Measuring the Complexity of Consciousness.
The grand quest for a scientific understanding of consciousness has given rise to many new theoretical and empirical paradigms for investigating the phenomenology of consciousness as well as clinical disorders associated to it. A major challenge in this field is to formalize computational measures that can reliably quantify global brain states from data. In particular, information-theoretic complexity measures such as integrated information have been proposed as measures of conscious awareness. This suggests a new framework to quantitatively classify states of consciousness. However, it has proven increasingly difficult to apply these complexity measures to realistic brain networks. In part, this is due to high computational costs incurred when implementing these measures on realistically large network dimensions. Nonetheless, complexity measures for quantifying states of consciousness are important for assisting clinical diagnosis and therapy. This article is meant to serve as a lookup table of measures of consciousness, with particular emphasis on clinical applicability. We consider both, principle-based complexity measures as well as empirical measures tested on patients. We address challenges facing these measures with regard to realistic brain networks, and where necessary, suggest possible resolutions.


Normal, Problematic and Compulsive Consumption of Sexually Explicit Media: Clinical Findings using the Compulsive Pornography Consumption (CPC) Scale among Men who have Sex with Men.
To assess problematic sexually explicit media (SEM) consumption, and to identify clinically meaningful cut-off points, we examined clinical correlates using the new Compulsive Pornography Consumption (CPC) scale among 1165 participating MSM. Building on scale practices in measuring compulsive sexual behavior, two cut-off points were identified. While most (76-80%) MSM do not report compulsive symptoms, about 16-20% report levels of problematic SEM consumption, including 7% with extreme scores consistent with DSM criteria for compulsive disorders. Demographic, sexual, and HIV risk differences were identified between the three groups. Researchers and clinicians are encouraged to consider using the CPC scale for comprehensive assessment of compulsive sexual behavior.


A Portable Passive Rehabilitation Robot for Upper-Extremity Functional Resistance Training.
Loss of arm function is common in individuals with neurological damage, such as stroke or cerebral palsy. Robotic devices that address muscle strength deficits in a task-specific manner can assist in the recovery of arm function; however, current devices are typically large, bulky, and expensive to be routinely used in the clinic or at home. This study sought to address this issue by developing a portable planar passive rehabilitation robot, PaRRo. We designed PaRRo with a mechanical layout that incorporated kinematic redundancies to generate forces that directly oppose the user's movement. Cost-efficient eddy current brakes were used to provide scalable resistances. The lengths of the robot's linkages were optimized to have a reasonably large workspace for human planar reaching. We then performed theoretical analysis of the robot's resistive force generating capacity and steerable workspace using MATLAB simulations. We also validated the device by having a subject move the end-effector along different paths at a set velocity using a metronome while simultaneously collecting surface electromyography (EMG) and end-effector forces felt by the user. Results from simulation experiments indicated that the robot was capable of producing sufficient end-effector forces for functional resistance training. We also found the endpoint forces from the user were similar to the theoretical forces expected at any direction of motion. EMG results indicated that the device was capable of providing adjustable resistances based on subjects' ability levels, as the muscle activation levels scaled with increasing magnet exposures. These results indicate that PaRRo is a feasible approach to provide functional resistance training to the muscles along the upper extremity. The proposed robotic device could provide a technological breakthrough that will make rehabilitation robots accessible for small outpatient rehabilitation centers and in-home therapy.


Soil erosion and risk-assessment for on- and off-farm impacts: a test case using the Midhurst area, West Sussex, UK.
Soil erosion on agricultural land is a growing problem in Western Europe and constitutes a threat to soil quality and to the ability of soils to provide environmental services. The off-site impacts of runoff and eroded soil, principally eutrophication of water bodies, sedimentation of gravel-bedded rivers, loss of reservoir capacity, muddy flooding of roads and communities, are increasingly recognised and costed. The shift of funding in the European Union (EU) from production-related to avoidance of pollution and landscape protection, raises issues of cross-compliance: public support for agriculture has to be seen to give value-for-money. In this context risk-assessment procedures have been introduced to help farmers recognise sites where either certain crops should not be grown or anti-erosion measures are required. In England, Defra [Defra, 2005a. Controlling Soil Erosion: a Manual for the Assessment and Management of Agricultural Land at Risk of Water Erosion in Lowland England. Revised September 2005. Department for Environment, Food and Rural Affairs, London] sets out a system of risk-assessment, including ranking of crops susceptible to erosion and anti-erosion measures, that may be selected. We assess this system using field data for an area of erodible soils in the Rother valley, Sussex. The Defra approach correctly identifies most at-risk fields and, taken together with land-use maps, allows non-compliance with advice to be highlighted. We suggest a simple extension to the system which would further identify at-risk fields in terms of possible damage to roads and rivers from muddy runoff. The increased risk of erosion in the study area is associated with certain crops: potatoes, winter cereals, maize and grazed turnips and seems unlikely to be the result of changes in rainfall which over the last 130 years are minimal. We have not evaluated proposed anti-erosion measures in the area because few have been put into practice. The European Water Framework Directive will increasingly focus attention on agricultural fields as a source of river pollution. Assessing the risk of erosion and the need for field testing of suggested approaches, are not simply issues for the EU, but for the management of global agricultural systems.


Popular Nutrition-Related Mobile Apps: An Agreement Assessment Against a UK Reference Method.
Nutrition-related apps are commonly used to provide information about the user's dietary intake, but limited research has been performed to assess how well their outputs agree with those from standard methods. The objective of our study was to evaluate the level of agreement of popular nutrition-related apps for the assessment of energy and available macronutrients and micronutrients against a UK reference method. We compared dietary analysis of 24-hour weighed food records (n=20) between 5 nutrition-related apps (Samsung Health, MyFitnessPal, FatSecret, Noom Coach, and Lose It!) and Dietplan6 (reference method), using app versions available in the United Kingdom. We compared estimates of energy, macronutrients (carbohydrate, protein, fat, saturated fat, and fiber), and micronutrients (sodium, calcium, iron, vitamin A, and vitamin C) using paired t tests and Wilcoxon signed-rank tests, correlation coefficients, and Bland-Altman plots. We obtained 24-hour weighed food records from 20 participants (15 female, 5 male participants; mean age 36.3 years; mean body mass index 22.9 kg/m2) from previous controlled studies conducted at the Hugh Sinclair Unit of Human Nutrition, University of Reading, Reading, UK. Participants had recorded their food consumption over a 24-hour period using standard protocols. The difference in estimation of energy and saturated fat intake between Dietplan6 and the diet apps was not significant. Estimates of protein and sodium intake were significantly lower using Lose It! and FatSecret than using Dietplan6. Lose It! also gave significantly lower estimates for other reported outputs (carbohydrate, fat, fiber, and sodium) than did Dietplan6. Samsung Health and MyFitnessPal significantly underestimated calcium, iron, and vitamin C compared with Dietplan6, although there was no significant difference for vitamin A. We observed no other significant differences between Dietplan6 and the apps. Correlation coefficients ranged from r=-.12 for iron (Samsung Health vs Dietplan6) to r=.91 for protein (FatSecret vs Dietplan6). Noom Coach was limited to energy output, but it had a high correlation with Dietplan6 (r=.91). Samsung Health had the greatest variation of correlation, with energy at r=.79. Bland-Altman analysis revealed potential proportional bias for vitamin A. The findings suggest that the apps provide estimates of energy and saturated fat intake comparable with estimates by Dietplan6. With the exception of Lose It!, the apps also provided comparable estimates of carbohydrate, total fat, and fiber. FatSecret and Lose It! tended to underestimate protein and sodium. Estimates of micronutrient intake (calcium, iron, vitamin A, and vitamin C) by 2 apps (Samsung Health and MyFitnessPal) were inconsistent and less reliable. Lose It! was the app least comparable with Dietplan6. As the use and availability of apps grows, this study helps clinicians and researchers to make better-informed decisions about using these apps in research and practice.


Prevalence of smoking and other smoking-related behaviours among students aged 13 to 15 years in Montenegro: results from the Global Youth Tobacco Survey of 2008.
The Global Youth Tobacco Survey (GYTS) is an international study that provides data on youth tobacco use for development of tobacco control programs. It is a school-based survey that uses a standardised methodology for sampling, core questionnaire items, training protocol, field procedures, and data management. This article reports the findings from a GYTS conducted in Montenegro in 2008, which included 5723 adolescents. More than 30 % of students aged 13 to 15 tried smoking, 5.1 % smoked cigarettes, and 3.6 % of students used tobacco products other than cigarettes. Four in 10 ever smokers started to smoke before the age of 10. More than half the students reported secondary smoke exposure at home. Almost all (96.5 %) current smokers bought cigarettes in a store. Two in 10 students owned an artifact with a cigarette or tobacco brand logo on it. The GYTS study has shown that there is an urgent need to introduce effective child-oriented smoking prevention programmes in early elementary school classes. These should be accompanied by public awareness campaigns on smoke-free homes.


Improved Cerebrospinal Fluid-Based Discrimination between Alzheimer's Disease Patients and Controls after Correction for Ventricular Volumes.
Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer's disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., Aβ42, total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF Aβ42 levels inversely correlated to VV/TIV in the whole study population (Aβ42: r = -0.28; p < 0.0001). For CSF t-tau and p-tau, this association only reached statistical significance in the combined MCI and AD group (t-tau: r = -0.15; p-tau: r = -0.13; both p < 0.01). Correction for differences in VV/TIV improved the differentiation of AD versus controls based on CSF Aβ42 alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF Aβ42 levels.


Amelioration of Prenatal Lead-Induced Learning and Memory Impairments by Methanolic Extract of Zataria Multiflora in Male Rats.
The current study aimed at evaluating the effects of Zataria Multiflora (ZM) on learning and memory of adult male offspring rats with prenatal lead-exposure. Pregnant rats in the case group received tap water containing 0.2% lead acetate throughout the gestation period. Control rats had free access to lead-free tap water. Two male offspring (two-month-old, weighing 180-200 g) from each mother were randomly selected and treated with either Z. Multiflora (50, 200, 400, and 800 mg/kg/Intraperitoneally (I.P)/20 day) or saline. Spatial memory of the control, saline, and ZM-treated rats was evaluated by a training trial and probe test using Morris water maze (6-8 rat/group). The obtained results showed memory deficits including increased escape latency, and a greater traveled distance, as well as decrements in the frequency of crossings into target quadrants in prenatally lead-exposed male offspring compared with the controls. ZM treatment (200 mg/kg/i.p) ameliorated the memory deficits in male offspring by increasing the time spent and traveled distance in the trigger zone (P<0.01 vs. saline).There was no significant difference in swimming speed between the groups. The results showed memory deficits in prenatally lead-exposed male offspring. ZM treatment (especially 200 mg/kg) had beneficial effects on cognitive behavior and was indicated as the improvement of lead-induced memory deficits in prenatally lead-exposed male rats. The exact mechanism(s) is not determined yet, but it could be mediated through the anticholinesterase and antioxidant effects and also alterations in Central Nervous System (CNS) and neurotransmission in the central nervous system.


Activation of postnatal neural stem cells requires nuclear receptor TLX.
Neural stem cells (NSCs) continually produce new neurons in postnatal brains. However, the majority of these cells stay in a nondividing, inactive state. The molecular mechanism that is required for these cells to enter proliferation still remains largely unknown. Here, we show that nuclear receptor TLX (NR2E1) controls the activation status of postnatal NSCs in mice. Lineage tracing indicates that TLX-expressing cells give rise to both activated and inactive postnatal NSCs. Surprisingly, loss of TLX function does not result in spontaneous glial differentiation, but rather leads to a precipitous age-dependent increase of inactive cells with marker expression and radial morphology for NSCs. These inactive cells are mispositioned throughout the granular cell layer of the dentate gyrus during development and can proliferate again after reintroduction of ectopic TLX. RNA-seq analysis of sorted NSCs revealed a TLX-dependent global expression signature, which includes the p53 signaling pathway. TLX regulates p21 expression in a p53-dependent manner, and acute removal of p53 can rescue the proliferation defect of TLX-null NSCs in culture. Together, these findings suggest that TLX acts as an essential regulator that ensures the proliferative ability of postnatal NSCs by controlling their activation through genetic interaction with p53 and other signaling pathways.


Combining multidimensional genomic measurements for predicting cancer prognosis: observations from TCGA.
With accumulating research on the interconnections among different types of genomic regulations, researchers have found that multidimensional genomic studies outperform one-dimensional studies in multiple aspects. Among many sources of multidimensional genomic data, The Cancer Genome Atlas (TCGA) provides the public with comprehensive profiling data on >30 cancer types, making it an ideal test bed for conducting and comparing different analyses. In this article, the analysis goal is to apply several existing methods and associate multidimensional genomic measurements with cancer outcomes in particular prognosis, with special focus on the predictive power of genomic signatures. We exploit clinical data and four types of genomic measurement including mRNA gene expression, DNA methylation, microRNA and copy number alterations for breast invasive carcinoma, glioblastoma multiforme, acute myeloid leukemia and lung squamous cell carcinoma collected by TCGA. To accommodate the high dimensionality, we extract important features using Principal Component Analysis, Partial Least Squares and Least Absolute Shrinkage and Selection Operator (Lasso), which are representative of dimension reduction and variable selection techniques and have been extensively adopted, and fit Cox survival models with combined important features. We calibrate the predictive power of each type of genomic measurement for the prognosis of four cancer types and find that the results vary across cancers. Our analysis also suggests that for most of the cancers in our study and the adopted methods, there is no substantial improvement in prediction when adding other genomic measurement after gene expression and clinical covariates have been included in the model. This is consistent with the findings that molecular features measured at the transcription level affect clinical outcomes more directly than those measured at the DNA/epigenetic level.


Risk factors in carpal tunnel syndrome.
We have undertaken a large case-control study using the UK General Practice Research Database to quantify the relative contributions of the common risk factors for carpal tunnel syndrome (CTS) in the community. Cases were patients with a diagnosis of CTS and, for each, four controls were individually matched by age, sex and general practice. Our dataset included 3,391 cases, of which 2,444 (72%) were women, with a mean age at diagnosis of 46 (range 16-96) years. Multivariate analysis showed that the risk factors associated with CTS were previous wrist fracture (OR=2.29), rheumatoid arthritis (OR=2.23), osteoarthritis of the wrist and carpus (OR=1.89), obesity (OR=2.06), diabetes (OR=1.51), and the use of insulin (OR=1.52), sulphonylureas (OR=1.45), metformin (OR=1.20) and thyroxine (OR=1.36). Smoking, hormone replacement therapy, the combined oral contraceptive pill and oral corticosteroids were not associated with CTS. The results were similar when cases were restricted to those who had undergone carpal tunnel decompression.


Pragmatic randomized controlled trial of long-term psychoanalytic psychotherapy for treatment-resistant depression: the Tavistock Adult Depression Study (TADS).
This pragmatic randomized controlled trial tested the effectiveness of long-term psychoanalytic psychotherapy (LTPP) as an adjunct to treatment-as-usual according to UK national guidelines (TAU), compared to TAU alone, in patients with long-standing major depression who had failed at least two different treatments and were considered to have treatment-resistant depression. Patients (N=129) were recruited from primary care and randomly allocated to the two treatment conditions. They were assessed at 6-monthly intervals during the 18 months of treatment and at 24, 30 and 42 months during follow-up. The primary outcome measure was the 17-item version of the Hamilton Depression Rating Scale (HDRS-17), with complete remission defined as a HDRS-17 score ≤8, and partial remission defined as a HDRS-17 score ≤12. Secondary outcome measures included self-reported depression as assessed by the Beck Depression Inventory - II, social functioning as evaluated by the Global Assessment of Functioning, subjective wellbeing as rated by the Clinical Outcomes in Routine Evaluation - Outcome Measure, and satisfaction with general activities as assessed by the Quality of Life Enjoyment and Satisfaction Questionnaire. Complete remission was infrequent in both groups at the end of treatment (9.4% in the LTPP group vs. 6.5% in the control group) as well as at 42-month follow-up (14.9% vs. 4.4%). Partial remission was not significantly more likely in the LTPP than in the control group at the end of treatment (32.1% vs. 23.9%, p=0.37), but significant differences emerged during follow-up (24 months: 38.8% vs. 19.2%, p=0.03; 30 months: 34.7% vs. 12.2%, p=0.008; 42 months: 30.0% vs. 4.4%, p=0.001). Both observer-based and self-reported depression scores showed steeper declines in the LTPP group, alongside greater improvements on measures of social adjustment. These data suggest that LTPP can be useful in improving the long-term outcome of treatment-resistant depression. End-of-treatment evaluations or short follow-ups may miss the emergence of delayed therapeutic benefit.


Prostate-specific Antigen as a Risk Factor for Skeletal Metastasis in Native Ethnic African Men with Prostate Cancer: A Case-control Study.
Prostate cancer is the most common noncutaneous cancer in males. Men of African origin are at a significantly higher risk as reflected in the higher incidence and mortality rates in this racial group. Metastases incidence increases parallel to serum levels of prostate-specific antigen (PSA), contributing significantly to morbidity and mortality. Staging of the disease involves bone scans, which are sensitive in detecting skeletal metastases. Suggestions that these scans may be omitted in some situations in patients with low prostate specific antigen levels have drawn attention to the matter. In this case-control study, using radiology and pathology records, a registry of prostate cancer patients recorded as being of dark-skinned ethnicity was obtained. Images were presented to image reviewers blinded to the PSA level, to determine the presence of skeletal metastases. The risk factor for the outcome of interest (skeletal metastases) was PSA level above 20 ng/mL. The reliability of image reporting was also assessed. Of the 122 patients, skeletal metastases were present in 50 (41%) while these were absent in 72 (59%). The prevalence of metastases among the high PSA group was 55.9% [95% confidence interval (CI) 44.1-67.7%] and among the normal/low PSA group was 22.2% (95% CI 11.1-33.3%). The odds ratio (OR) for skeletal metastases in the exposed (high PSA) group was 4.4 (95% CI, 2.01-9.78.) Intraobserver agreement on image interpretation was 88.5% with a Kappa statistic of 0.76. A relatively higher prevalence of skeletal metastasis is seen in regional dark-skinned African males with prostate cancer at both low and high prostate specific antigen levels. Bone scanning in this population should therefore, be considered even at PSA levels below 20 ng/mL.


Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era.
Salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT) is the standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL). Salvage regimens have never been compared; their efficacy in the rituximab era is unknown. Patients with CD20(+) DLBCL in first relapse or who were refractory after first-line therapy were randomly assigned to either rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) or rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP). Responding patients received high-dose chemotherapy and ASCT. The median age of the 396 patients enrolled (R-ICE, n = 202; R-DHAP, n = 194) was 55 years. Similar response rates were observed after three cycles of R-ICE (63.5%; 95% CI, 56% to 70%) and R-DHAP (62.8%; 95 CI, 55% to 69%). Factors affecting response rates (P < .001) were refractory disease/relapse less than versus more than 12 months after diagnosis (46% v 88%, respectively), International Prognostic Index (IPI) of more than 1 versus 0 to 1 (52% v 71%, respectively), and prior rituximab treatment versus no prior rituximab (51% v 83%, respectively). There was no significant difference between R-ICE and R-DHAP for 3-year event-free survival (EFS) or overall survival. Three-year EFS was affected by prior rituximab treatment versus no rituximab (21% v 47%, respectively), relapse less than versus more than 12 months after diagnosis (20% v 45%, respectively), and IPI of 2 to 3 versus 0 to 1 (18% v 40%, respectively). In the Cox model, these parameters were significant (P < .001). In patients who experience relapse more than 12 months after diagnosis, prior rituximab treatment does not affect EFS. Patients with early relapses after rituximab-containing first-line therapy have a poor prognosis, with no difference between the effects of R-ICE and R-DHAP.


Assessing crop damage from dicamba on non-dicamba-tolerant soybean by hyperspectral imaging through machine learning.
Dicamba effectively controls several broadleaf weeds. The off-target drift of dicamba spray or vapor drift can cause severe injury to susceptible crops, including non-dicamba-tolerant crops. In a field experiment, advanced hyperspectral imaging (HSI) was used to study the spectral response of soybean plants to different dicamba rates, and appropriate spectral features and models for assessing the crop damage from dicamba were developed. In an experiment with six different dicamba rates, an ordinal spectral variation pattern was observed at both 1 week after treatment (WAT) and 3 WAT. The soybean receiving a dicamba rate ≥0.2X exhibited unrecoverable damage. Two recoverability spectral indices (HDRI and HDNI) were developed based on three optimal wavebands. Based on the Jeffries-Matusita distance metric, Spearman correlation analysis and independent t-test for sensitivity to dicamba spray rates, a number of wavebands and classic spectral features were extracted. The models for quantifying dicamba spray levels were established using the machine learning algorithms of naive Bayes, random forest and support vector machine. The spectral response of soybean injury caused by dicamba sprays can be clearly captured by HSI. The recoverability spectral indices developed were able to accurately differentiate the recoverable and unrecoverable damage, with an overall accuracy (OA) higher than 90%. The optimal spectral feature sets were identified for characterizing dicamba spray rates under recoverable and unrecoverable situations. The spectral features plus plant height can yield relatively high accuracy under the recoverable situation (OA = 94%). These results can be of practical importance in weed management. © 2019 Society of Chemical Industry.


Infrared Vibrational Nanospectroscopy by Self-Referenced Interferometry.
Infrared vibrational scattering scanning near-field optical microscopy (s-SNOM) has emerged as a new frontier in imaging science due to its potential to provide nanoscale spatially resolved chemical spectroscopy for the investigation of molecular, soft-matter, and biological materials. As a phase-sensitive technique able to yield the full complex dielectric function of materials, different interferometric schemes have been developed involving asymmetric interferometry between sample and reference arms. In this work, we take advantage of a greatly simplified symmetric geometry that uses the spatially coherent background scattered light from within the confocal sample volume as a reference field for signal amplification in both self-homodyne and self-heterodyne interferometry. On the basis of a simple model for tip-sample scattering and interferometric detection, we demonstrate the measurement of the vibrational response of molecular materials in good agreement with established values. In addition to a compact design, enhanced signal levels, and a reduced sensitivity to fluctuations and drift, including those from the light source, self-referenced interferometry brings benefits for routine s-SNOM chemical spectroscopy, remaining robust even under a wide range of challenging experimental environments.


Estimating the burden of α-thalassaemia in Thailand using a comprehensive prevalence database for Southeast Asia.
Severe forms of α-thalassaemia, haemoglobin H disease and haemoglobin Bart's hydrops fetalis, are an important public health concern in Southeast Asia. Yet information on the prevalence, genetic diversity and health burden of α-thalassaemia in the region remains limited. We compiled a geodatabase of α-thalassaemia prevalence and genetic diversity surveys and, using geostatistical modelling methods, generated the first continuous maps of α-thalassaemia mutations in Thailand and sub-national estimates of the number of newborns with severe forms in 2020. We also summarised the current evidence-base for α-thalassaemia prevalence and diversity for the region. We estimate that 3595 (95% credible interval 1,717-6,199) newborns will be born with severe α-thalassaemia in Thailand in 2020, which is considerably higher than previous estimates. Accurate, fine-scale epidemiological data are necessary to guide sustainable national and regional health policies for α-thalassaemia management. Our maps and newborn estimates are an important first step towards this aim. This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).


Near-infrared photochemistry at interfaces based on upconverting nanoparticles.
Near-infrared (NIR) light is better suited than ultraviolet (UV) light for biomedical applications because it penetrates deeper into tissue and causes less photodamage to biological systems. The use of NIR light to control biointerfaces has attracted increasing interest. Here, we review NIR photoreactions at interfaces based on upconverting nanoparticles (UCNPs). UCNPs can convert NIR light to UV or visible light, which can then induce photoreactions of photosensitive compounds. This process is referred to as UCNP-assisted photochemistry. Recently, we and others demonstrated UCNP-assisted photochemistry at interfaces to control interfacial properties of nano-carriers, implants, emulsions, and cells. We introduce the fundamentals of UCNP-assisted photochemistry at interfaces, highlight its potential applications, and discuss remaining challenges.


Robust high spatio-temporal line-scanning fMRI in humans at 7T using multi-echo readouts, denoising and prospective motion correction.
Functional magnetic resonance imaging (fMRI), typically using blood oxygenation level-dependent (BOLD) contrast weighted imaging, allows the study of brain function with millimeter spatial resolution and temporal resolution of one to a few seconds. At a mesoscopic scale, neurons in the human brain are spatially organized in structures with dimensions of hundreds of micrometers, while they communicate at the millisecond timescale. For this reason, it is important to develop an fMRI method with simultaneous high spatial and temporal resolution. Line-scanning promises to reach this goal at the cost of volume coverage. Here, we release a comprehensive update to human line-scanning fMRI. First, we investigated multi-echo line-scanning with five different protocols varying the number of echoes and readout bandwidth while keeping the TR constant. In these, we compared different echo combination approaches in terms of BOLD activation (sensitivity) and temporal signal-to-noise ratio. Second, we implemented an adaptation of NOise reduction with DIstribution Corrected principal component analysis (NORDIC) thermal noise removal for line-scanning fMRI data. Finally, we tested three image-based navigators for motion correction and investigated different ways of performing fMRI analysis on the timecourses which were influenced by the insertion of the navigators themselves. The presented improvements are relatively straightforward to implement; multi-echo readout and NORDIC denoising together, significantly improve data quality in terms of tSNR and t-statistical values, while motion correction makes line-scanning fMRI more robust. Multi-echo acquisitions and denoising have previously been applied in 3D magnetic resonance imaging. Their combination and application to 1D line-scanning is novel. The current proposed method greatly outperforms the previous line-scanning acquisitions with single-echo acquisition, in terms of tSNR (4.0 for single-echo line-scanning and 36.2 for NORDIC-denoised multi-echo) and t-statistical values (3.8 for single-echo line-scanning and 25.1 for NORDIC-denoised multi-echo line-scanning). Line-scanning fMRI was advanced compared to its previous implementation in order to improve sensitivity and reliability. The improved line-scanning acquisition could be used, in the future, for neuroscientific and clinical applications.


Surface passivation limited UO2 oxidative dissolution in the presence of FeS.
Iron sulfide minerals produced during in situ bioremediation of U can serve as an oxygen scavenger to retard uraninite (UO2) oxidation upon oxygen intrusion. Under persistent oxygen supply, however, iron sulfides become oxidized and depleted, giving rise to elevated dissolved oxygen (DO) levels and remobilization of U(IV). The present study investigated the mechanism that regulates UO2 oxidative dissolution rate in a flow-through system when oxygen breakthrough occurred as a function of mackinawite (FeS) and carbonate concentrations. The formation and evolution of surface layers on UO2 were characterized using XAS and XPS. During FeS inhibition period, the continuous supply of carbonate and calcium in the influent effectively complexed and removed oxidized U(VI) to preserve an intermediate U4O9 surface. When the FeS became depleted by oxidization, a transient, rapid dissolution of UO2 was observed along with DO breakthrough in the reactor. This rate was greater than during the preceding FeS inhibition period and control experiments in the absence of FeS. With increasing DO, the rate slowed and the rate-limiting step shifted from surface oxidation to U(VI) detachment as U(VI) passivation layers developed. In contrast, increasing the carbonate concentrations facilitated detachment of surface-associated U(VI) complexes and impeded the formation of U(VI) passivation layer. This study demonstrates the critical role of U(VI) surface layer formation versus U(VI) detachment in controlling UO2 oxidative dissolution rate during periods of variable oxygen presence under simulated groundwater conditions.


UCP1 induction during recruitment of brown adipocytes in white adipose tissue is dependent on cyclooxygenase activity.
The uncoupling protein 1 (UCP1) is a hallmark of brown adipocytes and pivotal for cold- and diet-induced thermogenesis. Here we report that cyclooxygenase (COX) activity and prostaglandin E(2) (PGE(2)) are crucially involved in induction of UCP1 expression in inguinal white adipocytes, but not in classic interscapular brown adipocytes. Cold-induced expression of UCP1 in inguinal white adipocytes was repressed in COX2 knockout (KO) mice and by administration of the COX inhibitor indomethacin in wild-type mice. Indomethacin repressed beta-adrenergic induction of UCP1 expression in primary inguinal adipocytes. The use of PGE(2) receptor antagonists implicated EP(4) as a main PGE(2) receptor, and injection of the stable PGE(2) analog (EP(3/4) agonist) 16,16 dm PGE(2) induced UCP1 expression in inguinal white adipose tissue. Inhibition of COX activity attenuated diet-induced UCP1 expression and increased energy efficiency and adipose tissue mass in obesity-resistant mice kept at thermoneutrality. Our findings provide evidence that induction of UCP1 expression in white adipose tissue, but not in classic interscapular brown adipose tissue is dependent on cyclooxygenase activity. Our results indicate that cyclooxygenase-dependent induction of UCP1 expression in white adipose tissues is important for diet-induced thermogenesis providing support for a surprising role of COX activity in the control of energy balance and obesity development.


Consequences of Making the Inactive Active Through Changes in Antisense Oligonucleotide Chemistries.
Antisense oligonucleotides are short, single-stranded nucleic acid analogues that can interfere with pre-messenger RNA (pre-mRNA) processing and induce excision of a targeted exon from the mature transcript. When developing a panel of antisense oligonucleotides to skip every dystrophin exon, we found great variation in splice switching efficiencies, with some antisense oligonucleotides ineffective, even when directed to canonical splice sites and transfected into cells at high concentrations. In this study, we re-evaluated some of these ineffective antisense oligonucleotide sequences after incorporation of locked nucleic acid residues to increase annealing potential. Antisense oligonucleotides targeting exons 16, 23, and 51 of human DMD transcripts were synthesized as two different chemistries, 2'-O-methyl modified bases on a phosphorothioate backbone or mixmers containing several locked nucleic acid residues, which were then transfected into primary human myotubes, and DMD transcripts were analyzed for exon skipping. The ineffective 2'-O-methyl modified antisense oligonucleotides induced no detectable exon skipping, while all corresponding mixmers did induce excision of the targeted exons. Interestingly, the mixmer targeting exon 51 induced two unexpected transcripts arising from partial skipping of exon 51 with retention of 95 or 188 bases from the 5' region of exon 51. These results indicated that locked nucleic acid/2'-O-methyl mixmers are more effective at inducing exon skipping, however, this improvement may come at the cost of activating alternative cryptic splice sites and off-target effects on gene expression.


Shaping of the Female Human Brain by Sex Hormones: A Review.
Traditionally sex hormones have been associated with reproductive and developmental processes only. Since the 1950s we know that hormones can have organizational effects on the developing brain and initiate hormonal transition periods such as puberty. However, recent evidence shows that sex hormones additionally structure the brain during important hormonal transition periods across a woman's life including short-term fluctuations during the menstrual cycle. However, a comprehensive review focusing on structural changes during all hormonal transition phases of women is still missing. Therefore, in this review structural changes across hormonal transition periods (i.e., puberty, menstrual cycle, oral contraceptive intake, pregnancy and menopause) were investigated in a structured way and correlations with sex hormones evaluated. Results show an overall reduction in grey matter and region-specific decreases in prefrontal, parietal and middle temporal areas during puberty. Across the menstrual cycle grey matter plasticity in the hippocampus, the amygdala as well as temporal and parietal regions were most consistently reported. Studies reporting on pre- and post-pregnancy measurements revealed volume reductions in midline structures as well as prefrontal and temporal cortices. During perimenopause, the decline in sex hormones was paralleled with a reduction in hippocampal and parietal cortex volume. Brain volume changes were significantly correlated with estradiol, testosterone and progesterone levels in some studies, but directionality remains inconclusive between studies. These results indicate that sex hormones play an important role in shaping women's brain structure during different transition periods and are not restricted to specific developmental periods.


Subcortical afferents to the hippocampal formation in the monkey.
The distribution of neurons in the basal telencephalon, the diencephalon, and the brainstem that project to the hippocampal formation has been analyzed in mature cynomolgus monkeys (Macaca fascicularis) by the injection of horseradish peroxidase into different rostro-caudal levels of the hippocampal formation. After injections which involve Ammon's horn, the dentate gyrus, and the subicular complex, retrogradely labeled neurons are found in the following regions: in the amygdala (specifically in the anterior amygdaloid area, the basolateral nucleus, and the periamygdaloid cortex); in the medial septal nucleus and the nucleus of the diagonal band; in the ventral part of the claustrum; in the substantia innominata and the basal nucleus of Meynert; in the rostral thalamus (specifically in the anterior nuclear complex, the laterodorsal nucleus, the paraventricular and parataenial nuclei, the nucleus reuniens, and the nucleus centralis medialis); in the lateral preoptic and lateral hypothalamic areas, and especially in the supramammillary and retromammillary regions; in the ventral tegmental area, the tegmental reticular fields, the raphe nuclei (specifically in nucleus centralis superior and the dorsal raphe nucleus), in the nucleus reticularis tegmenti pontis, the central gray, the dorsal tegmental nucleus, and in the locus coeruleus.


Variations in Hip Shape Are Associated with Radiographic Knee Osteoarthritis: Cross-sectional and Longitudinal Analyses of the Johnston County Osteoarthritis Project.
Hip shape by statistical shape modeling (SSM) is associated with hip radiographic osteoarthritis (rOA). We examined associations between hip shape and knee rOA given the biomechanical interrelationships between these joints. Bilateral baseline hip shape assessments [for those with at least 1 hip with a Kellgren-Lawrence arthritis grading scale (KL) 0 or 1] from the Johnston County Osteoarthritis Project were available. Proximal femur shape was defined on baseline pelvis radiographs and evaluated by SSM, producing mean shape and continuous variables representing independent modes of variation (14 modes = 95% of shape variance). Outcomes included prevalent [baseline KL ≥ 2 or total knee replacement (TKR)], incident (baseline KL 0/1 with followup ≥ 2), and progressive knee rOA (KL increase of ≥ 1 or TKR). Limb-based logistic regression models for ipsilateral and contralateral comparisons were adjusted for age, sex, race, body mass index (BMI), and hip rOA, accounting for intraperson correlations. We evaluated 681 hips and 682 knees from 342 individuals (61% women, 83% white, mean age 62 yrs, BMI 29 kg/m(2)). Ninety-nine knees (15%) had prevalent rOA (4 knees with TKR). Lower modes 2 and 3 scores were associated with ipsilateral prevalent knee rOA, and only lower mode 3 scores were associated with contralateral prevalent knee rOA. No statistically significant associations were seen for incident or progressive knee rOA. Variations in hip shape were associated with prevalent, but not incident or progressive, knee rOA in this cohort, and may reflect biomechanical differences between limbs, genetic influences, or common factors related to both hip shape and knee rOA.


The Importance of Calcium Ions for Determining Mitochondrial Glycerol-3-Phosphate Dehydrogenase Activity When Measuring Uncoupling Protein 1 (UCP1) Function in Mitochondria Isolated from Brown Adipose Tissue.
Glycerol-3-phosphate is an excellent substrate for FAD-linked mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) in brown adipose tissue mitochondria and is regularly used as the primary substrate to measure oxygen consumption and reactive oxygen consumption by these mitochondria. mGPDH converts cytosolic glycerol-3-phosphate to dihydroxyacetone phosphate, feeding electrons directly from the cytosolic side of the mitochondrial inner membrane to the CoQ-pool within the inner membrane. mGPDH activity is allosterically activated by calcium, and when calcium chelators are present in the mitochondrial preparation medium and/or experimental incubation medium, calcium must be added to insure maximal mGPDH activity. It was demonstrated that in isolated brown adipose tissue mitochondria (1) mGPDH enzyme activity is maximal at free calcium ion concentrations in the 350 nM-1 μM range, (2) that ROS production also peaks in the 10-100 nM range in the presence of a UCP1 inhibitory ligand (GDP) but wanes with further increasing calcium concentration, and (3) that oxygen consumption rates peak in the 10-100 nM range with rates being maintained at higher calcium concentrations. This article provides easy-to-follow protocols to facilitate the measurement of mGPDH-dependent UCP1 activity in the presence of calcium for isolated brown adipose tissue mitochondria.


Amyloid-β peptide(1-40) elimination from cerebrospinal fluid involves low-density lipoprotein receptor-related protein 1 at the blood-cerebrospinal fluid barrier.
Amyloid-β peptide (Aβ) concentration in CSF is potentially a diagnostic and therapeutic target for Alzheimer's disease (AD). The purpose of this study was to clarify the elimination mechanism of human Aβ(1-40) [hAβ (1-40)] from CSF. After intracerebroventricular (ICV) administration, [(125) I]hAβ(1-40) was eliminated from the rat CSF with a half-life of 17.3 min. The elimination of [(125) I]hAβ(1-40) was significantly inhibited by human receptor-associated protein (RAP) and the elimination was attenuated in either anti-low-density lipoprotein receptor-related protein (LRP)1 antibody-treated or RAP-deficient mice, suggesting that a member(s) of the low-density lipoprotein receptor gene family is involved in the elimination of hAβ(1-40) from CSF. The amounts of LRP1 and LRP2 proteins were determined by means of liquid chromatography-tandem mass spectrometry, and the LRP1 content in rat choroid plexus was determined to be 3.7 fmol/μg protein, whereas the LRP2 content was below the detection limit (<0.2 fmol/μg protein). Conditionally, immortalized rat choroid plexus epithelial cells exhibited predominant apical-to-basal and apical-to-cell transport of [(125) I]hAβ(1-40). These results indicated that hAβ(1-40) is actively eliminated from CSF and this process is at least partly mediated by LRP1 expressed at choroid plexus epithelial cells, which therefore play a role in determining CSF concentrations of hAβ(1-40).


Spermatogonial stem cells derived from infertile Wv/Wv mice self-renew in vitro and generate progeny following transplantation.
Loss-of-function mutation of the Kit gene causes a severe defect in spermatogenesis that results in infertility due to the inability of its cognate ligand, KIT ligand (KITL), to stimulate spermatogonial proliferation and differentiation. Although self-renewal of mouse spermatogonial stem cells (SSCs) depends on glial cell line-derived neurotrophic factor (GDNF), there is no unequivocal evidence that SSCs with a KIT deficiency can self-renew in vivo or in vitro. In the testis of W(v)/W(v) mice, in which the KIT tyrosine kinase activity is impaired, spermatogonia with SSC phenotype were identified. When W(v)/W(v) spermatogonia were cultured in an SSC culture system supplemented with GDNF in a 10% O(2) atmosphere, they formed clumps and proliferated continuously. An atmosphere of 10% O(2) was better than 21% O(2) to support SSC self-renewal. When W(v)/W(v) clump-forming germ cells were transplanted into testes of infertile wild-type busulfan-treated mice, they colonized the seminiferous tubules but did not differentiate. However, when transplanted into the testes of infertile W/W(v) pups, they restored spermatogenesis and produced spermatozoa, and progeny were generated using microinsemination. These results clearly show that SSCs exist in W(v)/W(v) testes and that they proliferate in vitro similar to wild-type SSCs, indicating that a functional KIT protein is not required for SSC self-renewal. Furthermore, the results indicate that a defect of KIT/KITL signaling of W(v)/W(v) SSCs does not prevent spermatogonial differentiation and spermatogenesis in some recipient strains.


Offloading and Transmission Strategies for IoT Edge Devices and Networks.
We present a machine and deep learning method to offload trained deep learning model and transmit packets efficiently on resource-constrained internet of things (IoT) edge devices and networks. Recently, the types of IoT devices have become diverse and the volume of data has been increasing, such as images, voice, and time-series sensory signals generated by various devices. However, transmitting large amounts of data to a server or cloud becomes expensive owing to limited bandwidth, and leads to latency for time-sensitive operations. Therefore, we propose a novel offloading and transmission policy considering energy-efficiency, execution time, and the number of generated packets for resource-constrained IoT edge devices that run a deep learning model and a reinforcement learning method to find an optimal contention window size for effective channel access using a contention-based medium access control (MAC) protocol. A Reinforcement learning is used to improve the performance of the applied MAC protocol. Our proposed method determines the offload and transmission strategies that are better to directly send fragmented packets of raw data or to send the extracted feature vector or the final output of deep learning networks, considering the operation performance and power consumption of the resource-constrained microprocessor, as well as the power consumption of the radio transceiver and latency for transmitting the all the generated packets. In the performance evaluation, we measured the performance parameters of ARM Cortex-M4 and Cortex-M7 processors for the network simulation. The evaluation results show that our proposed adaptive channel access and learning-based offload and transmission methods outperform conventional role-based channel access schemes. They transmit packets of raw data and are effective for IoT edge devices and network protocols.


ACVIM small animal consensus statement on Lyme disease in dogs: diagnosis, treatment, and prevention.
The purpose of this report is to offer a consensus opinion of ACVIM diplomates on the diagnosis, treatment, and prevention of Borrelia burgdorferi infections in dogs (canine Lyme disease). Clinical syndromes known to commonly be associated with canine Lyme disease include polyarthritis and glomerulopathy. Serological test results can be used to document exposure to B. burgdorferi but not prove illness. Although serum enzyme-linked immunosorbent assay/indirect fluorescent antibody assay titers can stay positive for months to years after treatment, quantitative C6 peptide antibody paired tests need more study. Serological screening of healthy dogs is controversial because it can lead to overdiagnosis or overtreatment of normal dogs, most of which never develop Lyme disease. However, serological screening can provide seroprevalence and sentinel data and stimulate owner education about tick infections and control. Although it is unknown whether treatment of seropositive healthy dogs is beneficial, the consensus is that seropositive dogs should be evaluated for proteinuria and other coinfections and tick control prescribed. Tick control can include a product that repels or protects against tick attachment, thereby helping to prevent transmission of coinfections as well as Borrelia spp. Seropositive dogs with clinical abnormalities thought to arise from Lyme disease generally are treated with doxycycline (10 mg/kg q24h for 1 month). Proteinuric dogs might need longer treatment as well as medications and diets for protein-losing nephropathy. The ACVIM diplomates believe the use of Lyme vaccines still is controversial and most do not administer them. It is the consensus opinion that additional research is needed to study predictors of illness, "Lyme nephropathy," and coinfections in Lyme endemic areas.


Intraluminal negative pressure wound therapy for optimizing pharyngeal reconstruction.
Pharyngocutaneous fistula formation after pharyngeal reconstruction is one of the most common and challenging problems to manage. Despite many advances in management, the published success rates indicate a role for any adjuvant therapy that could potentially decrease this complication. To describe the use of intraluminal negative pressure dressings (NPDs) in pharyngeal reconstruction. Retrospective case series at a tertiary care academic hospital. Twelve laryngectomy patients underwent pharyngeal reconstruction augmented by placement of an intrapharyngeal NPD in combination with the introduction of vascularized tissue from August 2011 to May 2012. All patients had potential risk factors for compromised wound healing defined as previous radiation therapy, hypothyroidism, diabetes mellitus, compromised nutrition, or established pharyngocutaneous fistula. An NPD was placed in an intraluminal position spanning the length of the pharyngeal defect as part of the reconstructive procedure. The negative pressure sponge was attached to a standard nasogastric tube to which negative pressure was applied. External closure of the pharynx was then achieved with regional or free tissue transfer. Pharyngeal closure rates, timing until return to oral diet, identification of wound healing risk factors, and adverse events related to use of the device. Eleven of 12 patients (92%) achieved pharyngeal closure with reconstruction using negative pressure wound therapy. All patients had at least 1 potential risk factor for compromised wound healing, with 11 of 12 (92%) having 2 or more. Seven patients had an established pharyngocutaneous fistula, and 5 patients underwent primary reconstruction after laryngopharyngectomy. In 6 of these 7 patients undergoing fistula repair, pharyngeal closure was achieved, and they resumed an oral diet at 1 week postoperatively. The other had successful leak repair initially, but 1 week later developed a separate area of wound breakdown and a second fistula. All 5 patients in whom an intraluminal NPD was placed at the time of initial vacularized tissue reconstruction were able to resume an oral diet by 3 weeks postoperatively, with 3 of them eating by mouth at 1 week postoperatively. No serious adverse events could be attributed to the use of intraluminal NPDs. Intraluminal negative pressure wound therapy is feasible and safe. Future research should be conducted to determine its potential in optimizing pharyngeal reconstruction in high-risk patients.


Digit Ratio (2D:4D): A Biomarker for Prenatal Sex Steroids and Adult Sex Steroids in Challenge Situations.
Digit ratio (2D:4D) denotes the relative length of the second and fourth digits. This ratio is considered to be a biomarker of the balance between fetal testosterone (T) and estrogen (E) in a narrow window of early ontogeny. Evidence for this assertion is derived from direct and indirect measures of prenatal hormonal exposure (in experimental animals, via amniotic fluid samples and in the study of sex-typical traits) in relation to 2D:4D. In contrast, the relationships between 2D:4D and levels of sex steroids in adults are less clear, as many correlational studies of 2D:4D and adult sex steroids have concluded that this association is statistically non-significant. Here, we suggest that in order to understand the link between 2D:4D and sex hormones, one must consider both fetal organizing and adult activating effects of T and E. In particular, we hypothesize that 2D:4D correlates with organizing effects on the endocrine system that moderate activating effects in adulthood. We argue that this is particularly evident in "challenging" conditions such as aggressive and sexual encounters, in which individuals show increased levels of T. We discuss this refinement of the 2D:4D paradigm in relation to the links between 2D:4D and sports performance, and aggression.


Virological response to a triple nucleoside/nucleotide analogue regimen over 48 weeks in HIV-1-infected adults in Africa.
To evaluate virologic response up to 48 weeks, and emergence of HIV-1 resistance mutations at 24 weeks, in therapy-naive adults initiating zidovudine/lamivudine/tenofovir DF. : A cohort within the DART trial. Plasma HIV-1 RNA was assayed in 300 adults with baseline CD4 cell count < 200 cells/mul from sites in Uganda and Zimbabwe using the Roche Amplicor assay v1.5. Samples with HIV-1 RNA > 1000 copies/ml at 24 weeks were sequenced in the pol region. Median baseline CD4 cell count was 101 cells/mul and HIV-1 RNA 279,910 copies/ml (mean, 5.4 log10). At 48 weeks, 61% (165/272) had HIV-1 RNA < 50 and 72% (196/272) < 400 copies/ml, compared with 59% (167/281) and 79% (221/281) at 24 weeks. At 24 and 48 weeks, 15 and 24% respectively had HIV-1 RNA > 1000 copies/ml (6 and 17% > 10 000 copies/ml), and mean CD4 cell count increases were 103 and 127 cells/mul, respectively. Higher baseline CD4 cell count was the most important predictor of virological suppression at 48 weeks, with little effect of baseline viral load. Eighteen of 20 genotypes from week 24 samples with HIV-1 RNA > 1000 copies/ml showed key resistance mutations in reverse transcriptase. Fourteen had M184V [10 with one to four additional nucleoside analogue mutations (NAMs)]; one had three NAMs only; and the remaining three had K65R. One participant with M184V had major non-nucleoside reverse transcriptase inhibitor-associated mutations, despite no disclosed treatment with this class. Zidovudine/lamivudine/tenofovir has good virological efficacy in advanced HIV disease. In this population, who were infected with HIV-1 subtypes A, C or D, M184V with or without NAMs was the most common route to resistance, whereas K65R was identified less often.


Ageing memory: use versus impairment.
An uncued recall technique was used to compare recall of autobiographical events by two groups of elderly volunteers of equivalent general intelligence (assessed by unadjusted scores on the AH4 intelligence test). One group lived in residential care, and the other led independent lives. Residential care subjects recalled and spontaneously rehearsed more memories from their early than their recent lives, whereas the reverse was true for the independent elderly. The effects of senile confusional states were also investigated by testing a subgroup of cognitively impaired subjects, also in residential care. Although unimpaired elderly in care produced more early than recent memories, they were still able to produce substantial numbers of recent memories. Impaired subjects produced very few memories, those they did produce were mainly early ones. Frequency of rehearsal (or reminiscence) seemed to affect the probability of elicitation of a memory. People in institutions more often rehearse memories of early events. Frequency of rehearsal is thus a function of the use which people in different situations make of their memories. Cognitive impairment due to organic neurological changes in the elderly had a characteristic effect on the abundance of recall from recent life.


Cytokine secretion from monocytes persists differentially after activator removal-One mechanism of long-term biological response to implants.
Biomedical implants significantly improve the quality of life in an ever-increasing number of patients. However, inflammation of tissues around implants remains a long-term, post-placement sequelae that may contribute to implant failure. Infection-mediated failure is partly a consequence of inappropriate host response and chronic inflammation, and is mediated primarily by the secretory products of monocytes and macrophages. Although the secretion of inflammatory mediators from activated monocytes is well characterized, the resolution of mediator levels post-activation is relatively unstudied. The current study defines the time course of cytokine secretion by activated human monocytes after the activator has been removed. THP1 human monocytes were activated by LPS, and cytokine secretion was monitored over time after LPS removal using enzyme-linked immunosorbent assays (TNFalpha or IL8) or a cytokine array. The release of cytokines was compared with conditions without LPS removal. As expected, secretion of nearly all cytokines was reduced when LPS was removed, but the amount of the reduction was highly cytokine-dependent. Furthermore, levels of cytokines were stable in medium alone but not in cell-culture, suggesting an active process to either degrade or internalize secreted cytokines. Our results are consistent with clinical experience that inflammation resolves rapidly after treatment to remove bacteria or inflamed tissue. However, the differential cytokine regulation indicates a sophisticated coordination of cytokine levels probably associated with management of the wound healing response after removal of the bacterial insult. This wound healing response is one critical component of the long-term success of biomedical implants.


Progress in biomimetic leverages for marine antifouling using nanocomposite coatings.
Because of the environmental and economic casualties of biofouling on maritime navigation, modern studies have been devoted toward formulating advanced nanoscale composites in the controlled development of effective marine antifouling self-cleaning surfaces. Natural biomimetic surfaces have the advantages of micro-/nanoroughness and minimized free energy characteristics that can motivate the dynamic fabrication of superhydrophobic antifouling surfaces. This review provides an architectural panorama of the biomimetic antifouling designs and their key leverages to broaden horizons in the controlled fabrication of nanocomposite building blocks as force-driven marine antifouling models. As primary antifouling designs, understanding the key functions of surface geometry, heterogeneity, superhydrophobicity, and complexity of polymer/nanofiller composite building blocks on fouling-resistant systems is crucial. This review also discusses a wide range of fouling release coating systems that satisfy the growing demand in a sustainable future environment. For instance, the integration of block, segmented copolymer-based coatings and inorganic-organic hybrid nanofillers enhanced the model's antifouling properties with mechanical, superhydrophobic, chemically inert, and robust surfaces. These nanoscale antifouling systems offered surfaces with minimized free energy, micro-/nanoroughness, anisotropic heterogeneity, superior hydrophobicity, tunable non-wettability, antibacterial efficiency, and mechanical robustness. The confined fabrication of nanoscale orientation, configuration, arrangement, and direction along the architectural composite building blocks would yield excellent air-entrapping ability along the interfacial surface grooves and interfaces, which optimized the antifouling coating surfaces for long-term durability. This review provides systematic evidence of the effect of structurally folded nanocomposites, nanofiller tectonics, and building blocks on the creation of outstanding superhydrophobicity, self-cleaning surfaces, and potential antifouling coatings. The development of modern research gateways is a candidate for the sustainable future of antifouling coatings.


Hemopoietic cell expression of the chemokine decoy receptor D6 is dynamic and regulated by GATA1.
D6 scavenges inflammatory chemokines and is essential for the regulation of inflammatory and immune responses. Mechanisms explaining the cellular basis for D6 function have been based on D6 expression by lymphatic endothelial cells. In this study, we demonstrate that functional D6 is also expressed by murine and human hemopoietic cells and that this expression can be regulated by pro- and anti-inflammatory agents. D6 expression was highest in B cells and dendritic cells (DCs). In myeloid cells, LPS down-regulated expression, while TGF-beta up-regulated expression. Activation of T cells with anti-CD3 and soluble CD28 up-regulated mRNA expression 20-fold, while maturation of human macrophage and megakaryocyte precursors also up-regulated D6 expression. Competition assays demonstrated that chemokine uptake was D6 dependent in human leukocytes, whereas mouse D6-null cells failed to uptake and clear inflammatory chemokines. Furthermore, we present evidence indicating that D6 expression is GATA1 dependent, thus explaining D6 expression in myeloid progenitor cells, mast cells, megakaryocytes, and DCs. We propose a model for D6 function in which leukocytes, within inflamed sites, activate D6 expression and thus trigger resolution of inflammatory responses. Our data on D6 expression by circulating DCs and B cells also suggest alternative roles for D6, perhaps in the coordination of innate and adaptive immune responses. These data therefore alter our models of in vivo D6 function and suggest possible discrete, and novel, roles for D6 on lymphatic endothelial cells and leukocytes.


Individual differences in (dis)honesty are represented in the brain's functional connectivity at rest.
Measurement of the determinants of socially undesirable behaviors, such as dishonesty, are complicated and obscured by social desirability biases. To circumvent these biases, we used connectome-based predictive modeling (CPM) on resting state functional connectivity patterns in combination with a novel task which inconspicuously measures voluntary cheating to gain access to the neurocognitive determinants of (dis)honesty. Specifically, we investigated whether task-independent neural patterns within the brain at rest could be used to predict a propensity for (dis)honest behavior. Our analyses revealed that functional connectivity, especially between brain networks linked to self-referential thinking (vmPFC, temporal poles, and PCC) and reward processing (caudate nucleus), reliably correlates, in an independent sample, with participants' propensity to cheat. Participants who cheated the most also scored highest on several self-report measures of impulsivity which underscores the generalizability of our results. Notably, when comparing neural and self-report measures, the neural measures were found to be more important in predicting cheating propensity.


Ginkgo biloba extract enhances glucose tolerance in hyperinsulinism-induced hepatic cells.
Ginkgo biloba, an herbal medication, is capable of lowering glucose, fat, and lipid peroxide in diabetic patients. In the current study, we tested the hypothesis that Ginkgo biloba extract (GBE) prevented hyperinsulinism-induced glucose intolerance in hepatocytes. We investigated the effects of GBE on glucose consumption, glucokinase activity, and mRNA levels of key genes in glucose metabolism and the insulin signaling pathway. To better show its efficacy, we included a control group that was treated with rosiglitazone, a type of thiazolidinedione (TZD). The data indicated that GBE repressed glucose uptake under normal conditions, while it dramatically improved glucose tolerance under insulin-resistant conditions. Furthermore, after analyzing gene expression, we suggest that GBE chiefly exerts its effects by stimulating IRS-2 transcription. It should be noted that, unlike rosiglitazone, GBE did not stimulate excessive glucose uptake as it improved glucose tolerance. It is said that GBE treatment could avoid drug-induced obesity. Our data suggest that GBE has the potential to prevent insulin resistance and is a promising anti-diabetic drug.


Topical cystic fibrosis transmembrane conductance regulator gene replacement for cystic fibrosis-related lung disease.
Cystic fibrosis is caused by a defective gene encoding a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), and is characterised by chronic lung infection resulting in inflammation and progressive lung damage that results in a reduced life expectancy. To determine whether topical CFTR gene replacement therapy to the lungs in people with cystic fibrosis is associated with improvements in clinical outcomes, and to assess any adverse effects. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings.Date of most recent search: 22 August 2013.An additional search of the National Institutes for Health (NIH) Genetic Modification Clinical Research Information System (GeMCRIS) was also performed for the years 1992 to 2013.Date of most recent search: 04 September 2013. Randomised controlled trials comparing topical CFTR gene delivery to the lung, using either viral or non-viral delivery systems, with placebo or an alternative delivery system in people with confirmed cystic fibrosis. The authors independently extracted data and assessed study quality. Authors of included studies were contacted and asked for any available additional data. Meta-analysis was limited due to differing study designs. Three randomised controlled trials met the inclusion criteria for this review, involving a total of 155 participants. Fourteen studies were excluded. The included studies differed in terms of CFTR gene replacement agent and study design, which limited the meta-analysis.Although the first Moss study reported a significant improvement in respiratory function (forced expiratory volume at one second) 30 days after participants had received their first dose of gene therapy agent, this finding was not confirmed in their larger second study or in our meta-analysis.In participants who received the CFTR gene transfer agents in the Alton study, "influenza-like" symptoms were found (risk ratio 7.00 (95% confidence interval 1.10 to 44.61)). There were no other significant increases in adverse events in any of the studies.Alton measured ion transport in the lower airways and demonstrated significant changes toward normal values in the participants who received gene transfer agents (P < 0.0001), mean difference 6.86 (95% confidence interval 3.77 to 9.95). In these participants there was also evidence of increased salt transport in cells obtained by brushing the lower airway. These outcomes, whilst important, are not of direct clinical relevance. There is currently no evidence to support the use of CFTR gene transfer agents as a treatment for lung disease in people with cystic fibrosis. Future studies need to investigate clinically important outcome measures.


The ADOR mechanism for the synthesis of new zeolites.
A novel methodology, called ADOR (assembly-disassembly-organisation-reassembly), for the synthesis of zeolites is reviewed here in detail. The ADOR mechanism stems from the fact that certain chemical weakness against a stimulus may be present in a zeolite framework, which can then be utilized for the preparation of new solids through successive manipulation of the material. In this review, we discuss the critical factors of germanosilicate zeolites required for application of the ADOR protocol and describe the mechanism of hydrolysis, organisation and condensation to form new zeolites starting from zeolite UTL. Last but not least, we discuss the potential of this methodology to form other zeolites and the prospects for future investigations.


Discovery and clinical application of a novel prostate cancer marker: alpha-methylacyl CoA racemase (P504S).
The recent discovery of the overexpression of P504S/alpha-methylacyl coenzyme A racemase (AMACR) in prostate cancer is a successful example of translating an advanced molecular finding into clinical practice. AMACR (P504S) has been proven to be one of the few biomarkers that can help distinguish cancer from benign cells, with high sensitivity and specificity for prostate carcinoma. It is the first gene identified by the analysis of complementary DNA microarray profiles from prostate tissue to be used as a tissue tumor marker in clinical practice and to improve the diagnosis of prostate cancer. This review focuses on the study of AMACR (P504S) expression in prostate cancer, premalignant lesions, benign prostate tissues, and other normal and malignant tissues and a discussion of its clinical usefulness. We emphasize the interpretation of the AMACR immunohistochemical results in routine surgical pathology practice and also discuss the potential future applications of this marker and the possible role of AMACR in the pathogenesis of cancer development.


Analysis of transformation with Epstein-Barr virus and phenotypic characteristics of lymphoblastoid cell lines established from patients with hairy cell leukemia.
In order to assess the role of Epstein-Barr virus (EBV) in patients with hairy cell leukemia (HCL), we have sought to characterize 1) the ability of EBV to infect and transform hairy leukemic cells in vitro and 2) the phenotypes of cell lines putatively derived from those leukemic cells. Analysis of EBV-induced transformation and the kinetics of Epstein-Barr nuclear antigen (EBNA) induction in leukemic preparations indicated that most leukemic cells were not susceptible to EBV infection but that at least a small subpopulation of leukemic cells could be infected with EBV. Lymphoblastoid cells lines were established after exposure of peripheral blood or splenic cells from HCL patients to B95-8 or QIMR-WIL EBV. Splenic leukemic cell preparations were more sensitive targets for EBV transformation than were peripheral blood cell samples. The newly established cell lines, but not long-established B lines such as Raji, demonstrated high levels of synthesis of p35, (a protein complex expressed abundantly by cells of a subset of HCL patients) and high levels of tartrate-resistant acid phosphatase (an enzyme relatively diagnostic for HCL). Lymphoblastoid lines from one patient with HCL expressed lambda light chains and no kappa chains as did the patient's leukemic cells. Virus expression in these lines showed that HCL-derived lines had spontaneous early antigen (EA) and viral capsid antigen (VCA) expression. Transforming EBV could be rescued from HCL-derived cell lines but not from cord blood-derived lines.


Procedural Patterns and Safety of Atrial Fibrillation Ablation: Findings From Get With The Guidelines-Atrial Fibrillation.
Catheter ablation is an increasingly used treatment for symptomatic atrial fibrillation (AF). However, there are limited prospective, nationwide data on patient selection and procedural characteristics. This study describes patient characteristics, techniques, treatment patterns, and safety outcomes of patients undergoing AF ablation. A total of 3139 patients undergoing AF ablation between 2016 and 2018 in the Get With The Guidelines-Atrial Fibrillation registry from 24 US centers were included. Patient demographics, medical history, procedural details, and complications were abstracted. Differences between paroxysmal and patients with persistent AF were compared using Pearson χ2 and Wilcoxon rank-sum tests. Patients undergoing AF ablation were predominantly male (63.9%) and White (93.2%) with a median age of 65. Hypertension was the most common comorbidity (67.6%), and patients with persistent AF had more comorbidities than patients with paroxysmal AF. Drug refractory, paroxysmal AF was the most common ablation indication (class I, 53.6%) followed by drug refractory, persistent AF (class I, 41.8%). Radiofrequency ablation with contact force sensing was the most common ablation modality (70.5%); 23.7% of patients underwent cryoballoon ablation. Pulmonary vein isolation was performed in 94.6% of de novo ablations; the most common adjunctive lesions included left atrial roof or posterior/inferior lines, and cavotricuspid isthmus ablation. Complications were uncommon (5.1%) and were life-threatening in 0.7% of cases. More than 98% of AF ablations among participating sites are performed for class I or class IIA indications. Contact force-guided radiofrequency ablation is the dominant technique and pulmonary vein isolation the principal lesion set. In-hospital complications are uncommon and rarely life-threatening.


The brain as the engine of sex differences in the organization of movement in rats.
Sex differences in the kinematic organization of non-reproductive behavior are often relegated to byproducts of sex differences in body morphology. We review evidence showing not only that male and female rats organize their posture and stepping differently during a variety of actions, but that these differences arise from sex differences in the organization of movement in the central nervous system (CNS). Indeed, the expression and choice of sex-typical patterns of movement can be altered by CNS injury. The pattern of hormonal regulation of these sex differences is also not organized as commonly held theory would predict. As expected, males castrated shortly after birth are female-typical in their motor organization. Females ovariectomized at birth, however, are male-typical in their patterns of movement. Thus, female-typical patterns of movement organization are not the default form, but rather are dependent on the effects of gonadal steroids to feminize the developing CNS. The implications of these findings are discussed with regards to our understanding of the evolution of sex differences in CNS anatomy and behavior both for animals and humans.


Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes.
Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment.


Evidence for a subcortical origin of mirror movements after stroke: a longitudinal study.
Following a stroke, mirror movements are unintended movements that appear in the non-paretic hand when the paretic hand voluntarily moves. Mirror movements have previously been linked to overactivation of sensorimotor areas in the non-lesioned hemisphere. In this study, we hypothesized that mirror movements might instead have a subcortical origin, and are the by-product of subcortical motor pathways upregulating their contributions to the paretic hand. To test this idea, we first characterized the time course of mirroring in 53 first-time stroke patients, and compared it to the time course of activities in sensorimotor areas of the lesioned and non-lesioned hemispheres (measured using functional MRI). Mirroring in the non-paretic hand was exaggerated early after stroke (Week 2), but progressively diminished over the year with a time course that parallelled individuation deficits in the paretic hand. We found no evidence of cortical overactivation that could explain the time course changes in behaviour, contrary to the cortical model of mirroring. Consistent with a subcortical origin of mirroring, we predicted that subcortical contributions should broadly recruit fingers in the non-paretic hand, reflecting the limited capacity of subcortical pathways in providing individuated finger control. We therefore characterized finger recruitment patterns in the non-paretic hand during mirroring. During mirroring, non-paretic fingers were broadly recruited, with mirrored forces in homologous fingers being only slightly larger (1.76 times) than those in non-homologous fingers. Throughout recovery, the pattern of finger recruitment during mirroring for patients looked like a scaled version of the corresponding control mirroring pattern, suggesting that the system that is responsible for mirroring in controls is upregulated after stroke. Together, our results suggest that post-stroke mirror movements in the non-paretic hand, like enslaved movements in the paretic hand, are caused by the upregulation of a bilaterally organized subcortical system.


Fluorimetric detection of Mg2+ and DNA with 9-(alkoxyphenyl)benzo[b]quinolizinium derivatives.
A benzo[b]quinolizinium-benzo-15-crown-5 ether conjugate 2a is presented that enables the fluorimetric detection of Mg(2+) and DNA by a significant light-up effect, along with a change of the emission wavelength with different analytes (Mg(2+): 495 nm; DNA: 550 nm). The mechanism of the excited-state deactivation of 2a was investigated by steady-state fluorescence spectroscopy in media of varied viscosity and compared with the photophysical properties of methoxyphenyl-substituted benzo[b]quinolizinium 2b (m,p-diOMe), 2c (m-OMe), and 2d (p-OMe) as reference compounds. Compounds 2a-c, which share the m-alkoxyphenyl substituent as the common feature, have low emission quantum yields (Φ(F) < 10(-2) in water) but exhibit a significant increase of their fluorescence intensity in viscous glycerol solutions. In contrast, the viscosity of the medium does not influence the emission properties of the parent phenyl-substituted benzo[b]quinolizinium 2e and of the p-methoxyphenyl-substituted derivative 2d. Based on these observations it is concluded that the excited-state deactivation in 2a-c is mainly due to the rotation of the m-alkoxy group about the C(ar)-O bond. The interaction of 2a-c with DNA or Mg(2+) ions was studied by spectrophotometric titrations and CD spectroscopy. Notably, the association of 2a or 2b with DNA or 2a with Mg(2+) ions induces a strong fluorescence enhancement (15- and 40-fold for DNA, 450-fold for Mg(2+)), which is rationalized by the suppression of the torsional-relaxation of the alkoxy-substituent in the excited state. Additionally, the cation-induced light-up effect of 2a is selective towards Mg(2+) ions as compared with other cations such as NH(4)(+), Li(+), Na(+), K(+) and Ba(2+).


Convergence of the SUMO and MAPK pathways on the ETS-domain transcription factor Elk-1.
The ETS-domain transcription factor Elk-1 is regulated by phosphorylation in response to activation of the MAPK (mitogen-activated protein kinase) pathways. This phosphorylation triggers a series of molecular events that convert Elk-1 from a transcriptionally silent state into a highly active state and then back to a basal level. At the same time, activation of the ERK (extracellular-signal-regulated kinase) MAPK pathway leads to loss of modification of Elk-1 by SUMO (small ubiquitin-related modifier). As SUMO imparts repressive properties on Elk-1, ERK-mediated SUMO loss leads to de-repression at the same time as the ERK pathway promotes activation of Elk-1. Thus a two-step mechanism is employed to convert Elk-1 into its fully activated state. Here, the molecular events underlying these changes in Elk-1 status, and the role of PIASxalpha [protein inhibitor of activated STAT (signal transducer and activator of transcription) xalpha] as a co-activator that facilitates this process, are discussed.


Toxicity of pulp and paper solid organic waste constituents to soil organisms.
This study examined the potential biological hazard of pulp and paper waste solids. The solids examined were chosen on the basis of the range of wood-related organic extractives and were either primary solids screened from the effluent stream before secondary treatment, or biosolids from aerated stabilisation lagoons. Acute effects were tested at the level of plants, invertebrates and soil microbes using an oat germination and growth test, earthworm survival and reproduction test, an enchytraeid worm survival and reproduction test, and standard measures of microbial respiration. This was further benchmarked against a marine bacteria toxicity test using extract of the waste solids. Resin acids and resin acid neutrals made up the greatest proportion of organic extractives measured in biosolids whereas resin acids and fatty acids were the main constituents detected in primary solids. Examination of the tissue of earthworms from the tests revealed no net bioconcentration of the organic extractives. The waste solids were not acutely toxic to any of the soil organisms as tested without any dilution. Conversely, extracts of the waste solids demonstrated toxicity in the marine bacteria. In some cases, the solid waste material enhanced the growth of plants, earthworm reproduction and microbial respiration. The only adverse affect was that reproduction of enchytraeids was reduced by some of the waste solid treatments. However these effects did not appear to be associated with concentrations of resin acid neutrals and resin acids in these materials. Overall pulp and paper wastes were relatively benign in terms of toxicity to the soil organisms tested.


Implementation and scientific evaluation of rehabilitative sports groups for prostate cancer patients: study protocol of the ProRehab Study.
Although treatment regimen have improved in the last few years, prostate cancer patients following a radical prostatectomy still experience severe disease- and treatment-related side effects, including urinary incontinence, erectile dysfunction and psychological issues. Despite high incidence rates and the common adverse effects there is a lack of supportive measures for male patients and specific physical exercise recommendations for prostate cancer patients during rehabilitation or in the aftercare are still missing. The ProRehab Project aims to establish rehabilitative sports groups particularly for prostate cancer patients and to evaluate the effects of the offered exercise program. Starting 8-12 weeks after prostatectomy or combination therapy, prostate cancer patients will exercise for 15 months within a patient preference randomized controlled trial. One exercise session will be conducted within a pre-established rehabilitative sports group, while the other will be completed independently. Patients in the control group will not participate in the intervention. The main outcomes of the study include aerobic fitness, quality of life, incontinence and erectile dysfunction. By combining science, practice, and public relations the first rehabilitative sports groups for prostate cancer patients in Germany have been set up and thus contribute to the care structure for prostate cancer patients. By offering a 15-month physical exercise intervention that is conducted in supervised group sessions, long-term lifestyle changes and therefore improvements in quality of life in prostate cancer patients can be expected. German Clinical Trials Register DRKS00004184.


An animal model for Lyme arthritis.
A model of Lyme arthritis has been developed in laboratory rats. Intraperitoneal inoculation of a low-passage tick isolate of B. burgdorferi into neonatal and weanling LEW/N rats resulted in multisystemic infection and arthritis. Spirochetes were isolated from blood, liver, kidney, spleen, brain, and joints of inoculated rats. Arthritis, associated with the presence of spirochetes, developed in multiple joints by day 14 and persisted through day 90 after inoculation. Arthritic lesions resembled those found in human Lyme disease lesions. Lesions were not found in other organs, although spirochetes were present. Neonatal F344 and SD rats were also susceptible to infection and induction of arthritis. Three different isolates of B. burgdorferi were shown to be pathogenic. Pathogenicity of one isolate was retained after at least 11 in vitro passages. Formalin-killed spirochetes were not pathogenic. Other features of the Lyme disease complex have yet to be seen in the rat, but long-term studies are required to completely define the rat model. This highly reproducible model should allow in-depth studies on the pathogenetic mechanisms of this important human disease.


Ocean acidification weakens the structural integrity of coralline algae.
The uptake of anthropogenic emission of carbon dioxide is resulting in a lowering of the carbonate saturation state and a drop in ocean pH. Understanding how marine calcifying organisms such as coralline algae may acclimatize to ocean acidification is important to understand their survival over the coming century. We present the first long-term perturbation experiment on the cold-water coralline algae, which are important marine calcifiers in the benthic ecosystems particularly at the higher latitudes. Lithothamnion glaciale, after three months incubation, continued to calcify even in undersaturated conditions with a significant trend towards lower growth rates with increasing pCO2 . However, the major changes in the ultra-structure occur by 589 μatm (i.e. in saturated waters). Finite element models of the algae grown at these heightened levels show an increase in the total strain energy of nearly an order of magnitude and an uneven distribution of the stress inside the skeleton when subjected to similar loads as algae grown at ambient levels. This weakening of the structure is likely to reduce the ability of the alga to resist boring by predators and wave energy with severe consequences to the benthic community structure in the immediate future (50 years).


Critical role of endothelial hydrogen peroxide in post-ischemic neovascularization.
Reactive oxygen species (ROS) play an important role in angiogenesis in endothelial cells (ECs) in vitro and neovascularization in vivo. However, little is known about the role of endogenous vascular hydrogen peroxide (H2O2) in postnatal neovascularization. We used Tie2-driven endothelial specific catalase transgenic mice (Cat-Tg mice) and hindlimb ischemia model to address the role of endogenous H2O2 in ECs in post-ischemic neovascularization in vivo. Here we show that Cat-Tg mice exhibit significant reduction in intracellular H2O2 in ECs, blood flow recovery, capillary formation, collateral remodeling with larger extent of tissue damage after hindlimb ischemia, as compared to wild-type (WT) littermates. In the early stage of ischemia-induced angiogenesis, Cat-Tg mice show a morphologically disorganized microvasculature. Vascular sprouting and tube elongation are significantly impaired in isolated aorta from Cat-Tg mice. Furthermore, Cat-Tg mice show a decrease in myeloid cell recruitment after hindlimb ischemia. Mechanistically, Cat-Tg mice show significant decrease in eNOS phosphorylation at Ser1177 as well as expression of redox-sensitive vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemotactic protein-1 (MCP-1) in ischemic muscles, which is required for inflammatory cell recruitment to the ischemic tissues. We also observed impaired endothelium-dependent relaxation in resistant vessels from Cat-Tg mice. Endogenous ECs-derived H2O2 plays a critical role in reparative neovascularization in response to ischemia by upregulating adhesion molecules and activating eNOS in ECs. Redox-regulation in ECs is a potential therapeutic strategy for angiogenesis-dependent cardiovascular diseases.


Fast large-tip-angle multidimensional and parallel RF pulse design in MRI.
Large-tip-angle multidimensional radio-frequency (RF) pulse design is a difficult problem, due to the nonlinear response of magnetization to applied RF at large tip-angles. In parallel excitation, multidimensional RF pulse design is further complicated by the possibility for transmit field patterns to change between subjects, requiring pulses to be designed rapidly while a subject lies in the scanner. To accelerate pulse design, we introduce a fast version of the optimal control method for large-tip-angle parallel excitation. The new method is based on a novel approach to analytically linearizing the Bloch equation about a large-tip-angle RF pulse, which results in an approximate linear model for the perturbations created by adding a small-tip-angle pulse to a large-tip-angle pulse. The linear model can be evaluated rapidly using nonuniform fast Fourier transforms, and we apply it iteratively to produce a sequence of pulse updates that improve excitation accuracy. We achieve drastic reductions in design time and memory requirements compared to conventional optimal control, while producing pulses of similar accuracy. The new method can also compensate for nonidealities such as main field inhomogeneties.


Coupling of air/metal and substrate/metal surface plasmon polaritons in Au slit arrays fabricated on quartz substrate.
We report on the coupling of the air/metal mode and the substrate/metal mode surface plasmon polaritons in one-dimensional metallic slit arrays fabricated on a dielectric substrate. Anti-crossing is exhibited at an incident angle where the two independent modes can be resonantly excited at a specific wavelength. The size of the anti-crossing gap was measured while changing the metal thickness.


Phylogenomics of sterol synthesis: insights into the origin, evolution, and diversity of a key eukaryotic feature.
The availability of complete genomes from a wide sampling of eukaryotic diversity has allowed the application of phylogenomics approaches to study the origin and evolution of unique eukaryotic cellular structures, but these are still poorly applied to study unique eukaryotic metabolic pathways. Sterols are a good example because they are an essential feature of eukaryotic membranes. The sterol pathway has been well dissected in vertebrates, fungi, and land plants. However, although different types of sterols have been identified in other eukaryotic lineages, their pathways have not been fully characterized. We have carried out an extensive analysis of the taxonomic distribution and phylogeny of the enzymes of the sterol pathway in a large sampling of eukaryotic lineages. This allowed us to tentatively indicate features of the sterol pathway in organisms where this has not been characterized and to point out a number of steps for which yet-to-discover enzymes may be at work. We also inferred that the last eukaryotic common ancestor already harbored a large panel of enzymes for sterol synthesis and that subsequent evolution over the eukaryotic tree occurred by tinkering, mainly by gene losses. We highlight a high capacity of sterol synthesis in the myxobacterium Plesiocystis pacifica, and we support the hypothesis that the few bacteria that harbor homologs of the sterol pathway have likely acquired these via horizontal gene transfer from eukaryotes. Finally, we propose a potential candidate for the elusive enzyme performing C-3 ketoreduction (ERG27 equivalent) in land plants and probably in other eukaryotic phyla.


Attitudes and Awareness Regarding Hepatitis B and Hepatitis C Amongst Health-care Workers of a Tertiary Hospital in India.
Hepatitis is an inflammatory disease of the liver. In sever cases, it may lead to permanent liver damage including liver cirrhosis or hepato-cellular carcinoma and may ultimately lead to death. Health-care workers (HCWs), due to their regular contact with patients are at a high-risk of acquiring this disease. The aim of this study was to assess the knowledge and attitude toward hepatitis B and C infection among the health-care interns and correlate the level of awareness to the attitude they behold toward the disease. A closed ended questionnaire consisting of questions to evaluate the knowledge regarding hepatitis B and C infection and attitude of the (HCWs/interns) was duly filled by 255 participants including, 100 dental, 100 medical, and 55 nursing interns. Statistical analysis was carried out using the Chi-square test, ANOVA test, post-hoc test and Pearson's correlation. Although most of the interns were aware of the existence of hepatitis B and C infection, the level of awareness regarding the modes of transmission and vaccination was found to be dissatisfactory. Awareness level regarding the infection among nursing interns was statistically significantly lower than the dental and medical interns. A direct positive correlation as found between awareness score and behavior score, which reveals that interns with better awareness level had better attitudes toward the infection and prevention of its transmission. There is an urgent need to increase the level and quality of training among HCWs to prevent the spread of hepatitis B virus and hepatitis C virus.


STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers.
The cohesin subunit STAG2 has emerged as a recurrently inactivated tumor suppressor in human cancers. Using candidate approaches, recent studies have revealed a synthetic lethal interaction between STAG2 and its paralog STAG1 To systematically probe genetic vulnerabilities in the absence of STAG2, we have performed genome-wide CRISPR screens in isogenic cell lines and identified STAG1 as the most prominent and selective dependency of STAG2-deficient cells. Using an inducible degron system, we show that chemical genetic degradation of STAG1 protein results in the loss of sister chromatid cohesion and rapid cell death in STAG2-deficient cells, while sparing STAG2-wild-type cells. Biochemical assays and X-ray crystallography identify STAG1 regions that interact with the RAD21 subunit of the cohesin complex. STAG1 mutations that abrogate this interaction selectively compromise the viability of STAG2-deficient cells. Our work highlights the degradation of STAG1 and inhibition of its interaction with RAD21 as promising therapeutic strategies. These findings lay the groundwork for the development of STAG1-directed small molecules to exploit synthetic lethality in STAG2-mutated tumors.