerase chain reaction (PCR) assay at T1, T2 and T3. A linear mixed model was used to assess whether neuroticism could predict TL prospectively after adjusting for age, sex, body mass index (BMI), frequency of sports, smoking status, presence of chronic diseases and level of education. Neuroticism was a significant negative predictor of TL at follow-up (B = -0.004, p = 0.044) after adjusting for sex, age, baseline TL and various biological and lifestyle factors. High neuroticism is significantly and prospectively associated with telomere attrition independent of lifestyle and other risk factors.


IMPMD: An Integrated Method for Predicting Potential Associations Between miRNAs and Diseases.
With the rapid development of biological research, microRNAs (miRNAs) have increasingly attracted worldwide attention. The increasing biological studies and scientific experiments have proven that miRNAs are related to the occurrence and development of a large number of key biological processes which cause complex human diseases. Thus, identifying the association between miRNAs and disease is helpful to diagnose the diseases. Although some studies have found considerable associations between miRNAs and diseases, there are still a lot of associations that need to be identified. Experimental methods to uncover miRNA-disease associations are time-consuming and expensive. Therefore, effective computational methods are urgently needed to predict new associations. In this work, we propose an integrated method for predicting potential associations between miRNAs and diseases (IMPMD). The enhanced similarity for miRNAs is obtained by combination of functional similarity, gaussian similarity and Jaccard similarity. To diseases, it is obtained by combination of semantic similarity, gaussian similarity and Jaccard similarity. Then, we use these two enhanced similarities to construct the features and calculate cumulative score to choose robust features. Finally, the general linear regression is applied to assign weights for Support Vector Machine, K-Nearest Neighbor and Logistic Regression algorithms. IMPMD obtains AUC of 0.9386 in 10-fold cross-validation, which is better than most of the previous models. To further evaluate our model, we implement IMPMD on two types of case studies for lung cancer and breast cancer. 49 (Lung Cancer) and 50 (Breast Cancer) out of the top 50 related miRNAs are validated by experimental discoveries. We built a software named IMPMD which can be freely downloaded from https://github.com/Sunmile/IMPMD.


Biomarkers of HIV-associated Cancer.
Cancer biomarkers have provided great opportunities for improving the management of cancer patients by enhancing the efficiency of early detection, diagnosis, and efficacy of treatment. Every cell type has a unique molecular signature, referred to as biomarkers, which are identifiable characteristics such as levels or activities of a myriad of genes, proteins, or other molecular features. Biomarkers can facilitate the molecular definition of cancer, provide information about the course of cancer, and predict response to chemotherapy. They offer the hope of early detection as well as tracking disease progression and recurrence. Current progress in the characterization of molecular genetics of HIV-associated cancers may form the basis for improved patient stratification and future targeted or individualized therapies. Biomarker use for cancer staging and personalization of therapy at the time of diagnosis could improve patient care. This review focuses on the relevance of biomarkers in the most common HIV-associated malignancies, namely, Kaposi sarcoma, non-Hodgkin's lymphoma, and invasive cervical cancer.


Positron emission tomography/computed tomography scanning for the diagnosis of occult sepsis in the critically injured.
Although the site of nosocomial sepsis in the critically ill ventilated patient is usually identifi able, it may remain occult, despite numerous investigations. The rapid results and precise anatomical location of the septic source using positron emission tomography (PET) scanning, in combination with computed tomography (CT), has promoted this modality as the diagnostic tool of choice for pyrexias of unknown origin. The objective of this study was to report our experience using PET/CT scanning for the localisation of a septic focus in critically injured patients in whom no source could be identifi ed using conventional investigations. Two patients with gunshot wounds and two who had sustained multiple fractures following motor vehicle collisions developed pyrexias of unknown origin during their stay in the trauma intensive care unit. Routine screening for a septic focus was unrewarding, and 18F-fl uorodeoxyglucose PET/CT scanning was used to identify the possible source. PET/CT scanning identifi ed the septic focus in all patients. Abscesses were drained successfully in those with penetrating trauma and in one with blunt polytrauma. Pulmonary tuberculosis, not apparent on initial radiology, was identifi ed using PET/CT in one patient with blunt thoracic trauma. PET/CT scanning appears to both confi rm and localise the source of sepsis in a variety of pathologies in critically ill patients who develop pyrexias for which no source can be identifi ed by conventional screening techniques.


Wetting Transition on Liquid-Repellent Surfaces Probed by Surface Force Measurements and Confocal Imaging.
Superhydrophobic surfaces in the Cassie-Baxter wetting state retain an air layer at the surface which prevents liquid water from reaching into the porous surface structure. In this work we explore how addition of ethanol, which reduces the surface tension, influences the wetting properties of superhydrophobic and smooth hydrophobic surfaces. Wetting properties are measured by dynamic contact angles, and the air layer at the superhydrophobic surface is visualized by laser scanning confocal microscopy. Colloidal probe atomic force microscopy measurements between a hydrophobic microsphere and the macroscopic surfaces showed that the presence of ethanol strongly affects the interaction forces. When the macroscopic surface is superhydrophobic, attractive forces extending up to a few micrometers are observed on retraction in water and in 20 vol % ethanol, signifying the presence of a large and growing gas capillary. Submicrometer attractive forces are observed between the probe particle and a smooth hydrophobic surface, and in this case a smaller gas capillary is formed. Addition of ethanol results in markedly different effects between superhydrophobic and hydrophobic surfaces. In particular, we show that the receding contact angle on the superhydrophobic surface is of paramount importance for describing the interaction forces.


Activation of Fgf-4 and HoxD gene expression by BMP-2 expressing cells in the developing chick limb.
Bone morphogenetic protein-2 (BMP-2) has been implicated in the polarizing region signalling pathway, which specifies pattern across the antero-posterior of the developing vertebrate limb. Retinoic acid and Sonic Hedgehog (SHH) can act as polarizing signals; when applied anteriorly in the limb bud, they induce mirror-image digit duplications and ectopic Bmp-2 expression in anterior mesenchyme. In addition, the two signals can activate Fgf-4 expression in anterior ridge and HoxD expression in anterior mesenchyme. We tested the role of BMP-2 in this signalling cascade by ectopically expressing human BMP-2 (hBMP-2) at the anterior margin of the early wing bud using a replication defective retroviral vector, and found that ectopic expression of Fgf-4 was induced in the anterior part of the apical ectodermal ridge, followed later by ectopic expression of Hoxd-11 and Hoxd-13 in anterior mesenchyme. This suggests that BMP-2 is involved in regulating Fgf-4 and HoxD gene expression in the normal limb bud. Ectopically expressed hBMP-2 also induced duplication of digit 2 and bifurcation of digit 3, but could not produce the mirror-image digit duplications obtained with SHH-expressing cells. These results suggest that BMP-2 may be involved primarily in maintenance of the ridge, and in the link between patterning and outgrowth of the limb bud.


Context-dependent role for chromatin remodeling component PBRM1/BAF180 in clear cell renal cell carcinoma.
A subset of clear cell renal cell carcinoma (ccRCC) tumors exhibit a HIF1A gene mutation, yielding two ccRCC tumor types, H1H2 type expressing both HIF1α and HIF2α, and H2 type expressing HIF2α, but not functional HIF1α protein. However, it is unclear how the H1H2 type ccRCC tumors escape HIF1's tumor-suppressive activity. The polybromo-1 (PBRM1) gene coding for the BAF180 protein, a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, is inactivated in 40% ccRCCs, the function and mechanism of BAF180 mutation is unknown. Our previous study indicates that BAF180-containing SWI/SNF chromatin remodeling complex is a co-activator for transcription factor HIF to induce HIF target genes. Thus, our questions are if BAF180 is involved in HIF-mediated hypoxia response and if PBRM1/BAF180 mutation has any association with the HIF1A retention in H1H2 type ccRCC. We report here that BAF180 is mutated in H1H2 ccRCC cell lines and tumors, and BAF180 re-expression in H1H2 ccRCC cell lines reduced cell proliferation/survival, indicating that BAF180 has tumor-suppressive role in these cells. However, BAF180 is expressed in HIF1-deficient H2 ccRCC cell lines and tumors, and BAF180 knockdown in H2 type ccRCC cell lines reduced cell proliferation/survival, indicating that BAF180 has tumor-promoting activity in these cells. In addition, our data show that BAF180 functions as co-activator for HIF1- and HIF2-mediated transcriptional response, and BAF180's tumor-suppressive and -promoting activity in ccRCC cell lines depends on co-expression of HIF1 and HIF2, respectively. Thus, our studies reveal that BAF180 function in ccRCC is context dependent, and that mutation of PBRM1/BAF180 serves as an alternative strategy for ccRCC tumors to reduce HIF1 tumor-suppressive activity in H1H2 ccRCC tumors. Our studies define distinct functional subgroups of ccRCCs based on expression of BAF180, and suggest that BAF180 inhibition may be a novel therapeutic target for patients with H2, but not H1H2, ccRCC tumors.


Substance use and psychosocial functioning in schizophrenia among new enrollees in the NIMH CATIE study.
This study examined the relationship between substance use and psychosocial functioning in schizophrenia. Participants were enrolled in the Clinical Antipsychotic Trials of Intervention Effectiveness. This study used baseline assessments and examined psychosocial functioning assessed by the Quality of Life Scale. Participants were classified as being abstinent, using substances, or having a substance use disorder. Of the 1,460 participants, 23 percent used substances and 37 percent had a substance use disorder. Of the 544 with a substance use disorder, 87 percent used alcohol, 44 percent used marijuana, and 36 percent used cocaine. Compared with participants who used substances, those with a substance use disorder had higher rates of polysubstance use. Compared with those who were abstinent, those who used substances had higher overall psychosocial functioning, and those with a substance use disorder had similar overall functioning but lower scores on the common objects and activities subscales. Among participants with a substance use disorder, those who used cocaine had lower overall functioning. Compared with abstinence, substance use and substance use disorder, unless they involved cocaine use, were generally associated with higher or equivalent overall psychosocial functioning. Patterns of substance use were similar to those in the community, suggesting that treatment of substance use disorders in schizophrenia should focus on reconnecting substance users to nonusing peer groups.


Biosynthesis of polyhydroxyalkanoates containing 2-hydroxybutyrate from unrelated carbon source by metabolically engineered Escherichia coli.
We have previously reported in vivo biosynthesis of polylactic acid (PLA) and poly(3-hydroxybutyrate-co-lactate) [P(3HB-co-LA)] employing metabolically engineered Escherichia coli strains by the introduction of evolved Clostridium propionicum propionyl-CoA transferase (Pct(Cp)) and Pseudomonas sp. MBEL 6-19 polyhydroxyalkanoate (PHA) synthase 1 (PhaC1(Ps6-19)). Using this in vivo PLA biosynthesis system, we presently report the biosynthesis of PHAs containing 2-hydroxybutyrate (2HB) monomer by direct fermentation of a metabolically engineered E. coli strain. The recombinant E. coli ldhA mutant XLdh strain expressing PhaC1( Ps6-19) and Pct(Cp) was developed and cultured in a chemically defined medium containing 20 g/L of glucose and varying concentrations of 2HB and 3HB. PHAs consisting of 2HB, 3HB, and a small fraction of lactate were synthesized. Their monomer compositions were dependent on the concentrations of 2HB and 3HB added to the culture medium. Even though the ldhA gene was completely deleted in the chromosome of E. coli, up to 6 mol% of lactate was found to be incorporated into the polymer depending on the culture condition. In order to synthesize PHAs containing 2HB monomer without feeding 2HB into the culture medium, a heterologous metabolic pathway for the generation of 2HB from glucose was constructed via the citramalate pathway, in which 2-ketobutyrate is synthesized directly from pyruvate and acetyl-CoA. Introduction of the Lactococcus lactis subsp. lactis Il1403 2HB dehydrogenase gene (panE) into E. coli allowed in vivo conversion of 2-ketobutyrate to 2HB. The metabolically engineered E. coli XLdh strain expressing the phaC1437, pct540, cimA3.7, and leuBCD genes together with the L. lactis Il1403 panE gene successfully produced PHAs consisting of 2HB, 3HB, and a small fraction of lactate by varying the 3HB concentration in the culture medium. As the 3HB concentration in the medium increased the 3HB monomer fraction in the polymer, the polymer content increased. When Ralstonia eutropha phaAB genes were additionally expressed in this recombinant E. coli XLdh strain, P(2HB-co-3HB-co-LA) having small amounts of 2HB and LA monomers could also be produced from glucose as a sole carbon source. The metabolic engineering strategy reported here should be useful for the production of PHAs containing 2HB monomer.


Effects of mindfulness meditation on chronic pain: a randomized controlled trial.
This randomized controlled clinical trial investigated the effects of mindfulness meditation on chronic pain. A total of 109 patients with nonspecific chronic pain were randomized to either a standardized mindfulness meditation program (mindfulness-based stress reduction [MBSR]) or to a wait list control. Pain, physical function, mental function, pain acceptance, and health-related quality of life were measured. The SF36 vitality scale was chosen as the primary outcome measure; the primary end point was after completing the MBSR course. Within a 2.5-year period, 43 of the 109 randomized patients completed the mindfulness program, while 47 remained in the control group. Data were compared at three time points: at baseline, after completion of the course/waiting period, and at the 6-month follow-up. Significant effect (Cohen's d = 0.39) was found on the primary outcome measure, the SF36 vitality scale. On the secondary variables, significant medium to large size effects (Cohen's d = 0.37-0.71) were found for lower general anxiety and depression, better mental quality of life (psychological well-being), feeling in control of the pain, and higher pain acceptance. Small (nonsignificant) effect sizes were found for pain measures. There were no significant differences in the measures just after the intervention vs the 6-month follow-up. A standardized mindfulness program (MBSR) contributes positively to pain management and can exert clinically relevant effects on several important dimensions in patients with long-lasting chronic pain.


Common Genetic Variations Associated with the Persistence of Immunity following Childhood Immunization.
Vaccines have revolutionized public health, preventing millions of deaths each year, particularly in childhood. Yet, there is considerable variability in the magnitude and persistence of vaccine-induced immunity. Maintenance of specific antibody is essential for continuity of vaccine-induced serological protection. We conducted a genome-wide association study into the persistence of immunity to three childhood vaccines: capsular group C meningococcal (MenC), Haemophilus influenzae type b, and tetanus toxoid (TT) vaccines. We detail associations between variants in a locus containing a family of signal-regulatory proteins and the persistence MenC immunity. We postulate a regulatory role for the lead SNP, with supporting epigenetic and expression quantitative trait loci data. Furthermore, we define associations between SNPs in the human leukocyte antigen (HLA) locus and the persistence of TT-specific immunity. Moreover, we describe four classical HLA alleles, HLA DRB1∗0301, HLA DQB1∗0201, HLA DQB1∗0602, and HLA DRB1∗1501, associated with TT-specific immunity, independent of the lead SNP association.


A theoretical model of phase transitions in human hand movements.
Earlier experimental studies by one of us (Kelso, 1981a, 1984) have shown that abrupt phase transitions occur in human hand movements under the influence of scalar changes in cycling frequency. Beyond a critical frequency the originally prepared out-of-phase, antisymmetric mode is replaced by a symmetrical, in-phase mode involving simultaneous activation of homologous muscle groups. Qualitatively, these phase transitions are analogous to gait shifts in animal locomotion as well as phenomena common to other physical and biological systems in which new "modes" or spatiotemporal patterns arise when the system is parametrically scaled beyond its equilibrium state (Haken, 1983). In this paper a theoretical model, using concepts central to the interdisciplinary field of synergetics and nonlinear oscillator theory, is developed, which reproduces (among other features) the dramatic change in coordinative pattern observed between the hands.


Oligonol improves memory and cognition under an amyloid β(25-35)-induced Alzheimer's mouse model.
Alzheimer's disease is an age-dependent progressive neurodegenerative disorder that results in impairments of memory and cognitive function. It is hypothesized that oligonol has ameliorative effects on memory impairment and reduced cognitive functions in mice with Alzheimer's disease induced by amyloid β(25-35) (Aβ(25-35)) injection. The protective effect of an oligonol against Aβ(25-35)-induced memory impairment was investigated in an in vivo Alzheimer's mouse model. The aggregation of Aβ25-35 was induced by incubation at 37°C for 3 days before injection into mice brains (5 nmol/mouse), and then oligonol was orally administered at 100 and 200 mg/kg of body weight for 2 weeks. Memory and cognition were observed in T-maze, object recognition, and Morris water maze tests. The group injected with Aβ(25-35) showed impairments in both recognition and memory. However, novel object recognition and new route awareness abilities were dose dependently improved by the oral administration of oligonol. In addition, the results of the Morris water maze test indicated that oligonol exerted protective activity against cognitive impairment induced by Aβ(25-35). Furthermore, nitric oxide formation and lipid peroxidation were significantly elevated by Aβ(25-35), whereas oligonol treatment significantly decreased nitric oxide formation and lipid peroxidation in the brain, liver, and kidneys. The present results suggest that oligonol improves Aβ(25-35)-induced memory deficit and cognition impairment.


Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis.
Resveratrol, a naturally occurring polyphenol, has cancer chemopreventive properties in preclinical models. It has been shown to downregulate the levels of insulin-like growth factor-1 (IGF-I) in rodents. The purpose of the study was to assess its safety, pharmacokinetics, and effects on circulating levels of IGF-I and IGF-binding protein-3 (IGFBP-3) after repeated dosing. Forty healthy volunteers ingested resveratrol at 0.5, 1.0, 2.5, or 5.0 g daily for 29 days. Levels of resveratrol and its metabolites were measured by high performance liquid chromatography-UV in plasma obtained before and up to 24 hours after a dose between days 21 and 28. IGF-I and IGFBP-3 were measured by ELISA in plasma taken predosing and on day 29. Resveratrol was safe, but the 2.5 and 5 g doses caused mild to moderate gastrointestinal symptoms. Resveratrol-3-O-sulfate, resveratrol-4'-O-glucuronide, and resveratrol-3-O-glucuronide were major plasma metabolites. Maximal plasma levels and areas under the concentration versus time curve for the metabolites dramatically exceeded those for resveratrol, in the case of areas under the concentration versus time curve, by up to 20.3-fold. Compared with predosing values, the ingestion of resveratrol caused a decrease in circulating IGF-I and IGFBP-3 (P<0.04 for both), respectively, in all volunteers. The decrease was most marked at the 2.5 g dose level. The results suggest that repeated administration of high doses of resveratrol generates micromolar concentrations of parent and much higher levels of glucuronide and sulfate conjugates in the plasma. The observed decrease in circulating IGF-I and IGFBP-3 might contribute to cancer chemopreventive activity.


Rhamnolipids Produced by Indigenous Acinetobacter junii from Petroleum Reservoir and its Potential in Enhanced Oil Recovery.
Biosurfactant producers are crucial for incremental oil production in microbial enhanced oil recovery (MEOR) processes. The isolation of biosurfactant-producing bacteria from oil reservoirs is important because they are considered suitable for the extreme conditions of the reservoir. In this work, a novel biosurfactant-producing strain Acinetobacter junii BD was isolated from a reservoir to reduce surface tension and emulsify crude oil. The biosurfactants produced by the strain were purified and then identified via electrospray ionization-Fourier transform ion cyclotron resonance mass spectrometry (ESI FT-ICR-MS). The biosurfactants generated by the strain were concluded to be rhamnolipids, the dominant rhamnolipids were C26H48O9, C28H52O9, and C32H58O13. The optimal carbon source and nitrogen source for biomass and biosurfactant production were NaNO3 and soybean oil. The results showed that the content of acid components increased with the progress of crude oil biodegradation. A glass micromodel test demonstrated that the strain significantly increased oil recovery through interfacial tension reduction, wettability alteration and the mobility of microorganisms. In summary, the findings of this study indicate that the newly developed BD strain and its metabolites have great potential in MEOR.


Long-Term Outcome and Predictors of Noninstitutionalized Survival Subsequent to Prolonged Intensive Care Unit Stay After Cardiac Surgical Procedures.
There are minimal data on long-term functional survival (alive and not institutionalized) in patients undergoing cardiac operations who require a prolonged intensive care unit length of stay (prICULOS). We sought to describe 1- and 5-year functional survival in patients who had a prICULOS (ICULOS ≥ 5 days) and determine predictors of functional survival at 1 year. Data were obtained from linked clinical and administrative databases from January 1, 2000 to December 31, 2011 to conduct this retrospective single-region analysis. Logistic regression was used to develop a model predicting functional survival at 1 year for patients who had a prICULOS after cardiac operations. There were 9,545 admissions to the ICU after cardiac operations; of these patients, 728 (7.6%) experienced a prICULOS. There was an increasing trend in patients who had a prICULOS over this study period. The functional survival at 1 and 5 years from the surgical procedure for the non-prICULOS versus the prICULOS cohort was 1 year (94.9% versus 73.9%) and 5 years (84.9% versus 53.8%) (p < 0.001). Factors associated with lower rates of functional survival at 1 year were age 80 years or older, female sex, peripheral vascular disease, preoperative renal dysfunction, cerebrovascular disease, preoperative infection, need for extracorporeal membrane oxygenation/ventricular assist device (ECMO/VAD) after cardiotomy, number of days on mechanical ventilation, and number of days in the ICU beyond 5 days (area under the receiver operating characteristic [ROC] curve = 0.766). The majority of patients who had a prICULOS experienced successful functional survival up to 5 years after cardiac operations. Identification of risk factors for poor functional survival may be of assistance to clinicians, patients, and families for prognostication and decision making.


Fatty acid composition of the milk lipids of Nepalese women: correlation between fatty acid composition of serum phospholipids and melting point.
Milk was collected from 36 Nepalese women, 15 to 32 years of age, in order to investigate relationships between the proportions of intermediate chain-length (C10-C14) fatty acids and critical n-3 and n-6 polyunsaturated fatty acids in the milk lipids they were producing. Serum was also obtained from these lactating women and the fatty acid composition of their serum phospholipid fraction was determined and compared with that of the corresponding milk lipid fraction. Compared to women in technologically advanced parts of the world, the serum phospholipids of the Nepalese women contained nutritionally adequate proportions of linoleic acid (LA) (16.8%), alpha-linolenic acid (ALA) (0.53%), arachidonic acid (AA) (5.69%), and docosahexaenoic acid (DHA) (1.42%). However, although the milk lipids contained adequate proportions of ALA (1.81%), AA (0.43%), and DHA (0.23%), the lipids contained low to moderate percentages of LA (mean, 9.05%). Positive correlations were observed between the proportions of AA (P=0.001, r=0.50) and ALA (P=0.03, r=0.36) in the serum phospholipids and milk lipids of the women. As the proportion of C10-Cl4 fatty acids in the milk lipids increased from 10% to 40%, there was preferential retention of three critical n-3 and n-6 fatty acids (ALA, AA, and DHA) at the expense of two relatively abundant nonessential fatty acids, namely stearic acid and oleic acid. In addition, using fatty acid melting point data and the mol fraction of the 9 most abundant fatty acids in the milk, we estimated the mean melting point (MMP) of the milk lipids of the Nepalese women. The MMPs ranged from 29.3 to 40.5 degrees C (median, 35.5 degrees C). These results indicate that: 1) the levels of AA and ALA in the blood of lactating mothers influence the levels of these fatty acids in the milk they produce; 2) when the mammary gland produces a milk that is rich in C10-Cl4 fatty acids, it somehow regulates triglyceride synthesis in such a way as to ensure that the milk will provide the exclusively breast-fed infant with the amounts of the critical n-3 and n-6 fatty acids it requires for normal growth and development; and 3) the melting point of the milk lipid fraction is determined mainly by the mol % of the intermediate chain-length (C10-C14) fatty acids, oleic acid, linoleic acid, and alpha-linolenic acid.


Alcohol belongs here: Assessing alcohol-related inhibitory control with a contextual go/no-go task.
There is a growing awareness of the need to explore the social and environmental milieus that drive alcohol consumption and related cognitions. The current study examined the extent to which alcohol-congruent and incongruent drinking contexts modulate alcohol-related inhibitory control using a novel go/no-go task. One hundred and eight participants (Mage = 20 years; SD = 4.87) were instructed to inhibit their responses to visual alcoholic (alcohol/no-go condition, n = 50) or nonalcoholic stimuli (alcohol/go condition, n = 58) depicted in an alcohol-congruent (pub), incongruent (library), or context-free (control) condition. Participants in the alcohol/go condition exhibited higher false alarm rates (FAR) toward nonalcoholic stimuli and faster reaction times (RTs) to alcoholic stimuli depicted in the alcohol-congruent and incongruent context compared with the alcohol/no-go condition. In contrast, FAR toward alcoholic stimuli (alcohol/no-go condition) were not significantly affected by drinking context, but RT was faster when nonalcoholic stimuli were presented in alcohol-incongruent (i.e., library) compared with alcohol-congruent (i.e., pub) contexts. The discussion turns to potential explanations for these findings, suggesting that social drinkers might exhibit approach tendencies toward alcoholic images that translate into errors toward nonalcoholic stimuli, and that image complexity influences response inhibition. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Intestinal microbial ecology in premature infants assessed with non-culture-based techniques.
To use high throughput techniques to analyze intestinal microbial ecology in premature neonates, who are highly susceptible to perturbations of the luminal environment associated with necrotizing enterocolitis (NEC) and late-onset sepsis. With non-culture-based techniques, we evaluated intestinal microbiota shortly after birth and during hospitalization in 23 neonates born at 23 to 32 weeks gestational age. Microbiota compositions were compared in 6 preterm infants in whom NEC, signs of systemic inflammation, or both developed with matched control subjects by using 16S ribosomal RNA pyrosequencing. Microbial DNA was detected in meconium, suggesting an intrauterine origin. Differences in diversity were detected in infants whose mothers intended to breast feed (P = .03), babies born to mothers with chorioamnionitis (P = .06), and in babies born at <30 weeks gestation (P = .03). A 16S ribosomal RNA sequence analysis detected Citrobacter-like sequences only in cases with NEC (3 of 4) and an increased frequency of Enterococcus-like sequences in cases and Klebsiella in control subjects (P = .06). The overall microbiota profiles in cases with NEC were not distinguishable from that in control subjects. Microbial DNA in meconium of premature infants suggests prenatal influences.


Molecular and functional identification of the Na(+)/H(+) exchange isoforms NHE1 and NHE3 in isolated bovine articular chondrocytes.
Cartilage matrix turnover is sensitive to changes in intracellular pH (pH(i)) and previous studies have shown that articular chondrocytes regulate pH(i) predominantly using an amiloride-sensitive Na(+) / H(+) exchanger (NHE) with hallmark properties of the housekeeper isoform NHE1. Immunoblotting studies have, however, demonstrated that bovine chondrocytes express both the NHE1 and NHE3 isoforms of Na(+) / H(+) exchange. In the present study the effect of exposure to serum on acid extrusion from chondrocytes has been studied. The pH-sensitive fluoroprobe BCECF was used to measure pH(i) in isolated bovine articular chondrocytes, and proton equivalent membrane transporters were characterised for cells isolated in the absence and presence of 5% fetal bovine serum (FBS). The contribution of NHE isoforms to acid extrusion, following ammonium-induced acidification, was assessed using a combination of ion substitution and the specific NHE1 inhibitor HOE694. While Na(+) -dependent acid extrusion was entirely inhibited by HOE694 in FBS untreated cells, the operation of both NHE1 and NHE3 was detected in cells exposed to FBS. In parallel, RT-PCR and immunohistochemistry experiments demonstrated both NHE1 and NHE3 mRNA and expression of both proteins respectively. While serum growth factors are virtually excluded from healthy cartilage they could permeate a damaged matrix. The regulatory characteristics of NHE3 are distinct from NHE1 so that an altered pattern of response to components of mechanical stress such as hyperosmolarity may be associated with increased access of growth factors in diseased tissue.


Differential sex allocation in sand lizards: bright males induce daughter production in a species with heteromorphic sex chromosomes.
In sand lizards (Lacerta agilis), males with more and brighter nuptial coloration also have more DNA fragments visualized in restriction fragment length polymorphism analysis of their major histocompatibility complex class I loci (and, hence, are probably more heterozygous at these loci). Such males produce more viable offspring, with a particularly strong viability effect on daughters. This suggests that females should adjust both their reproductive investment and offspring sex ratio in relation to male coloration (i.e. differential allocation). Our results show that experimental manipulation of partner coloration in the wild results in significantly higher maternal effort and a 10% higher proportion of daughters than sons. This supports the hypothesis that females increase their maternal energetic expenditure and adjust their offspring sex ratio in response to high-quality partners. However, it also suggests that this has probably evolved through natural selection for increased offspring viability (primarily through production of daughters), rather than through increased mate attraction (e.g. sexy sons).


IM-TORNADO: a tool for comparison of 16S reads from paired-end libraries.
16S rDNA hypervariable tag sequencing has become the de facto method for accessing microbial diversity. Illumina paired-end sequencing, which produces two separate reads for each DNA fragment, has become the platform of choice for this application. However, when the two reads do not overlap, existing computational pipelines analyze data from read separately and underutilize the information contained in the paired-end reads. We created a workflow known as Illinois Mayo Taxon Organization from RNA Dataset Operations (IM-TORNADO) for processing non-overlapping reads while retaining maximal information content. Using synthetic mock datasets, we show that the use of both reads produced answers with greater correlation to those from full length 16S rDNA when looking at taxonomy, phylogeny, and beta-diversity. IM-TORNADO is freely available at http://sourceforge.net/projects/imtornado and produces BIOM format output for cross compatibility with other pipelines such as QIIME, mothur, and phyloseq.


Octreotide (long-acting release formulation) treatment in patients with graves' orbitopathy: clinical results of a four-month, randomized, placebo-controlled, double-blind study.
There are few effective, safe modalities for the management of Graves' ophthalmopathy (GO), a cell-mediated immune comorbidity of thyroid disease. Somatostatin analogs inhibit lymphocyte proliferation and activation, and accumulate in the orbital tissue of patients with GO. A double-blind, placebo-controlled study of a long-acting somatostatin analog [16 wk of long-acting release formulation of octreotide (octreotide-LAR)] was conducted in 51 patients with mild active GO with the aim of preventing deterioration and precluding the need for more aggressive therapeutic modalities, such as glucocorticoids or radiotherapy. No treatment effect was observed for the primary end point (a composite parameter defining the outcome as either success or failure on the basis of changes in class/grade of the severity index and Clinical Activity Scale of GO). The Clinical Activity Scale score was reduced for patients treated with octreotide-LAR, but without any significant difference with respect to patients receiving placebo. However, octreotide-LAR significantly reduced proptosis (as measured by exophthalmometry). This was associated with nonsignificant differences in favor of octreotide-LAR in a series of proptosis-related parameters: class III grade, opening of the upper eyelid, the difference in ocular pressure between primary position and upgaze, and extraocular muscle involvement. By magnetic resonance imaging evaluation the extraocular muscle volumes appeared reduced, but nonsignificantly. No significant correlation between the initial uptake of the somatostatin analog indium-labeled and the response to treatment was observed. One patient in the octreotide-LAR group developed gallstones. In this study, octreotide-LAR did not seem suitable to mitigate activity in mild GO. Surprisingly, it significantly reduced proptosis, one of the most debilitating symptoms of GO. Additional studies are warranted to define the benefit to risk ratio of the somatostatin analogs in this indication.


Effects of ELF (1-120 Hz) and modulated (50 Hz) RF fields on the efflux of calcium ions from brain tissue in vitro.
We have previously shown that 16-Hz, sinusoidal electromagnetic fields can cause enhanced efflux of calcium ions from chick brain tissue, in vitro, in two intensity regions centered on 6 and 40 Vp-p/m. Alternatively, 1-Hz and 30-Hz fields at 40 Vp-p/m did not cause enhanced efflux. We now demonstrate that although there is no enhanced efflux associated with a 42-Hz field at 30, 40, 50, or 60 Vp-p/m, a 45-Hz field causes enhanced efflux in an intensity range around 40 Vp-p/m that is essentially identical to the response observed for 16-Hz fields. Fields at 50 Hz induce enhanced efflux in a narrower intensity region between 45 and 50 Vp-p/m, while radiofrequency carrier waves, amplitude modulated at 50 Hz, also display enhanced efflux over a narrow power density range. Electromagnetic fields at 60 Hz cause enhanced efflux only at 35 and 40 Vp-p/m, intensities slightly lower than those that are effective at 50 Hz. Finally, exposures over a series of frequencies at 42.5 Vp-p/m reveal two frequency regions that elicit enhanced efflux--one centered on 15 Hz, the other extending from 45 to 105 Hz.


The invitro assessment of antibacterial effect of papaya seed extract against bacterial pathogens isolated from urine, wound and stool.
Carica papaya family Caricaceacae is one of the herbal remedies, which has recently become a subject of research focus. It is used in traditional medicine for variety of purposes in treating infectious and noninfectious diseases. The objective of this study was to assess the antibacterial effect of papaya seed extract against bacterial pathogens isolated from wound, urine and stool. This analytical experimental study was conducted in Jimma University, School of Medical Laboratory Technology, Microbiology laboratory between February to March 2005. The antibacterial activity of methanol extract of papaya seed was investigated against specific pathogenic bacteria isolated from wound, urine and stool by an agar dilution technique and the crude preparation was assessed by an agar diffusion technique. The growth or inhibition of control strains of Escherichia coli, Staphylococcus aureus, Salmonella typhi, and Pseudomonas aeruginosa as well as the clinical isolates of these bacteria were determined in growth media. Results obtained in this study indicate that the minimum inhibitory concentration of papaya seed extract for 50% of the test bacteria was 18.38mg/ml and for S. typhi the MIC was at 11.8 mg/ml of extract. However, the growth inhibitory effect of papaya seed extract was not observed for P. aeruginosa up to 26.25 mg /ml of extract. Even though, the minimum bactericidal concentration is higher than the minimum inhibitory concentration of papaya seed extract (13.13 mg/ml, 11.8 mg/ml respectively) against S. typhi control and clinical isolates, the minimum bactericidal concentration for 50% of the tested bacteria was found to be similar with the minimum inhibitory concentration of the test bacteria, Papaya seed could be used as an effective antibacterial agent for the tested organisms. Nevertheless, preclinical studies including invivo animal models and clinical trial on the effect of the seed are essential before advocating large-scale therapy.


A midlife crisis for the mitochondrial free radical theory of aging.
Since its inception more than four decades ago, the Mitochondrial Free Radical Theory of Aging (MFRTA) has served as a touchstone for research into the biology of aging. The MFRTA suggests that oxidative damage to cellular macromolecules caused by reactive oxygen species (ROS) originating from mitochondria accumulates in cells over an animal's lifespan and eventually leads to the dysfunction and failure that characterizes aging. A central prediction of the theory is that the ability to ameliorate or slow this process should be associated with a slowed rate of aging and thus increased lifespan. A vast pool of data bearing on this idea has now been published. ROS production, ROS neutralization and macromolecule repair have all been extensively studied in the context of longevity. We review experimental evidence from comparisons between naturally long- or short-lived animal species, from calorie restricted animals, and from genetically modified animals and weigh the strength of results supporting the MFRTA. Viewed as a whole, the data accumulated from these studies have too often failed to support the theory. Excellent, well controlled studies from the past decade in particular have isolated ROS as an experimental variable and have shown no relationship between its production or neutralization and aging or longevity. Instead, a role for mitochondrial ROS as intracellular messengers involved in the regulation of some basic cellular processes, such as proliferation, differentiation and death, has emerged. If mitochondrial ROS are involved in the aging process, it seems very likely it will be via highly specific and regulated cellular processes and not through indiscriminate oxidative damage to macromolecules.


Quantum confined electron-phonon interaction in silicon nanocrystals.
We study the micro-Raman spectra of colloidal silicon nanocrystals as a function of size, excitation wavelength, and excitation intensity. We find that the longitudinal optical (LO) phonon spectrum is asymmetrically broadened toward the low energy side and exhibits a dip or antiresonance on the high-energy side, both characteristics of a Fano line shape. The broadening depends on both nanocrystal size and Raman excitation wavelength. We propose that the Fano line shape results from interference of the optical phonon response with a continuum of electronic states that become populated by intraband photoexcitation of carriers. The asymmetry exhibits progressive enhancement with decreasing particle size and with increasing excitation energy for a given particle size. We compare our observations with those reported for p- and n-doped bulk Si, where Fano interference has also been observed, but we find opposite wavelength dependence of the asymmetry for the bulk and nanocrystalline Si. Our results have important implications for potentially controlling carrier energy relaxation channels in strongly confined Si nanocrystals.


Application of a species-specific PCR-RFLP to identify Ancylostoma eggs directly from canine faeces.
Apart from their veterinary importance, the hookworms Ancylostoma caninum, Ancylostoma braziliense and Ancylostoma caninum are also capable of causing zoonotic disease in humans. A highly sensitive and species-specific PCR-RFLP technique was utilised to detect and differentiate the various canine Ancylostoma spp directly from eggs in faeces. This technique was utilised to screen 101 canine faecal samples from parasite endemic tea growing communities in Assam, India, as part as an ongoing epidemiological investigation into canine parasitic zoonoses. The prevalence of hookworms in dogs was found to be 98% using a combination of PCR and conventional microscopy. Overall, 36% of dogs were found positive for single hookworm infections with A. caninum, 24% positive for single infections with A. braziliense and 38% had mixed infections with both A. caninum and A. braziliense. No dogs were found positive for A. ceylanicum in the community under study. The high prevalence of A. caninum and A. braziliense in dogs in this community may account for the high incidence of cutaneous larva migrans (CLM) observed among the human population residing at the tea estates. The PCR-RFLP technique described herein allows epidemiological screening of canine hookworms to be conducted rapidly, with ease and accuracy, and has the potential to be applied to a number of different clinical, pharmacological and epidemiological situations.


Reducing hepatic PKD activity lowers circulating VLDL cholesterol.
Protein kinase D (PKD) is emerging as an important kinase regulating energy balance and glucose metabolism; however, whether hepatic PKD activity can be targeted to regulate these processes is currently unclear. In this study, hepatic PKD activity was reduced using adeno-associated virus vectors to express a dominant-negative (DN) version of PKD1, which impairs the action of all three PKD isoforms. In chow-fed mice, hepatic DN PKD expression increased whole-body glucose oxidation, but had only mild effects on glucose and insulin tolerance and no effects on glucose homeostasis following fasting and refeeding. However, circulating VLDL cholesterol was reduced under these conditions and was associated with hepatic fatty acid accumulation, but not lipids involved in lipoprotein synthesis. The limited effects on glucose homeostasis in DN PKD mice was despite reduced expression of gluconeogenic genes under both fasted and refed conditions, and enhanced pyruvate tolerance. The requirement for PKD for gluconeogenic capacity was supported by in vitro studies in cultured FAO hepatoma cells expressing DN PKD, which produced less glucose under basal conditions. Although these pathways are increased in obesity, the expression of DN PKD in the liver of mice fed a high-fat diet had no impact on glucose tolerance, insulin action, pyruvate tolerance or plasma VLDL. Together, these data suggest that PKD signalling in the liver regulates metabolic pathways involved in substrate redistribution under conditions of normal nutrient availability, but not under conditions of overnutrition such as in obesity.


Acute compartment syndrome in the pelvic limb of a cow following biopsy of a skeletal muscle-associated hemangiosarcoma.
A 6-year-old Holstein cow was examined because of chronic lameness and swelling near the stifle joint of the left pelvic limb. A mass was palpated in the soft tissues lateral to the proximal aspect of the left tibia. Multiple attempts to obtain a biopsy specimen of the mass resulted in acute compartment syndrome of the femoral compartment (tensor fasciae latae and biceps femoris muscles) and lateral tibial compartment (cranial tibial and peroneus tertius muscles) with associated sciatic nerve paralysis. Surgical decompression via tensor fasciae latae and biceps femoris incision resolved the sciatic nerve paralysis. On the fifth day following surgery, the cow began to develop signs of increased respiratory effort. Thoracic radiography revealed a pulmonary metastatic micronodular pattern. The cow was euthanized because its condition deteriorated. Metastatic hemangiosarcoma was confirmed at necropsy, and the primary tumor was the mass that was lateral to the tibia and within the biceps femoris muscle. Hemangiosarcoma should be considered a differential diagnosis for lameness in cattle when no orthopedic cause can be identified. Close patient surveillance is strongly recommended in the event that a vascular tumor is present because catastrophic consequences are possible. To our knowledge, this is the first report of acute compartment syndrome in a pelvic limb of a bovine patient and the only report of hemangiosarcoma in the skeletal muscle of cattle.


A case of idiopathic bursal synovial chondromatosis resembling rheumatoid arthritis.
Primary synovial osteochondromatosis is an unusual condition, which generally involves otherwise normal joints. Joints commonly affected in descending order of frequency are knee, hip, glenohumeral joint, elbow and ankle, though any articulation may be involved. Synovial osteochondromatosis has been also encountered in tendon sheaths and periarticular bursa. We report a case with the clinical findings, radiographic features, surgical and histological data of primary subacromial-subdeltoid bursa synovitis. X-ray radiographs of the right glenohumeral joint as well as CT and MRI of the right shoulder zone were performed. A soft tissue mass around the lateral margin of the proximal humerus without evidence of any calcification/ossification or erosion of the adjacent cortex was detected on both X-Rays and CT images. Multiple nodules of almost equal size appeared that were isointense on T1-weighted spin-echo images and slightly hyperintense on T2 weighted spin-echo images compared with the signal intensity of the surrounding skeletal muscles. The main differential diagnosis was pigmented villonodular synovitis, rheumatoid arthritis with rice bodies and secondary synovial osteochondromatosis. Based on the results of all modalities the diagnosis of primary synovial chondromatosis of subdeltoid/ subacromial bursa was concluded.


Factors associated with self-reported medical errors among healthcare workers: a cross-sectional study from Oman.
Despite efforts to improve patient safety, medical errors remain prevalent among healthcare workers. The aim of this study was to investigate the relationships between self-reported medical errors, occupational outcomes and socio-demographic variables. The study employed a cross-sectional design to survey healthcare workers at a large tertiary hospital in Muscat, Oman. The survey questionnaire included socio-demographic variables, a self-assessment of medical errors, work-life balance, occupational burnout and work-related bullying. A total of 297 healthcare workers participated in this study. In this sample, the average of self-reported medical errors was 5.4 ± 3.3. The prevalence of work-life imbalance, bullying and moderate/high burnout was 90.2%, 31.3% and 19.5%, respectively. Multivariate analysis showed that gender, nationality, age, profession, occupational burnout and bullying were significantly associated with self-reported medical error. Being male was associated with higher self-reported medical errors compared to female workers (β = 1.728, P < 0.001). Omani workers reported higher medical errors compared to their non-Omani colleagues (β = 2.668, P < 0.001). Similarly, healthcare workers in a younger age group reported higher medical errors compared with those in the older age group (β = ‒1.334, P < 0.001). Physicians reported higher medical error than nurses (β = 3.126, P < 0.001). Among occupational outcomes, self-reported medical errors increased with higher burnout rates (β = 1.686, P = 0.003) and frequent exposure to bullying (β = 1.609, P < 0.001). Improving patient safety has become paramount in the modern age of quality improvement. In this study, medical errors reported by healthcare workers were strongly related to their degree of burnout and exposure to work-related bullying practice. This study makes a unique and tangible contribution to the current knowledge of medical errors among healthcare workers in Oman.


Hox gene expression during development of the phoronid Phoronopsis harmeri.
Phoronida is a small group of marine worm-like suspension feeders, which together with brachiopods and bryozoans form the clade Lophophorata. Although their development is well studied on the morphological level, data regarding gene expression during this process are scarce and restricted to the analysis of relatively few transcription factors. Here, we present a description of the expression patterns of Hox genes during the embryonic and larval development of the phoronid Phoronopsis harmeri. We identified sequences of eight Hox genes in the transcriptome of Ph. harmeri and determined their expression pattern during embryonic and larval development using whole mount in situ hybridization. We found that none of the Hox genes is expressed during embryonic development. Instead their expression is initiated in the later developmental stages, when the larval body is already formed. In the investigated initial larval stages the Hox genes are expressed in the non-collinear manner in the posterior body of the larvae: in the telotroch and the structures that represent rudiments of the adult worm. Additionally, we found that certain head-specific transcription factors are expressed in the oral hood, apical organ, preoral coelom, digestive system and developing larval tentacles, anterior to the Hox-expressing territories. The lack of Hox gene expression during early development of Ph. harmeri indicates that the larval body develops without positional information from the Hox patterning system. Such phenomenon might be a consequence of the evolutionary intercalation of the larval form into an ancestral life cycle of phoronids. The observed Hox gene expression can also be a consequence of the actinotrocha representing a "head larva", which is composed of the most anterior body region that is devoid of Hox gene expression. Such interpretation is further supported by the expression of head-specific transcription factors. This implies that the Hox patterning system is used for the positional information of the trunk rudiments and is, therefore, delayed to the later larval stages. We propose that a new body form was intercalated to the phoronid life cycle by precocious development of the anterior structures or by delayed development of the trunk rudiment in the ancestral phoronid larva.


DNA-repair protein hHR23a alters its protein structure upon binding proteasomal subunit S5a.
The Rad23 family of proteins, including the human homologs hHR23a and hHR23b, stimulates nucleotide excision repair and has been shown to provide a novel link between proteasome-mediated protein degradation and DNA repair. In this work, we illustrate how the proteasomal subunit S5a regulates hHR23a protein structure. By using NMR spectroscopy, we have elucidated the structure and dynamic properties of the 40-kDa hHR23a protein and show it to contain four structured domains connected by flexible linker regions. In addition, we reveal that these domains interact in an intramolecular fashion, and by using residual dipolar coupling data in combination with chemical shift perturbation analysis, we present the hHR23a structure. By itself, hHR23a adopts a closed conformation defined by the interaction of an N-terminal ubiquitin-like domain with two ubiquitin-associated domains. Interestingly, binding of the proteasomal subunit S5a disrupts the hHR23a interdomain interactions and thereby causes it to adopt an opened conformation.


Vascular endothelial growth factor enhances profibrotic activities through modulation of calcium homeostasis in human atrial fibroblasts.
Vascular endothelial growth factor (VEGF), a pivotal activator of angiogenesis and calcium (Ca2+) signaling in endothelial cells, was shown to increase collagen production in atrial fibroblasts. In this study, we evaluated whether VEGF may regulate Ca2+ homeostasis in atrial fibroblasts and contribute to its profibrogenesis. Migration, and proliferation analyses, patch-clamp assay, Ca2+ fluorescence imaging, and western blotting were performed using VEGF-treated (300 pg/mL or 1000 pg/mL) human atrial fibroblasts with or without coadministration of Ethylene glycol tetra-acetic acid (EGTA, 1 mmol/L), or KN93 (a Ca2+/calmodulin-dependent protein kinase II [CaMKII] inhibitor, 10 μmol/L). VEGF (1000 pg/mL) increased migration, myofibroblast differentiation, pro-collagen type I, pro-collagen type III production, and phosphorylated VEGF receptor 1 expression of fibroblasts. VEGF (1000 pg/mL) increased the nonselective cation current (INSC) of transient receptor potential (TRP) channels and potassium current of intermediate-conductance Ca2+-activated K+ (KCa3.1) channels thereby upregulating Ca2+ entry. VEGF upregulated phosphorylated ERK expression. An ERK inhibitor (PD98059, 50 μmol/L) attenuated VEGF-activated INSC of TRP channels. The presence of EGTA attenuated the profibrotic effects of VEGF on pro-collagen type I, pro-collagen type III production, myofibroblast differentiation, and migratory capabilities of fibroblasts. VEGF upregulated the expression of phosphorylated CaMKII in fibroblasts, which was attenuated by EGTA. In addition, KN93 reduced VEGF-increased pro-collagen type I, pro-collagen type III production, myofibroblast differentiation, and the migratory capabilities of fibroblasts. In conclusion, we found that VEGF increases atrial fibroblast activity through CaMKII signaling by enhancing Ca2+ entry. Our findings provide benchside evidence leading to a potential novel strategy targeting atrial myopathy and arrhythmofibrosis.


Structured multiple endosymbiosis of bacteria and archaea in a ciliate from marine sulfidic sediments: a survival mechanism in low oxygen, sulfidic sediments?
Marine micro-oxic to sulfidic environments are sites of intensive biogeochemical cycling and elemental sequestration, where prokaryotes are major driving forces mediating carbon, nitrogen, sulfur, phosphorus, and metal cycles, important from both biogeochemical and evolutionary perspectives. Associations between single-celled eukaryotes and bacteria and/or archaea are common in such habitats. Here we describe a ciliate common in the micro-oxic to anoxic, typically sulfidic, sediments of Santa Barbara Basin (CA, USA). The ciliate is 95% similar to Parduzcia orbis (18S rRNA). Transmission electron micrographs reveal clusters of at least three different endobiont types organized within membrane-bound sub-cellular regions. Catalyzed reporter deposition-fluorescent in situ hybridization and 16S rRNA clone libraries confirm the symbionts include up to two sulfate reducers (Desulfobulbaceae, Desulfobacteraceae), a methanogen (Methanobacteriales), and possibly a Bacteroidete (Cytophaga) and a Type I methanotroph, suggesting synergistic metabolisms in this environment. This case study is discussed in terms of implications to biogeochemistry, and benthic ecology.


Promoting the translation of intentions into action by implementation intentions: behavioral effects and physiological correlates.
The present review addresses the physiological correlates of planning effects on behavior. Although intentions to act qualify as predictors of behavior, accumulated evidence indicates that there is a substantial gap between even strong intentions and subsequent action. One effective strategy to reduce this intention-behavior gap is the formation of implementation intentions that specify when, where, and how to act on a given goal in an if-then format ("If I encounter situation Y, then I will initiate action Z!"). It has been proposed that implementation intentions render the mental representation of the situation highly accessible and establish a strong associative link between the mental representations of the situation and the action. These process assumptions have been examined in behavioral research, and in physiological research, a field that has begun to investigate the temporal dynamics of and brain areas involved in implementation intention effects. In the present review, we first summarize studies on the cognitive processes that are central to the strategic automation of action control by implementation intentions. We then examine studies involving critical samples with impaired self-regulation. Lastly, we review studies that have applied physiological measures such as heart rate, cortisol level, and eye movement, as well as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) studies on the neural correlates of implementation intention effects. In support of the assumed processes, implementation intentions increased goal attainment in studies on cognitive processes and in critical samples, modulated brain waves related to perceptual and decision processes, and generated less activity in brain areas associated with effortful action control. In our discussion, we reflect on the status quo of physiological research on implementation intentions, methodological and conceptual issues, related research, and propose future directions.


Endocrine changes in cerebrospinal fluid, pituitary effluent, and peripheral plasma of anesthetized ponies.
To investigate the effects of inhalation and total IV anesthesia on pituitary-adrenal activity in ponies. 9 healthy ponies: 5 geldings and 4 mares. Catheters were placed in the cavernous sinus below the pituitary gland and in the subarachnoid space via the lumbosacral space. After 72 hours, administration of acepromazine was followed by induction of anesthesia with thiopentone and maintenance with halothane (halothane protocol), or for the IV protocol, anesthesia induction with detomidine and ketamine was followed by maintenance with IV infusion of a detomidine-ketamine-guaifenesin combination. Arterial blood pressure and gas tensions were measured throughout anesthesia. Peptide and catecholamine concentrations were measured in pituitary effluent, peripheral plasma, and CSF. Peripheral plasma cortisol, glucose, and lactate concentrations also were measured. Intravenous anesthesia caused less cardiorespiratory depression than did halothane. ACTH, metenkephalin, arginine vasopressin, and norepinephrine pituitary effluent and peripheral plasma concentrations were higher during halothane anesthesia, with little change during intravenous anesthesia. Pituitary effluent plasma beta-endorphin and peripheral plasma cortisol concentrations increased during halothane anesthesia only. Dynorphin concentrations did not change in either group. Hyperglycemia developed during intravenous anesthesia only. Minimal changes occurred in CSF hormonal concentrations during anesthesia. The pituitary gland has a major role in maintaining circulating peptides during anesthesia. Compared with halothane, IV anesthesia appeared to suppress pituitary secretion.


Relationship between protein thermodynamic constraints and variation of evolutionary rates among sites.
Evolutionary-rate variation among sites within proteins depends on functional and biophysical properties that constrain protein evolution. It is generally accepted that proteins must be able to fold stably in order to function. However, the relationship between stability constraints and among-sites rate variation is not well understood. Here, we present a biophysical model that links the thermodynamic stability changes due to mutations at sites in proteins ([Formula: see text]) to the rate at which mutations accumulate at those sites over evolutionary time. We find that such a 'stability model' generally performs well, displaying correlations between predicted and empirically observed rates of up to 0.75 for some proteins. We further find that our model has comparable predictive power as does an alternative, recently proposed 'stress model' that explains evolutionary-rate variation among sites in terms of the excess energy needed for mutants to adopt the correct active structure ([Formula: see text]). The two models make distinct predictions, though, and for some proteins the stability model outperforms the stress model and vice versa. We conclude that both stability and stress constrain site-specific sequence evolution in proteins.