In vitro decidualisation of human endometrial stromal cells is enhanced by seminal fluid extracellular vesicles.
Extracellular vesicles are highly abundant in seminal fluids and have a known role enhancing sperm function. Clinical pregnancy rates after IVF treatment are improved after female exposure to seminal fluid. Seminal fluid extracellular vesicles (SF-EVs) are candidate enhancers, however, whether SF-EVs interact with cells from the endometrium and modulate the implantation processes is unknown. Here, we investigated whether SF-EVs interact with endometrial stromal cells (ESCs) and enhance decidualisation, a requisite for implantation. SF-EVs, isolated from human seminal fluid (n = 11) by ultracentrifugation, were characterised by nanoparticle tracking analysis and Western blotting, and purified using size exclusion chromatography. Non-decidualised and decidualised primary ESCs (n = 5) were then treated with SF-EVs. Binding of bio-maleimide-labelled SF-EVs was detected by flow cytometry and fluorescence microscopy. Prolactin and IGFBP-1 protein levels in culture media were also analysed after single and multiple SF-EV exposure. SF-EVs size ranged from 50 to 300 nm, and they expressed exosomal markers (ALIX, SYNTENIN-1, CD9 and CD81). SF-EVs bound to non-decidualised and decidualised ESCs at similar levels. ESCs prolactin secretion was increased after single (p = 0.0044) and multiple (p = 0.0021) SF-EV exposure. No differences were found in IGFBP-1 protein levels. In conclusion, SF-EVs enhance in vitro ESC decidualisation and increase secretion of prolactin, an essential hormone in implantation. This elucidates a novel role of SF-EVs on endometrial receptivity. Abbreviations: ECACC: European Collection of Authenticated Cell Cultures; ESCs: endometrial stromal cells; EVs: extracellular vesicles; FCS: foetal calf serum; HRP: horse-radish peroxidase; IFNγ: interferon-gamma; IGF: insulin-like growth factor; IGFBP-1: insulin-like growth factor binding protein 1; IVF: in vitro fertilisation; MVB: multivesicular bodies; NTA: nanoparticle tracking analysis; PRLR-/-: homozygous prolactin receptor knockout; RT: room temperature; SF-EVs: seminal fluid extracellular vesicles; STR: short tandem repeat; TGFβ: transforming growth factor β; uNK: uterine natural killer.


Counter-Selection of Antimalarial Resistance Polymorphisms by Intermittent Preventive Treatment in Pregnancy.
Innovative approaches are needed to limit antimalarial resistance evolution. Understanding the role of intermittent preventive treatment in pregnancy (IPTp) on the selection for resistance and the impact such selection has on pregnancy outcomes can guide future interventions. Plasmodium falciparum isolates (n = 914) from 2 randomized clinical trials were screened for pfmdr1 copy number variation and pfcrt, pfmdr1, pfdhfr, and pfdhps resistance markers. The trials were conducted between 2010 and 2013 in Benin, Gabon, Kenya, and Mozambique to establish the efficacy of IPTp-mefloquine (MQ) compared with IPTp-sulphadoxine-pyrimethamine (SP) in human immunodeficiency virus (HIV)-uninfected and to IPTp-placebo in HIV-infected women. In HIV-uninfected women, the prevalence of pfcrt mutants, pfdhfr/pfdhps quintuple mutants, and pfmdr1 copy number was similar between women receiving IPT-SP and IPTp-MQ. However, prevalence of pfmdr1 polymorphism 86Y was lower in the IPTp-MQ group than in the IPTp-SP group, and within the IPTp-MQ group it was lower at delivery compared with recruitment. No effect of IPTp-MQ on resistance markers was observed among HIV-infected women. The carriage of resistance markers was not associated with pregnancy outcomes. Selection of wild-type pfmdr1 polymorphism N86 by IPTp-MQ highlights the strong selective pressure IPTp can exert and the opportunity for using negative cross-resistance in drug choice for clinical treatment and IPTp.


Practice parameters for the management of single brain metastasis.
In January 1998 the Guidelines and Outcomes Committee of the American Association of Neurological Surgeons (AANS) issued a charge for the development of evidence-based practice parameters focusing on the treatment of patients with single metastasis to the brain. The charge was imposed in response to the significant controversy surrounding questions relating to the optimal management strategies for patients with single brain metastasis. A team consisting of physicians from the AANS, the American Academy of Neurology, and the American Association of Therapeutic Radiation Oncology convened and the literature was reviewed. Methodically drawing from the best of Class I, II, and III levels of available evidence, authors sought to determine how the literature addressed and disposed of the question of the optimal management for an adult with a known history of cancer and a single metastatic brain lesion. Framing the question in this specific manner allowed researchers to focus directly on treatment issues, without having to consider diagnostic issues. The results of the evidence-based analysis demonstrated that there was insufficient information to establish standards of care. Data from the literature does, however, support a guideline stating that surgical resection accompanied by whole brain radiation therapy is associated with the best survival rate. Additional lower-quality evidence supports an option for management with radiosurgery.


Neuroinflammation in Autism: Plausible Role of Maternal Inflammation, Dietary Omega 3, and Microbiota.
Several genetic causes of autism spectrum disorder (ASD) have been identified. However, more recent work has highlighted that certain environmental exposures early in life may also account for some cases of autism. Environmental insults during pregnancy, such as infection or malnutrition, seem to dramatically impact brain development. Maternal viral or bacterial infections have been characterized as disruptors of brain shaping, even if their underlying mechanisms are not yet fully understood. Poor nutritional diversity, as well as nutrient deficiency, is strongly associated with neurodevelopmental disorders in children. For instance, imbalanced levels of essential fatty acids, and especially polyunsaturated fatty acids (PUFAs), are observed in patients with ASD and other neurodevelopmental disorders (e.g., attention deficit hyperactivity disorder (ADHD) and schizophrenia). Interestingly, PUFAs, and specifically n-3 PUFAs, are powerful immunomodulators that exert anti-inflammatory properties. These prenatal dietary and immunologic factors not only impact the fetal brain, but also affect the microbiota. Recent work suggests that the microbiota could be the missing link between environmental insults in prenatal life and future neurodevelopmental disorders. As both nutrition and inflammation can massively affect the microbiota, we discuss here how understanding the crosstalk between these three actors could provide a promising framework to better elucidate ASD etiology.


Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis.
To explore the association of supplementary and dietary vitamin E and C intake with the progression of coronary artery disease. A subgroup analysis of the on-trial antioxidant vitamin intake database acquired in the Cholesterol Lowering Atherosclerosis Study, a randomized, placebo-controlled, serial angiographic clinical trial evaluating the risk and benefit of colestipol-niacin on coronary artery disease progression. Community- and university-based cardiac catheterization laboratories. A total of 156 men aged 40 to 59 years with previous coronary artery bypass graft surgery. Supplementary and dietary vitamin E and C intake (nonrandomized) in association with cholesterol-lowering diet and either colestipol-niacin or placebo (randomized). Change per subject in the percentage of vessel diameter obstructed because of stenosis (%S) determined by quantitative coronary angiography after 2 years of randomized therapy on all lesions, mild/moderate lesions (< 50%S), and severe lesions (> or = 50%S). Overall, subjects with supplementary vitamin E intake of 100 IU per day or greater demonstrated less coronary artery lesion progression than did subjects with supplementary vitamin E intake less than 100 IU per day for all lesions (P = .04) and for mild/moderate lesions (P = .01). Within the drug group, benefit of supplementary vitamin E intake was found for all lesions (P = .02) and mild/moderate lesions (P = .01). Within the placebo group, benefit of supplementary vitamin E intake was not found. No benefit was found for use of supplementary vitamin C exclusively or in conjunction with supplementary vitamin E, use of multivitamins, or increased dietary intake of vitamin E or vitamin C. These results indicate an association between supplementary vitamin E intake and angiographically demonstrated reduction in coronary artery lesion progression. Verification from carefully designed, randomized, serial arterial imaging end point trials is needed.


WLD: a robust local image descriptor.
Inspired by Weber's Law, this paper proposes a simple, yet very powerful and robust local descriptor, called the Weber Local Descriptor (WLD). It is based on the fact that human perception of a pattern depends not only on the change of a stimulus (such as sound, lighting) but also on the original intensity of the stimulus. Specifically, WLD consists of two components: differential excitation and orientation. The differential excitation component is a function of the ratio between two terms: One is the relative intensity differences of a current pixel against its neighbors, the other is the intensity of the current pixel. The orientation component is the gradient orientation of the current pixel. For a given image, we use the two components to construct a concatenated WLD histogram. Experimental results on the Brodatz and KTH-TIPS2-a texture databases show that WLD impressively outperforms the other widely used descriptors (e.g., Gabor and SIFT). In addition, experimental results on human face detection also show a promising performance comparable to the best known results on the MIT+CMU frontal face test set, the AR face data set, and the CMU profile test set.


Nature's Shortcut to Protein Folding.
This Feature Article presents a view of the protein folding transition based on the hypothesis that Nature has built features within the sequences that enable a Shortcut to efficient folding. Nature's Shortcut is proposed to be the early establishment of a set of nonlocal weak contacts, constituting protein loops that significantly constrain regions of the collapsed disordered protein into a native-like low-resolution fluctuating topology of major sections of the backbone. Nature's establishment of this scaffold of nonlocal contacts is claimed to bypass what would otherwise be a nearly hopeless unaided search for the final three-dimensional structure in proteins longer than ∼100 amino acids. To support this main contention of the Feature Article, the loop hypothesis (LH) description of early folding events is experimentally tested with time-resolved Förster resonance energy transfer techniques for adenylate kinase, and the data are shown to be consistent with theoretical predictions from the sequential collapse model (SCM). The experimentally based LH and the theoretically founded SCM are argued to provide a unified picture of the role of nonlocal contacts as constituting Nature's Shortcut to protein folding. Importantly, the SCM is shown to reliably predict key nonlocal contacts utilizing only primary sequence information. This view on Nature's Shortcut is open to the protein community for further detailed assessment, including its practical consequences, by suitable application of advanced experimental and computational techniques.


Reasoning deficits in ecstasy (MDMA) polydrug users.
Previous research has shown that ecstasy users are impaired in thinking and reasoning. The present study sought to explore the possibility that syllogistic reasoning errors in ecstasy users were due to an inability to construct a model of the premises due to working memory limitations. Twenty-nine ecstasy users and 25 nonecstasy user controls completed abstract syllogistic reasoning problems varying in difficulty. Pairs of premises were provided, and participants were required to generate conclusions that followed necessarily from them. On the easier problems, both groups performed at well above chance although nonusers achieved significantly more correct responses. Consistent with existing research, on the more difficult problems, errors by nonusers were characterised by incorrect conclusions suggesting that while nonusers have the working memory capacity to construct a single model of the premises, this is not an exhaustive representation and usually results in an erroneous conclusion. On the other hand, for all problem types, ecstasy users, rather than produce incorrect responses, were more likely to fail to generate a conclusion. The present results are consistent with the possibility that ecstasy users with their reduced working memory capacity may experience difficulty in constructing even a single model of the premises. While this might be attributable to the effects of 3,4-methlylenedioxymethamphetamine neurotoxicity, many of the ecstasy users in the present study were polydrug users. Thus, the possibility that other drugs including cannabis and cocaine might contribute to the present results cannot be excluded.


Inherited thrombophilic risk factors in a large cohort of individuals referred to Italian thrombophilia centers: distinct roles in different clinical settings.
Despite inherited thrombophilic risk factors being strongly associated with vein thrombosis, decisions on whether to screen subjects for these factors vary in different clinical settings. We calculated the prevalence of inherited thrombophilic risk factors in a large cohort of patients (n=1,238) with different clinical manifestations of vein thromboembolism. In the present cohort, screening for inherited thrombophilia was worthwhile among patients who developed vein thrombosis of the leg or cerebral vein thrombosis. Carriers of FV Leiden or FII A(20210) mutation more frequently had had deep vein thrombosis of the leg (OR: 4.35; 95% CI: 3.39-5.60), superficial vein thrombosis (OR: 3.34; 95% CI: 2.06-5.41), or cerebral vein thrombosis (OR: 2.77; 95% CI: 1.10-6.96). The screening program appeared to have a limited relevance in patients with isolated pulmonary embolism (OR: 2.13; 95% CI: 1.28-3.54), or mesenteric vein thrombosis (OR: 2.05; 95% CI: 1.22-3.44). The lack of association with inherited thrombophilia does not justify routine screening of patients with thrombosis of the upper extremities or with retinal vein thrombosis.


Radiographical risk factors for major intraoperative blood loss during laminoplasty in patients with ossification of the posterior longitudinal ligament.
A retrospective multi-institutional study. To clarify the distribution of intraoperative blood loss during cervical laminoplasty for ossification of the posterior longitudinal ligament (OPLL), and to identify the radiographical risk factors for the occurrence of major blood loss in patients with OPLL undergoing laminoplasty. The incidence of major intraoperative blood loss during laminoplasty for OPLL is unknown. All patients who underwent cervical laminoplasty for OPLL between April 2005 and March 2008 at 27 institutions across Japan were included in this analysis. We investigated the patients' characteristics and surgical data, and compared the radiographical characteristics of OPLL in patients with and without major blood loss. The estimated intraoperative blood loss was reported for 545 patients (429 male and 116 female; mean age, 62.7 yr). The mean intraoperative blood loss was 223 g (median, 130 g; range, minimal to 3350 g). Excluding 1 patient with intraoperative vertebral artery injury, major blood loss greater than 500 g was reported in 45 patients (8.3%). Patients with major blood loss were more likely to have neurological complications (5/45 vs. 12/499) and a longer hospital stay (29.5 d vs. 28.8 d) in comparison with those without major blood loss. The occupying ratio of OPLL was greater in the major blood loss group (48.3% vs. 42.2%; P = 0.02). A multivariate analysis revealed an occupying ratio of 60% or greater to be associated with an increased risk of major intraoperative blood loss (odds ratio, 2.4; 95% confidence interval, 1.1-5.3). Laminoplasty for OPLL is associated with a risk of major intraoperative blood loss, which can potentially give rise to devastating postoperative complications. An occupying ratio of 60% or greater is a risk factor for major blood loss during laminoplasty in patients with OPLL.


Two conformationally vicinal thiols at the active site of Leishmania donovani adenosine kinase.
Inactivation of adenosine kinase (Adk) from Leishmania donovani correlates with the modification of two conformationally vicinal cysteine residues. In contrast, Adk from hamster liver, despite being sensitive to monothiol-blocking reagents, was insensitive to dithiol modifiers. Inactivation kinetics and substrate-protection studies along with double-modification experiments successively with N-ethylmaleimide in the presence of Ado and sodium m-arsenite-2,3-dimercaptopropanol or diazenedicarboxylic acid bis-N,N'-dimethylamide supported assignment of the two thiols at the Ado-binding site. Cystine bridge formation impaired the ability of the modified enzyme to bind to the substrate. Tryptophan fluorescence of the enzyme was quenched after modification by dithiol-blocking reagents with concomitant loss of activity. However, treatment of the enzyme with methylmethanethiosulphonate (MMTS) led to complete inactivation without a marked change in protein fluorescence. Ado protected both fluorescence and catalytic activity against inactivation by both MMTS and dithiol-blocking reagents. Stern-Volmer quenching analysis of the native and Ado-complexed enzyme suggested that, of the four tryptophan residues, at least one is located at or near the active site. Furthermore quenching constants of native, Ado-complexed and dithiol-modified enzyme in the presence of either acrylamide or KI indicated spatial proximity of tryptophan and two cysteine residues within the hydrophobic domain of the Ado-binding site. Taken together the results suggest important function(s) for the cysteine residue(s). A schematic model is proposed to explain the inactivation of the enzyme by both monothiol- and dithiol-blocking reagents.


Abincol® (Lactobacillus plantarum LP01, Lactobacillus lactis subspecies cremoris LLC02, Lactobacillus delbrueckii LDD01), an oral nutraceutical, pragmatic use in patients with chronic intestinal disorders.
Chronic intestinal disorders (CID), including inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease, irritable bowel syndrome (IBS), and diverticular disease (DD), are diseases that relapse episodes. There is evidence that patients with CID have intestinal dysbiosis, so probiotics may counterbalance the impaired microbiota. Therefore, the current survey evaluated the efficacy and safety of Abincol®, an oral nutraceutical containing a probiotic mixture with Lactobacillus plantarum LP01 (1 billion of living cells), Lactobacillus lactis subspecies cremoris LLC02 (800 millions of living cells), and Lactobacillus delbrueckii LDD01 (200 millions of living cells), in 3,460 outpatients (1,660 males and 1,800 females, mean age 55 years) with chronic intestinal disorders. Patients took 1 stick/daily for 8 weeks. Abincol® significantly diminished the presence and the severity of intestinal symptoms and improved stool form. In conclusion, the current survey suggests that Abincol® may be considered an effective and safe therapeutic option in the management of patients with chronic intestinal disorders.


Vitamin D and its role in skeletal muscle.
This review discusses the clinical and laboratory studies that have examined a role of vitamin D in skeletal muscle. Many observational studies, mainly in older populations, indicate that vitamin D status is positively associated with muscle strength and physical performance and inversely associated with risk of falling. Clinical trials of vitamin D supplementation in older adults with low vitamin D status mostly report improvements in muscle performance and reductions in falls. The underlying mechanisms are probably both indirect via calcium and phosphate and direct via activation of the vitamin D receptor (VDR) on muscle cells by 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. VDR activation at the genomic level regulates transcription of genes involved in calcium handling and muscle cell differentiation and proliferation. A putative membrane-associated VDR activates intracellular signaling pathways also involved in calcium handling and signaling and myogenesis. Additional evidence comes from VDR knockout mouse models with abnormal muscle morphology and physical function, and VDR polymorphisms which are associated with differences in muscle strength. Recent identification of CYP27B1 bioactivity in skeletal muscle cells and in regenerating adult mouse muscle lends support to the direct action of both 25-hydroxyvitamin D and 1,25(OH)(2)D in muscle. Despite these research advances, many questions remain. Further research is needed to fully characterize molecular mechanisms of vitamin D action on muscle cells downstream of the VDR, describe the effects on muscle morphology and contractility, and determine whether these molecular and cellular effects translate into clinical improvements in physical function.


Prevalence and clinical correlates of pathological affective display in Alzheimer's disease.
This study examined the prevalence and correlates of pathological affect in Alzheimer's disease. A consecutive series of 103 patients with Alzheimer's disease were examined with a comprehensive psychiatric assessment that included the pathological laughing and crying scale (PLACS). Forty patients (39%) showed pathological affect: 25% showed crying episodes, and 14% showed laughing or mixed (laughing and crying) episodes. Patients with pathological affect crying showed significantly higher depression scores and a significantly higher frequency of major depression and dysthymia than patients with no pathological affect. Patients with mixed pathological affect showed significantly more subcortical atrophy on CT than patients with pathological affect crying. Forty seven per cent of the patients with pathological affect had no congruent mood disorder, and they showed a significantly longer duration of illness and more severe anosognosia than patients with pathological affect that was congruent with an underlying mood disorder. The study validates the PLACS, and shows the high prevalence of pathological affect in Alzheimer's disease.


Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System?
Respiratory viruses infect the human upper respiratory tract, mostly causing mild diseases. However, in vulnerable populations, such as newborns, infants, the elderly and immune-compromised individuals, these opportunistic pathogens can also affect the lower respiratory tract, causing a more severe disease (e.g., pneumonia). Respiratory viruses can also exacerbate asthma and lead to various types of respiratory distress syndromes. Furthermore, as they can adapt fast and cross the species barrier, some of these pathogens, like influenza A and SARS-CoV, have occasionally caused epidemics or pandemics, and were associated with more serious clinical diseases and even mortality. For a few decades now, data reported in the scientific literature has also demonstrated that several respiratory viruses have neuroinvasive capacities, since they can spread from the respiratory tract to the central nervous system (CNS). Viruses infecting human CNS cells could then cause different types of encephalopathy, including encephalitis, and long-term neurological diseases. Like other well-recognized neuroinvasive human viruses, respiratory viruses may damage the CNS as a result of misdirected host immune responses that could be associated with autoimmunity in susceptible individuals (virus-induced neuro-immunopathology) and/or viral replication, which directly causes damage to CNS cells (virus-induced neuropathology). The etiological agent of several neurological disorders remains unidentified. Opportunistic human respiratory pathogens could be associated with the triggering or the exacerbation of these disorders whose etiology remains poorly understood. Herein, we present a global portrait of some of the most prevalent or emerging human respiratory viruses that have been associated with possible pathogenic processes in CNS infection, with a special emphasis on human coronaviruses.


How can movement quality be promoted in clinical practice? A phenomenological study of physical therapist experts.
In recent years, physical therapists have paid greater attention to body awareness. Clinicians have witnessed the benefits of supporting their patients' learning of movement awareness through the promotion of their movement quality. The aim of this study was to investigate how physical therapist experts promote movement quality in their usual clinical settings. A phenomenological research design that included a sampling strategy was devised. Using specific criteria, 6 lead physical therapists nominated a group of physical therapist experts from the fields of neurology, primary health care, and mental health. Fifteen informants, 5 from each field, agreed to participate. In-depth interviews were conducted with a semistructured interview guide. The informants were invited to simply describe what they had experienced to be successful therapeutic processes for promoting movement quality. Each interview was audiotaped and transcribed. The data analysis was based on a multistep model. Three main themes emerged from the data. First, the physical therapists' embodied presence and movement awareness served as a precondition and an orientation for practice. Embodied presence is a bodily felt sense, a form of personal knowing that evokes understanding and fosters meaning. Second, creating a platform for promoting movement quality revealed implementation of psychological attitudes. Third, action strategies for promoting movement quality suggested a movement awareness learning cycle and components for clinical use. This study demonstrated specific attitudes and skills used by physical therapist experts to promote movement quality in their clinical practice. These results may serve as a therapeutic framework for promoting movement quality in clinical physical therapy, although further research is needed.


Assessment of the reduction in levels of exposure to harmful and potentially harmful constituents in Japanese subjects using a novel tobacco heating system compared with conventional cigarettes and smoking abstinence: A randomized controlled study in confinement.
Smoking conventional cigarettes (CCs) exposes smokers to harmful and potentially harmful constituents (HPHCs). The Tobacco Heating System 2.2 (THS 2.2), a candidate modified risk tobacco product, was developed to reduce or eliminate the formation of HPHCs, while preserving as much as possible the taste, sensory experience, nicotine delivery profile and ritual characteristics of CC. This randomized, controlled, open-label study in confinement for 5 day exposure aimed to demonstrate the reduction in exposure to selected HPHCs, to assess nicotine uptake and subjective effects, in participants switching to THS 2.2 (n = 80) compared to participants continuing smoking CCs (n = 40) and abstaining from smoking (n = 40). The subjects were randomized according to sex and daily CC consumption. The levels of biomarkers of exposure to HPHCs were significantly reduced in participants switching to THS 2.2, compared to CC use. More importantly, the magnitude of exposure reduction observed was close to that which was seen in participants who abstained from smoking for 5 days, while nicotine uptake was maintained. Reduction in urge-to-smoke was comparable between THS and CC groups, however THS 2.2 was slightly less satisfactory than CCs. The new, alternative tobacco product THS 2.2 was well tolerated.


Youth tobacco prevention mass media campaigns: past, present, and future directions.
This paper focuses on countermarketing efforts aimed at curbing youth smoking. We review the literature on the effectiveness of tobacco countermarketing campaigns, characterise current state and national campaign approaches, present findings from qualitative approaches and laboratory experiments that explore a variety of messages (for example, health consequences, industry manipulation), and discuss newer, non-traditional approaches to countermarketing. In conclusion, we outline research needed to fill gaps in our existing knowledge and discuss future directions in tobacco countermarketing aimed at youth.


Cardiovascular complications following chronic treatment with cocaine and testosterone in adolescent rats.
Concomitant use of anabolic androgenic steroids and cocaine has increased in the last years. However, the effects of chronic exposure to these substances during adolescence on cardiovascular function are unknown. Here, we investigated the effects of treatment for 10 consecutive days with testosterone and cocaine alone or in combination on basal cardiovascular parameters, baroreflex activity, hemodynamic responses to vasoactive agents, and cardiac morphology in adolescent rats. Administration of testosterone alone increased arterial pressure, reduced heart rate (HR), and exacerbated the tachycardiac baroreflex response. Cocaine-treated animals showed resting bradycardia without changes in arterial pressure and baroreflex activity. Combined treatment with testosterone and cocaine did not affect baseline arterial pressure and HR, but reduced baroreflex-mediated tachycardia. None of the treatments affected arterial pressure response to either vasoconstrictor or vasodilator agents. Also, heart to body ratio and left and right ventricular wall thickness were not modified by drug treatments. However, histological analysis of left ventricular sections of animals subjected to treatment with testosterone and cocaine alone and combined showed a greater spacing between cardiac muscle fibers, dilated blood vessels, and fibrosis. These data show important cardiovascular changes following treatment with testosterone in adolescent rats. However, the results suggest that exposure to cocaine alone or combined with testosterone during adolescence minimally affect cardiovascular function.


Dynamics of mitochondrial heteroplasmy in three families investigated via a repeatable re-sequencing study.
Originally believed to be a rare phenomenon, heteroplasmy - the presence of more than one mitochondrial DNA (mtDNA) variant within a cell, tissue, or individual - is emerging as an important component of eukaryotic genetic diversity. Heteroplasmies can be used as genetic markers in applications ranging from forensics to cancer diagnostics. Yet the frequency of heteroplasmic alleles may vary from generation to generation due to the bottleneck occurring during oogenesis. Therefore, to understand the alterations in allele frequencies at heteroplasmic sites, it is of critical importance to investigate the dynamics of maternal mtDNA transmission. Here we sequenced, at high coverage, mtDNA from blood and buccal tissues of nine individuals from three families with a total of six maternal transmission events. Using simulations and re-sequencing of clonal DNA, we devised a set of criteria for detecting polymorphic sites in heterogeneous genetic samples that is resistant to the noise originating from massively parallel sequencing technologies. Application of these criteria to nine human mtDNA samples revealed four heteroplasmic sites. Our results suggest that the incidence of heteroplasmy may be lower than estimated in some other recent re-sequencing studies, and that mtDNA allelic frequencies differ significantly both between tissues of the same individual and between a mother and her offspring. We designed our study in such a way that the complete analysis described here can be repeated by anyone either at our site or directly on the Amazon Cloud. Our computational pipeline can be easily modified to accommodate other applications, such as viral re-sequencing.


Automatic induction of projection pursuit indices.
Projection techniques are frequently used as the principal means for the implementation of feature extraction and dimensionality reduction for machine learning applications. A well established and broad class of such projection techniques is the projection pursuit (PP). Its core design parameter is a projection index, which is the driving force in obtaining the transformation function via optimization, and represents in an explicit or implicit way the user's perception of the useful information contained within the datasets. This paper seeks to address the problem related to the design of PP index functions for the linear feature extraction case. We achieve this using an evolutionary search framework, capable of building new indices to fit the properties of the available datasets. The high expressive power of this framework is sustained by a rich set of function primitives. The performance of several PP indices previously proposed by human experts is compared with these automatically generated indices for the task of classification, and results show a decrease in the classification errors.


Cost-Effectiveness of Mitral Valve Repair Versus Replacement for Severe Ischemic Mitral Regurgitation: A Randomized Clinical Trial From the Cardiothoracic Surgical Trials Network
The CTSN (Cardiothoracic Surgical Trials Network) recently reported no difference in left ventricular end-systolic volume index or in survival at 2 years between patients with severe ischemic mitral regurgitation (MR) randomized to mitral valve repair or replacement. However, replacement provided more durable correction of MR and fewer cardiovascular readmissions. Yet, costeffectiveness outcomes have not been addressed. We conducted a cost-effectiveness analysis of the surgical treatment of ischemic MR based on the CTSN trial (n=126 for repair; n=125 for replacement). Patient-level data on readmissions, survival, qualityof- life, and US hospital costs were used to estimate costs and quality-adjusted life years per patient over the trial duration and a 10-year time horizon. We performed microsimulation for extrapolation of outcomes beyond the 2 years of trial data. Bootstrap and deterministic sensitivity analyses were done to address parameter uncertainty. In-hospital cost estimates were $78 216 for replacement versus $72 761 for repair (difference: $5455; 95% uncertainty interval [UI]: −7784–21 193) while 2-year costs were $97 427 versus $96 261 (difference: $1166; 95% UI: −16 253–17 172), respectively. Quality-adjusted life years at 2 years were 1.18 for replacement versus 1.23 for repair (difference: −0.05; 95% UI: −0.17 to 0.07). Over 5 and 10 years, the benefits of reduction in cardiovascular readmission rates with replacement increased, and survival minimally improved compared with repair. At 5 years, cumulative costs and quality-adjusted life years showed no difference on average, but by 10 years, there was a small, uncertain benefit for replacement: $118 023 versus $119 837 (difference: −$1814; 95% UI: −27 144 to 22 602) and qualityadjusted life years: 4.06 versus 3.97 (difference: 0.09; 95% UI: −0.87 to 1.08). After 10 years, the incremental cost-effectiveness of replacement continued to improve. Our cost-effectiveness analysis predicts potential savings in cost and gains in quality-adjusted survival at 10 years when mitral valve replacement is compared with repair for severe ischemic MR. These projected benefits, however, were small and subject to variability. Efforts to further delineate predictors of long-term outcomes in patients with severe ischemic MR are needed to optimize surgical decisions for individual patients, which should yield more cost-effective care. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00807040.


Control of KirBac3.1 potassium channel gating at the interface between cytoplasmic domains.
KirBac channels are prokaryotic homologs of mammalian inwardly rectifying potassium (Kir) channels, and recent structures of KirBac3.1 have provided important insights into the structural basis of gating in Kir channels. In this study, we demonstrate that KirBac3.1 channel activity is strongly pH-dependent, and we used x-ray crystallography to determine the structural changes that arise from an activatory mutation (S205L) located in the cytoplasmic domain (CTD). This mutation stabilizes a novel energetically favorable open conformation in which changes at the intersubunit interface in the CTD also alter the electrostatic potential of the inner cytoplasmic cavity. These results provide a structural explanation for the activatory effect of this mutation and provide a greater insight into the role of the CTD in Kir channel gating.


Mutational profile and EBV strains of extranodal NK/T-cell lymphoma, nasal type in Latin America.
Extranodal NK/T-cell lymphoma (ENKTL) is an Epstein-Barr virus (EBV) associated lymphoma, prevalent in Asia and Latin America. Studies in Asian cohorts have identified some recurrent gene mutations in ENKTL; however, the mutational landscape of ENKTL in Latin America is unknown. In this study, we investigated the mutational profile and EBV strains of 71 ENKTL cases from Latin America (42 from Mexico, 17 from Peru, and 12 from Argentina) and compared it with Asian cohorts. The mutational analysis was performed by next generation sequencing (NGS) using an Ion AmpliSeq™ custom panel covering for the most frequently mutated genes identified in ENKTL. STAT3 was the most frequent mutated gene (16 cases: 23%), followed by MSN (10 cases; 14%), BCOR (9 cases; 13%), DDX3X (6 cases; 8%), TP53 (6 cases; 8%), MGA (3 cases; 4%), JAK3 (2 cases; 3%), and STAT5B (1 case; 1%). Mutations in STAT3, BCOR, and DDX3X were nearly mutually exclusive, suggesting different molecular pathways involved in the pathogenesis of ENKTL; whereas mutations in MGA, MSN, and TP53 were concomitant with other mutations. Most cases (75%) carried Type A EBV without the 30-bp LMP1 gene deletion. The overall survival was significantly associated with serum LDH level, Eastern Cooperative Oncology Group (ECOG) performance status, International Prognostic Index (IPI) score, and therapy (p < 0.05), but not associated with any mutation, EBV strain or deletion in EBV LMP1 gene. In conclusion, mutational analysis of ENKTL from Latin America reveals frequent gene mutations leading to activation of the JAK-STAT pathway (25%), mostly STAT3. Compared to Asian cohorts, BCOR, DDX3X and TP53 mutations were also identified but with different frequencies. None of these mutations were associated with prognosis.


Diurnally entrained anticipatory behavior in archaea.
By sensing changes in one or few environmental factors biological systems can anticipate future changes in multiple factors over a wide range of time scales (daily to seasonal). This anticipatory behavior is important to the fitness of diverse species, and in context of the diurnal cycle it is overall typical of eukaryotes and some photoautotrophic bacteria but is yet to be observed in archaea. Here, we report the first observation of light-dark (LD)-entrained diurnal oscillatory transcription in up to 12% of all genes of a halophilic archaeon Halobacterium salinarum NRC-1. Significantly, the diurnally entrained transcription was observed under constant darkness after removal of the LD stimulus (free-running rhythms). The memory of diurnal entrainment was also associated with the synchronization of oxic and anoxic physiologies to the LD cycle. Our results suggest that under nutrient limited conditions halophilic archaea take advantage of the causal influence of sunlight (via temperature) on O(2) diffusivity in a closed hypersaline environment to streamline their physiology and operate oxically during nighttime and anoxically during daytime.


Mycophenolate mofetil decreases rejection in simultaneous pancreas-kidney transplantation when combined with tacrolimus or cyclosporine.
Historically, the acute rejection rates in simultaneous pancreas-kidney (SPK) recipients have been extremely high (50-80%), with many second and third rejection episodes despite the use of quadruple immunosuppression (antibody induction and cyclosporine [CsA]-azathioprine [AZA]-based maintenance immunosuppression). Although this acute rejection has rarely led to graft loss, it has been a great cause of morbidity and of significantly increased cost. In an attempt to decrease the acute rejection rate and related morbidity in SPK transplant recipients, we compared two "state-of-the-art" immunosuppression regimens in a prospective, randomized, single-center study. Patients who received SPK transplants were randomized to receive either tacrolimus (TAC) and mycophenolate mofetil (MMF, n=18) or CsA (Neoral formulation) and MMF (n=18). All patients received OKT3 induction and prednisone, which was tapered to 5 mg/day by 6 months after transplantation. All rejection episodes were biopsy proven. In addition, metabolic control (HgbA1C, hypertension, serum cholesterol), drug toxicity, and infection also were measured. Data were compared with that of a historical group (n=18) who received conventional CsA (Sandimmune formulation) and AZA-based immunosuppression. The incidence of biopsy-proven acute rejection was 11% in both the TAC-MMF and CsA-MMF groups with only two patients in each group experiencing a rejection episode. This rejection rate was significantly decreased from that of the CsA-AZA historical group (77%, P<0.01). There were no significant differences in infection rates, including cytomegalovirus, or in metabolic control (HgbA1C, hypertension, and cholesterol levels). All patients remained on their initial immunosuppression regimen for the first 3 months after transplantation. Between 3 and 6 months after transplantation, three patients were switched from TAC to CsA for recurrent migraine headaches, posttransplant diabetes, and chronic cytomegalovirus infection. Two patients in the CsA-MMF group died of nonimmunologic causes (aspiration pneumonia and arrhythmia) between 3 and 6 months after transplantation. The data from this study show that MMF treatment significantly decreases the incidence of biopsy-proven acute rejection in SPK transplant recipients compared with AZA-treated historical controls. In addition, we conclude that TAC and CsA (Neoral), when combined with MMF, yield similar, low acute rejection rates with similar graft function and metabolic control.


Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function.
Tumor growth induced a significant increase of myeloid-derived suppressor cells (MDSCs) in the tumor-bearing host. In our previous study, we showed that MDSCs induced tumor-specific T-cell tolerance and the development of T regulatory cells (Tregs). Tumor-derived factors have been implicated in the accumulation of MDSCs. We hypothesize that reduction of MDSC accumulation in tumor-bearing hosts, through the blockade of tumor factors, can prevent T-cell anergy and Treg development and thereby improve immune therapy for the treatment of advanced tumors. Several tumor-derived factors were identified by gene array analysis. Among the candidate factors, stem- cell factor (SCF) is expressed by various human and murine carcinomas and was selected for further study. Mice bearing tumor cells with SCF siRNA knockdown exhibited significantly reduced MDSC expansion and restored proliferative responses of tumor-infiltrating T cells. More importantly, blockade of SCF receptor (ckit)-SCF interaction by anti-ckit prevented tumor-specific T-cell anergy, Treg development, and tumor angiogenesis. Furthermore, the prevention of MDSC accumulation in conjunction with immune activation therapy showed synergistic therapeutic effect when treating mice bearing large tumors. This information supports the notion that modulation of MDSC development may be required to achieve effective immune-enhancing therapy for the treatment of advanced tumors.


Anthropometric measurements of adolescent and professional classical ballet dancers.
This study examined anthropometric measures of 83 female adolescent students attending the Boston Ballet summer program and 15 professional dancers from the Boston Ballet Company. Thirty-one were in the least advanced level (group A), 38 were in the moderately advanced level (group B) and 14 were in the most advanced level (group C). The adolescent dancers devoted between 17 and 23 hours per week in dance training, while professional dancers spent 39.2 hours per week in class and rehearsals. Compared to normative data, the dancers tended to be tall and slim. The skinfold, diameter, and circumference measurements were found to be very similar among groups A, B and C, and between group C and the company members. The somatograms demonstrated that the ballet dancers had relatively smaller upper arms and larger calves and ankles compared with the reference female. The data from this study suggest that the body type characteristics associated with professional classical ballet dancers are already apparent in the pre-professional adolescent dancers.


Functional dissociations of risk and reward processing in the medial prefrontal cortex.
Making a risky decision is a complex process that involves evaluation of both the value of the options and the associated risk level. Yet the neural processes underlying these processes have not so far been clearly identified. Using functional magnetic resonance imaging and a task that simulates risky decisions, we found that the dorsal region of the medial prefrontal cortex (MPFC) was activated whenever a risky decision was made, but the degree of this activity across subjects was negatively correlated with their risk preference. In contrast, the ventral MPFC was parametrically modulated by the received gain/loss, and the activation in this region was positively correlated with an individual's risk preference. These results extend existing neurological evidence by showing that the dorsal and ventral MPFC convey different decision signals (i.e., aversion to uncertainty vs. approach to rewarding outcomes), where the relative strengths of these signals determine behavioral decisions involving risk and uncertainty.


Association of food consumption with total volumes of visceral and subcutaneous abdominal adipose tissue in a Northern German population.
Excess accumulation of visceral adipose tissue (VAT) is a known risk factor for cardiometabolic diseases; further, subcutaneous abdominal adipose tissue (SAAT) and the ratio of both (VAT:SAAT ratio) have been discussed as potentially detrimental. Information about the association between diet and adipose tissue is scarce. This study aimed to identify food group intake associated with VAT and SAAT and the VAT:SAAT ratio in a Northern German population. A cross-sectional analysis was conducted in 344 men and 241 women who underwent an MRI to quantify total volumes of VAT and SAAT. Intake of fourteen food groups was assessed with a self-administered 112-item FFQ. Linear regression models adjusted for age, sex, energy intake, physical activity, intake of other food groups and mutual adjustment for VAT and SAAT were calculated to analyse the associations between standardised food group intake and VAT and SAAT, or the VAT:SAAT ratio. Intakes of potatoes (P=0·043) and cakes (P=0·003) were positively and inversely, respectively, associated with both VAT and SAAT. By contrast, intake of cereals was negatively associated with VAT (P=0·045) only, whereas intakes of eggs (P=0·006) and non-alcoholic beverages (P=0·042) were positively associated with SAAT only. The association between eggs and non-alcoholic beverages with SAAT remained significant after further consideration of VAT. Intake of non-alcoholic beverages was also inversely associated with the VAT:SAAT ratio (P=0·001). Our analysis adds to the evidence that intake of foods is independently associated with VAT or SAAT volumes.


Reactive oxygen species production, genotoxicity and telomere length in FE1-Muta™Mouse lung epithelial cells exposed to carbon nanotubes.
Carbon nanotubes (CNTs) are fiber-like nanomaterials, which are used in various applications with possible exposure to humans. The genotoxicity and carcinogenic potential of CNTs remain to be fully understood. This study assessed the genotoxicity of three different multi-walled carbon nanotubes (MWCNTs) (MWCNT-7, NM-401 and NM-403) and one single-walled carbon nanotube (SWCNT) (NM-411) in FE1-Muta™Mouse lung epithelial (MML) cells using the alkaline comet assay. With the 2',7'-dichlorodihydrofluorescein diacetate fluorescent probe, we assessed the effect of CNT-exposure on the intracellular production of reactive oxygen species (ROS). We measured the effect of a 10-week CNT exposure on telomere length using quantitative PCR. Two of the included MWCNTs (NM-401 and MWCNT-7) and the SWCNT (NM-411) caused a significant increase in the level of DNA damage at concentrations up to 40 µg/ml (all concentrations pooled, p < 0.05), but no concentration-response relationships were found. All of the CNTs caused an increase in intracellular ROS production compared to unexposed cells (ptrend < 0.05). Results from the long-term exposure showed longer telomere length in cells exposed to MWCNTs compared to unexposed cells (p < 0.01). In conclusion, our results indicated that the included CNTs cause ROS production and DNA strand breaks in FE1-MML cells. Moreover, the MWCNTs, but not the SWCNT, had an impact on telomere length in a long-term exposure scenario.


Increasing power-law range in avalanche amplitude and energy distributions.
Power-law-type probability density functions spanning several orders of magnitude are found for different avalanche properties. We propose a methodology to overcome empirical constraints that limit the range of truncated power-law distributions. By considering catalogs of events that cover different observation windows, the maximum likelihood estimation of a global power-law exponent is computed. This methodology is applied to amplitude and energy distributions of acoustic emission avalanches in failure-under-compression experiments of a nanoporous silica glass, finding in some cases global exponents in an unprecedented broad range: 4.5 decades for amplitudes and 9.5 decades for energies. In the latter case, however, strict statistical analysis suggests experimental limitations might alter the power-law behavior.


Multilocus Sequence Typing (MLST) and Random Polymorphic DNA (RAPD) Comparisons of Geographic Isolates of Neoparamoeba perurans, the Causative Agent of Amoebic Gill Disease.
Neoparamoba perurans, is the aetiological agent of amoebic gill disease (AGD), a disease that affects farmed Atlantic salmon worldwide. Multilocus sequence typing (MLST) and Random Amplified Polymorphic DNA (RAPD) are PCR-based typing methods that allow for the highly reproducible genetic analysis of population structure within microbial species. To the best of our knowledge, this study represents the first use of these typing methods applied to N. perurans with the objective of distinguishing geographical isolates. These analyses were applied to a total of 16 isolates from Australia, Canada, Ireland, Scotland, Norway, and the USA. All the samples from Australia came from farm sites on the island state of Tasmania. Genetic polymorphism among isolates was more evident from the RAPD analysis compared to the MLST that used conserved housekeeping genes. Both techniques consistently identified that isolates of N. perurans from Tasmania, Australia were more similar to each other than to the isolates from other countries. While genetic differences were identified between geographical isolates, a BURST analysis provided no evidence of a founder genotype. This suggests that emerging outbreaks of AGD are not due to rapid translocation of this important salmonid pathogen from the same area.


Evaluation and comparison between smartphone and photomicrography based whole slide imaging.
In recent years, a new concept has emerged at the forefront of slide-based diagnosis and telepathology. This is the concept of whole slide imaging. This has very recently also been tried with smartphones using complex software for photo analysis and stitching. This study is aimed to evaluate and compare the use of Jenoptik photomicrograph camera and smartphone camera-based whole slide imaging (WSI) for various microscopic preparations and slides. The study also uses a commonly available IOS smartphone device, a commonly available phone to microscope attachment, and the most commonly used Adobe Photoshop software for all stitching purposes. To evaluate and compare smartphone and photomicrography-based whole slide imaging. The study was conducted at the Department of Oral Pathology and Microbiology in Bapuji Dental College and Hospital, Davangere. The samples included in this study are 10 slides of routine hematoxylin and eosin stain slides and 10 ground section slides of teeth and bone samples. Continuous photographs of the entire slide were captured using an IOS device and a Jenoptik camera attached research microscope at 10× magnification. The photographs were stitched using Adobe Photoshop 2017 software to obtain a whole slide image. Then, two observers analyzed the whole slide image for a possible diagnosis and thus compared the efficiency of both the methods. The statistical Chi-square test and analysis of variance (ANOVA) H test were done using Statistical Package for the Social Sciences (SPSS) 2010 Software. Percentage of measure of agreement was 79.5%, 83.7% and 86.3%, 89.1% for the whole slide images taken in the smartphone and photomicrograph and analyzed by Observer 1 and Observer 2, respectively. In this study, it can be seen that the WSI by research microscopes is better than that with a smartphone and a compound microscope but still both the methods are equally good and can be followed with accurate results.


Management of undescended testes: European Association of Urology/European Society for Paediatric Urology Guidelines.
Undescended testis is the most common endocrinological disease in the male newborn period. Incidence varies between 1.0% and 4.6% in full-term neonates, with rates as high as 45% in preterm neonates. Failure or delay of treatment can result in reduced fertility and/or increased testicular cancer risk in adulthood. To provide recommendations for the diagnosis and treatment of boys with undescended testes which reduce the risk of impaired fertility and testicular cancer in adulthood. Embase and Pubmed were searched for all relevant publications, from 1990 to 2015 limited to English language. Data were narratively synthesized in light of methodological and clinical heterogeneity. The risk of bias of each included study was assessed. There is consensus that early treatment, by 18 months at the latest, for undescended testes is mandatory to avoid possible sequelae regarding fertility potential and cancer risk. The current standard therapy is orchidopexy, while hormonal therapy is still under debate. However, in some individuals the successful scrotal placement of previously undescended testes may not prevent potential negative long-term outcomes regarding fertility and testicular malignancy. There is good evidence for early placement of undescended testes in the scrotal position to prevent potential impairment of fertility and reduce the risk of testicular malignancy. No consensus exists on the various forms of hormonal treatment, which are assessed on an individual basis.


Benefits and Risks of Fosaprepitant in Patients Receiving Emetogenic Regimens.
Fosaprepitant dimeglumine (Emend IV®) is an IV antiemetic that may be beneficial to patients receiving highly emetogenic regimens. Aprepitant (Emend®) is an oral medication that is administered for three consecutive days, whereas fosaprepitant is a single-dose IV medication that is administered on the day of chemotherapy for 20-30 minutes (depending on the IV access type). Fosaprepitant may be useful, yet it can also present a risk for hypersensitivity reactions and phlebitis. Oncology nurses must be aware of the signs and symptoms of these potential adverse events to properly care for their patients.


Long-Term Neurobehavioral Consequences of a Single Ketamine Neonatal Exposure in Rats: Effects on Cellular Viability and Glutamate Transport in Frontal Cortex and Hippocampus.
The neonatal exposure to general anesthetics has been associated with neuronal apoptosis and dendritic spines morphologic changes in the developing brain. Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used in pediatric patients to induce general anesthesia, analgesia, and perioperative sedation. In the present study, we investigated short- and long-term effects of a single ketamine (20 mg/kg, s.c.) neonatal exposure at postnatal day 7 in rats on the hippocampal and frontal cortical cellular viability. Additionally, putative neurochemical alterations and neurobehavioral impairments were evaluated in the adulthood. Ketamine neonatal administration selectively decreased cellular viability in the hippocampus, but not in the frontal cortex, 24 h after the treatment. Interestingly, a single ketamine neonatal exposure prevented the vulnerability to glutamate-induced neurotoxicity in the frontal cortex of adult rats. No short- or long-term damage to cellular membranes, as an indicative of cell death, was observed in hippocampal or cortical slices. However, ketamine induced a long-term increase in hippocampal glutamate uptake. Regarding behavioral analysis, neonatal ketamine exposure did not alter locomotor activity and anxiety-related parameters evaluated in the open-field test. However, ketamine administration disrupted the hippocampal-dependent object recognition ability of adult rats, while improved the motor coordination addressed on the rotarod. These findings indicate that a single neonatal ketamine exposure induces a short-term reduction in the hippocampal, but not in cortical, cellular viability, and long-term alterations in hippocampal glutamate transport, improvement on motor performance, and short-term recognition memory impairment.


Interprofessional teamwork in stroke care: Is it visible or important to patients and carers?
Interprofessional teamwork is seen in healthcare policy and practice as a key strategy for providing safe, efficient and holistic healthcare and is an accepted part of evidence-based stroke care. The impact of interprofessional teamwork on patient and carer experience(s) of care is unknown, although some research suggests a relationship might exist. This study aimed to explore patient and carer perceptions of good and poor teamwork and its impact on experiences of care. Critical incident interviews were conducted with 50 patients and 33 carers in acute, inpatient rehabilitation and community phases of care within two UK stroke care pathways. An analytical framework, derived from a realist synthesis of 13 'mechanisms' (processes) of interprofessional teamwork, was used to identify positive and negative 'indicators' of teamwork. Participants identified several mechanisms of teamwork, but it was not a subject most talked about readily. This suggests that interprofessional teamwork is not a concept that is particularly important to stroke patients and carers; they do not readily perceive any impacts of teamwork on their experiences. These findings are a salient reminder that what might be expected by healthcare professionals to be important influences on experience may not be perceived to be so by patients and carers.


Aspergillus fumigatus exoβ(1-3)glucanases family GH55 are essential for conidial cell wall morphogenesis.
The cell wall of Aspergillus fumigatus is predominantly composed of polysaccharides. The central fibrillar core of the cell wall is composed of a branched β(1-3)glucan, to which the chitin and the galactomannan are covalently bound. Softening of the cell wall is an essential event during fungal morphogenesis, wherein rigid cell wall structures are cleaved by glycosyl hydrolases. In this study, we characterised the role of the glycosyl hydrolase GH55 members in A. fumigatus fungal morphogenesis. We showed that deletion of the six genes of the GH55 family stopped conidial cell wall maturation at the beginning of the development process, leading to abrogation of conidial separation: the shape of conidia became ovoid, and germination was delayed. In conclusion, the reorganisation and structuring of the conidial cell wall mediated by members of the GH55 family is essential for their maturation, normal dissemination, and germination.


Insight into formation and biological characteristics of Aspergillus tubingensis-based aerobic granular sludge (AT-AGS) in wastewater treatment.
The long start-up time and facile biomass loss of aerobic granular sludge (AGS) impede its application for actual wastewater treatment. The present study investigates a novel assist-aggregation strategy based on Aspergillus tubingensis (AT) mycelium pellets to accelerate sludge granulation, and engineered Fe3O4 nanoparticles (NPs) were used to further enhance flocculent sludge (FS) aggregation. The AT mycelium pellets, modified by 0.5 g/L Fe3O4@SiO2-QC NPs (AT-V), had a more compact internal structure than the unmodified group (AT-I). The content of extracellular polymeric substances (EPS) and the zeta potential values were observed to increase from 39.86 mg/gVSS and -9.19 mv for AT-I to 69.64 mg/gVSS and 2.35 mv for AT-V, respectively. In optimized cultivation conditions, the aggregated sludge biomass of AT-V reached 1.54 g/g. An original AT-based AGS (AT-AGS) with a high biological activity (64.45 mgO2/gVSS·h as specific oxygen uptake rate) and enhanced velocity (58.22 m/h) was developed in only 9 days. The removal efficiencies of total nitrogen (TN) and total phosphorus (TP) of the AT-AGS were 12.24% and 16.29% higher than those of the inoculated FS under high feeding load. Additionally, the analysis of cyclic diguanylate (c-di-GMP) and con-focal microscope images implied that polysaccharide (PS) of EPS played an important role in maintaining the stability of the AT-AGS. Finally, the dominant functional species contributing to sludge aggregation and pollutants removal of the AT-AGS showed a larger richness and diversity than those of the inoculated FS. This study might provide a novel high-efficiency strategy for the fast formation of AGS.


Integrated system for temperature-controlled fast protein liquid chromatography comprising improved copolymer modified beaded agarose adsorbents and a travelling cooling zone reactor arrangement.
An integrated approach to temperature-controlled chromatography, involving copolymer modified agarose adsorbents and a novel travelling cooling zone reactor (TCZR) arrangement, is described. Sepharose CL6B was transformed into a thermoresponsive cation exchange adsorbent (thermoCEX) in four synthetic steps: (i) epichlorohydrin activation; (ii) amine capping; (iii) 4,4'-azobis(4-cyanovaleric acid) immobilization; and 'graft from' polymerization of poly(N-isopropylacrylamide-co-N-tert-butylacrylamide-co-acrylic acid-co-N,N'-methylenebisacrylamide). FT-IR, (1)H NMR, gravimetry and chemical assays allowed precise determination of the adsorbent's copolymer composition and loading, and identified the initial epoxy activation step as a critical determinant of 'on-support' copolymer loading, and in turn, protein binding performance. In batch binding studies with lactoferrin, thermoCEX's binding affinity and maximum adsorption capacity rose smoothly with temperature increase from 20 to 50 °C. In temperature shifting chromatography experiments employing thermoCEX in thermally jacketed columns, 44-51% of the lactoferrin adsorbed at 42 °C could be desorbed under binding conditions by cooling the column to 22 °C, but the elution peaks exhibited strong tailing. To more fully exploit the potential of thermoresponsive chromatography adsorbents, a new column arrangement, the TCZR, was developed. In TCZR chromatography, a narrow discrete cooling zone (special assembly of copper blocks and Peltier elements) is moved along a bespoke fixed-bed separation columnfilled with stationary phase. In tests with thermoCEX, it was possible to recover 65% of the lactoferrin bound at 35 °C using 8 successive movements of the cooling zone at a velocity of 0.1mm/s; over half of the recovered protein was eluted in the first peak in more concentrated form than in the feed. Intra-particle diffusion of desorbed protein out of the support pores, and the ratio between the velocities of the cooling zone and mobile phase were identified as the main parameters affecting TCZR performance. In contrast to conventional systems, which rely on cooling the whole column to effect elution and permit only batch-wise operation, TCZR chromatography generates sharp concentrated elution peaks without tailing effects and appears ideally suited for continuous operation.


The challenge of instinctive behaviour and Darwin's theory of evolution.
In the Origin of Species (1859), Darwin argued that his revolutionary theory of evolution by natural selection represented a significant breakthrough in the understanding of instinctive behaviour. However, many aspects in the development of his thinking on behavioural phenomena indicate that the explanation of this particular organic feature was by no means an easy one, but that it posed an authentic challenge - something that Darwin himself always recognized. This paper explores Darwin's treatment of instincts within his theory of natural selection. Particular attention is given to elucidate how he tackled the difficulties of explaining instincts as evolving mental features. He had to explain and demonstrate its inheritance, variation, and gradual accumulation within populations. The historical and philosophical aspects of his theory are highlighted, as well as his study of the case in which the explanation of instincts represented a 'special difficulty'; that is, the sterile castes of social insects.


Association between trends in clinical variables and outcome in intensive care patients with faecal peritonitis: analysis of the GenOSept cohort.
Patients admitted to intensive care following surgery for faecal peritonitis present particular challenges in terms of clinical management and risk assessment. Collaborating surgical and intensive care teams need shared perspectives on prognosis. We aimed to determine the relationship between dynamic assessment of trends in selected variables and outcomes. We analysed trends in physiological and laboratory variables during the first week of intensive care unit (ICU) stay in 977 patients at 102 centres across 16 European countries. The primary outcome was 6-month mortality. Secondary endpoints were ICU, hospital and 28-day mortality. For each trend, Cox proportional hazards (PH) regression analyses, adjusted for age and sex, were performed for each endpoint. Trends over the first 7 days of the ICU stay independently associated with 6-month mortality were worsening thrombocytopaenia (mortality: hazard ratio (HR) = 1.02; 95% confidence interval (CI), 1.01 to 1.03; P < 0.001) and renal function (total daily urine output: HR =1.02; 95% CI, 1.01 to 1.03; P < 0.001; Sequential Organ Failure Assessment (SOFA) renal subscore: HR = 0.87; 95% CI, 0.75 to 0.99; P = 0.047), maximum bilirubin level (HR = 0.99; 95% CI, 0.99 to 0.99; P = 0.02) and Glasgow Coma Scale (GCS) SOFA subscore (HR = 0.81; 95% CI, 0.68 to 0.98; P = 0.028). Changes in renal function (total daily urine output and renal component of the SOFA score), GCS component of the SOFA score, total SOFA score and worsening thrombocytopaenia were also independently associated with secondary outcomes (ICU, hospital and 28-day mortality). We detected the same pattern when we analysed trends on days 2, 3 and 5. Dynamic trends in all other measured laboratory and physiological variables, and in radiological findings, changes in respiratory support, renal replacement therapy and inotrope and/or vasopressor requirements failed to be retained as independently associated with outcome in multivariate analysis. Only deterioration in renal function, thrombocytopaenia and SOFA score over the first 2, 3, 5 and 7 days of the ICU stay were consistently associated with mortality at all endpoints. These findings may help to inform clinical decision making in patients with this common cause of critical illness.


A maximum pseudo-likelihood approach for estimating species trees under the coalescent model.
Several phylogenetic approaches have been developed to estimate species trees from collections of gene trees. However, maximum likelihood approaches for estimating species trees under the coalescent model are limited. Although the likelihood of a species tree under the multispecies coalescent model has already been derived by Rannala and Yang, it can be shown that the maximum likelihood estimate (MLE) of the species tree (topology, branch lengths, and population sizes) from gene trees under this formula does not exist. In this paper, we develop a pseudo-likelihood function of the species tree to obtain maximum pseudo-likelihood estimates (MPE) of species trees, with branch lengths of the species tree in coalescent units. We show that the MPE of the species tree is statistically consistent as the number M of genes goes to infinity. In addition, the probability that the MPE of the species tree matches the true species tree converges to 1 at rate O(M -1). The simulation results confirm that the maximum pseudo-likelihood approach is statistically consistent even when the species tree is in the anomaly zone. We applied our method, Maximum Pseudo-likelihood for Estimating Species Trees (MP-EST) to a mammal dataset. The four major clades found in the MP-EST tree are consistent with those in the Bayesian concatenation tree. The bootstrap supports for the species tree estimated by the MP-EST method are more reasonable than the posterior probability supports given by the Bayesian concatenation method in reflecting the level of uncertainty in gene trees and controversies over the relationship of four major groups of placental mammals. MP-EST can consistently estimate the topology and branch lengths (in coalescent units) of the species tree. Although the pseudo-likelihood is derived from coalescent theory, and assumes no gene flow or horizontal gene transfer (HGT), the MP-EST method is robust to a small amount of HGT in the dataset. In addition, increasing the number of genes does not increase the computational time substantially. The MP-EST method is fast for analyzing datasets that involve a large number of genes but a moderate number of species.


Animal derived products may conflict with religious patients' beliefs.
Implants and drugs with animal and human derived content are widely used in medicine and surgery, but information regarding ingredients is rarely obtainable by health practitioners. A religious perspective concerning the use of animal and human derived drug ingredients has not thoroughly been investigated. The purpose of this study was to clarify which parts of the medical and surgical treatments offered in western world-hospitals that conflicts with believers of major religions. Religious and spiritual leaders of the six largest religions worldwide (18 branches) were contacted. A standardised questionnaire was sent out regarding their position on the use of human and animal derived products in medical and surgical treatments. Of the 18 contacted religious branches, 10 replied representing the 6 largest religions worldwide. Hindus and Sikhs did not approve of the use of bovine or porcine derived products, and Muslims did not accept the use of porcine derived drugs, dressings or implants. Christians (including Jehovah's Witnesses), Jews and Buddhists accepted the use of all animal and human derived products. However, all religions accepted the use of all these products in case of an emergency and only if alternatives were not available. The views here suggest that religious codes conflict with some treatment regimens. It is crucial to obtain informed consent from patients for the use of drugs and implants with animal or human derived content. However, information on the origin of ingredients in drugs is not always available to health practitioners.


Impending extinction crisis of the world's primates: Why primates matter.
Nonhuman primates, our closest biological relatives, play important roles in the livelihoods, cultures, and religions of many societies and offer unique insights into human evolution, biology, behavior, and the threat of emerging diseases. They are an essential component of tropical biodiversity, contributing to forest regeneration and ecosystem health. Current information shows the existence of 504 species in 79 genera distributed in the Neotropics, mainland Africa, Madagascar, and Asia. Alarmingly, ~60% of primate species are now threatened with extinction and ~75% have declining populations. This situation is the result of escalating anthropogenic pressures on primates and their habitats-mainly global and local market demands, leading to extensive habitat loss through the expansion of industrial agriculture, large-scale cattle ranching, logging, oil and gas drilling, mining, dam building, and the construction of new road networks in primate range regions. Other important drivers are increased bushmeat hunting and the illegal trade of primates as pets and primate body parts, along with emerging threats, such as climate change and anthroponotic diseases. Often, these pressures act in synergy, exacerbating primate population declines. Given that primate range regions overlap extensively with a large, and rapidly growing, human population characterized by high levels of poverty, global attention is needed immediately to reverse the looming risk of primate extinctions and to attend to local human needs in sustainable ways. Raising global scientific and public awareness of the plight of the world's primates and the costs of their loss to ecosystem health and human society is imperative.


Exogenous gene expression and protein targeting in lens fiber cells.
To test the ability of lens fiber cells at various stages of differentiation to transcribe and translate microinjected DNA templates. Expression plasmids encoding green fluorescent protein (GFP) or a GFP-tagged membrane protein (human CD46) were microinjected into organ-cultured embryonic chicken lenses. Protein expression was visualized by confocal microscopy. GFP expression was detected within 12 hours of microinjection, evenly distributed throughout the cytoplasm of the injected cell. All nucleated fiber cells were competent to express GFP, whereas the anucleated central fiber cells were not. When GFP was fused to the C-terminal of CD46, the fusion protein was synthesized intact and properly inserted in the fiber cell plasma membrane. In contrast, N-terminal fusions were cleaved during synthesis, resulting in retention of the GFP tag in the endoplasmic reticulum. Microinjection of expression plasmids is an effective technique for introducing exogenous genes into individual fiber cells. With this approach, the results show that fiber cells are transcriptionally and translationally competent until the time of organelle loss, and that fiber cells deep within the lens are capable of synthesizing new plasma membrane proteins. The techniques described here should have broad application in studies of fiber cell differentiation and provide a useful complement to conventional transgenic approaches.


Regulation of cardiac hypertrophic signaling by prolyl isomerase Pin1.
Cardiac hypertrophy results from the complex interplay of differentially regulated cascades based on the phosphorylation status of involved signaling molecules. Although numerous critical regulatory kinases and phosphatases have been identified in the myocardium, the intracellular mechanism for temporal regulation of signaling duration and intensity remains obscure. In the nonmyocyte context, control of folding, activity, and stability of proteins is mediated by the prolyl isomerase Pin1, but the role of Pin1 in the heart is unknown. To establish the role of Pin1 in the heart. Here, we show that either genetic deletion or cardiac overexpression of Pin1 blunts hypertrophic responses induced by transaortic constriction and consequent cardiac failure in vivo. Mechanistically, we find that Pin1 directly binds to Akt, mitogen activated protein kinase (MEK), and Raf-1 in cultured cardiomyocytes after hypertrophic stimulation. Furthermore, loss of Pin1 leads to diminished hypertrophic signaling of Akt and MEK, whereas overexpression of Pin1 increases Raf-1 phosphorylation on the autoinhibitory site Ser259, leading to reduced MEK activation. Collectively, these data support a role for Pin1 as a central modulator of the intensity and duration of 2 major hypertrophic signaling pathways, thereby providing a novel target for regulation and control of cardiac hypertrophy.


Injectable preformed scaffolds with shape-memory properties.
Injectable biomaterials are increasingly being explored to minimize risks and complications associated with surgical implantation. We describe a strategy for delivery via conventional needle-syringe injection of large preformed macroporous scaffolds with well-defined properties. Injectable 3D scaffolds, in the form of elastic sponge-like matrices, were prepared by environmentally friendly cryotropic gelation of a naturally sourced polymer. Cryogels with shape-memory properties may be molded to a variety of shapes and sizes, and may be optionally loaded with therapeutic agents or cells. These scaffolds have the capability to withstand reversible deformations at over 90% strain level, and a rapid volumetric recovery allows the structurally defined scaffolds to be injected through a small-bore needle with nearly complete geometric restoration once delivered. These gels demonstrated long-term release of biomolecules in vivo. Furthermore, cryogels impregnated with bioluminescent reporter cells provided enhanced survival, higher local retention, and extended engraftment of transplanted cells at the injection site compared with a standard injection technique. These injectable scaffolds show great promise for various biomedical applications, including cell therapies.


Interprofessional podiatric surgical simulation a pilot study.
Interprofessional collaboration is key to quality outcomes in the health-care systems of today. Simulation is a common tool in podiatric medical education, and interprofessional education has become more common in podiatric medicine programs. Interprofessional simulation is the blending of these educational strategies. A quantitative design was used to determine the impact of an isolated interprofessional podiatric surgical simulation between nurse anesthesia and podiatric medical students. Statistically significant differences were observed among participants between preintervention and postintervention surveys using the revised Interdisciplinary Education Perception Scale. Interprofessional simulation can be an effective educational opportunity for podiatric medical and nurse anesthesia students.


The impact of poor adult health on labor supply in the Russian Federation.
We examine the labor supply consequences of poor health in the Russian Federation, a country with exceptionally adverse adult health outcomes. In both baseline OLS models and in models with individual fixed effects, more serious ill-health events, somewhat surprisingly, generally have only weak effects on hours worked. At the same time, their effect on the extensive margin of labor supply is substantial. Moreover, when combining the effects on both the intensive and extensive margins, the effect of illness on hours worked increases considerably for a range of conditions. In addition, for most part of the age distribution, people with poor self-assessed health living in rural areas are less likely to stop working, compared to people living in cities. While there is no conclusive explanation for this finding, it could be related to the existence of certain barriers that prevent people with poor health from withdrawing from the labor force in order to take care of their health.


Role of prolactin in regulating gonadotropin secretion and gonad function in female rats.
The role of prolactin in female reproduction has been studied extensively in two systems; in the regulation of corpus luteum function, and in the regulation of gonadotropin secretion. In the rat, prolactin is an essential component of the luteotropic complex since it is the hormone responsible for transforming a corpus luteum of the estrous cycle into a corpus luteum of pseudopregnancy or pregnancy, which allows progesterone secretion to be maintained. The biphasic surges of prolactin initiated by cervical stimulation at the time of ovulation continue to be important throughout pseudopregnancy to maintain elevated levels of progesterone. During pregnancy, the luteotropic requirements change so that prolactin is no longer required after midpregnancy. In addition to its luteotropic effects, prolactin also has antigonadotropic effects that contribute significantly to the suppression of gonadotropin secretion during lactation. Suckling-induced prolactin secretion contributes to the suppression of both basal gonadotropin secretion and the postcastration rise in gonadotropins during lactation. Prolactin may have some effect at the pituitary to suppress responsiveness to luteinizing hormone-releasing hormone (LHRH), but its primary site of action appears to be the hypothalamus. Prolactin may be acting at the hypothalamus either to cause a decrease in LHRH secretion or to cause the release of substances that inhibit pituitary gonadotropin secretion directly.


Critical Roles of a RhoGEF-Anillin Module in Septin Architectural Remodeling during Cytokinesis.
How septin architecture is remodeled from an hourglass to a double ring during cytokinesis in fungal and animal cells remains unknown. Here, we show that during the hourglass-to-double-ring transition in budding yeast, septins acquire a "zonal architecture" in which paired septin filaments that are organized along the mother-bud axis associate with circumferential single septin filaments, the Rho guanine-nucleotide-exchange factor (RhoGEF) Bud3, and the anillin-like protein Bud4 exclusively at the outer zones and with myosin-II filaments in the middle zone. Deletion of Bud3 or its Bud4-interacting domain, but not its RhoGEF domain, leads to a complete loss of the single filaments, whereas deletion of Bud4 or its Bud3-interacting domain destabilizes the transitional hourglass, especially at the mother side, with partial loss of both filament types. Deletion of Bud3 and Bud4 together further weakens the transitional structure and abolishes the double ring formation while causing no obvious defect in actomyosin ring constriction. This and further analyses suggest that Bud3 stabilizes the single filaments, whereas Bud4 strengthens the interaction between the paired and single filaments at the outer zones of the transitional hourglass, as well as in the double ring. This study reveals a striking zonal architecture for the transitional hourglass that pre-patterns two cytokinetic structures-a septin double ring and an actomyosin ring-and also defines the essential roles of a RhoGEF-anillin module in septin architectural remodeling during cytokinesis at the filament level.


Development and UFLC-MS/MS Characterization of a Product-Specific Standard for Phenolic Quantification of Maple-Derived Foods.
The phenolic contents of plant foods are commonly quantified by the Folin-Ciocalteu assay based on gallic acid equivalents (GAEs). However, this may lead to inaccuracies because gallic acid is not always representative of the structural heterogeneity of plant phenolics. Therefore, product-specific standards have been developed for the phenolic quantification of several foods. Currently, maple-derived foods (syrup, sugar, sap/water, and extracts) are quantified for phenolic contents based on GAEs. Because lignans are the predominant phenolics present in maple, herein, a maple phenolic lignan-enriched standard (MaPLES) was purified (by chromatography) and characterized (by UFLC-MS/MS with lignans previously isolated from maple syrup). Using MaPLES and secoisolariciresinol (a commercially available lignan), the phenolic contents of the maple-derived foods increased 3-fold compared to GAEs. Therefore, lignan-based standards are more appropriate for phenolic quantification of maple-derived foods versus GAEs. Also, MaPLES can be utilized for the authentication and detection of fake label claims on maple products.


Takeaway food consumption and its associations with diet quality and abdominal obesity: a cross-sectional study of young adults.
Few studies have investigated the associations of takeaway food consumption with overall diet quality and abdominal obesity. Young adults are high consumers of takeaway food so we aimed to examine these associations in a national study of young Australian adults. A national sample of 1,277 men and 1,585 women aged 26-36 completed a self-administered questionnaire on demographic and lifestyle factors, a 127 item food frequency questionnaire, usual daily frequency of fruit and vegetable consumption and usual weekly frequency of takeaway food consumption. Dietary intake was compared with the dietary recommendations from the Australian Guide to Healthy Eating. Waist circumference was measured for 1,065 men and 1,129 women. Moderate abdominal obesity was defined as >/= 94 cm for men and >/= 80 cm for women. Prevalence ratios (PR) were calculated using log binomial regression. Takeaway food consumption was dichotomised, with once a week or less as the reference group. Consumption of takeaway food twice a week or more was reported by more men (37.9%) than women (17.7%, P < 0.001). Compared with those eating takeaway once a week or less, men eating takeaway twice a week or more were significantly more likely to be single, younger, current smokers and spend more time watching TV and sitting, whereas women were more likely to be in the workforce and spend more time watching TV and sitting. Participants eating takeaway food at least twice a week were less likely (P < 0.05) to meet the dietary recommendation for vegetables, fruit, dairy, extra foods, breads and cereals (men only), lean meat and alternatives (women only) and overall met significantly fewer dietary recommendations (P < 0.001). After adjusting for confounding variables (age, leisure time physical activity, TV viewing and employment status), consuming takeaway food twice a week or more was associated with a 31% higher prevalence of moderate abdominal obesity in men (PR: 1.31; 95% CI: 1.07, 1.61) and a 25% higher prevalence in women (PR: 1.25; 95% CI: 1.04, 1.50). Eating takeaway food twice a week or more was associated with poorer diet quality and a higher prevalence of moderate abdominal obesity in young men and women.


Future clinical uses of neurophysiological biomarkers to predict and monitor treatment response for schizophrenia.
Advances in psychiatric neuroscience have transformed our understanding of impaired and spared brain functions in psychotic illnesses. Despite substantial progress, few (if any) laboratory tests have graduated to clinics to inform diagnoses, guide treatments, and monitor treatment response. Providers must rely on careful behavioral observation and interview techniques to make inferences about patients' inner experiences and then secondary deductions about impacted neural systems. Development of more effective treatments has also been hindered by a lack of translational quantitative biomarkers that can span the brain-behavior treatment knowledge gap. Here, we describe an example of a simple, low-cost, and translatable electroencephalography (EEG) measure that offers promise for improving our understanding and treatment of psychotic illnesses: mismatch negativity (MMN). MMN is sensitive to and/or predicts response to some pharmacologic and nonpharmacologic interventions and accounts for substantial portions of variance in clinical, cognitive, and psychosocial functioning in schizophrenia (SZ). This measure has recently been validated for use in large-scale multisite clinical studies of SZ. Finally, MMN greatly improves our ability to forecast which individuals at high clinical risk actually develop a psychotic illness. These attributes suggest that MMN can contribute to personalized biomarker-guided treatment strategies aimed at ameliorating or even preventing the onset of psychosis.


Quantitative investigation of connections of the prefrontal cortex in the human and macaque using probabilistic diffusion tractography.
The functions of prefrontal cortex (PFC) areas are constrained by their anatomical connections. There is little quantitative information about human PFC connections, and, instead, our knowledge of primate PFC connections is derived from tracing studies in macaques. The connections of subcortical areas, in which white matter penetration and hence diffusion anisotropy are greatest, can be studied with diffusion-weighted imaging (DWI) tractography. We therefore used DWI tractography in four macaque and 10 human hemispheres to compare the connections of PFC regions with nine subcortical regions, including several fascicles and several subcortical nuclei. A distinct connection pattern was identified for each PFC and each subcortical region. Because some of the fascicles contained connections with posterior cortical areas, it was also possible to draw inferences about PFC connection patterns with posterior cortical areas. Notably, it was possible to identify similar circuits centered on comparable PFC regions in both species; PFC regions probably engage in similar patterns of regionally specific functional interaction with other brain areas in both species. In the case of one area traditionally assigned to the human PFC, the pars opercularis, the distribution of connections was not reminiscent of any macaque PFC region but, instead, resembled the pattern for macaque ventral premotor area. Some limitations to the DWI approach were apparent; the high diffusion anisotropy in the corpus callosum made it difficult to compare connection probability values in the adjacent cingulate region.


Jumping sans legs: does elastic energy storage by the vertebral column power terrestrial jumps in bony fishes?
Despite having no obvious anatomical modifications to facilitate movement over land, numerous small fishes from divergent teleost lineages make brief, voluntary terrestrial forays to escape poor aquatic conditions or to pursue terrestrial prey. Once stranded, these fishes produce a coordinated and effective "tail-flip" jumping behavior, wherein lateral flexion of the axial body into a C-shape, followed by contralateral flexion of the body axis, propels the fish into a ballistic flight-path that covers a distance of multiple body lengths. We ask: how do anatomical structures that evolved in one habitat generate effective movement in a novel habitat? Within this context, we hypothesized that the mechanical properties of the axial skeleton play a critical role in producing effective overland movement, and that tail-flip jumping species demonstrate enhanced elastic energy storage through increased body flexural stiffness or increased body curvature, relative to non-jumping species. To test this hypothesis, we derived a model to predict elastic recoil work from the morphology of the vertebral (neural and hemal) spines. From ground reaction force (GRF) measurements and high-speed video, we calculated elastic recoil work, flexural stiffness, and apparent material stiffness of the body for Micropterus salmoides (a non-jumper) and Kryptolebias marmoratus (adept tail-flip jumper). The model predicted no difference between the two species in work stored by the vertebral spines, and GRF data showed that they produce the same magnitude of mass-specific elastic recoil work. Surprisingly, non-jumper M. salmoides has a stiffer body than tail-flip jumper K. marmoratus. Many tail-flip jumping species possess enlarged, fused hypural bones that support the caudal peduncle, which suggests that the localized structures, rather than the entire axial skeleton, may explain differences in terrestrial performance.


Tuning Optical Properties by Controlled Aggregation: Electroluminescence Assisted by Thermally-Activated Delayed Fluorescence from Thin Films of Crystalline Chromophores.
Several photophysical properties of chromophores depend crucially on intermolecular interactions. Thermally-activated delayed fluorescence (TADF) is often influenced by close packing of the chromophore assembly. In this context, the metal-organic framework (MOF) approach has several advantages: it can be used to steer aggregation such that the orientation within aggregated structures can be predicted using rational approaches. We demonstrate this design concept for a DPA-TPE (diphenylamine-tetraphenylethylene) chromophore, which is non-emissive in its solvated state due to vibrational quenching. Turning this DPA-TPE into a ditopic linker makes it possible to grow oriented MOF thin films exhibiting pronounced green electroluminescence with low onset voltages. Measurements at different temperatures clearly demonstrate the presence of TADF. Finally, this work reports that the layer-by-layer process used for MOF thin film deposition allows the integration of the TADF-DPA-TPE in a functioning LED device.


Cognitive control in adolescence: neural underpinnings and relation to self-report behaviors.
Adolescence is commonly characterized by impulsivity, poor decision-making, and lack of foresight. However, the developmental neural underpinnings of these characteristics are not well established. To test the hypothesis that these adolescent behaviors are linked to under-developed proactive control mechanisms, the present study employed a hybrid block/event-related functional Magnetic Resonance Imaging (fMRI) Stroop paradigm combined with self-report questionnaires in a large sample of adolescents and adults, ranging in age from 14 to 25. Compared to adults, adolescents under-activated a set of brain regions implicated in proactive top-down control across task blocks comprised of difficult and easy trials. Moreover, the magnitude of lateral prefrontal activity in adolescents predicted self-report measures of impulse control, foresight, and resistance to peer pressure. Consistent with reactive compensatory mechanisms to reduced proactive control, older adolescents exhibited elevated transient activity in regions implicated in response-related interference resolution. Collectively, these results suggest that maturation of cognitive control may be partly mediated by earlier development of neural systems supporting reactive control and delayed development of systems supporting proactive control. Importantly, the development of these mechanisms is associated with cognitive control in real-life behaviors.


Runx1/AML1 hematopoietic transcription factor contributes to skeletal development in vivo.
The requirement of Runx2 (Cbfal/AML3), a runt homology domain transcription factor essential for bone formation and osteoblast differentiation, is well established. Although Runx2 is expressed in the developing embryo prior to ossification, yet in the absence of Runx2 initial formation of the skeleton is normal, suggesting a potential redundancy in function of Runx family members. Here we addressed expression of the hematopoietic family member Runx1 (AML1/Cbfa2) in relation to skeletal development using a LacZ knock-in mouse model (Runx1(lz/+)). The resulting fusion protein reflects Runx1 promoter activity in its native context. Our studies show that Runx1 is expressed by prechondrocytic tissue forming the cartilaginous anlagen in the embryo, resting zone chondrocytes, suture lines of the calvarium, and in periosteal and perichondral membranes of all bone. Runx1 continues to be expressed in these tissues in adult mice, but is absent in mature cartilage or mineralized bone. However, hyaline cartilage outside the bone environment (trachea, xiphoid tissues), and epithelium of many soft tissues (trachea, thyroid, lung, skin) also express Runx1. The robust expression of Runx1 in vivo in chondroblasts at sites of cartilage growth and in osteoblasts at sites of new bone formation, suggests that Runx1 expression may be related to osteochondroprogenitor cell differentiation. This observation is further supported by high expression of Runx1 in ex vivo cultures of marrow stromal cells and calvarial derived osteoblasts from Runx1(lz/+) mice. These data indicate that Runx1 may contribute to the early stages of skeletogenesis and continues to function in the progenitor cells of tissues that support bone formation in the adult.