Effect of sulfur hexafluoride gas on antibacterial activity of antibiotics in vitro against agents causing endophthalmitis.
We conducted a study to evaluate the effect of sulfur hexafluoride gas (SF(6)) on the antibacterial activity of antibiotics in vitro against Staphylococcus aureus, Staphylococcus epidermidis and Pseudomonas aeruginosa, which are common endophthalmitis-causing agents. In this experimental study, antibiotic susceptibility tests were prepared according to the National Committee for Clinical Laboratory Standards macrobroth dilution method. Müller-Hinton broth was the test medium. Standard P. aeruginosa (ATCC 27853), S. epidermidis (ATCC 12228) and S. aureus (ATCC 29213) strains were studied. For P. aeruginosa ceftazidime, ofloxacin and tobramycin dilutions, and for S. epidermidis and S. aureus, cefazolin, ofloxacin and tobramycin dilutions were prepared identically in two sets of tubes. One set of tubes, into which pure SF(6) was injected, was defined as the SF(6) group. The other set of tubes, into which no SF(6) was injected, was taken as the control group. To determine the minimal bactericidal concentrations of the antibiotics, subcultures were made onto Müller-Hinton agar, and the colonies were counted after 18 h of incubation at 37 degrees C. The minimal inhibitory concentrations of the antibiotics in the SF(6) group were found to be identical with those of the control group. However, the minimal bactericidal concentrations of the antibiotics were found to be at least two dilutions lower in the SF(6) group than in the control group, except for the minimal bactericidal concentration of cefazolin for S. aureus, which was found to be one dilution lower in the SF(6) group. SF(6) was found to potentiate the in vitro antibacterial activity of ofloxacin and tobramycin against S. aureus, S. epidermidis and P. aeruginosa, ceftazidime against P. aeruginosa, and cefazolin against S. epidermidis. Experimental animal studies are required to determine the role of SF(6) in the management of endophthalmitis.


Visualization of Temporal Similarity in Field Data.
This paper presents a visualization approach for detecting and exploring similarity in the temporal variation of field data. We provide an interactive technique for extracting correlations from similarity matrices which capture temporal similarity of univariate functions. We make use of the concept to extract periodic and quasiperiodic behavior at single (spatial) points as well as similarity between different locations within a field and also between different data sets. The obtained correlations are utilized for visual exploration of both temporal and spatial relationships in terms of temporal similarity. Our entire pipeline offers visual interaction and inspection, allowing for the flexibility that in particular time-dependent data analysis techniques require. We demonstrate the utility and versatility of our approach by applying our implementation to data from both simulation and measurement.


Ah receptor antagonism represses head and neck tumor cell aggressive phenotype.
The aryl hydrocarbon receptor (AhR) has been shown to play a role in an increasing number of cellular processes. Recent reports have linked the AhR to cell proliferation, cytoskeletal arrangement, and tumor invasiveness in various tumor cell types. The AhR plays a role in the de-repression of the interleukin (IL)6 promoter in certain tumor cell lines, allowing for increased transcriptional activation by cytokines. Here, we show that there is a significant level of constitutive activation of the AhR in cells isolated from patients with head and neck squamous cell carcinoma (HNSCC). Constitutive activation of the AhR in HNSCCs was blocked by antagonist treatment, leading to a reduction in IL6 expression. In addition, the AhR exhibits a high level of expression in HNSCCs than in normal keratinocytes. These findings led to the hypothesis that the basal AhR activity in HNSCCs plays a role in the aggressive phenotype of these tumors and that antagonist treatment could mitigate this phenotype. This study provides evidence that antagonism of the AhR in HNSCC tumor cells, in the absence of exogenous receptor ligands, has a significant effect on tumor cell phenotype. Treatment of these cell lines with the AhR antagonists 6, 2', 4'-trimethoxyflavone, or the more potent GNF351, decreased migration and invasion of HNSCC cells and prevented benzo[a]pyrene-mediated induction of the chemotherapy efflux protein ABCG2. Thus, an AhR antagonist treatment has been shown to have therapeutic potential in HNSCCs through a reduction in aggressive cell phenotype.


NGMASTER:in silico multi-antigen sequence typing for Neisseria gonorrhoeae.
Whole-genome sequencing (WGS) provides the highest resolution analysis for comparison of bacterial isolates in public health microbiology. However, although increasingly being used routinely for some pathogens such as Listeria monocytogenes and Salmonella enterica, the use of WGS is still limited for other organisms, such as Neisseria gonorrhoeae. Multi-antigen sequence typing (NG-MAST) is the most widely performed typing method for epidemiological surveillance of gonorrhoea. Here, we present NGMASTER, a command-line software tool for performing in silico NG-MAST on assembled genome data. NGMASTER rapidly and accurately determined the NG-MAST of 630 assembled genomes, facilitating comparisons between WGS and previously published gonorrhoea epidemiological studies. The source code and user documentation are available at https://github.com/MDU-PHL/ngmaster.


Twenty-five years of bicycle helmet promotion for children in Skaraborg District, Sweden.
The purpose of this study is to describe some of the results of a long-term bicycle helmet campaign for children in Skaraborg District, Sweden. The hospital discharge data for bicycle-related injuries occurring in children under the age of 15 were reviewed, to assess changes in patterns for head and other body injuries. The study shows that head injuries to children as a result of bicycle injuries were reduced between 94 and 99% in the study areas. The tremendous gains in safety for children who ride bicycles in Skaraborg District were the result of not only national policy changes that occurred in the latter half of this study period but also the result of local collaborations based on the Safe Communities model, which were organised during the first part of the study period.


One Hour a Week: Moving to Prevent Disability in Adults With Lower Extremity Joint Symptoms.
Physical activity guidelines recommend minimum thresholds. This study sought to identify evidence-based thresholds to maintain disability-free status over 4years among adults with lower extremity joint symptoms. Prospective multisite Osteoarthritis Initiative accelerometer monitoring cohort data from September 2008 through December 2014 were analyzed. Adults (n=1,564) aged ≥49years at elevated disability risk because of lower extremity joint symptoms were analyzed for biennial assessments of disability-free status from gait speed ≥1meter/second (mobility disability-free) and self-report of no limitations in activities of daily living (activities of daily living disability-free). Classification tree analyses conducted in 2017-2018 identified optimal thresholds across candidate activity intensities (sedentary, light, moderate-vigorous, total light and moderate-vigorous activity, and moderate-vigorous accrued in bouts lasting ≥10 minutes). Minimal thresholds of 56 and 55 moderate-vigorous minutes/week best predicted disability-free status over 4years from mobility and activities of daily living disabilities, respectively, across the candidate measures. Thresholds were consistent across sex, BMI, age, and knee osteoarthritis presence. Mobility disability onset was one eighth as frequent (3% vs 24%, RR=0.14, 95% CI=0.09, 0.20) and activities of daily living disability onset was almost half (12% vs 23%, RR=0.55, 95% CI=0.44, 0.70) among people above versus below the minimum threshold. Attaining an evidence-based threshold of approximately 1-hour moderate-vigorous activity/week significantly increased the likelihood of maintaining disability-free status over 4years. This minimum threshold tied to maintaining independent living abilities has value as an intermediate goal to motivate adults to take action towards the many health benefits of a physically active lifestyle.


Evidence for a Peierls phase-transition in a three-dimensional multiple charge-density waves solid.
The effect of dimensionality on materials properties has become strikingly evident with the recent discovery of graphene. Charge ordering phenomena can be induced in one dimension by periodic distortions of a material's crystal structure, termed Peierls ordering transition. Charge-density waves can also be induced in solids by strong coulomb repulsion between carriers, and at the extreme limit, Wigner predicted that crystallization itself can be induced in an electrons gas in free space close to the absolute zero of temperature. Similar phenomena are observed also in higher dimensions, but the microscopic description of the corresponding phase transition is often controversial, and remains an open field of research for fundamental physics. Here, we photoinduce the melting of the charge ordering in a complex three-dimensional solid and monitor the consequent charge redistribution by probing the optical response over a broad spectral range with ultrashort laser pulses. Although the photoinduced electronic temperature far exceeds the critical value, the charge-density wave is preserved until the lattice is sufficiently distorted to induce the phase transition. Combining this result with ab initio electronic structure calculations, we identified the Peierls origin of multiple charge-density waves in a three-dimensional system for the first time.


Tweeting From Left to Right: Is Online Political Communication More Than an Echo Chamber?
We estimated ideological preferences of 3.8 million Twitter users and, using a data set of nearly 150 million tweets concerning 12 political and nonpolitical issues, explored whether online communication resembles an "echo chamber" (as a result of selective exposure and ideological segregation) or a "national conversation." We observed that information was exchanged primarily among individuals with similar ideological preferences in the case of political issues (e.g., 2012 presidential election, 2013 government shutdown) but not many other current events (e.g., 2013 Boston Marathon bombing, 2014 Super Bowl). Discussion of the Newtown shootings in 2012 reflected a dynamic process, beginning as a national conversation before transforming into a polarized exchange. With respect to both political and nonpolitical issues, liberals were more likely than conservatives to engage in cross-ideological dissemination; this is an important asymmetry with respect to the structure of communication that is consistent with psychological theory and research bearing on ideological differences in epistemic, existential, and relational motivation. Overall, we conclude that previous work may have overestimated the degree of ideological segregation in social-media usage.


Microvesicles in active lupus nephritis show Toll-like receptor 9-dependent co-expression of galectin-3 binding protein and double-stranded DNA.
Circulating microvesicles (MVs) from patients with systemic lupus erythematosus (SLE) express the type 1 interferon (IFN)-inducible protein galectin-3 binding protein (G3BP), which may enhance their deposition in the glomerular basement membrane. The release of G3BP-expressing MVs from normal peripheral blood mononuclear cells (PBMCs) is induced by Toll-like receptor 9 (TLR-9) ligands, and these vesicles contain autoantibody-accessible double-stranded DNA (dsDNA). This study compares the release of MVs expressing G3BP and dsDNA from PBMCs derived from SLE patients with or without active lupus nephritis (LN) and from healthy donors, and taps further into the potential dependency on IFN-α for their generation and impacts of TLR-7/TLR-9 co-stimulation. PBMCs from 10 healthy donors and 12 SLE patients, six of whom had active LN at study inclusion, were stimulated in-vitro with recombinant human IFN-α and the TLR-9 agonists oligodeoxynucleotide (ODN)2216 or ODN2395 alone or in combination with the TLR-7 agonist gardiquimod. MVs in the supernatants were subsequently isolated by differential centrifugation and their expression of G3BP and dsDNA was quantified by flow cytometry. Stimulation with ODN2395 significantly increased the release of MVs co-expressing G3BP and dsDNA from PBMCs isolated from healthy donors and SLE patients. The expression of G3BP on individual MVs and the proportion of G3BP and dsDNA double-positive MVs released were increased in active LN patients. Neither co-stimulation with gardiquimod nor with the IFN-α inhibitor IN-1 had any effect on the MV release induced by ODN2395. In conclusion, the TLR-9-mediated inducibility of MVs co-expressing G3BP and dsDNA is increased in SLE patients with active LN.


White matter lesions: Spatial heterogeneity, links to risk factors, cognition, genetics, and atrophy.
To investigate spatial heterogeneity of white matter lesions or hyperintensities (WMH). MRI scans of 1,836 participants (median age 52.2 ± 13.16 years) encompassing a wide age range (22-84 years) from the cross-sectional Study of Health in Pomerania (Germany) were included as discovery set identifying spatially distinct components of WMH using a structural covariance approach. Scans of 307 participants (median age 73.8 ± 10.2 years, with 747 observations) from the Baltimore Longitudinal Study of Aging (United States) were included to examine differences in longitudinal progression of these components. The associations of these components with vascular risk factors, cortical atrophy, Alzheimer disease (AD) genetics, and cognition were then investigated using linear regression. WMH were found to occur nonuniformly, with higher frequency within spatially heterogeneous patterns encoded by 4 components, which were consistent with common categorizations of deep and periventricular WMH, while further dividing the latter into posterior, frontal, and dorsal components. Temporal trends of the components differed both cross-sectionally and longitudinally. Frontal periventricular WMH were most distinctive as they appeared in the fifth decade of life, whereas the other components appeared later in life during the sixth decade. Furthermore, frontal WMH were associated with systolic blood pressure and with pronounced atrophy including AD-related regions. AD polygenic risk score was associated with the dorsal periventricular component in the elderly. Cognitive decline was associated with the dorsal component. These results support the hypothesis that the appearance of WMH follows age and disease-dependent regional distribution patterns, potentially influenced by differential underlying pathophysiologic mechanisms, and possibly with a differential link to vascular and neurodegenerative changes.


Modulation depth of static four-phase-divided wind imaging interferometer.
The static four-phase-divided imaging interferometry is a new technology of passive detection for the upper atmospheric wind field. It is featured with real-time detection, no moving parts, stability, and so on. In this paper, its basic theory is discussed, and its characteristics are briefly introduced. Furthermore, its key technical parameter, modulation depth, is analyzed. The relationships of modulation depth with the incident angle and temperature of the working environment are derived by using computer simulation. It is shown that the modulation depth decreases with the increase of the temperature and incident angle. The study provides a theoretical basis to increase the modulation depth of the interferometer, and it is of significance for the development of the upper atmosphere detection technique and theory.


Ultracompact and broadband polarization beam splitter based on polarization-dependent critical guiding condition.
An ultracompact and broadband polarization beam splitter (PBS) based on the polarization-dependent critical guiding condition of an asymmetrical directional coupler is proposed. The device consists of a pair of silicon waveguides with different height and width. Due to the different cutoff conditions for the TE and TM polarization modes, it is possible to have the TM mode guided in one waveguide while the TE mode is supported in both. Therefore, only the phase-matching condition for the cross-coupling of the TE mode needs to be considered. This approach not only simplifies the design procedures but also significantly improves device performance with smaller total length and larger bandwidth. Finally, regardless of the contribution of S-bend waveguides, our proposed PBS has a coupling region as short as 0.2 μm, which is the shortest reported until now. The simulation result shows that the extinction ratios for the TE and TM polarization are 13.5 and 16.6 dB at their respective output ports, and their insertion losses are 0.29 and 0.13 dB, respectively. Numerical simulations also show that the device offers a very large bandwidth (∼140 nm) with large extinction ratio (>10 dB) and low insertion loss (<1 dB).


The coding of uniform colour figures in monkey visual cortex.
Psychophysical studies indicate that perception of the colour and brightness of a surface depends on neural signals evoked by the borders of the surface rather than its interior. The visual cortex emphasizes contrast borders, but it is unclear whether colour surface signals also exist, whether colour border signals are orientation selective or mainly non-oriented, and whether cortical processing tends to separate colour and form information. To address these questions we examined the representation of uniform colour figures by recording single neuron activity from areas V1 and V2 in alert macaque monkeys during behaviourally induced fixation. Three aspects of coding were quantified: colour, orientation and edge selectivity. The occurrence of colour selectivity was not correlated with orientation or edge selectivity. The fraction of colour-selective cells was the same (64 % in layers 2 and 3 of V1, 45 % in V2) for oriented and non-oriented cells, and for edge-selective and surface-responsive cells. Oriented cells were often highly selective in colour space, and about 40 % of them were selective for edge polarity or border ownership. Thus, contrary to the idea of feature maps, colour, orientation and edge polarity are multiplexed in cortical signals. The results from V2 were similar to those from upper-layer V1, indicating that cortical processing does not strive to separate form and colour information. Oriented cells were five times more frequent than non-oriented cells. Thus, the vast majority of colour-coded cells are orientation tuned. Based on response profiles across a 4 deg square figure, and the relative frequency of oriented and non-oriented cells, we estimate that the cortical colour signal is 5-6 times stronger for the edges than for the surface of the figure. The frequency of oriented colour cells and their ability to code edge polarity indicate that these cells play a major role in the representation of surface colour.


Integration of Breast Cancer Secretomes with Clinical Data Elucidates Potential Serum Markers for Disease Detection, Diagnosis, and Prognosis.
Cancer cells secrete factors that influence adjacent cell behavior and can lead to enhanced proliferation and metastasis. To better understand the role of these factors in oncogenesis and disease progression, estrogen and progesterone receptor positive MCF-7 cells, triple negative breast cancer MDA-MB-231, DT22, and DT28 cells, and MCF-10A non-transformed mammary epithelial cells were grown in 3D cultures. A special emphasis was placed on triple negative breast cancer since these tumors are highly aggressive and no targeted treatments are currently available. The breast cancer cells secreted factors of variable potency that stimulated proliferation of the relatively quiescent MCF-10A cells. The conditioned medium from each cell line was subjected to mass spectrometry analysis and a variety of secreted proteins were identified including glycolytic enzymes, proteases, protease inhibitors, extracellular matrix proteins, and insulin-like growth factor binding proteins. An investigation of the secretome from each cell line yielded clues about strategies used for breast cancer proliferation and metastasis. Some of the proteins we identified may be useful in the development of a serum-based test for breast cancer detection, diagnosis, prognosis, and monitoring.


A clinician's guide to recurrent isolated sleep paralysis.
This review summarizes the empirical and clinical literature on sleep paralysis most relevant to practitioners. During episodes of sleep paralysis, the sufferer awakens to rapid eye movement sleep-based atonia combined with conscious awareness. This is usually a frightening event often accompanied by vivid, waking dreams (ie, hallucinations). When sleep paralysis occurs independently of narcolepsy and other medical conditions, it is termed "isolated" sleep paralysis. Although the more specific diagnostic syndrome of "recurrent isolated sleep paralysis" is a recognized sleep-wake disorder, it is not widely known to nonsleep specialists. This is likely due to the unusual nature of the condition, patient reluctance to disclose episodes for fear of embarrassment, and a lack of training during medical residencies and graduate education. In fact, a growing literature base has accrued on the prevalence, risk factors, and clinical impact of this condition, and a number of assessment instruments are currently available in both self-report and interview formats. After discussing these and providing suggestions for accurate diagnosis, differential diagnosis, and patient selection, the available treatment options are discussed. These consist of both pharmacological and psychotherapeutic interventions which, although promising, require more empirical support and larger, well-controlled trials.


Spectrophotometric Characterization of the Action of Tyrosinase on p-Coumaric and Caffeic Acids: Characteristics of o-Caffeoquinone.
New methods are proposed to determine the activity of tyrosinase on caffeic and p-coumaric acids. Because o-quinone from caffeic acid is unstable in its presence, it has been characterized through spectrophotometric measurements of the disappearance of coupled reducing agents, such as nicotinamide adenine dinucleotide reduced form. It has also been characterized by a chronometric method, measuring the time that a known concentration of ascorbic acid takes to be consumed. The activity on p-coumaric acid has been followed by measuring the formation of o-quinone of caffeic acid at the isosbestic point originated between caffeic acid and o-caffeoquinone and measuring the formation of o-quinone at 410 nm, which is stable in the presence of p-coumaric acid (both of them in the presence of catalytic amounts of caffeic acid, maintaining the ratio between p-coumaric acid and caffeic acid constant; R = 0.025). The kcat value of tyrosinase obtained for caffeic acid was higher than that obtained for p-coumaric acid, while the affinity was higher for p-coumaric acid. These values agree with those obtained in docking studies involving these substrates and oxytyrosinase.


Human monocytes constitutively express membrane-bound, biologically active, and interferon-gamma-upregulated interleukin-15.
Interleukin-15 (IL-15) is a potent regulator of T-, B-, and natural killer cell proliferation and displays unusually tight controls of secretion. Even though IL-15 mRNA is constitutively expressed in monocytes/macrophages and is upregulated by a variety of stimuli, evidence for IL-15 cytokine secretion is only found exceptionally, eg, conditions of pathological, chronic inflammation. This raises the possibility that monocytes express membrane-bound IL-15 rather than secrete it. The current study explores this hypothesis. We demonstrate here that biologically active IL-15 is indeed detectable in a constitutively expressed, membrane-bound form on normal human monocytes, as well as on monocytic cell lines (MONO-MAC-6, THP-1, and U937), but not on human T or B cells (MT4, M9, C5966, JURKAT, DAUDI, RAJI, and Epstein-Barr virus-immortalized B-cell clones). Furthermore, cell surface-bound IL-15 is upregulated upon interferon-gamma stimulation. Interestingly, monocyte/macrophage inhibitory cytokines such as IL-4 and IL-13 fail to downregulate both constitutive and induced cell-surface expression of IL-15. Membrane-bound IL-15 does not elute with acetate buffer or trypsin treatment, suggesting that it is an integral membrane protein and that it is not associated with the IL-15 receptor complex. Finally, membrane-bound IL-15 stimulates T lymphocytes to proliferate in vitro, indicating that it is biologically active. These findings enlist IL-15 in the fairly small family of cytokines for which the presence of a biologically active membrane-bound form has been demonstrated (eg, IL-1, tumor necrosis factor-alpha, and IL-10) and invites the speculation that most of the biological effects of IL-15 under physiological conditions are exerted by the cell surface-bound form.


Promotion of mitotic catastrophe via activation of PTEN by paclitaxel with supplement of mulberry water extract in bladder cancer cells.
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. Mulberry fruit is rich in phenolic compounds and flavonoids and exhibits chemopreventive activities. In this study, mulberry water extract (MWE) was used as a supplement to synergize with the effects of paclitaxel in the treatment of the TSGH 8301 human bladder cancer cell line. Treatment with paclitaxel combined with MWE (paclitaxel/MWE) enhanced the cytotoxicity of paclitaxel and induced severe G2/M arrest, mitotic catastrophe and subsequent apoptosis, as shown by MTT assay, HE staining and flow cytometry analyses. Differences in the expression and activation of Aurora A and Plk1 between cells treated with paclitaxel/MWE and paclitaxel alone suggested that the combined treatment caused a defect in the early steps of cytokinesis. Paclitaxel/MWE decreased EEA1 immunofluorescence staining and increased the expression of PTEN, indicating that the regimen inhibited the formation of the recycling endosome, which is required for cytokinesis. Paclitaxel/MWE also retarded tumor growth in a TSGH 8301 xenograft model via activation of PTEN and Caspase 3. These data demonstrated a synergistic effect on the anticancer efficacy of paclitaxel through MWE supplementation by promoting mitotic catastrophe through the activation of PTEN, providing a novel and effective therapeutic option for bladder cancer treatment strategies.


Validity Assessment of Referral Decisions at a VA Health Care System Polytrauma System of Care.
There has been intensive interest to ensure equitable and appropriate access to the specialized rehabilitative services of the VA Polytrauma System of Care (PSC) for patients sustaining polytrauma and traumatic brain injuries (TBI). A retrospective cohort study with prospective data acquisition was conducted to assess validity and objectivity of the acceptance decision algorithm to the VA Palo Alto Health Care System (VAPAHCS) PSC. Our hypotheses are (1) VAPAHCS PSC referral decisions were appropriate and without bias and (2) the identified needs of redirected referrals were addressed. This analysis included 1,025 referrals (906 patients); 813 patients (89.7%) were accepted, and 93 (10.3%) were redirected. Redirected cases were older, were more often active duty service members, and were not from the West Coast. There were more females redirected due to concomitant spinal cord injury. These are rationale differences. In redirected patients, the most commonly identified rehabilitation needs were psychological support, mobility/physical therapy, and communication/speech services; >75% of patients had these services offered elsewhere outside of the PSC resources. While balancing financial stewardship and meeting our mission to provide outstanding rehabilitative care to veterans and service members, we demonstrated that acceptance decisions were valid and without bias, and redirected patients received appropriate alternate resources.


Pacific decadal oscillation hindcasts relevant to near-term climate prediction.
Decadal-scale climate variations over the Pacific Ocean and its surroundings are strongly related to the so-called Pacific decadal oscillation (PDO) which is coherent with wintertime climate over North America and Asian monsoon, and have important impacts on marine ecosystems and fisheries. In a near-term climate prediction covering the period up to 2030, we require knowledge of the future state of internal variations in the climate system such as the PDO as well as the global warming signal. We perform sets of ensemble hindcast and forecast experiments using a coupled atmosphere-ocean climate model to examine the predictability of internal variations on decadal timescales, in addition to the response to external forcing due to changes in concentrations of greenhouse gases and aerosols, volcanic activity, and solar cycle variations. Our results highlight that an initialization of the upper-ocean state using historical observations is effective for successful hindcasts of the PDO and has a great impact on future predictions. Ensemble hindcasts for the 20th century demonstrate a predictive skill in the upper-ocean temperature over almost a decade, particularly around the Kuroshio-Oyashio extension (KOE) and subtropical oceanic frontal regions where the PDO signals are observed strongest. A negative tendency of the predicted PDO phase in the coming decade will enhance the rising trend in surface air-temperature (SAT) over east Asia and over the KOE region, and suppress it along the west coasts of North and South America and over the equatorial Pacific. This suppression will contribute to a slowing down of the global-mean SAT rise.


Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2.
Nedd4 and Nedd4-2 are ubiquitin-protein ligases known to regulate a number of membrane proteins including receptors and ion transporters. Regulation of the epithelial Na(+) channel by Nedd4 and Nedd4-2 is mediated via interactions between the PY motifs of the epithelial sodium channel subunits and the Nedd4/Nedd4-2 WW domains. This example serves as a model for the regulation of other PY motif-containing ion channels by Nedd4 and Nedd4-2. We found that the carboxyl termini of the six voltage-gated Na(+) (Na(v)) channels contain typical PY motifs (PPXY), and a further Na(v) contains a PY motif variant (LPXY). Not only did we demonstrate by Far-Western analysis that Nedd4 and Nedd4-2 interact with the PY motif-containing Na(v) channels, but we also showed that these channels have conserved WW domain binding specificity. We further showed that the carboxyl termini fusion proteins of one central nervous system and one peripheral nervous system-derived Na(+) channel (Na(v)1.2 and Na(v)1.7, respectively) are readily ubiquitinated by Nedd4-2. In Xenopus oocytes, Nedd4-2 strongly inhibited the activities of all three Na(v)s (Na(v)1.2, Na(v)1.7, and Na(v)1.8) tested. Interestingly, Nedd4 suppressed the activity of Na(v)1.2 and Na(v)1.7 but was a poor inhibitor of Na(v)1.8. Our results provide evidence that Nedd4 and Nedd4-2 are likely to be key regulators of specific neuronal Na(v) channels in vivo.


Structure, regulation, signaling, and targeting of abl kinases in cancer.
Abl kinases are prototypic cytoplasmic tyrosine kinases and are involved in a variety of chromosomal aberrations in different cancers. This causes the expression of Abl fusion proteins, such as Bcr-Abl, that are constitutively activated and drivers of tumorigenesis. Over the past decades, biochemical and functional studies on the molecular mechanisms of Abl regulation have gone hand in hand with progression of our structural understanding of autoinhibited and active Abl conformations. In parallel, Abl oncoproteins have become prime molecular targets for cancer therapy, using adenosine triphosphate (ATP)-competitive kinase inhibitors, such as imatinib. Abl-targeting drugs serve as a paradigm for our understanding of kinase inhibitor action, specificity, and resistance development. In this review article, I will review the molecular mechanisms that are responsible for the regulation of Abl kinase activity and how oncogenic Abl fusions signal. Furthermore, past and ongoing efforts to target Abl oncoproteins using ATP-competitive and allosteric inhibitors, as well as future possibilities using combination therapy, will be discussed.


Diterpenoid alkaloids of Aconitum laciniatum and mitigation of inflammation by 14-O-acetylneoline in a murine model of ulcerative colitis.
Aconitum laciniatum is used in Bhutanese traditional medicine for treating various chronic infections and inflammatory conditions. We carried out in-depth isolation and characterization of the phytochemicals from the root component and determined the anti-inflammatory effects of the isolated compounds against chemically-induced colitis in mice. Five diterpenoid alkaloids - pseudaconitine, 14-veratroylpseudaconine, 14-O-acetylneoline, neoline, and senbusine A - were isolated from A. laciniatum for the first time. Two of the alkaloids were tested for anti-inflammatory properties in the TNBS-induced colitis model in mice. Various parameters were measured to assess pathology including weight loss, clinical and macroscopic scores, histological structure and IFN-γ production in the gut. Of the two alkaloids tested, 14-O-acetylneoline showed significant protection against different parameters of colitic inflammation. Compared to control mice that received TNBS alone, mice treated with 14-O-acetylneoline experienced significantly less weight loss and had significantly lower clinical scores, macroscopic pathology and grades of histological inflammation. Moreover, colonic IFN-γ mRNA levels were significantly reduced in mice that received 14-O-acetylneoline compared to control mice that received TNBS alone. This alkaloid is now considered a novel anti-colitis drug lead compound.


Naked DNA vaccination of Atlantic salmon Salmo salar against IHNV.
A naked plasmid DNA encoding the glycoprotein (pCMV4-G) of a 1976 isolate of infectious hematopoietic necrosis virus (IHNV) obtained from steelhead Oncorhynchus mykiss was used to vaccinate Atlantic salmon Salmo salar against IHNV. Eight weeks post-vaccination the fish were challenged with a strain of IHNV originally isolated from farmed Atlantic salmon undergoing an epizootic. Fish injected with the glycoprotein-encoding plasmid were significantly (p < 0.05) protected against IHNV by both immersion and cohabitation challenge. Survivors of the first challenges were pooled and re-challenged by immersion 12 wk after the initial challenge. Significant (p < 0.05) protection was observed in all of the previously challenged groups including those receiving the complete vaccine. Fish injected with the glycoprotein-encoding plasmid produced low levels of virus-neutralizing antibodies prior to the first challenge. Neutralizing antibodies increased in all groups after exposure to the IHNV. Passive transfer of pooled sera from pCMV4-G vaccinates and IHN survivors provided relative survivals of 40 to 100% compared to fish injected with sera collected from fish immunized with control vaccines or left unhandled. In this study, DNA vaccination effectively protected Atlantic salmon smolts against challenges with IHNV.


Mutations in the p53 gene are frequent in primary, resected non-small cell lung cancer. Lung Cancer Study Group.
The p53 gene has been implicated as a tumor suppressor gene with mutations found in common human cancers. We examined 51 early stage, primary, resected non-small cell lung cancer specimens using an RNAase protection assay and cDNA sequencing. Mutations changing the p53 coding sequence were found in 23/51 (45%) tumor specimens, but not in the corresponding normal lung, were distributed between codons 132 to 283, and included tumors with and without 17p allele loss. Fifteen of the 23 mutations lay in the predicted binding regions for SV40 large T antigen, and 14 were located in regions highly conserved between species. G to T transversions were a common result of p53 mutations in lung cancer compared to other cancers suggesting exposure to different mutagens. In univariate and multivariate analysis the presence of p53 mutations was associated with younger age and squamous histology. However, the presence of p53 mutations was not significantly associated with tumor stage, nodal status or sex and was found in all histologic types of lung cancer. We conclude that somatic mutations in the p53 gene play an important role in the pathogenesis of early stage non-small cell lung cancer.


Effects of prior exercise on force-velocity test performance and quadriceps EMG.
This study investigated the effects of prior exercise on performance during a subsequent force-velocity (FV) exercise test. After determination of the individual maximal aerobic power (MAP) during maximal graded exercise testing, fifteen trained male subjects (age: 25 +/- 3 y) were randomly assigned to perform the FV exercise test without prior exercise (NPE) or preceded by prior exercise (PE) (10 min at 60 % of MAP, followed after 1-min rest interval by four intervals of 30-s cycling at 100 % MAP with 15-s rest intervals, then 10 min recovery). Blood samples were drawn at rest, and then for each work load at the 3rd minute of recovery. Skin temperature (T (sk)) from the rectus femoris and heart rate (HR) were measured continuously during prior exercise, the FV test, and during the 5-min recovery period at the end of each FV test. The Root Mean Square (RMS) of the surface electromyogram (EMG) signals obtained from the vastus lateralis (VL), vastus medialis (VM), and rectus femoris (RF) were calculated during each sprint for each FV test. The lactate increase for each load (deltaLa) during the FV test was significantly less following PE than NPE. However, the lactate concentration (La) was significantly higher in the FV test following PE than NPE. There was an improvement in power output during the first two sprints (2 and 4 kg) following PE compared to NPE. There was also a more pronounced decrease in VL, VM, and RF RMS in PE compared to NPE. Our results showed that the first few sprints may provide sufficient prior exercise for the FV test. The higher lactate concentration following PE than NPE, despite no difference in maximum power, suggests that a large lactate accumulation may not be detrimental to FV test performance. However, a greater lactate concentration and T(sk) may be associated with a decrease in RMS.


Clonal heterogeneity of the sensitivity of human colon carcinoma cell lines to TGE beta isoforms.
Spontaneously arising, TGF beta 1-resistant colonies were isolated directly from the soft agarose plates of MOSER human colon carcinoma cells grown in the presence of TGF beta 1 but in the absence of serum. The colonies were cloned by limiting dilution and screened in a monolayer proliferation assay for sensitivity to TGF beta 1 and TGF beta 2 isoforms. Cell clones selectively sensitive or resistant to these isoforms in the growth inhibition assay displayed similar differential sensitivities to TGF beta isoforms for production of the extracellular matrix proteins laminin and fibronectin, as well as for the expression of the colon cell differentiation marker carcinoembryonic antigen. Differential receptor binding profiles for TGF beta 1 and TGF beta 2 were observed among the clones. The isolation of cell clones selectively resistant or sensitive to TGF beta isoforms as well as the identification of differential receptor binding profiles among the clones indicate the heterogeneity of TGF beta responsiveness that exists naturally in human colon tumor cells and stress the importance of defining mechanisms underlying differential responsiveness to TGF beta isoforms.


Associations between exposure to bovine herpesvirus 1 (BoHV-1) and milk production, reproductive performance, and mortality in Irish dairy herds.
As cost-benefit analyses are required to prioritize and promote disease control and eradication programs within a jurisdiction, national data relating to disease-related production losses are particularly useful. The objectives of the current study were to use Irish bovine herpesvirus 1 (BoHV-1) prevalence data in dairy herds, obtained by bulk milk sampling on 4 occasions over the 2009 lactation, to document associations between milk production, fertility performance, mortality, and BoHV-1 herd status. Bulk milk (n = 305) antibody ELISA was used to classify farms as positive or negative in terms of endemic BoHV-1. Cow-level (milk parameters only) and herd-level performance data were sourced from the Irish Cattle Breeding Federation. Ordinary linear and negative binomial regressions were used to investigate associations between milk, fertility, and mortality performance and herd-level BoHV-1 results (both categorical and continuous variables). Only slight effects on the rates of carryover cows, nonpregnant cows, and total deaths were highlighted with increasing ELISA sample/positive (%) values (incidence rate ratio = 1.001). Multiparous cows in herds BoHV-1 bulk milk antibody positive recorded a reduction in milk yield per cow per year of 250.9 L in the multivariable linear model. Milk fat and protein yields were also affected by herd BoHV-1 status, again highlighting sub-optimal milk production in BoHV-1 bulk milk-positive herds. The current study has highlighted an economical method of investigating losses due to endemic infection using repeated bulk milk sampling over a single lactation. These data can contribute to analyzing the cost-benefit of applying BoHV-1 control strategies both on farm and at a national level.


Animal personality as a cause and consequence of contest behaviour.
We review the evidence for a link between consistent among-individual variation in behaviour (animal personality) and the ability to win contests over limited resources. Explorative and bold behaviours often covary with contest behaviour and outcome, although there is evidence that the structure of these 'behavioural syndromes' can change across situations. Aggression itself is typically repeatable, but also subject to high within-individual variation as a consequence of plastic responses to previous fight outcomes and opponent traits. Common proximate mechanisms (gene expression, endocrine control and metabolic rates) may underpin variation in both contest behaviour and general personality traits. Given the theoretical links between the evolution of fighting and of personality, we suggest that longitudinal studies of contest behaviour, combining behavioural and physiological data, would be a useful context for the study of animal personalities.


Spectroscopic and Theoretical Study of Spin-Dependent Electron Transfer in an Iron(III) Superoxo Complex.
It was shown previously (J. Am. Chem. Soc. 2014, 136, 10846) that bubbling of O2 into a solution of Fe(II)(BDPP) (H2BDPP = 2,6-bis[[(S)-2-(diphenylhydroxymethyl)-1-pyrrolidinyl]methyl]pyridine) in tetrahydrofuran at -80 °C generates a high-spin (SFe = (5)/2) iron(III) superoxo adduct, 1. Mössbauer studies revealed that 1 is an exchange-coupled system, [Formula: see text], where SR = (1)/2 is the spin of the superoxo radical, of which the spectra were not well enough resolved to determine whether the coupling was ferromagnetic (S = 3 ground state) or antiferromagnetic (S = 2). The glass-forming 2-methyltetrahydrofuran solvent yields highly resolved Mössbauer spectra from which the following data have been extracted: (i) the ground state of 1 has S = 3 (J < 0); (ii) |J| > 15 cm(-1); (iii) the zero-field-splitting parameters are D = -1.1 cm(-1) and E/D = 0.02; (iv) the major component of the electric-field-gradient tensor is tilted ≈7° relative to the easy axis of magnetization determined by the MS = ±3 and ±2 doublets. The excited-state MS = ±2 doublet yields a narrow parallel-mode electron paramagnetic resonance signal at g = 8.03, which was used to probe the magnetic hyperfine splitting of (17)O-enriched O2. A theoretical model that considers spin-dependent electron transfer for the cases where the doubly occupied π* orbital of the superoxo ligand is either "in" or "out" of the plane defined by the bent Fe-OO moiety correctly predicts that 1 has an S = 3 ground state, in contrast to the density functional theory calculations for 1, which give a ground state with both the wrong spin and orbital configuration. This failure has been traced to a basis set superposition error in the interactions between the superoxo moiety and the adjacent five-membered rings of the BDPP ligand and signals a fundamental problem in the quantum chemistry of O2 activation.


Reconciling novelty and complexity through a rational analysis of curiosity.
Curiosity is considered to be the essence of science and an integral component of cognition. What prompts curiosity in a learner? Previous theoretical accounts of curiosity remain divided-novelty-based theories propose that new and highly uncertain stimuli pique curiosity, whereas complexity-based theories propose that stimuli with an intermediate degree of uncertainty stimulate curiosity. In this article, we present a rational analysis of curiosity by considering the computational problem underlying curiosity, which allows us to model these distinct accounts of curiosity in a common framework. Our approach posits that a rational agent should explore stimuli that maximally increase the usefulness of its knowledge and that curiosity is the mechanism by which humans approximate this rational behavior. Critically, our analysis show that the causal structure of the environment can determine whether curiosity is driven by either highly uncertain or moderately uncertain stimuli. This suggests that previous theories need not be in contention but are special cases of a more general account of curiosity. Experimental results confirm our predictions and demonstrate that our theory explains a wide range of findings about human curiosity, including its subjectivity and malleability. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Three-dimensional hyaluronic acid grafts promote healing and reduce scar formation in skin incision wounds.
Hyaluronic acid (HA) has been found to play important roles in tissue regeneration and wound-healing processes. Fetal tissue with a high concentration of HA heals rapidly without scarring. The present study employed HA formed into three-dimensional strands with or without keratinocytes to treat full-thickness skin incision wounds in rats. Wound closure rates of HA strand grafts both with and without keratinocytes were substantially enhanced. The closure times of both HA grafts were less than 1 day (average 16 h), about 1/7 that of the contralateral control incisions (114 h, p <.01). Average wound areas after 10 days were HA-only graft: 0.151 mm2 +/- 0.035; HA + cell grafts: 0.143 mm2 +/- 0.036 and controls: 14.434 mm2 +/- 1.175, experimental areas were 1% of the controls (p < 0.01). Transforming growth factor (TGF) beta1 measured by immunostaining was remarkably reduced in HA-treated wounds compared to the controls. In conclusion, HA grafts appeared to produce a fetal-like environment with reduced TGF-beta1, which is known to be elevated in incipient scars. The HA strands with or without cultured cells may potentially improve clinical wound healing as well as reduce scar formation.


Design and fabrication of diffractive microlens arrays with continuous relief for parallel laser direct writing.
Diffractive microlens arrays with continuous relief are designed, fabricated, and characterized by using Fermat's principle to create an array of spots on the photoresist-coated surface of a substrate for parallel laser direct writing. Experimental results indicate that a diffraction efficiency of 71.4% and a spot size of 1.97 microm (FWHM) can be achieved at normal incidence and a writing laser wavelength of 441.6 nm with an array of F/4 fabricated on fused silica, and the developed array can be used to improve the utilization ratio of writing laser energy.


Herbivore-induced volatiles in the perennial shrub, Vaccinium corymbosum, and their role in inter-branch signaling.
Herbivore feeding activates plant defenses at the site of damage as well as systemically. Systemic defenses can be induced internally by signals transported via phloem or xylem, or externally transmitted by volatiles emitted from the damaged tissues. We investigated the role of herbivore-induced plant volatiles (HIPVs) in activating a defense response between branches in blueberry plants. Blueberries are perennial shrubs that grow by initiating adventitious shoots from a basal crown, which produce new lateral branches. This type of growth constrains vascular connections between shoots and branches within plants. While we found that leaves within a branch were highly connected, vascular connectivity was limited between branches within shoots and absent between branches from different shoots. Larval feeding by gypsy moth, exogenous methyl jasmonate, and mechanical damage differentially induced volatile emissions in blueberry plants, and there was a positive correlation between amount of insect damage and volatile emission rates. Herbivore damage did not affect systemic defense induction when we isolated systemic branches from external exposure to HIPVs. Thus, internal signals were not capable of triggering systemic defenses among branches. However, exposure of branches to HIPVs from an adjacent branch decreased larval consumption by 70% compared to those exposed to volatiles from undamaged branches. This reduction in leaf consumption did not result in decreased volatile emissions, indicating that leaves became more responsive to herbivory (or "primed") after being exposed to HIPVs. Chemical profiles of leaves damaged by gypsy moth caterpillars, exposed to HIPVs, or non-damaged controls revealed that HIPV-exposed leaves had greater chemical similarities to damaged leaves than to control leaves. Insect-damaged leaves and young HIPV-exposed leaves had higher amounts of endogenous cis-jasmonic acid compared to undamaged and non-exposed leaves, respectively. Our results show that exposure to HIPVs triggered systemic induction of direct defenses against gypsy moth and primed volatile emissions, which can be an indirect defense. Blueberry plants appear to rely on HIPVs as external signals for inter-branch communication.


The long-lasting effects of JDTic, a kappa opioid receptor antagonist, on the expression of ethanol-seeking behavior and the relapse drinking of female alcohol-preferring (P) rats.
The current study assessed the effects of the selective kappa opioid antagonist JDTic on alcohol (EtOH)-seeking behavior, EtOH relapse, and maintenance responding for EtOH. Adult alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) on a fixed-ratio 5 (FR-5) and water on a FR-1 schedule of reinforcement during 1-hr sessions. After 10 weeks, rats underwent extinction training for seven sessions. Rats were then maintained in their home cages for 3 weeks without EtOH access. All rats received an injection (s.c.) of 0, 1, 3, or 10 mg/kg JDTic (n=11-14/group) after the first week of the home cage period. Rats were then tested using the Pavlovian Spontaneous Recovery paradigm (PSR; an animal model of alcohol-seeking) for four sessions during which, responses on the EtOH and water levers were recorded but did not produce their respective reinforcer. Following PSR testing rats were returned to their home cages without access to EtOH for one week prior to the start of EtOH relapse testing. To examine EtOH relapse responding, rats were returned to the operant chambers and the EtOH (FR5) and water (FR1) levers were active. Finally, rats were then tested over 17 operant sessions to assess the effects of JDTic on maintenance responding for EtOH. Rats received 0, 1, 3, or 10 mg/kg JDTic (counterbalanced from the initial experiment) 30 minutes prior to the initial maintenance session. JDTic administered 14 and 25 days prior to testing dose-dependently reduced the expression of an EtOH PSR and relapse responding. In contrast, JDTic did not alter EtOH responding under maintenance conditions. Overall, the results of this study indicate that different mechanisms mediate EtOH self-administration under relapse and maintenance conditions and kappa opioid receptors are involved in mediating EtOH-seeking behavior and relapse responding but not on-going EtOH self-administration.


Four cases of corneal perforation in patients with chronic graft-versus-host disease.
To report the clinical features and investigate the underlying pathological processes of spontaneous corneal perforation in patients with ocular chronic graft-versus-host disease (cGVHD). A full ophthalmological evaluation of corneal perforation in four patients with cGVHD was performed. Three of them underwent deep anterior lamellar keratoplasty and samples from two of three patients were used for histopathological analyses. Three patients were successfully treated by corneal transplantation. One patient was treated with a therapeutic soft contact lens, and the wound healed within 2 days. The common clinical features of these patients were (1) the presence of definite dry eye related to cGVHD in 3 of 4 patients and probable dry eye in one patient, (2) a central or paracentral site of corneal ulceration and perforation, with no sign of infection, and (3) prior use of a topical or systemic corticosteroid, and/or topical non-steroidal anti-inflammatory drugs. Immunohistochemical findings revealed an increased number of cluster of differentiation 68(+) (CD68(+)) macrophages and matrix metalloproteinase 9 (MMP-9) expression in the tissue surrounding the perforation. Our report extends current information on the clinical features and pathological processes of corneal perforation in cGVHD by showing increased MMP-9 expression and the accumulation of CD68(+) positive macrophages in the affected areas.


A simple method for the production of large volume 3D macroporous hydrogels for advanced biotechnological, medical and environmental applications.
The development of bulk, three-dimensional (3D), macroporous polymers with high permeability, large surface area and large volume is highly desirable for a range of applications in the biomedical, biotechnological and environmental areas. The experimental techniques currently used are limited to the production of small size and volume cryogel material. In this work we propose a novel, versatile, simple and reproducible method for the synthesis of large volume porous polymer hydrogels by cryogelation. By controlling the freezing process of the reagent/polymer solution, large-scale 3D macroporous gels with wide interconnected pores (up to 200 μm in diameter) and large accessible surface area have been synthesized. For the first time, macroporous gels (of up to 400 ml bulk volume) with controlled porous structure were manufactured, with potential for scale up to much larger gel dimensions. This method can be used for production of novel 3D multi-component macroporous composite materials with a uniform distribution of embedded particles. The proposed method provides better control of freezing conditions and thus overcomes existing drawbacks limiting production of large gel-based devices and matrices. The proposed method could serve as a new design concept for functional 3D macroporous gels and composites preparation for biomedical, biotechnological and environmental applications.


Motor imagery and stroke rehabilitation: a critical discussion.
Motor disorders are a frequent consequence of stroke and much effort is invested in the re-acquisition of motor control. Although patients often regain some of their lost function after therapy, most remain chronically disabled. Functional recovery is achieved largely through reorganization processes in the damaged brain. Neural reorganization depends on the information provided by sensorimotor efferent-afferent feedback loops. It has, however, been shown that the motor system can also be activated "offline" by imagining (motor imagery) or observing movements. The discovery of mirror neurones, which fire not only when an action is executed, but also when one observes another person performing the same action, also show that our action system can be used "online" as well as offline. It is an intriguing question as to whether the information provided by motor imagery or motor observation can lead to functional recovery and plastic changes in patients after stroke. This article reviews the evidence for motor imagery or observation as novel methods in stroke rehabilitation.


The neuropeptide VIP potentiates intestinal innate type 2 and type 3 immunity in response to feeding.
The nervous system and the immune system both rely on an extensive set of modalities to perceive and act on perturbations in the internal and external environments. During feeding, the intestine is exposed to nutrients that may contain noxious substances and pathogens. Here we show that Vasoactive Intestinal Peptide (VIP), produced by the nervous system in response to feeding, potentiates the production of effector cytokines by intestinal type 2 and type 3 innate lymphoid cells (ILC2s and ILC3s). Exposure to VIP alone leads to modest activation of ILCs, but strongly potentiates ILCs to concomitant or subsequent activation by the inducer cytokines IL-33 or IL-23, via mobilization of cAMP and energy by glycolysis. Consequently, VIP increases resistance to intestinal infection by the helminth Trichuris muris and the enterobacteria Citrobacter rodentium. These findings uncover a functional neuro-immune crosstalk unfolding during feeding that increases the reactivity of innate immunity necessary to face potential threats associated with food intake.


Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: entering a new century, do we do better?
Hematopoietic stem cell transplantation remains the only treatment for most patients with severe combined immunodeficiencies (SCIDs) or other primary immunodeficiencies (non-SCID PIDs). To analyze the long-term outcome of patients with SCID and non-SCID PID from European centers treated between 1968 and 2005. The product-limit method estimated cumulative survival; the log-rank test compared survival between groups. A Cox proportional-hazard model evaluated the impact of independent predictors on patient survival. In patients with SCID, survival with genoidentical donors (n = 25) from 2000 to 2005 was 90%. Survival using a mismatched relative (n = 96) has improved (66%), similar to that using an unrelated donor (n = 46; 69%; P = .005). Transplantation after year 1995, a younger age, B(+) phenotype, genoidentical and phenoidentical donors, absence of respiratory impairment, or viral infection before transplantation were associated with better prognosis on multivariate analysis. For non-SCID PID, in contrast with patients with SCID, we confirm that, in the 2000 to 2005 period, using an unrelated donor (n = 124) gave a 3-year survival rate similar to a genoidentical donor (n = 73), 79% for both. Survival was 76% in phenoidentical transplants (n = 23) and worse in mismatched related donor transplants (n = 47; 46%; P = .016). This is the largest cohort study of such patients with the longest follow-up. Specific issues arise for different patient groups. Patients with B-SCID have worse survival than other patients with SCID, despite improvements in each group. For non-SCID PID, survival is worse than SCID, although more conditions are now treated. Individual disease categories now need to be analyzed so that disease-specific prognosis may be better understood and the best treatments planned.


Cross-species transcriptomic approach reveals genes in hamster implantation sites.
The mouse model has greatly contributed to understanding molecular mechanisms involved in the regulation of progesterone (P4) plus estrogen (E)-dependent blastocyst implantation process. However, little is known about contributory molecular mechanisms of the P4-only-dependent blastocyst implantation process that occurs in species such as hamsters, guineapigs, rabbits, pigs, rhesus monkeys, and perhaps humans. We used the hamster as a model of P4-only-dependent blastocyst implantation and carried out cross-species microarray (CSM) analyses to reveal differentially expressed genes at the blastocyst implantation site (BIS), in order to advance the understanding of molecular mechanisms of implantation. Upregulation of 112 genes and downregulation of 77 genes at the BIS were identified using a mouse microarray platform, while use of the human microarray revealed 62 up- and 38 down-regulated genes at the BIS. Excitingly, a sizable number of genes (30 up- and 11 down-regulated genes) were identified as a shared pool by both CSMs. Real-time RT-PCR and in situ hybridization validated the expression patterns of several up- and down-regulated genes identified by both CSMs at the hamster and mouse BIS to demonstrate the merit of CSM findings across species, in addition to revealing genes specific to hamsters. Functional annotation analysis found that genes involved in the spliceosome, proteasome, and ubiquination pathways are enriched at the hamster BIS, while genes associated with tight junction, SAPK/JNK signaling, and PPARα/RXRα signalings are repressed at the BIS. Overall, this study provides a pool of genes and evidence of their participation in up- and down-regulated cellular functions/pathways at the hamster BIS.


Fluorescence in situ hybridization for ambiguous melanocytic tumors.
The large majority of melanocytic lesions can be reliably classified as either benign or malignant based upon morphology alone, but a minority of lesions remains difficult to classify by traditional histologic methods. Recently, a panel of fluorescence in situ hybridization (FISH) probes targeting loci on chromosomes 6 and 11 has emerged as a powerful tool to discriminate melanoma from nevi. This has been validated in numerous difficult diagnostic scenarios. In addition, this same FISH panel has been shown to provide independent prognostic information in traditional melanomas. There is accumulating evidence that FISH targeting these loci as well as several other key chromosomal loci such as 9p21 and 8q24 can provide valuable prognostic information in histologically ambiguous melanocytic tumors. However, since the vast majority of atypical spitz tumors have an indolent course, larger studies including adequate numbers of cases with adverse events is necessary to provide sufficient proof of its role in clinically relevant cases. In this review, we discuss the current literature and studies to date on this topic.


Structural characterization and phylogenetic relationships of myotoxin II from Atropoides (Bothrops) nummifer snake venom, a Lys49 phospholipase A(2) homologue.
In order to analyze its structure-function relationships, the complete amino acid sequence of myotoxin II from Atropoides (Bothrops) nummifer from Costa Rica was determined. This toxin is a Lys49-type phospholipase A(2) (PLA(2)) homologue, devoid of catalytic activity, structurally belonging to class IIA. In addition to the Asp49 --> Lys change in the (inactive) catalytic center, substitutions in the calcium-binding loop suggest that its lack of enzymatic activity is due to the loss of ability to bind Ca(2+). The toxin occurs as a homodimer of basic subunits of 121 residues. Its sequence has highest similarity to Lys49 PLA(2)s from Cerrophidion, Trimeresurus, Bothrops and Agkistrodon species, which form a subfamily of proteins that diverged early from Asp49 PLA(2)s present in the same species, as shown by phylogenetic analysis. The tertiary structure of the toxin was modeled, based on the coordinates of Cerrophidion godmani myotoxin II. Its exposed C-terminal region 115-129 shows several differences in comparison to the homologous sequences of other Lys49 PLA(2)s, i.e. from Agkistrodon p. piscivorus and Bothrops asper. Region 115-129 of the latter two proteins has been implicated in myotoxic activity, on the basis of the direct membrane-damaging of their corresponding synthetic peptides. However, peptide 115-129 of A. nummifer myotoxin II did not exert toxicity upon cultured skeletal muscle cells or mature muscle in vivo. Differences in several amino acid residues, either critical for toxicity, or influencing the conformation of free peptide 115-129 from A. nummifer myotoxin II, may account for its lack of direct membrane-damaging properties.


Community outbreaks of asthma associated with inhalation of soybean dust. Toxicoepidemiological Committee.
Since 1981, 26 outbreaks of asthma have been detected in the city of Barcelona. The geographic clustering of cases close to the harbor led us to consider the harbor as the probable source of the outbreaks. We therefore studied the association between the unloading of 26 products from ships in the harbor and outbreaks of asthma in 1985 and 1986. All 13 asthma-epidemic days in these two years coincided with the unloading of soybeans (lower 95 percent confidence limit of the risk ratio, 7.2). Of the remaining 25 products, only the unloading of wheat was related to the epidemics of asthma, although when adjusted for the unloading of soybeans the relation was not statistically significant. High-pressure areas and mild southeasterly to southwesterly winds, which favored the movement of air from the harbor to the city, were registered on all epidemic days. Particles of starch and episperm cells that were recovered from air samplers placed in the city had morphologic characteristics identical to those of soybean particles. Furthermore, the lack of bag filters at the top of one of the harbor silos into which soybeans were unloaded allowed the release of soybean dust into the air. We conclude that these outbreaks of asthma in Barcelona were caused by the inhalation of soybean dust released during the unloading of soybeans at the city harbor.


Fabrication of "strong" columnar Cu2-xSe superstructures assisted by inorganic ligands.
In this report, Cu(2-x)Se nanoplates with columnar superstructures have been synthesized via a facile, "green", phosphine-free, low-cost colloidal method. An inorganic tin(iv) selenium complex (Sn(2)Se(6))(4-) was attached on the surfaces of Cu(2-x)Se nanoplates directly during the synthesis of Cu(2-x)Se nanoplates. With the assistance of (Sn(2)Se(6))(4-) complexes, Cu(2-x)Se nanoplates showed "strong" self-assembly behavior and the stability of Cu(2-x)Se nanoplate superstructures was increased. Such columnar superstructures were still kept even if most of the coordinating organic ligands were removed by washing. The mechanism of the formation of "strong" columnar Cu(2-x)Se superstructures had been studied. We found the "strong" self-assemblies of Cu(2-x)Se nanoplates were formed only with the coexistence of oleylamine (OAM) and Sn-X in the synthesis process. The inorganic ligand not only played a key role in the construction of the "strong" columnar Cu(2-x)Se superstructure but also greatly improved their superior electrical property.


Detection of early cognitive processing by event-related phase synchronization analysis.
In order to investigate the temporal characteristics of cognitive processing, we apply multivariate phase synchronization analysis to event-related potentials. The experimental design combines a semantic incongruity in a sentence context with a physical mismatch (color change). In the ERP average, these result in an N400 component and a P300-like positivity, respectively. Synchronization analysis shows an effect of global desynchronization in the theta band around 288 ms after stimulus presentation for the semantic incongruity, while the physical mismatch elicits an increase of global synchronization in the alpha band around 204 ms. Both of these effects clearly precede those in the ERP average. Moreover, the delay between synchronization effect and ERP component correlates with the complexity of the cognitive processes.


Acute Care QUAliTy in chronic Kidney disease (ACQUATIK): a prospective cohort study exploring outcomes of patients with chronic kidney disease.
Chronic kidney disease (CKD) is common and carries a high risk of morbidity, including hospital admissions and readmissions and mortality. This is largely attributed to an increased risk of cardiovascular disease. Patients with CKD are less likely to receive evidence-based treatments for cardiovascular disease. However, these treatments are based on trials which generally exclude patients with CKD. It is therefore unclear whether this patient group derives the same benefits without an increased risk of adverse effects. The Acute Care QUAliTy in chronic Kidney disease (ACQUATIK) study is a prospective, observational, multicentre cohort study. Over 4000 patients will be recruited with an enrolment period of 2 years and a follow-up period of 2-4 years. Patients under follow-up by a renal team will be excluded. Data will be obtained from patient and hospital records during the index admission. Preadmission data will be extracted from general practice records based on the Quality and Outcomes Framework. Diagnosis, comorbidities and procedure data pertaining to the index and subsequent admissions will be extracted from the Hospital Episode Statistics database and long-term mortality data will be tracked using the Office of National Statistics. This information will allow us to examine a complete patient journey through primary and secondary care, providing unequalled levels of information on treatment and outcomes of patients with CKD. The combined data set will be used to compare outcomes and treatments among patients with CKD versus patients without CKD. The primary end point is hospital readmission rates. The relationship between age, sex, ethnicity, socioeconomic status and concurrent comorbidities will be analysed to determine their influence on outcomes and treatments. The ACQUATIK study has been approved by the NRES Committee West Midlands-South Birmingham-Reference 13/WM/0317. The results from ACQUATIK will be submitted for publication in peer-reviewed journals and presented at primary and secondary care conferences. ISRCTN37237454.


Systematic review of soil ecosystem services in tropical regions.
Soil ecosystem service (SES) approaches evidence the importance of soil for human well-being, contribute to improving dialogue between science and decision-making and encourage the translation of scientific results into public policies. Herein, through systematic review, we assess the state of the art of SES approaches in tropical regions. Through this review, 41 publications were identified; while most of these studies considered SES, a lack of a consistent framework to define SES was apparent. Most studies measured soil natural capital and processes, while only three studies undertook monetary valuation. Although the number of publications increased (from 1 to 41), between 2001 and 2019, the total number of publications for tropical regions is still small. Countries with the largest number of publications were Brazil (n = 8), Colombia (n = 6) and Mexico (n = 4). This observation emphasizes an important knowledge gap pertaining to SES approaches and their link to tropical regions. With global momentum behind SES approaches, there is an opportunity to integrate SES approaches into policy and practice in tropical regions. The use of SES evaluation tools in tropical regions could transform how land use decisions are informed, mitigating soil degradation and protecting the ecosystems that soil underpins.


Ventral hernia and patient experience of an elastic girdle.
Abdominal girdles are used to prevent hernia and to facilitate the in-growth of mesh following ventral hernia surgery or instead of surgery. Scientific evidence supporting the use of girdle, including patient experience, is lacking. The aim was to investigate patient experience of wearing an elastic girdle in terms of support and tolerability. A trans-sectional study with quantitative onset was performed. Telephone interviews following a strict protocol were performed 2 years after girdle prescription. Of the 89 eligible patients, 67 completed the interview. The questionnaire constituted 13 questions. Of the 52 women and 15 men, two thirds had ventral hernia surgery. Patients over 70 years more often used girdle as a substitute for surgery. Most patients (64%) were satisfied with the girdle and 94% used it as prescribed. Five out of 53 who used girdles preoperatively stated no improvement in their inconvenience. Almost all patients (97%) had some problem with the girdle. In this first study on patient experience, nearly all patients used it as prescribed and subjective benefit was achieved even though side effects were present in most cases. Individual fitting and improved information about when and how to use the girdle is important for patient comfort and optimal function. This study attended patient experience of negative side effects from wearing a girdle. Improvement may be reached concerning comfort from the patients' perspective. The importance of both written and oral information has been revealed.


The effect of three low-cost engineering treatments on driver fatigue: A driving simulator study.
Three engineering treatments were implemented in a driving simulator study to assess the effect of road-based measures on alleviating the symptoms of fatigue. Using results from previous research on the effect of circadian rhythms on fatigue-related crashes, two groups of male drivers were recruited for this study: young shift workers under the age of 35, who attended immediately after their night shift, and older drivers over the age of 45, who completed the study during the 'post lunch dip' period, after consuming lunch. Eye tracking (PERCLOS) and lateral driver performance measures were used to assess whether baseline measures of fatigue changed after drivers experienced each of the three treatments, which included variable message signs, chevrons and rumble strips. Results showed a marked difference in these measures between drivers' baseline (not fatigued) and experimental (fatigued) visits. There were also some reductions in lateral deviation and eye closure (as measured by PERCLOS) when the treatments were encountered, but no marked difference between the three treatments. These results suggest that in addition to driver- and vehicle-based methods currently employed to mitigate the effects of fatigue, the inclusion of such engineering measures may help alleviate fatigue-related impairments in driving, particularly if such treatments are implemented during long stretches of straight monotonous roads which are known to be associated with fatigue-related crashes. However, positive effects of the treatments were short lived, prompting the need for further investigations on their optimal frequency of presentation and combination to achieve maximum impact from these low-cost, road-based treatments.


p16 is superior to ProEx C in identifying high-grade squamous intraepithelial lesions (HSIL) of the anal canal.
Although the incidence of human papillomavirus (HPV)-associated anal neoplasia is increasing, interobserver and intraobserver reproducibility in the grading of biopsy specimens from this area remains unacceptably low. Attempts to produce a more reproducible grading scheme have led to the use of biomarkers for the detection of high-risk HPV (HR-HPV). We evaluated the performance of standard morphology and biomarkers p16, ProEx C, and Ki-67 in a set of 75 lesions [17 nondysplastic lesions, 23 low-grade squamous intraepithelial lesions (LSIL)/condyloma, 20 high-grade squamous intraepithelial lesions (HSIL), 15 invasive squamous cell carcinomas] from the anal and perianal region in 65 patients and correlated these findings with HPV subtype on the basis of a type-specific multiplex real-time polymerase chain reaction assay designed to detect HR-HPV. A subset of cases with amplifiable HPV DNA was also sequenced. HSIL was typically flat (15/20), and only a minority (4/20) had koilocytes. In contrast, only 1 LSIL was flat (1/23), and the remainder were exophytic. The majority of LSIL had areas of koilocytic change (20/23). HR-HPV DNA was detected in the majority (89%) of invasive carcinomas and HSIL biopsies, 86% and 97% of which were accurately labeled by strong and diffuse block-positive p16 and ProEx C, respectively. LSIL cases, however, only infrequently harbored HR-HPV (13%); most harbored low-risk HPV (LR-HPV) types 6 and 11. Within the LSIL group, p16 outperformed ProEx C, resulting in fewer false-positive cases (5% vs. 75%). Ki-67 was also increased in HR-HPV-positive lesions, although biopsies with increased inflammation and reactive changes also showed higher Ki-67 indices. These data suggest that strong and diffuse block-positive nuclear and cytoplasmic labeling with p16 is a highly specific biomarker for the presence of HR-HPV in anal biopsies and that this finding correlates with high-grade lesions.


Impact of diabetes on postoperative outcomes following colon cancer surgery.
Diabetes is the sixth most common cause of death in the US and causes significant postoperative mortality and morbidity. To characterize the impact of diabetes among patients undergoing surgery for colorectal cancer. This is is a retrospective cohort study. Patients in the Nationwide Inpatient Sample (NIS) who had undergone colorectal cancer surgery between 1998 and 2005. Using multivariate regression, we determined the association of diabetes status with postoperative mortality, postoperative complications, and length of stay. An estimated 218,534 patients had undergone surgery for colorectal cancer. We categorized subjects by the presence of diabetes, the prevalence of which was 15%. Crude postoperative in-hospital mortality was lower among diabetics compared to non-diabetics (2.5% vs. 3.2%, P < 0.0001). Adjusted mortality was 23% lower in those with diabetes compared to non-diabetics (aOR 0.77; 95% CI: 0.71-0.84). Diabetics also had lower adjusted post-operative complications compared to non-diabetics (aOR 0.82; 95% CI: 0.79-0.84). In uninsured individuals and patients <50 years of age, there was no protective association between diabetes and either in-hospital mortality or postoperative complications. In patients undergoing colorectal cancer surgery, those with diabetes had a 23% lower mortality and fewer postoperative complications compared to non-diabetics. The mechanisms underlying this unexpected observation warrant further investigation.


Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis.
The ICAP1 (integrin cytoplasmic domain-associated protein-1) is a specific intracellular binding protein of beta1-integrins and the cerebral cavernous malformation (CCM) protein CCM1. ICAP1 recruits CCM1 to the cell membrane and activates CCM1 by changing its conformation. Because CCM1 plays a critical role for cardiovascular development, we hypothesized that its activator ICAP1 is involved in vascular differentiation. The objective of this study was to define the role of ICAP1 in endothelial cells. Loss of ICAP1 in primary human endothelial cells causes excessive angiogenic branching and network formation in vitro (3D sprouting angiogenesis) and in vivo (xenotransplantation of ICAP1-silenced human endothelial cells). ICAP1 increases cell motility and the initial formation of capillary sprouts but prevents vessel outgrowth. ICAP1 inhibits Rho kinase activity and ERK (extracellular signal-regulated kinase) phosphorylation and induces expression of the cell cycle inhibitors p21 and p27, leading to less endothelial proliferation. However, ICAP1 promotes endothelial survival and AKT phosphorylation. Global gene expression analyses revealed that the ICAP1 effects are mediated by strong activation of DELTA-NOTCH signaling. Active NOTCH1 or silencing of the NOTCH ligand DLL4 phenocopy the ICAP1 effects and blockade of NOTCH cleavage rescues the ICAP1-mediated defects in endothelial cells. Both ICAP1 and NOTCH1 reduce the expression of ESM1 (endothelial cell-specific molecule-1), and silencing of ESM1 disturbs vascular endothelial growth factor- or fibroblast growth factor 2-induced sprouting angiogenesis. In this study, we identified ICAP1 as a novel regulator to prevent excessive sprouting angiogenesis.


Retention of the Boston keratoprosthesis type 1: multicenter study results.
To report the retention rate of the Boston keratoprosthesis type 1 and to identify risk factors for keratoprosthesis loss. Cohort study. A total of 300 eyes of 300 patients who underwent implantation of the Boston keratoprosthesis type I device between January 2003 and July 2008 by 19 surgeons at 18 medical centers. Forms reporting preoperative, intraoperative, and postoperative parameters were prospectively collected and subsequently analyzed at a central data collection site. Keratoprosthesis retention. A total cumulative number of 422 life-years of device implantation are included in this analysis. The average duration of follow-up was 17.1 ± 14.8 months, with a range of 1 week to >6.1 years. Ninety-three percent of the 300 Boston keratoprosthesis implants were retained at their last follow-up, corresponding to a retention time of 396 patient-years or 1.42 years/keratoprosthesis. The probability of retention after 1 year and 2 years was 94% and 89%, respectively. During the study period, 21 (7%) eyes failed to retain the device; the reasons for keratoprosthesis loss include sterile keratolysis (9), fungal infections (8), dense retroprosthetic membranes (3), and bacterial endophthalmitis (1). Multivariate analysis demonstrated 3 independent risk factors for keratoprosthesis loss: autoimmune cause (hazard ratio [HR], 11.94; 95% confidence interval [CI], 3.31-43.11), ocular surface exposure requiring a concomitant tarsorrhaphy (HR, 3.43; 95% CI, 1.05-11.22), and number of prior failed penetrating keratoplasties (HR, 1.64; 95% CI, 1.18-2.28). The Boston keratoprosthesis type 1 seems to be a viable option for eyes that are not candidates for penetrating keratoplasty (PK). Ocular surface disease due to an autoimmune cause demonstrated the lowest retention rate. The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Population genetics study of isoniazid resistance mutations and evolution of multidrug-resistant Mycobacterium tuberculosis.
The molecular basis for isoniazid resistance in Mycobacterium tuberculosis is complex. Putative isoniazid resistance mutations have been identified in katG, ahpC, inhA, kasA, and ndh. However, small sample sizes and related potential biases in sample selection have precluded the development of statistically valid and significant population genetic analyses of clinical isoniazid resistance. We present the first large-scale analysis of 240 alleles previously associated with isoniazid resistance in a diverse set of 608 isoniazid-susceptible and 403 isoniazid-resistant clinical M. tuberculosis isolates. We detected 12 mutant alleles in isoniazid-susceptible isolates, suggesting that these alleles are not involved in isoniazid resistance. However, mutations in katG, ahpC, and inhA were strongly associated with isoniazid resistance, while kasA mutations were associated with isoniazid susceptibility. Remarkably, the distribution of isoniazid resistance-associated mutations was different in isoniazid-monoresistant isolates from that in multidrug-resistant isolates, with significantly fewer isoniazid resistance mutations in the isoniazid-monoresistant group. Mutations in katG315 were significantly more common in the multidrug-resistant isolates. Conversely, mutations in the inhA promoter were significantly more common in isoniazid-monoresistant isolates. We tested for interactions among mutations and resistance to different drugs. Mutations in katG, ahpC, and inhA were associated with rifampin resistance, but only katG315 mutations were associated with ethambutol resistance. There was also a significant inverse association between katG315 mutations and mutations in ahpC or inhA and between mutations in kasA and mutations in ahpC. Our results suggest that isoniazid resistance and the evolution of multidrug-resistant strains are complex dynamic processes that may be influenced by interactions between genes and drug-resistant phenotypes.


Interaction of neurotransmitters with a phospholipid bilayer: a molecular dynamics study.
We have performed a series of molecular dynamics simulations to study the interactions between the neurotransmitters (NTs) γ-aminobutyrate (GABA), glycine (GLY), acetylcholine (ACH) and glutamate (GLU) as well as the amidated/acetylated γ-aminobutyrate (GABA(neu)) and the osmolyte molecule glycerol (GOL) with a dipalmitoylphosphatidylcholine (DPPC) bilayer. In agreement with previously published experimental data, we found the lowest membrane affinity for the charged molecules and a moderate affinity for zwitterionic and polar molecules. The affinity can be ranked as follows: ACH-GLU<<GABA<GLY<<GABA(neu)<<GOL. The latter three penetrated the bilayer at most with the deepest location being close to the glycerol backbone of the phospholipids. Even at that position, these solutes were noticeably hydrated and carried ∼30-80% of the bulk water along. The mobility of hydration water at the solute is also affected by the penetration into the bilayer. Two time scales of exchanging water molecules could be determined. In the bulk phase, the hydration layer contains ∼20% slow exchanging water molecules which increases 2-3 times as the solutes entered the bilayer. Our results indicate that there is no intermediate exchange of slow moving water molecules from the solutes to the lipid atoms and vice versa. Instead, the exchange relies on the reservoir of unbounded ("free") water molecules in the interfacial bilayer region. Results from the equilibrium simulations are in good agreement with the results from umbrella sampling simulations, which were conducted for the four naturally occurring NTs. Free energy profiles for ACH and GLU show a minimum of ∼2-3 kJ/mol close to the bilayer interface, while for GABA and GLY, a minimum of respectively ∼2 kJ/mol and ∼5 kJ/mol is observed when these NTs are located in the vicinity of the lipid glycerol backbone. The most important interaction of NTs with the bilayer is the charged amino group of NTs with the lipid phosphate group.


Classifying Major Depressive Disorder Using fNIRS During Motor Rehabilitation.
Major depressive disorder (MDD) has shown to negatively impact physical recovery in a variety of medical events (e.g., stroke and spinal cord injuries). Yet depression assessments, which are typically subjective in nature, are seldom considered to develop or guide rehabilitation strategies. The present study developed a predictive depression assessment technique using functional near-infrared spectroscopy (fNIRS) that can be rapidly integrated or performed concurrently with existing physical rehabilitation tasks. Thirty-one volunteers, including 14 adults clinically diagnosed with MDD and 17 healthy adults, participated in the study. Brain oxy-hemodynamic (HbO) responses were recorded using a 16-channel wearable continuous-wave fNIRS device while the volunteers performed the Grasp and Release Test in four 16-minute blocks. Ten features, extracted from HbO signals, from each channel served as inputs to XGBoost and Random Forest algorithms developed for each block and combination of successive blocks. Top 5 common features resulted in a classification accuracy of 92.6%, sensitivity of 84.8%, and specificity of 91.7% using the XGBoost classifier. This study identified mean HbO, full width half maximum and kurtosis, as specific neuromarkers, for predicting MDD across specific depression-related regions of interests (i.e., dorsolateral and ventrolateral prefrontal cortex). Our results suggest that a wearable fNIRS head probe monitoring specific brain regions, and limiting extraction to few features, can enable quick setup and rapid assessment of depression in patients. The overarching goal is to embed predictive neurotechnology during post-stroke and post-spinal-cord-injury rehabilitation sessions to monitor patients' depression symptomology so as to actively guide decisions about motor therapies.


Introduction of soft X-ray spectromicroscopy as an advanced technique for plant biopolymers research.
Soft X-ray absorption spectroscopy coupled with nano-scale microscopy has been widely used in material science, environmental science, and physical sciences. In this work, the advantages of soft X-ray absorption spectromicroscopy for plant biopolymer research were demonstrated by determining the chemical sensitivity of the technique to identify common plant biopolymers and to map the distributions of biopolymers in plant samples. The chemical sensitivity of soft X-ray spectroscopy to study biopolymers was determined by recording the spectra of common plant biopolymers using soft X-ray and Fourier Transform mid Infrared (FT-IR) spectroscopy techniques. The soft X-ray spectra of lignin, cellulose, and polygalacturonic acid have distinct spectral features. However, there were no distinct differences between cellulose and hemicellulose spectra. Mid infrared spectra of all biopolymers were unique and there were differences between the spectra of water soluble and insoluble xylans. The advantage of nano-scale spatial resolution exploited using soft X-ray spectromicroscopy for plant biopolymer research was demonstrated by mapping plant cell wall biopolymers in a lentil stem section and compared with the FT-IR spectromicroscopy data from the same sample. The soft X-ray spectromicroscopy enables mapping of biopolymers at the sub-cellular (~30 nm) resolution whereas, the limited spatial resolution in the micron scale range in the FT-IR spectromicroscopy made it difficult to identify the localized distribution of biopolymers. The advantages and limitations of soft X-ray and FT-IR spectromicroscopy techniques for biopolymer research are also discussed.


Shift work, quality of life and work ability among Croatian hospital nurses.
This paper is a report of a study of the associations of shift work with work ability and quality of life (QoL) among clinical nurses. A cross-sectional study was conducted in 2007-2008 on 1124 nurses using the Work Ability Index Questionnaire and the Quality of Life Questionnaire (WHOQOL-BREF). Lower education was a predictor for low level of work ability and low physical health domain of QoL. Older age and having no partner were statistically significantly related to lower social interaction. Predictors significantly related to low environment domain of QoL were low education and shift work. Shift workers had higher level of level of work ability, but clinically insignificant. The study provides no evidence of a significant association between shift work and work ability or quality of life. Education has a positive association with nurses' work ability and quality of life.


Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats.
Encephalopathy of prematurity (EoP) is a term that encompasses the central nervous system (CNS) abnormalities associated with preterm birth. To best advance translational objectives and uncover new therapeutic strategies for brain injury associated with preterm birth, preclinical models of EoP must include similar mechanisms of prenatal global injury observed in humans and involve multiple components of the maternal-placental-fetal system. Ideally, models should produce a similar spectrum of functional deficits in the mature animal and recapitulate multiple aspects of the pathophysiology. To mimic human systemic placental perfusion defects, placental underperfusion and/or chorioamnionitis associated with pathogen-induced inflammation in early preterm birth, we developed a model of prenatal transient systemic hypoxia-ischemia (TSHI) combined with intra-amniotic lipopolysaccharide (LPS). In pregnant Sprague Dawley rats, TSHI via uterine artery occlusion on embryonic day 18 (E18) induces a graded placental underperfusion defect associated with increasing CNS damage in the fetus. When combined with intra-amniotic LPS injections, placental inflammation is increased and CNS damage is compounded with associated white matter, gait and imaging abnormalities. Prenatal TSHI and TSHI+LPS prenatal insults meet several of the criteria of an EoP model including recapitulating the intrauterine insult, causing loss of neurons, oligodendrocytes and axons, loss of subplate, and functional deficits in adult animals that mimic those observed in children born extremely preterm. Moreover, this model allows for the dissection of inflammation induced by divergent injury types.


Long-term outcomes among adult survivors of childhood central nervous system malignancies in the Childhood Cancer Survivor Study.
Adult survivors of childhood central nervous system (CNS) malignancies are at high risk for long-term morbidity and late mortality. However, patterns of late mortality, the long-term risks of subsequent neoplasms and debilitating medical conditions, and sociodemographic outcomes have not been comprehensively characterized for individual diagnostic and treatment groups. We collected information on treatment, mortality, chronic medical conditions, and neurocognitive functioning of adult 5-year survivors of CNS malignancies diagnosed between 1970 and 1986 within the Childhood Cancer Survivor Study. Using competing risk framework, we calculated cumulative mortality according to cause of death and cumulative incidence of subsequent neoplasms according to exposure and dose of cranial radiation therapy (RT). Neurocognitive impairment and socioeconomic outcomes were assessed with respect to dose of CNS radiotherapy to specific brain regions. Cumulative incidence of chronic medical conditions was compared between survivors and siblings using Cox regression models. All tests of statistical significance were two-sided. Among all eligible 5-year survivors (n = 2821), cumulative late mortality at 30 years was 25.8% (95% confidence interval [CI] = 23.4% to 28.3%), due primarily to recurrence and/or progression of primary disease. Patients who received cranial RT of 50 Gy or more (n = 813) had a cumulative incidence of a subsequent neoplasm within the CNS of 7.1% (95% CI = 4.5% to 9.6%) at 25 years from diagnosis compared with 1.0% (95% CI = 0% to 2.3%) for patients who had no RT. Survivors had higher risk than siblings of developing new endocrine, neurological, or sensory complications 5 or more years after diagnosis. Neurocognitive impairment was high and proportional to radiation dose for specific tumor types. There was a dose-dependent association between RT to the frontal and/or temporal lobes and lower rates of employment, and marriage. Survivors of childhood CNS malignancies are at high risk for late mortality and for developing subsequent neoplasms and chronic medical conditions. Care providers should be informed of these risks so they can provide risk-directed care and develop screening guidelines.


Changes in hepatic gene expression in dogs with experimentally induced nutritional iron deficiency.
We investigated hepatic gene expression in dogs with experimentally induced nutritional iron deficiency (ID). Our hypothesis was that ID would result in decreased hepcidin gene expression, and possibly in altered expression of other genes associated with iron metabolism. Liver biopsies were collected from each of 3 dogs before induction of ID, at the point of maximal ID, and after resolution of ID. Using Affymetrix microarray technology and analytical tools specifically designed for microarray data, we identified genes that had at least a 2-fold change in expression in response to ID. Four genes were selected for further analysis by reverse transcriptase PCR (RT-PCR). Dogs with ID had markedly decreased expression of the hepcidin gene (mean decrease of 40-fold for one probe and >100-fold for another probe) and increased expression of the transferrin receptor gene (mean increase of >7-fold). There was also mildly decreased expression of the "similar to calreticulin" gene and a gene of unknown function. Results of RT-PCR analysis were consistent with microarray findings. Changes in hepcidin and transferrin receptor gene expression were consistent with the known biology of iron metabolism. The decrease in expression of a gene identified as "similar to calreticulin," while not statistically significant, was consistent with the findings of other investigators that suggest iron plays a role in calreticulin expression.


Is resilience relevant to smoking abstinence for Indigenous Australians?
The prevalence rate of tobacco smoking remains high for Australian Indigenous people despite declining rates in other Australian populations. Given many Indigenous Australians continue to experience a range of social and economic structural problems, stress could be a significant contributing factor to preventing smoking abstinence. The reasons why some Indigenous people have remained resilient to stressful adverse conditions, and not rely on smoking to cope as a consequence, may provide important insights and lessons for health promotion policy and practice. In-depth interviews were employed to collect oral histories from 31 Indigenous adults who live in metropolitan Adelaide. Participants were recruited according to smoking status (non-smokers were compared with current smokers to gain a greater depth of understanding of how some participants have abstained from smoking). Perceived levels of stress were associated with encouraging smoking behaviour. Many participants reported having different stresses compared with non-Indigenous Australians, with some participants reporting having additional stressors such as constantly experiencing racism. Resilience often occurred when participants reported drawing upon internal psychological assets such as being motivated to quit and where external social support was available. These findings are discussed in relation to a recently developed psycho-social interactive model of resilience, and how this resilience model can be improved regarding the historical and cultural context of Indigenous Australians' experience of smoking.