Slow-light birefringence and polarization interferometry.
By performing two-beam coupling experiments in a liquid-crystal light valve, we report a large slow-light birefringence (SLB) phenomenon, with orthogonal polarization states traveling at very different group velocities. We show that SLB can be exploited for realizing a common-path polarization interferometer able to detect phase variations with enhanced sensitivity.


Synthesis, Crystal Structure, Magnetic Properties, and Stability of the Manganese-Rich "Mn3AlC" κ Phase.
κ-carbides of varying composition, seemingly responsible for age hardening in high-Al steel alloys, have been detected to precipitate both at grain boundaries and in the bulk grain of steels. Herein we report the bulk-phase synthesis of "Mn3AlC" by arc plasma sintering and rapid solidification. Single crystals have been found suitable for X-ray diffraction using Mo radiation and yield a lattice parameter of a = 3.875(2) Å. We find a mixed occupation of the 1a position by Al and Mn, which, together with the C position being fully occupied, leads to the actual composition Mn3.1Al0.9C. Additional energy-dispersive X-ray-scanning electron microscopy measurements support the composition and corroborate the homogeneity. SQUID data collected on the polycrystalline ferromagnetic sample exhibit a Curie temperature of about 295 ± 13 K and a soft magnetic behavior. The small but significant nonstoichiometry on 1a leads to a slightly larger lattice parameter, a higher electron count, and, thus, a lowered density of states at the Fermi level, indicative of increased phase stability.


Multi-angle lensless digital holography for depth resolved imaging on a chip.
A multi-angle lensfree holographic imaging platform that can accurately characterize both the axial and lateral positions of cells located within multi-layered micro-channels is introduced. In this platform, lensfree digital holograms of the micro-objects on the chip are recorded at different illumination angles using partially coherent illumination. These digital holograms start to shift laterally on the sensor plane as the illumination angle of the source is tilted. Since the exact amount of this lateral shift of each object hologram can be calculated with an accuracy that beats the diffraction limit of light, the height of each cell from the substrate can be determined over a large field of view without the use of any lenses. We demonstrate the proof of concept of this multi-angle lensless imaging platform by using light emitting diodes to characterize various sized microparticles located on a chip with sub-micron axial and lateral localization over approximately 60 mm(2) field of view. Furthermore, we successfully apply this lensless imaging approach to simultaneously characterize blood samples located at multi-layered micro-channels in terms of the counts, individual thicknesses and the volumes of the cells at each layer. Because this platform does not require any lenses, lasers or other bulky optical/mechanical components, it provides a compact and high-throughput alternative to conventional approaches for cytometry and diagnostics applications involving lab on a chip systems.


Reductive dechlorination of polychlorinated biphenyls by anaerobic microorganisms from sediments.
Microorganisms from Hudson River sediments reductively dechlorinated most polychlorinated biphenyls (PCBs) in Aroclor 1242 under anaerobic conditions, thus demonstrating PCB dechlorination by anaerobic bacteria in the laboratory. The most rapid dechlorination was observed at the highest PCB concentration used; at 700 parts per million Aroclor, 53 percent of the total chlorine was removed in 16 weeks, and the proportion of mono- and dichlorobiphenyls increased from 9 to 88 percent. Dechlorination occurred primarily from the meta and para positions; congeners that were substituted only in the ortho position (or positions) accumulated. These dechlorination products are both less toxic and more readily degraded by aerobic bacteria. These results indicate that reductive dechlorination may be an important environmental fate of PCBs, and suggest that a sequential anaerobic-aerobic biological treatment system for PCBs may be feasible.


Relaxation therapies for the management of primary hypertension in adults: a Cochrane review.
The objective of this review was to evaluate the effectiveness of relaxation to lower high blood pressure. We searched electronic bibliographic databases and grey literature to identify randomized controlled trials comparing relaxation therapies with no active treatment or sham therapy, enrolling adult participants with raised systolic blood pressure (SBP) > or = 140 mm Hg or diastolic blood pressure (DBP) > or = 85 mm Hg and follow-up > or = 8 weeks. Twenty-five trials with up to 5 years follow-up, assessing 1198 participants, met our inclusion criteria and were meta-analysed. Overall, relaxation resulted in small, statistically significant reductions in SBP (mean difference: -5.5 mm Hg, 95% CI: -8.2 to -2.8) and DBP (mean difference: -3.5 mm Hg, 95% CI: -5.3 to -1.6) compared to the control. Substantial heterogeneity between trials (I2 > 70%) was not explained by duration of follow-up, type of control, type of relaxation therapy or baseline blood pressure. The 9 trials that reported blinding of outcome assessors found a non-significant net reduction in blood pressure (SBP mean difference: -3.2 mm Hg, 95% CI: -7.7 to 1.4) associated with relaxation, as did the 15 trials comparing relaxation with sham therapy (SBP mean difference: -3.5 mm Hg, 95% CI: -7.1 to 0.2). Adequate randomization was confirmed in only seven trials and concealment of allocation in only one. In view of the poor quality of the included trials and unexplained variation between trials, the evidence in favour of a causal association between relaxation and blood pressure reduction is weak. Some of the apparent benefit of relaxation was probably due to aspects of treatment unrelated to relaxation.


Computed tomography analysis of the cranium of Champsosaurus lindoei and implications for the choristoderan neomorphic ossification.
Choristoderes are extinct neodiapsid reptiles that are well known for their unusual cranial anatomy, possessing an elongated snout and expanded temporal arches. Although choristodere skulls are well described externally, their internal anatomy remains unknown. An internal description was needed to shed light on peculiarities of the choristodere skull, such as paired gaps on the ventral surface of the skull that may pertain to the fenestra ovalis, and a putative neomorphic ossification in the lateral wall of the braincase. Our goals were: (i) to describe the cranial elements of Champsosaurus lindoei in three dimensions; (ii) to describe paired gaps on the ventral surface of the skull to determine if these are indeed the fenestrae ovales; (iii) to illustrate the morphology of the putative neomorphic bone; and (iv) to consider the possible developmental and functional origins of the neomorph. We examined the cranial anatomy of the choristodere Champsosaurus lindoei (CMN 8920) using high-resolution micro-computed tomography scanning. We found that the paired gaps on the ventral surface of the skull do pertain to the fenestrae ovales, an unusual arrangement that may be convergent with some plesiosaurs, some aistopods, and some urodeles. The implications of this morphology in Champsosaurus are unknown and will be the subject of future work. We found that the neomorphic bone is a distinct ossification, but is not part of the wall of the brain cavity or the auditory capsule. Variation in the developmental pathways of cranial bones in living amniotes was surveyed to determine how the neomorphic bone may have developed. We found that the chondrocranium and splanchnocranium show little to no variation across amniotes, and the neomorphic bone is therefore most likely to have developed from the dermatocranium; however, the stapes is a pre-existing cranial element that is undescribed in choristoderes and may be homologous with the neomorphic bone. If the neomorphic bone is not homologous with the stapes, the neomorph likely developed from the dermatocranium through incomplete fusion of ossification centres from a pre-existing bone, most likely the parietal. Based on the apparent morphology of the neomorph in Coeruleodraco, the neomorph was probably too small to play a significant structural role in the skull of early choristoderes and it may have arisen through non-adaptive means. In neochoristoderes, such as Champsosaurus, the neomorph was likely recruited to support the expanded temporal arches.


Origin of stick-slip motion in boundary lubrication.
Molecular dynamics simulations of atomically thin, fluid films confined between two solid plates are described. For a broad range of parameters, a generic stick-slip motion is observed, consistent with the results of recent boundary lubrication experiments. Static plates induce crystalline order in the film. Stick-slip motion involves periodic shear-melting transitions and recrystllization of the film. Uniform motion occurs at high velocities where the film no longer has time to order. These results indicate that the origin of stick-slip motion is thermodynamic instability of the sliding state, rather than a dynamic instability as usually assumed.


MZmine 2: modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data.
Mass spectrometry (MS) coupled with online separation methods is commonly applied for differential and quantitative profiling of biological samples in metabolomic as well as proteomic research. Such approaches are used for systems biology, functional genomics, and biomarker discovery, among others. An ongoing challenge of these molecular profiling approaches, however, is the development of better data processing methods. Here we introduce a new generation of a popular open-source data processing toolbox, MZmine 2. A key concept of the MZmine 2 software design is the strict separation of core functionality and data processing modules, with emphasis on easy usability and support for high-resolution spectra processing. Data processing modules take advantage of embedded visualization tools, allowing for immediate previews of parameter settings. Newly introduced functionality includes the identification of peaks using online databases, MSn data support, improved isotope pattern support, scatter plot visualization, and a new method for peak list alignment based on the random sample consensus (RANSAC) algorithm. The performance of the RANSAC alignment was evaluated using synthetic datasets as well as actual experimental data, and the results were compared to those obtained using other alignment algorithms. MZmine 2 is freely available under a GNU GPL license and can be obtained from the project website at: http://mzmine.sourceforge.net/. The current version of MZmine 2 is suitable for processing large batches of data and has been applied to both targeted and non-targeted metabolomic analyses.


Imaging using cylindrical vector beams in a high-numerical-aperture microscopy system.
Imaging of object structures using cylindrical vector beams in an aplanatic solid immersion lens (SIL) microscope is investigated. Based on a complete optical model of an aplanatic SIL microscope, images of some object structures using radial polarization, azimuthal polarization, and azimuthal vortex beams are simulated. Some interesting imaging effects of these object structures are observed. For example, counterintuitively, it is found that, compared to linear and circular polarizations, radial polarization requires a larger pinhole to acquire a good image and resolution. Similarly, it is shown that an azimuthal vortex beam provides good images for a variety of object structures and pinhole sizes. Theories and explanations are provided to justify the observed effects. The presented results play an important role in high-numerical-aperture optical imaging.


Clinical application of a repositioning scheme, using gold markers and electronic portal imaging.
To implement an on-line correction scheme based on implanted markers to reduce treatment margins in external beam radiation therapy (EBRT) of carcinoma of the prostate. In turn reduction in treatment margins reduces irradiated volumes and offers the possibility of reduced normal tissue complications or escalated target dose. Five or six gold markers were implanted in 10 patients treated for prostate carcinoma using EBRT. All patients were enlisted in an IRB-approved protocol. Before each fraction two portal images were obtained using a low dose (2MU). Positions of the markers were calculated from these images using an in-house developed program. Corrections were applied with a threshold of 2mm displacement. After correction the procedure was repeated. Overall systematic errors were reduced from 7.45, 1.29, and 5.12 mm to 0.65, 0.11, and 0.46 mm in, respectively, the antero-posterior, lateral, and cranio-caudal directions. Likewise, the overall SD were reduced from 5.99, 5.34, and 4.44 mm to 2.82, 2.64, and 2.22 mm, respectively. All reductions were highly significant (P < 0.01) using a t-test for systematic and an F-test for random errors. On an individual level all but three patients showed significant improvements in all directions for the random errors. All patients improved in at least one direction. Systematic errors were significantly lower in all patients. Simulated correction schemes using this data suggest that margin reduction using off-line reduction does not benefit substantially from on-line corrections in the first few fractions. Use of marker-based correction improves the patient position. Factors influencing the accuracy were: (1) number of seeds usable for correction, (2) distribution of markers throughout the volume of interest, and (3) objective instructions for patient realignment.


Oedema extension distance in intracerebral haemorrhage: Association with baseline characteristics and long-term outcome.
Oedema extension distance is a derived parameter that may reduce sample size requirements to demonstrate reduction in perihaematomal oedema in early phase acute intracerebral haemorrhage trials. We aimed to identify baseline predictors of oedema extension distance and its association with clinical outcomes. Using Virtual International Stroke Trials Archive-Intracerebral Haemorrhage, first Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial, and Minimally Invasive Surgery and rtPA for Intracerebral Hemorrhage Evacuation II datasets, we calculated oedema extension distance at baseline and at 72 h measured using computed tomography. Using linear regression, we tested for associations between baseline characteristics and oedema extension distance at 72 h. Ordinal regression (underlying assumptions validated) was used to test for associations between oedema extension distance at baseline and 72 h and oedema extension distance change between baseline and 72 h, and modified Rankin scale scores at 90 days, adjusted for baseline and 72 h prognostic factors. There were 1028 intracerebral haemorrhage cases with outcome data for analyses. Mean (standard deviation, SD) oedema extension distance at 72 h was 0.54 (0.26) cm, and mean oedema extension distance difference from baseline (EED72-0) was 0.24 (0.18) cm. Oedema extension distance at 72 h was greater with increasing baseline haematoma volume and baseline oedema extension distance. Increasing age, lobar haemorrhage, and intraventricular haemorrhage were independently associated with EED72-0. In multifactorial ordinal regression analysis, EED72-0 was associated with worse modified Rankin scale scores at 90 days (odds ratio 1.96, 95% confidence interval 1.00-3.82). Increase in oedema extension distance over 72 h is independently associated with decreasing functional outcome at 90 days. Oedema extension distance may be a useful surrogate outcome measure in early phase trials of anti-oedema or anti-inflammatory treatments in intracerebral haemorrhage.


Prospective isolation of murine hematopoietic stem cells by expression of an Abcg2/GFP allele.
Stem cells from a variety of tissues can be identified by a side population (SP) phenotype based on Hoechst 33342 dye efflux. The Abcg2 transporter is expressed in hematopoietic stem cells (HSCs) and confers this dye efflux activity. To further explore the relationship among Abcg2 expression, the SP phenotype, and HSC activity, we have generated mice in which a green fluorescent protein (GFP) reporter gene was inserted into the Abcg2 locus. In these mice, the majority of bone marrow (BM) cells that expressed the Abcg2/ GFP allele were Ter119(+) erythroid cells. The Abcg2/GFP allele was also expressed in approximately 10% of lineage-negative (Lin(-)) and in 91% of SP cells using stringent conditions for the SP assay. Flow cytometric sorting was used to isolate various Abcg2/GFP(+) BM cell populations that were then tested for HSC activity in transplant assays. There was significant enrichment for HSCs in sorted Lin(-)/ GFP(+) cells, with a calculated HSC frequency of approximately one in 75. There was no HSC activity detected in Lin(-)/GFP(+) cells. Altogether, these results show that Abcg2 is expressed on essentially all murine BM HSCs and can be used as a prospective marker for HSC enrichment.


A SNP and SSR based genetic map of asparagus bean (Vigna. unguiculata ssp. sesquipedialis) and comparison with the broader species.
Asparagus bean (Vigna. unguiculata ssp. sesquipedialis) is a distinctive subspecies of cowpea [Vigna. unguiculata (L.) Walp.] that apparently originated in East Asia and is characterized by extremely long and thin pods and an aggressive climbing growth habit. The crop is widely cultivated throughout Asia for the production of immature pods known as 'long beans' or 'asparagus beans'. While the genome of cowpea ssp. unguiculata has been characterized recently by high-density genetic mapping and partial sequencing, little is known about the genome of asparagus bean. We report here the first genetic map of asparagus bean based on SNP and SSR markers. The current map consists of 375 loci mapped onto 11 linkage groups (LGs), with 191 loci detected by SNP markers and 184 loci by SSR markers. The overall map length is 745 cM, with an average marker distance of 1.98 cM. There are four high marker-density blocks distributed on three LGs and three regions of segregation distortion (SDRs) identified on two other LGs, two of which co-locate in chromosomal regions syntenic to SDRs in soybean. Synteny between asparagus bean and the model legume Lotus. japonica was also established. This work provides the basis for mapping and functional analysis of genes/QTLs of particular interest in asparagus bean, as well as for comparative genomics study of cowpea at the subspecies level.


Therapeutic effects of mesenchymal stem cell-derived microvesicles on pulmonary arterial hypertension in rats.
Microvesicles (MVs) are nanoscale membrane fragments released from virtually all cell types upon activation or apoptosis, and may contribute to the beneficial effects of stem cell therapy. In this study, we investigated the therapeutic effects of mesenchymal stem cell (MSC) derived MVs (MSC-MVs) on pulmonary artery hypertension (PAH) in rats. MSC-MVs were isolated from rat bone marrow MSCs that were cultured in a serum-free conditioned medium. Transmission electron microscopy (TEM), flow cytometry and nanoparticle tracking analysis (NTA) were used to characterize the MVs. Adult SD rats were injected with monocrotaline (50 mg/kg, sc) to induce PAH. Three weeks later, the rats were intravenously injected with MSCs, MSC-MVs or saline for 2 weeks. At the end of treatments, the hemodynamic parameters and pathological right ventricular and pulmonary arterial remodeling were analyzed in each group. The MSC-MVs showed general morphologic characteristics of MVs and expressed annexin V and CD29 markers under TEM, and their size ranged from 40 to 300 nm. Intravenous injection of MSC-MVs or MSCs significantly ameliorated the mean pulmonary artery pressure (mPAP) and mean right ventricle pressure (mRVP) in PAH rats. Furthermore, intravenous injection of MSC-MVs or MSCs significantly decreased the right ventricle (RV) hypertrophy and pulmonary arteriole area index (AI) and thickness index (TI) in PAH rats. Intravenous injection of MSC-MVs or MSCs produces similar beneficial effects for treating PAH, and our results provide a basis for cell-free approach in stem cell therapy.


Early wound complications in advanced head and neck cancer treated with surgery and Ir 192 brachytherapy.
Brachytherapy, either as primary or adjuvant therapy, is increasingly used to treat head and neck cancer. Reports of complications from the use of brachytherapy as adjuvant therapy to surgical excision have been limited and primarily follow Iodine 125 (I125) therapy. Early complications include wound breakdown, infection, flap failure, and sepsis, and late complications may include osteoradionecrosis, bone marrow suppression, or carotid injuries. The authors sought to identify the early wound complications that follow adjuvant interstitial brachytherapy with iridium 192 (IrS92). A retrospective chart review of all patients receiving adjuvant brachytherapy at a tertiary medical center over a 4-year period. Nine patients receiving Ir192 brachytherapy via afterloading catheters placed during surgical resection for close or microscopically positive margin control were evaluated. It was used during primary therapy in six patients and at salvage surgery in three. Early complications were defined as those occurring within 6 weeks of surgical therapy. The overall complication rate was 55% (5/9), and included significant wound breakdown in two patients, minor wound dehiscence in three, and wound infection, bacteremia, and local tissue erosion in one patient each. All complications occurred in patients receiving flap reconstruction and one patient required further surgery to manage the complication. Complication rates were not associated with patient age, site, prior radiotherapy, timing of therapy, number of catheters, or dosimetry. The relatively high complication rate is acceptable, given the minor nature of most and the potential benefit of radiotherapy. Further study should be undertaken to identify those patients who will achieve maximum therapeutic benefit without prohibitive local complications.


Carryover effects of temperature and pCO2 across multiple Olympia oyster populations.
Predicting how populations will respond to ocean change across generations is critical to effective conservation of marine species. One emerging factor is the influence of parental exposures on offspring phenotype, known as intergenerational carryover effects. Parental exposure may deliver beneficial or detrimental characteristics to offspring that can influence larval recruitment patterns, thus shaping how populations and community structure respond to ocean change. Impacts of adult exposure to elevated winter temperature and pCO2 on reproduction and offspring viability were examined in the Olympia oyster (Ostrea lurida) using three populations of adult, hatchery-reared O. lurida, plus an additional cohort spawned from one of the populations. Oysters were sequentially exposed to elevated temperature (+4°C, at 10°C), followed by elevated pCO2 (+2,204 μatm, at 3,045 μatm) during winter months. Male gametes were more developed after elevated temperature exposure and less developed after high pCO2 exposure, but there was no impact on female gametes or sex ratios. Oysters previously exposed to elevated winter temperature released larvae earlier, regardless of pCO2 exposure. Those exposed to elevated winter temperature as a sole treatment released more larvae on a daily basis but, when also exposed to high pCO2 , there was no effect. These combined results indicate that elevated winter temperature accelerates O. lurida spermatogenesis, resulting in earlier larval release and increased production, with elevated pCO2 exposure negating effects of elevated temperature. Altered recruitment patterns may therefore follow warmer winters due to precocious spawning, but these effects may be masked by coincidental high pCO2 . Offspring were reared in common conditions for 1 yr, then deployed for 3 months in four estuarine bays with distinct environmental conditions. Offspring of parents exposed to elevated pCO2 had higher survival rates in two of the four bays. This carryover effect demonstrates that parental conditions can have substantial ecologically relevant impacts that should be considered when predicting impacts of environmental change. Furthermore, Olympia oysters may be more resilient in certain environments when progenitors are pre-conditioned in stressful conditions. Combined with other recent studies, our work suggests that the Olympia may be more equipped than other oysters for the challenge of a changing ocean.


A model system for targeted drug release triggered by biomolecular signals logically processed through enzyme logic networks.
A new Sense-and-Act system was realized by the integration of a biocomputing system, performing analytical processes, with a signal-responsive electrode. A drug-mimicking release process was triggered by biomolecular signals processed by different logic networks, including three concatenated AND logic gates or a 3-input OR logic gate. Biocatalytically produced NADH, controlled by various combinations of input signals, was used to activate the electrochemical system. A biocatalytic electrode associated with signal-processing "biocomputing" systems was electrically connected to another electrode coated with a polymer film, which was dissolved upon the formation of negative potential releasing entrapped drug-mimicking species, an enzyme-antibody conjugate, operating as a model for targeted immune-delivery and consequent "prodrug" activation. The system offers great versatility for future applications in controlled drug release and personalized medicine.


Defining Swallowing-Related Quality of Life Profiles in Individuals with Amyotrophic Lateral Sclerosis.
Although it is known that dysphagia contributes to significant malnutrition, pneumonia, and mortality in amyotrophic lateral sclerosis (ALS), it remains unclear how swallowing impairment impacts quality of life in this vulnerable patient population. The aim of the current study was to (1) delineate swallow-related quality of life (SR-QOL) profiles in individuals with ALS and (2) evaluate relationships between SR-QOL, degree of swallowing impairment, and ALS global disease progression. Eighty-one ALS patients underwent a standardized videofluoroscopic swallow study and completed the swallowing quality of life (SWAL-QOL) instrument and ALS functional rating scale-revised (ALSFRS-R). Penetration Aspiration Scale (PAS) scores were derived by a blinded rater. Correlation analyses and a between groups ANOVA (safe vs. penetrators vs. aspirators) were performed. Mean SWAL-QOL score for this cohort was 75.94 indicating a moderate degree of SR-QOL impairment with fatigue, eating duration, and communication representing the most affected domains. Correlations were revealed between the SWAL-QOL and (1) PAS (r = -0.39, p < 0.001) and (2) ALSFRS-R (r = 0.23, p < 0.05). Mean (SD) SWAL-QOL scores for safe versus penetrator versus aspirator groups were 81.2 (2.3) versus 77 (3.4) versus 58.7 (5.9), respectively, with a main effect observed [F(2,78) = 9.71, p < 0.001]. Post hoc testing revealed lower SWAL-QOL scores for aspirators versus safe swallowers (p < 0.001) and aspirators versus penetrators (p < 0.001). Overall, SR-QOL was moderately reduced in this cohort of ALS patients and profoundly impacted in ALS aspirators and individuals with advanced disease. These findings highlight the importance of early multidisciplinary intervention to not only avoid malnutrition, weight loss, and pulmonary sequelae but also the associated reduced QOL seen in these individuals.


The Barts Explanatory Model Inventory for Dementia: An item reduction approach based on responses from South Asian communities.
Cultural differences in how the symptoms, causes, consequences, and treatments of dementia are understood and interpreted by South Asian people are a commonly expressed reason for late- or nonuse of mental health and care services. However, systematic collection of information on South Asian perceptions of dementia is hindered by a lack of appropriate instrumentation. To produce a shortened version of the Barts Explanatory Model Inventory for Dementia (BEMI-D) schedule. A two stage item reduction approach was employed first using multidimensional scaling categorizing items as core, intermediate, or outlier. Then, item review was undertaken using three criteria: literature importance, clinical face validity, and sub-group prevalence. The analysis followed a nonmetric multidimensional scaling method based on a two-way proximity matrix. The original BEMI-D had 197 items allocated to four checklists: symptoms, causes, consequences, and treatments. The two stage item reduction approach resulted in the removal of 75 items. These reductions were achieved across all four checklists in relatively equal proportions. There was no evidence of substantive content loss in the revised schedule. The reduced version of the schedule comprises 122 items. A condensed version of the BEMI-D is more efficient as an assessment schedule that captures the culturally diverse perceptions of memory problems for South Asians offering a balanced trade-off between feasibility of use and content validity.


Efficacy of Ceftaroline against Methicillin-Susceptible Staphylococcus aureus Exhibiting the Cefazolin High-Inoculum Effect in a Rat Model of Endocarditis.
Certain Staphylococcus aureus strains exhibit an inoculum effect (InE) with cefazolin (CFZ) that has been associated with therapeutic failures in high-inoculum infections. We assessed the in vitro activities of ceftaroline (CPT), CFZ, and nafcillin (NAF) against 17 type A β-lactamase (βla)-producing, methicillin-susceptible S. aureus (MSSA) strains, including the previously reported TX0117, which exhibits the CFZ InE, and its βla-cured derivative, TX0117c. Additionally, we determined the pharmacokinetics of CPT in rats after single intramuscular doses of 20 and 40 mg/kg of body weight and evaluated the activities of CPT (40 mg/kg every 8 h [q8h]), CFZ, and NAF against TX0117 and TX0117c in a rat model of infective endocarditis. No InE was observed for CPT or NAF, whereas a marked InE was detected for CFZ (MIC, 8 to ≥128 μg/ml). CPT and NAF treatment against TX0117 resulted in mean bacterial counts of 2.3 and 2.1 log10 CFU/g in vegetations, respectively, compared to a mean of 5.9 log10 CFU/g in the CFZ-treated group (CPT and NAF versus CFZ, P = 0.001; CPT versus NAF, P = 0.9830). Both CFZ and CPT were efficacious against the βla-cured derivative, TX0117c, compared to time zero (t0) (P = <0.0001 and 0.0015, respectively). Our data reiterate the in vivo consequences of the CFZ InE and show that CPT is not affected by this phenomenon. CPT might be considered for high-inoculum infections caused by MSSA exhibiting the CFZ InE.


Swaying the Public? Impacts of Election Forecast Visualizations on Emotion, Trust, and Intention in the 2022 U.S. Midterms.
We conducted a longitudinal study during the 2022 U.S. midterm elections, investigating the real-world impacts of uncertainty visualizations. Using our forecast model of the governor elections in 33 states, we created a website and deployed four uncertainty visualizations for the election forecasts: single quantile dotplot (1-Dotplot), dual quantile dotplots (2-Dotplot), dual histogram intervals (2-Interval), and Plinko quantile dotplot (Plinko), an animated design with a physical and probabilistic analogy. Our online experiment ran from Oct. 18, 2022, to Nov. 23, 2022, involving 1,327 participants from 15 states. We use Bayesian multilevel modeling and post-stratification to produce demographically-representative estimates of people's emotions, trust in forecasts, and political participation intention. We find that election forecast visualizations can heighten emotions, increase trust, and slightly affect people's intentions to participate in elections. 2-Interval shows the strongest effects across all measures; 1-Dotplot increases trust the most after elections. Both visualizations create emotional and trust gaps between different partisan identities, especially when a Republican candidate is predicted to win. Our qualitative analysis uncovers the complex political and social contexts of election forecast visualizations, showcasing that visualizations may provoke polarization. This intriguing interplay between visualization types, partisanship, and trust exemplifies the fundamental challenge of disentangling visualization from its context, underscoring a need for deeper investigation into the real-world impacts of visualizations. Our preprint and supplements are available at https://doi.org/osf.io/ajq8f.


Changes in the Spinal Neural Circuits are Dependent on the Movement Speed of the Visuomotor Task.
Previous studies have shown that spinal neural circuits are modulated by motor skill training. However, the effects of task movement speed on changes in spinal neural circuits have not been clarified. The aim of this research was to investigate whether spinal neural circuits were affected by task movement speed. Thirty-eight healthy subjects participated in this study. In experiment 1, the effects of task movement speed on the spinal neural circuits were examined. Eighteen subjects performed a visuomotor task involving ankle muscle slow (nine subjects) or fast (nine subjects) movement speed. Another nine subjects performed a non-visuomotor task (controls) in fast movement speed. The motor task training lasted for 20 min. The amounts of D1 inhibition and reciprocal Ia inhibition were measured using H-relfex condition-test paradigm and recorded before, and at 5, 15, and 30 min after the training session. In experiment 2, using transcranial magnetic stimulation (TMS), the effects of corticospinal descending inputs on the presynaptic inhibitory pathway were examined before and after performing either a visuomotor (eight subjects) or a control task (eight subjects). All measurements were taken under resting conditions. The amount of D1 inhibition increased after the visuomotor task irrespective of movement speed (P < 0.01). The amount of reciprocal Ia inhibition increased with fast movement speed conditioning (P < 0.01), but was unchanged by slow movement speed conditioning. These changes lasted up to 15 min in D1 inhibition and 5 min in reciprocal Ia inhibition after the training session. The control task did not induce changes in D1 inhibition and reciprocal Ia inhibition. The TMS conditioned inhibitory effects of presynaptic inhibitory pathways decreased following visuomotor tasks (P < 0.01). The size of test H-reflex was almost the same size throughout experiments. The results suggest that supraspinal descending inputs for controlling joint movement are responsible for changes in the spinal neural circuits, and that task movement speed is one of the critical factors for inducing plastic changes in reciprocal Ia inhibition.


Identification of the MMS22L-TONSL complex that promotes homologous recombination.
Budding yeast Mms22 is required for homologous recombination (HR)-mediated repair of stalled or broken DNA replication forks. Here we identify a human Mms22-like protein (MMS22L) and an MMS22L-interacting protein, NFκBIL2/TONSL. Depletion of MMS22L or TONSL from human cells causes a high level of double-strand breaks (DSBs) during DNA replication. Both proteins accumulate at stressed replication forks, and depletion of MMS22L or TONSL from cells causes hypersensitivity to agents that cause S phase-associated DSBs, such as topoisomerase (TOP) inhibitors. In this light, MMS22L and TONSL are required for the HR-mediated repair of replication fork-associated DSBs. In cells depleted of either protein, DSBs induced by the TOP1 inhibitor camptothecin are resected normally, but the loading of the RAD51 recombinase is defective. Therefore, MMS22L and TONSL are required for the maintenance of genome stability when unscheduled DSBs occur in the vicinity of DNA replication forks.


How valuable are environmental health interventions? Evaluation of water and sanitation programmes in India.
To evaluate and quantify the economic benefits attributable to improvements in water supply and sanitation in rural India. We combined propensity-score "pre-matching" and rich pre-post panel data on 9500 households in 242 villages located in four geographically different districts to estimate the economic benefits of a large-scale community demand-driven water supply programme in Maharashtra, India. We calculated coping costs and cost of illness by adding across several elements of coping and illness and then estimated causal impacts using a difference-in-difference strategy on the pre-matched sample. The pre-post design allowed us to use a difference-in-difference estimator to measure "treatment effect" by comparing treatment and control villages during both periods. We compared average household costs with respect to out-of-pocket medical expenses, patients' lost income, caregiving costs, time spent on collecting water, time spent on sanitation, and water treatment costs due to filtration, boiling, chemical use and storage. Three years after programme initiation, the number of households using piped water and private pit latrines had increased by 10% on average, but no changes in hygiene-related behaviour had occurred. The behavioural changes observed suggest that the average household in a programme community could save as much as 7 United States dollars per month (or 5% of monthly household cash expenditures) in coping costs, but would not reduce illness costs. Poorer, socially marginalized households benefited more, in alignment with programme objectives. Given the renewed interest in water, sanitation and hygiene outcomes, evaluating the economic benefits of environmental interventions by means of causal research is important for understanding the true value of such interventions.


A mobile phone intervention to reduce binge drinking among disadvantaged men: study protocol for a randomised controlled cost-effectiveness trial.
Socially disadvantaged men are at a substantially higher risk of developing alcohol-related problems. The frequency of heavy drinking in a single session is high among disadvantaged men. Brief alcohol interventions were developed for, and are usually delivered in, healthcare settings. The group who binge drink most frequently, young to middle-aged disadvantaged men, have less contact with health services and there is a need for an alternative method of intervention delivery. Text messaging has been used successfully to modify other adverse health behaviours. This study will test whether text messages can reduce the frequency of binge drinking by disadvantaged men. Disadvantaged men aged 25 to 44 years who drank >8 units of alcohol at least twice in the preceding month will be recruited from the community. Two recruitment strategies will be used: contacting men listed in primary care registers, and a community outreach method (time-space sampling). The intended sample of 798 men will be randomised to intervention or control, stratifying by recruitment method. The intervention group will receive a series of text messages designed to reduce the frequency of binge drinking through the formation of specific action plans. The control group will receive behaviourally neutral text messages intended to promote retention in the study. The primary outcome measure is the proportion of men consuming >8 units on at least three occasions in the previous 30 days. Secondary outcomes include total alcohol consumption and the frequency of consuming more than 16 units of alcohol in one session in the previous month. Process measures, developed during a previous feasibility study, will monitor engagement with the key behaviour change components of the intervention. The study will incorporate an economic evaluation comparing the costs of recruitment and intervention delivery with the benefits of reduced alcohol-related harm. This study will assess the effectiveness of a brief intervention, delivered by text messages, aimed at reducing the frequency of binge drinking in disadvantaged men. The process measures will identify components of the intervention which contribute to effectiveness. The study will also determine whether any benefit of the intervention is justified by the costs of intervening. ISRCTN07695192. Date assigned: 14 August 2013.


What influences birth place preferences, choices and decision-making amongst healthy women with straightforward pregnancies in the UK? A qualitative evidence synthesis using a 'best fit' framework approach.
English maternity care policy has supported offering women choice of birth setting for over twenty years, but only 13% of women in England currently give birth in settings other than obstetric units (OUs). It is unclear why uptake of non-OU settings for birth remains relatively low. This paper presents a synthesis of qualitative evidence which explores influences on women's experiences of birth place choice, preference and decision-making from the perspectives of women using maternity services. Qualitative evidence synthesis of UK research published January 1992-March 2015, using a 'best-fit' framework approach. Searches were run in seven electronic data bases applying a comprehensive search strategy. Thematic framework analysis was used to synthesise extracted data from included studies. Twenty-four papers drawing on twenty studies met the inclusion criteria. The synthesis identified support for the key framework themes. Women's experiences of choosing or deciding where to give birth were influenced by whether they received information about available options and about the right to choose, women's preferences for different services and their attributes, previous birth experiences, views of family, friends and health care professionals and women's beliefs about risk and safety. The synthesis additionally identified that women's access to choice of place of birth during the antenatal period varied. Planning to give birth in OU was straightforward, but although women considering birth in a setting other than hospital OU were sometimes well-supported, they also encountered obstacles and described needing to 'counter the negativity' surrounding home birth or birth in midwife-led settings. Over the period covered by the review, it was straightforward for low risk women to opt for hospital birth in the UK. Accessing home birth was more complex and contested. The evidence on freestanding midwifery units (FMUs) is more limited, but suggests that women wanting to opt for an FMU birth experienced similar barriers. The extent to which women experienced similar problems accessing alongside midwifery units (AMUs) is unclear. Women's preferences for different birth options, particularly for 'hospital' vs non-hospital settings, are shaped by their pre-existing values, beliefs and experience, and not all women are open to all birth settings.


Oleuropein-Induced Apoptosis Is Mediated by Mitochondrial Glyoxalase 2 in NSCLC A549 Cells: A Mechanistic Inside and a Possible Novel Nonenzymatic Role for an Ancient Enzyme.
Oleuropein (OP) is a bioactive compound derived from plants of the genus Oleaceae exhibiting antitumor properties in several human cancers, including non-small-cell lung cancer (NSCLC). Recent evidence suggests that OP has proapoptotic effects on NSCLC cells via the mitochondrial apoptotic pathway. However, the exact molecular mechanisms behind the apoptogenic action of OP in NSCLC are still largely unknown. Glyoxalase 2 (Glo2) is an ancient enzyme belonging to the glyoxalase system involved in the detoxification of glycolysis-derived methylglyoxal. However, emerging evidence suggests that Glo2 may have also nonenzymatic roles in some malignant cells. In the present study, we evaluated whether and how Glo2 participated in the proapoptotic effects of OP in NSCLC A549 cells. Our results indicate that OP is able to induce apoptosis in A549 cells through the upregulation of mitochondrial Glo2 (mGlo2), mediated by the superoxide anion and Akt signaling pathway. Moreover, our data shows that the proapoptotic role of mGlo2, observed following OP exposure, occurs via the interaction of mGlo2 with the proapoptotic Bax protein. Conversely, OP does not alter the behavior of nonmalignant human BEAS-2B cells or mGlo2 expression, thus suggesting a specific anticancer role for this bioactive compound in NSCLC. Our data identify a novel pathway through which OP exerts a proapoptotic effect in NSCLC and suggest, for the first time, a novel, nonenzymatic antiapoptotic role for this ancient enzyme in NSCLC.


A robotic voice simulator and the interactive training for hearing-impaired people.
A talking and singing robot which adaptively learns the vocalization skill by means of an auditory feedback learning algorithm is being developed. The robot consists of motor-controlled vocal organs such as vocal cords, a vocal tract and a nasal cavity to generate a natural voice imitating a human vocalization. In this study, the robot is applied to the training system of speech articulation for the hearing-impaired, because the robot is able to reproduce their vocalization and to teach them how it is to be improved to generate clear speech. The paper briefly introduces the mechanical construction of the robot and how it autonomously acquires the vocalization skill in the auditory feedback learning by listening to human speech. Then the training system is described, together with the evaluation of the speech training by auditory impaired people.


A membrane binding domain in the ste5 scaffold synergizes with gbetagamma binding to control localization and signaling in pheromone response.
Activation of mitogen-activated protein (MAP) kinase cascade signaling by yeast mating pheromones involves recruitment of the Ste5 scaffold protein to the plasma membrane by the receptor-activated Gbetagamma dimer. Here, we identify a putative amphipathic alpha-helical domain in Ste5 that binds directly to phospholipid membranes and is required for membrane recruitment by Gbetagamma. Thus, Ste5 signaling requires synergistic Ste5-Gbetagamma and Ste5-membrane interactions, with neither alone being sufficient. Remarkably, the Ste5 membrane binding domain is a dual-function motif that also mediates nuclear import. Separation-of-function mutations show that signaling requires the membrane-targeting activity of this domain, not its nuclear-targeting activity, and heterologous lipid binding domains can substitute for its function. This domain also contains imperfections that reduce membrane affinity, and their elimination results in constitutive signaling, explaining some previous hyperactive Ste5 mutants. Therefore, weak membrane affinity is advantageous, ensuring a normal level of signaling quiescence in the absence of stimulus and imposing a requirement for Gbetagamma binding.


Diffuse photon density wavefront speed as a contrast for tomographic imaging of heterogeneous diffusive media.
An imaging algorithm is implemented for tomographically reconstructing contrast maps of the space variant speed of diffuse photon density wavefronts (DPDWFs) propagating in biological tissue-like diffusing media. This speed serves as a novel contrast not previously exploited in the literature. The algorithm employs early photon arrival times (EPATs) extracted from a set of time domain measurements. A relationship between EPATs and the speed of DPDWFs is exploited as the forward model. The forward model and its use in an inverse problem are supported by experimental results. These are carried out for 3D media with tissue-like optical properties. The resulting inverse problem is formulated as a set of algebraic equations and solved within a constrained linear least squares framework. The results indicate that the algorithm provides tomographic information on heterogeneities locations and distributions.


Rotation thromboelastometry (ROTEM) stability and reproducibility over time.
Thromboelastometry is a whole blood assay performed to evaluate the viscoelastic properties during blood clot formation and lysis. Rotation thromboelastography (ROTEM), Pentapharm GmbH, Munich, Germany) has overcome some of the limitations of classic thromboelastography. So far, no clinical validation on reproducibility (inter- and intra-assay variability) and sample stability over time has been published. To evaluate the pre-analytic aspects, sample stability over time was assessed in 48 patients in eight age groups. Citrated blood was stored at room temperature. Tests measured every 30 min from T 0 min up to T 120 min on two ROTEM devices were INTEM (ellagic acid activated intrinsic pathway), EXTEM (tissue factor-triggered extrinsic pathway) and FIBTEM (with platelet inhibitor (cytochalasin D) evaluating the contribution of fibrinogen to clot formation). Precision by intra- and inter-assay variability was evaluated at two points of time in 10 volunteers. Finally, reference intervals and effect of age and sex were evaluated. Blood was stable over 120 min and no significant differences in ROTEM results were found. Maximum clot firmness measurements had a coefficient of variation of <3% for EXTEM, <5% for INTEM and <6% for FIBTEM. For clot formation time, the coefficient of variation was <4% for EXTEM and <3% for INTEM. Coefficient of variation for angle alpha was <3% for EXTEM and <6% for INTEM. The coefficient of variation for clotting time was <15% for both EXTEM and INTEM. Small but significant differences between ROTEM devices were found for maximum clot firmness in FIBTEM and INTEM as well as clot formation time and alpha angle in INTEM. ROTEM yields stable results over 120 min with a minimal variability on the same ROTEM device. However, small but significant differences between ROTEM devices were observed. Analysis should be performed on the same ROTEM device if small differences are of importance for treatment.


Spot morphology of non-contact printed protein molecules on non-porous substrates with a range of hydrophobicities.
Non-contact inkjet printing technology is one of the most promising tools for producing microarrays. The quality of the microarray depends on the type of the substrate used for printing biomolecules. Various porous and non-porous substrates have been used in the past, but due to low production cost and easy availability, non-porous substrates like glass and plastic are preferred over porous substrates. On these non-porous substrates, obtaining spot uniformity and a high signal to noise ratio is a big challenge. In our research work, we have modified pristine glass slides using various silanes to produce a range of hydrophobic glass substrates. The hydrophobicities of the slides expressed in the contact angle (θ) of a sessile drop of water were 49°, 61°, 75°, 88° and 103°. Using a non-contact inkjet printer, microarrays of biotinylated biomolecules (BSA and IgG) were produced on these modified glass substrates, pristine (untreated) glass and also on HTA polystyrene slides. The uniformity of the spots, reflecting the distribution of the biomolecules in the spots, was analyzed and compared using confocal laser scanning microscopy (CLSM). The quality of the spots was superior on the glass slide with a contact angle of ∼75°. We also investigated the influence of the hydrophobicity of the substrate on a two-step, real diagnostic antibody assay. This nucleic acid microarray immunoassay (NAMIA) for the detection of Staphylococcus aureus showed that on highly hydrophilic (θ < 10°) and hydrophobic substrates (θ > 100°) the assay signal was low, whereas an excellent signal was obtained on the substrates with intermediate contact angles, θ ∼ 61° and θ ∼ 75°, respectively.


Family carers' experiences using support services in Europe: empirical evidence from the EUROFAMCARE study.
This article explores the experiences of family carers of older people in using support services in six European countries: Germany, Greece, Italy, Poland, Sweden, and the UK. Following a common protocol, data were collected from national samples of approximately 1,000 family carers per country and clustered into comparable subgroups to facilitate cross-national analysis. Carers' use of available support services is limited across Europe but is considerably higher in Germany, Sweden, and the UK than in Poland, Greece, and Italy. Service use is more prevalent among wives and carers with stronger support networks and less frequent among working daughters with high levels of burden, suggesting the need for a reconsideration of eligibility criteria and better targeting of service responses. Access to and use of services is characterized by a divide between carers in northwestern Europe, who experience few difficulties other than the older person's refusal to accept the support offered, and carers in southeastern Europe, where service affordability and poor transportation present remarkable barriers. Concerns regarding the timeliness and quality of support are common to all countries. European Union-wide efforts to improve carer support need to focus on improving the care system's ability to provide timely, high-quality care delivered by staff who treat the older person with dignity and respect, and to enhance cooperation between health professionals (in all countries), informal networks (especially in southeastern Europe), social services (particularly in Sweden and the UK), and voluntary organizations (in Germany and the UK).


Punicalagin inhibits neuroinflammation in LPS-activated rat primary microglia.
In this study, the effects of punicalagin on neuroinflammation in LPS-activated microglia were investigated. The ability of punicalagin to reduce the production of TNF-α, IL-6 and prostaglandin E2 was measured in culture medium using enzyme immunoassay. TNF-α and IL-6 gene expression in mouse hippocampal slices was measured with PCR. cyclooxygenase-2 and microsomal prostaglandin E synthase 1 protein and mRNA were evaluated with Western blotting and PCR, respectively. Further experiments to investigate effects of punicalagin on protein expressions of inflammatory targets were also determined with Western blotting. Pretreatment of rat primary microglia with punicalagin (5-40 μM) prior to LPS (10 ng/mL) stimulation produced a significant (p < 0.05) inhibition of TNF-α, IL-6 and prostaglandin E2 production. Punicalagin completely abolished TNF-α and IL-6 gene expression in LPS-stimulated hippocampal slices. Protein and mRNA expressions of cyclooxygenase-2 and microsomal prostaglandin E synthase 1 were also reduced by punicalagin pretreatment. Results show that punicalagin interferes with NF-κB signalling through attenuation of NF-κB-driven luciferase expression, as well as inhibition of IκB phosphorylation and nuclear translocation of p65 subunit in the microglia. These results suggest that punicalagin inhibits neuroinflammation in LPS-activated microglia through interference with NF-κB signalling, suggesting its potential as a nutritional preventive strategy in neurodegenerative disorders.


Accuracy of stereotaxic positioning of transcranial magnetic stimulation.
In cognitive neuroscience, optically tracked frameless stereotaxic navigation has been successfully used to precisely guide transcranial magnetic stimulation (TMS) to desired cortical areas for brain-mapping purposes. Thereby, potential sources of imprecision are the fixation of a reference frame to the head of the subject and the referencing procedure according to certain landmarks (LM). The aim of our study was to evaluate the accuracy of frameless stereotaxic coil positioning in a standard experimental setting. A parameter for accuracy is the reproducibility of LM coordinates. In order to test the stability of the referencing for stereotaxic positioning within a single TMS session (within-session stability), the coordinates of six predefined facial LM in nine subjects were recorded first after the initial registration and second after a 20 minutes TMS session. The two sets of coordinates were then compared. The reliability of the positioning coordinates between different TMS sessions (inter-session repeatability) was addressed by registering the subjects LM coordinates in two independent TMS sessions. The variance of the recorded coordinates was analyzed. Altogether, LM were registered 1728 times (192 measures per subject). Within-session stability: The mean Euclidean distance (MED) between the LM position coordinates before and after a TMS session was 1.6 mm, when pooling over all LM. Inter-session repeatability: The MED between the LM positions recorded after the reference procedures of two different sessions showed an average deviation of 2.5 mm. In conclusion, optically tracked frameless stereotaxic coil positioning is from the technical viewpoint of high stability and repeatability. It is therefore a precise method for TMS brain mapping studies or for repeated TMS treatments, with the need of topographically exact stimulation.


Antitumour antibiotics with potent activity against multidrug resistant (MDR) Staphylococcus aureus: a new approach to targeting resistant bacteria.
As hospital reports of strains of resistant bacteria are continuing to increase, a new approach is required for the identification of small molecules with antibacterial activity. Natural products that bind covalently to their biological target have been largely unexplored, although in the field of cancer chemotherapy, such molecules have been shown to counter resistance developed through efflux mechanisms. The azinomycins are potent antitumour agents that alkylate DNA and one of the natural products, compound 1, is a mono-alkylator that has been reported to retain potent antitumour activity. All four diastereomers of 1 were synthesized via a route involving late stage introduction of the epoxide stereocentre and separation of the resulting compounds. A non-alkylating analogue and a potential alkylator that cannot intercalate were also made. All four diastereomers are potent antibacterial agents in cell lines containing efflux-based resistance mechanisms. MIC values in the range of 0.25-1.0 microg/ml were observed. Comparison with the antitumour activity of the compounds suggests that the antibacterial activity stems from a similar mechanism of action involving DNA alkylation. As the ultimate molecular target of the azinomycins is unknown, bacterial strains may represent an interesting route for the discovery of the downstream mechanisms affected by DNA alkylation.


Effect of urban closed circuit television on assault injury and violence detection.
To evaluate the effect of closed circuit television (CCTV) surveillance on levels of assault injury and violence detection. Intervention versus control study design. Five town/cities with CCTV surveillance and five, matched control centres without CCTV surveillance in England. CCTV installation and surveillance. Assault related emergency department attendances and violent offences recorded by the police in CCTV and control centres in the four years, 1995-99, two years before and two years after CCTV installation, were compared. Assault related emergency department attendances decreased in intervention centres (3% decrease, ratio 0.96; 95% confidence interval (CI) 0.93 to 0.99) and increased in control centres (11% increase, ratio 1.11; 95% CI 1.08 to 1.14). Overall, changes in emergency department assault attendance in CCTV and control centres were significantly different (t test, p<0.05). Police recorded violence increased in CCTV (11% increase, ratio 1.16; 95% CI 1.08 to 1.24) and control centres (5% increase, ratio 1.06; 95% CI 0.99 to 1.13). Overall, changes in police recording in CCTV and control centres were not significantly different (t test, p>0.05). In CCTV centres, decreases in assault related emergency department attendances and increases in police violence detection were not uniform. CCTV surveillance was associated with increased police detection of violence and reductions in injury or severity of injury. CCTV centre variation deserves further study.


A protocol for developing an evaluation framework for an academic and private-sector partnership to assess the impact of major food and beverage companies' investments in community health in the United States.
Public health leaders increasingly recognize the importance of multi-sector partnerships and systems approaches to address obesity. Public-private partnerships (PPP), which are joint ventures between government agencies and private sector entities, may help facilitate this process, but need to be delivered through comprehensive, transparent frameworks to maximize potential benefits and minimize potential risks for all partners. The City University of New York (CUNY) School of Public Health and the Healthy Weight Commitment Foundation (HWCF) propose to engage in a unique academic-private-sector research partnership to evaluate the impact and effectiveness of the food and beverage industry's investment in obesity and hunger prevention and reduction through community-level healthful eating and active living programs. The CUNY-HWCF academic-private partnership protocol described here incorporates best practices from the literature on PPP into the partnership's design. The CUNY-HWCF partnership design demonstrates how established guidelines for partnership components will actively incorporate and promote the principles of successful PPPs identified in various research papers. These identified principles of successful PPP, including mutuality (a reciprocal relationship between entities), and equality among partners, recognition of partners' unique strengths and roles, alignment of resources and expertise toward a common cause, and coordination and delegation of responsibilities, will be embedded throughout the design of governance, management, funding, intellectual property and accountability structures. The CUNY-HWCF partnership responds to the call for increased multi-sector work in obesity prevention and control. This framework aims to promote transparency and the shared benefits of complementary expertise while minimizing shared risks and conflicts of interest. This framework serves as a template for future academic-private research partnerships.


Alpha and theta rhythm abnormality in Alzheimer's Disease: a study using a computational model.
Electroencephalography (EEG) studies in Alzheimer's Disease (AD) patients show an attenuation of average power within the alpha band (7.5-13 Hz) and an increase of power in the theta band (4-7 Hz). Significant body of evidence suggest that thalamocortical circuitry underpin the generation and modulation of alpha and theta rhythms. The research presented in this chapter is aimed at gaining a better understanding of the neuronal mechanisms underlying EEG band power changes in AD which may in the future provide useful biomarkers towards early detection of the disease and for neuropharmaceutical investigations. The study is based on a classic computational model of the thalamocortical circuitry which exhibits oscillation within the theta and the alpha bands. We are interested in the change in model oscillatory behaviour corresponding with changes in the connectivity parameters in the thalamocortical as well as sensory input pathways. The synaptic organisation as well as the connectivity parameter values in the model are modified based on recent experimental data from the cat thalamus. We observe that the inhibitory population in the model plays a crucial role in mediating the oscillatory behaviour of the model output. Further, increase in connectivity parameters in the afferent and efferent pathways of the inhibitory population induces a slowing of the output power spectra. These observations may have implications for extending the model for further AD research.


A review of screening tests for cognitive impairment.
The merit of screening for dementia and cognitive impairment has been the subject of recent debate. One of the main limitations in this regard is the lack of robust evidence to support the many screening tests available. Although plentiful in number, few such instruments have been well validated in the populations for which they are intended to be used. In addition, it is likely that "one size does not fit all" in cognitive screening, leading to the development of many specialised tests for particular types of impairment. In this review, we sought to ascertain the number of screening tools currently available, and to examine the evidence for their validity in detecting different diagnoses in a variety of populations. A further consideration was whether each screen elicited indices of a range of cognitive, affective and functional domains or abilities, as such information is a valuable adjunct to simple cut-off scores. Thirty-nine screens were identified and discussed with reference to three purposes: brief assessment in the doctor's office; large scale community screening programmes; and identifying profiles of impairment across different cognitive, psychiatric and functional domains/abilities, to guide differential diagnosis and further assessment. A small number of screens rated highly for both validity and content. This review is intended to serve as an evaluative resource, to guide clinicians and researchers in choosing among the wide range of screens which are currently available.


Comparative effects of pulsatile and nonpulsatile flow on plasma fibrinolytic balance in pediatric patients undergoing cardiopulmonary bypass.
In the brain, the components of the fibrinolytic system, tissue plasminogen activator (tPA) and its endogenous inhibitor plasminogen activator inhibitor-1 (PAI-1), regulate various neurophysiological and pathological responses. Fibrinolytic balance depends on PAI-1 and tPA concentrations. The objective of this study is to compare the effects of pulsatile and nonpulsatile perfusion on fibrinolytic balance in children undergoing pediatric cardiopulmonary bypass (CPB). Plasma PAI-1 antigen and tPA antigen were measured in 40 children (n = 20 pulsatile and n = 20 nonpulsatile group). Plasma samples (1.5 mL) were collected (i) prior to incision, (ii) 1 h after CPB, and (iii) 24 h after CPB. PAI-1 and tPA levels were measured at each time point. PAI-1 and tPA levels were significantly increased at 1 h after CPB, followed by a decrease at 24 h. Nonpulsatile but not pulsatile CPB lowered PAI-1 : tPA ratio significantly at 24 h (median PAI-1 : tPA ratio 4.63 ± 0.83:1.98 ± 0.48, P = 0.03, for the nonpulsatile group and 4.50 ± 0.92:3.56 ± 1.28, P = 0.2, for the pulsatile group). These results suggest that pulsatile flow maintains endogenous fibrinolytic balance after pediatric cardiopulmonary bypass. Further studies are needed to define the clinical significance of these differences.


The challenge of emerging and re-emerging infectious diseases.
Infectious diseases have for centuries ranked with wars and famine as major challenges to human progress and survival. They remain among the leading causes of death and disability worldwide. Against a constant background of established infections, epidemics of new and old infectious diseases periodically emerge, greatly magnifying the global burden of infections. Studies of these emerging infections reveal the evolutionary properties of pathogenic microorganisms and the dynamic relationships between microorganisms, their hosts and the environment.


Plasma concentrations of alpha-MSH, AgRP and leptin in lean and obese men and their relationship to differing states of energy balance perturbation.
A great deal of attention has focused on the central role of alpha melanocyte-stimulating hormone (alpha-MSH) and its antagonism at the melanocortin-4 receptor (MC4R) by agouti related protein (AgRP) in the regulation of energy balance. However, very little is known regarding the function of circulating AgRP and alpha-MSH in humans. We aimed to determine whether circulating alpha-MSH and AgRP are responsive to long-term perturbations in energy balance, in a manner consistent with their central putative functions. Circulating alpha-MSH, AgRP and leptin were measured in both lean (n = 11) and obese (n = 18) male volunteers, some of whom (lean n = 11, obese n = 12) were then allocated one of two weight-loss dietary strategies to achieve about 5% weight loss. This was achieved by either total starvation (for 4-6 days) for rapid weight loss or a very low calorie diet (VLCD, 2.6 MJ/day) (11-12 days) for less rapid weight loss, in both the lean and obese volunteers. At baseline, prior to any weight loss both plasma alpha-MSH (15.8 +/- 1.2 vs. 5.8 +/- 1.0 pmol/l +/- SEM; P < 0.001) and AgRP (49.4 +/- 2.4 vs. 10.1 +/- 0.9 pg/ml +/- SEM; P < 0.001) were elevated in obese subjects compared with lean. In both cases this correlated closely with fat mass (P < 0.001), percentage body fat (P < 0.001) and leptin (P < 0.05). Plasma AgRP increased significantly during a 6-day fast in lean individuals (11.1 +/- 1.6 vs. 21.6 +/- 3.1 pg/ml +/- SEM; P < 0.05) but not in the VLCD subjects or in the obese, while alpha-MSH was not affected by any changes in energy balance in either the lean or the obese volunteers. We show a difference in alpha-MSH and AgRP in lean and obese subjects that correlates closely with body fat at baseline. We demonstrate an increase in plasma AgRP during a 6-day fast in lean individuals that is coincident with a decrease in plasma leptin. This increase in AgRP was not due to weight loss per se as there was no change in AgRP as a result of the same weight loss in the VLCD intervention in lean individuals. The source of the increase in plasma AgRP and its physiological function in the periphery remains to be elucidated but we suggest that the dynamics of the change in plasma leptin may determine the elevation in fasting plasma AgRP in lean subjects.


TOPPView: an open-source viewer for mass spectrometry data.
Visualization of complex mass spectrometric data sets is becoming increasingly important in proteomics and metabolomics. We present TOPPView, an integrated data visualization and analysis tool for mass spectrometric data sets. TOPPView allows the visualization and comparison of individual mass spectra, two-dimensional LC-MS data sets and their accompanying metadata. By supporting standardized XML-based data exchange formats, data import is possible from any type of mass spectrometer. The integrated analysis tools of the OpenMS Proteomics Pipeline (TOPP) allow efficient data analysis from within TOPPView through a convenient graphical user interface. TOPPView runs on all major operating systems and is available free of charge under an open-source license at http://www.openms.de.


Prediction of human miRNA target genes using computationally reconstructed ancestral mammalian sequences.
MicroRNAs (miRNA) are short single-stranded RNA molecules derived from hairpin-forming precursors that play a crucial role as post-transcriptional regulators in eukaryotes and viruses. In the past years, many microRNA target genes (MTGs) have been identified experimentally. However, because of the high costs of experimental approaches, target genes databases remain incomplete. Although several target prediction programs have been developed in the recent years to identify MTGs in silico, their specificity and sensitivity remain low. Here, we propose a new approach called MirAncesTar, which uses ancestral genome reconstruction to boost the accuracy of existing MTGs prediction tools for human miRNAs. For each miRNA and each putative human target UTR, our algorithm makes uses of existing prediction tools to identify putative target sites in the human UTR, as well as in its mammalian orthologs and inferred ancestral sequences. It then evaluates evidence in support of selective pressure to maintain target site counts (rather than sequences), accounting for the possibility of target site turnover. It finally integrates this measure with several simpler ones using a logistic regression predictor. MirAncesTar improves the accuracy of existing MTG predictors by 26% to 157%. Source code and prediction results for human miRNAs, as well as supporting evolutionary data are available at http://cs.mcgill.ca/∼blanchem/mirancestar.


The microglial component of amyotrophic lateral sclerosis.
Microglia are the primary immune cells of the CNS, carrying out key homeostatic roles and undergoing context-dependent and temporally regulated changes in response to injury and neurodegenerative diseases. Microglia have been implicated in playing a role in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by extensive motor neuron loss leading to paralysis and premature death. However, as the pathomechansims of ALS are increasingly recognized to involve a multitude of different cell types, it has been difficult to delineate the specific contribution of microglia to disease. Here, we review the literature of microglial involvement in ALS and discuss the evidence for the neurotoxic and neuroprotective pathways that have been attributed to microglia in this disease. We also discuss accumulating evidence for spatiotemporal regulation of microglial activation in this context. A deeper understanding of the role of microglia in the 'cellular phase' of ALS is crucial in the development of mechanistically rationalized therapies.


Growth of high aspect ratio nanometer-scale magnets with chemical vapor deposition and scanning tunneling microscopy.
A combination of chemical vapor deposition and scanning tunneling microscopy techniques have been used to produce nanometer-scale, iron-containing deposits with high aspect ratios from an iron pentacarbonyl precursor both on a substrate and on the tunneling tip itself. The structure and composition of the resulting nanodeposits were determined by transmission electron microscopy and high spatial resolution Auger electron spectroscopy. Either polycrystalline, relatively pure, body-centered-cubic iron or disordered carbon-rich material can be deposited, depending on the bias conditions of the tip sample junction and the precursor pressure. Two mechanisms of decomposition are inferred from the growth phenomenology.


[Urodynamics of the bladder diverticulum in the adult male].
To evaluate the clinical and urodynamic characteristics of a series of adult males with BPH and bladder diverticula, and to analyze the changes in urodynamics in patients undergoing lower urinary tract surgery to relieve obstruction, with or without associated diverticulectomy. We studied 91 patients in two groups: Group 1- BPH: 67 cases (73.6%) and Group 2-BPH + diverticulum: 24 cases (25%). Mean age was 65.04 years. All patients underwent urological physical examination and complete urodynamic study including cystogram. In addition, we studied 19 patients with BPH and bladder diverticula (mean age 64.58 years) who underwent either endoscopic surgery (1 I cases; 57.9%) or endoscopic surgery plus diverticulectomy (8 cases, 42. 1%). Complete clinical study and urodynamics (including cystogram) were performed preoperative and three months after surgery. Statistical significance was established at 0.05. Comparative study between group 1 (BPH) and group 2 (BPH with diverticulum): there were significant differences in clinical data: acute urinary retention (6.1% vs. 25%;p<0.01), and urinary tract infection (3.1% vs. 21.7%;p=0,004). All evaluated cases had single diverticula (8 cases). Urodynamic studies showed: 1) Post-void residual after free flowmetry: 45.9 ml vs. 221.4 ml, p = 0.008. 2) Bladder capacity on cystometrogram: 211.2 ml vs. 350.8 ml, p = 0.024. 3) Voiding pressure/flow study: a) Voiding with abdominal press 23.9% vs. 50%, p = 0.02. b) URA 36.5 cm H2O vs. 48.5 cm H2O, p= 0.04, c) post void residual 70.7ml vs. 210.3 ml, p= 0.004. d) Bladder contractility measurements (Wmax- isometric contractility- and W80, W20- isotonic contractility) did not show significant differences between groups. Bladder contractility duration was significantly decreased in group 2. In the analysis of patients undergoing surgery to relieve obstruction (Group A- Surgery without diverticulectomy; Group B Surgery with diverticulectomy) there were not differences between groups in clinical data. Urethral resistance parameters (URA) decreased in both groups. Group A: from 43 cm H20 to 26.3 cm H2O. Group B: from 60.6 cm H2O to 48 cm H2O. This decrease was similar after either TURP or myocapsulotomy. Post void residual diminished in both groups. There were no statistical differences between groups in Wmax, W 80-20, or volume, number and site of the diverticula. On the contrary, bladder contractility duration diminished after diverticulectomy. Bladder diverticula appear in the cases with highest ureteral resistance values (lower urinary tract obstruction). Standard bladder contractility parameters were not diminished. Duration of detrusor contraction was the only contractility parameter significantly affected in cases of bladder diverticula and presented a significant association with the use of abdominal press while voiding. Diverticulectomy showed an improvement of bladder contractility with longer detrusor contraction duration, which supports its use in cases of BPH-associated diverticula. Both TURP and transurethral incision of the prostate diminished urethral resistance in a similar way, so that they may be considered alternative options. Our data should be confirmed with a bigger sample size.


Protocol describing a systematic review and mixed methods consensus process to define the deteriorated ward patient.
Most patients admitted to hospital recover with treatments that can be administered on the general ward. A small but important group deteriorate however and require augmented organ support in areas with increased nursing to patient ratios. In observational studies evaluating this cohort, proxy outcomes such as unplanned intensive care unit admission, cardiac arrest and death are used. These outcome measures introduce subjectivity and variability, which in turn hinders the development and accuracy of the increasing numbers of electronic medical record (EMR) linked digital tools designed to predict clinical deterioration. Here, we describe a protocol for developing a new outcome measure using mixed methods to address these limitations. We will undertake firstly, a systematic literature review to identify existing generic, syndrome-specific and organ-specific definitions for clinically deteriorated, hospitalised adult patients. Secondly, an international modified Delphi study to generate a short list of candidate definitions. Thirdly, a nominal group technique (NGT) (using a trained facilitator) will take a diverse group of stakeholders through a structured process to generate a consensus definition. The NGT process will be informed by the data generated from the first two stages. The definition(s) for the deteriorated ward patient will be readily extractable from the EMR. This study has ethics approval (reference 16399) from the Central Adelaide Local Health Network Human Research Ethics Committee. Results generated from this study will be disseminated through publication and presentation at national and international scientific meetings.


A comparative study on carbon footprint of rice production between household and aggregated farms from Jiangxi, China.
Quantifying the carbon footprint (CF) for crop production can help identify key options to mitigate greenhouse gas (GHG) emissions in agriculture. In the present study, both household and aggregated farm scales were surveyed to obtain the data of rice production and farming management practices in a typical rice cultivation area of Northern Jiangxi, China. The CFs of the different rice systems including early rice, late rice, and single rice under household and aggregated farm scale were calculated. In general, early rice had the lower CF in terms of land use and grain production being 4.54 ± 0.44 t CO2-eq./ha and 0.62 ± 0.1 t CO2-eq./t grain than single rice (6.84 ± 0.79 t CO2-eq./ha and 0.80 ± 0.13 t CO2-eq./t grain) and late rice (8.72 ± 0.54 t CO2-eq./ha and 1.1 ± 0.17 t CO2-eq./t grain). The emissions from nitrogen fertilizer use accounted for 33 % of the total CF on average and the direct CH4 emissions for 57 %. The results indicated that the CF of double rice cropping under aggregated farm being 0.86 ± 0.11 t CO2-eq./t grain was lower by 25 % than that being 1.14 ± 0.25 t CO2-eq./t grain under household farm, mainly due to high nitrogen use efficiency and low methane emissions. Therefore, developing the aggregated farm scale with efficient use of agro-chemicals and farming operation for greater profitability could offer a strategy for reducing GHG emissions in China's agriculture.


Down-regulation of Yes Associated Protein 1 expression reduces cell proliferation and clonogenicity of pancreatic cancer cells.
The Hippo pathway regulates organ size by inhibiting cell proliferation and promoting cell apoptosis upon its activation. The Yes Associated Protein 1 (YAP1) is a nuclear effector of the Hippo pathway that promotes cell growth as a transcription co-activator. In human cancer, the YAP1 gene was reported as amplified and over-expressed in several tumor types. Immunohistochemical staining of YAP1 protein was used to assess the expression of YAP1 in pancreatic tumor tissues. siRNA oligonucleotides were used to knockdown the expression of YAP1 and their effects on pancreatic cancer cells were investigated using cell proliferation, apoptosis, and anchorage-independent growth assays. The Wilcoxon signed-rank, Pearson correlation coefficient, Kendall's Tau, Spearman's Rho, and an independent two-sample t (two-tailed) test were used to determine the statistical significance of the data. Immunohistochemistry studies in pancreatic tumor tissues revealed YAP1 staining intensities were moderate to strong in the nucleus and cytoplasm of the tumor cells, whereas the adjacent normal epithelial showed negative to weak staining. In cultured cells, YAP1 expression and localization was modulated by cell density. YAP1 total protein expression increased in the nuclear fractions in BxPC-3 and PANC-1, while it declined in HPDE6 as cell density increased. Additionally, treatment of pancreatic cancer cell lines, BxPC-3 and PANC-1, with YAP1-targeting siRNA oligonucleotides significantly reduced their proliferation in vitro. Furthermore, treatment with YAP1 siRNA oligonucleotides diminished the anchorage-independent growth on soft agar of pancreatic cancer cells, suggesting a role of YAP1 in pancreatic cancer tumorigenesis. YAP1 is overexpressed in pancreatic cancer tissues and potentially plays an important role in the clonogenicity and growth of pancreatic cancer cells.


Mechanistic insights into heterogeneous methane activation.
While natural gas is an abundant chemical fuel, its low volumetric energy density has prompted a search for catalysts able to transform methane into more useful chemicals. This search has often been aided through the use of transition state (TS) scaling relationships, which estimate methane activation TS energies as a linear function of a more easily calculated descriptor, such as final state energy, thus avoiding tedious TS energy calculations. It has been shown that methane can be activated via a radical or surface-stabilized pathway, both of which possess a unique TS scaling relationship. Herein, we present a simple model to aid in the prediction of methane activation barriers on heterogeneous catalysts. Analogous to the universal radical TS scaling relationship introduced in a previous publication, we show that a universal TS scaling relationship that transcends catalysts classes also seems to exist for surface-stabilized methane activation if the relevant final state energy is used. We demonstrate that this scaling relationship holds for several reducible and irreducible oxides, promoted metals, and sulfides. By combining the universal scaling relationships for both radical and surface-stabilized methane activation pathways, we show that catalyst reactivity must be considered in addition to catalyst geometry to obtain an accurate estimation for the TS energy. This model can yield fast and accurate predictions of methane activation barriers on a wide range of catalysts, thus accelerating the discovery of more active catalysts for methane conversion.


Acinetobacter beijerinckii sp. nov. and Acinetobacter gyllenbergii sp. nov., haemolytic organisms isolated from humans.
The taxonomic status of 24 haemolytic, non-glucose acidifying Acinetobacter strains that did not belong to any previously described species was investigated by means of a polyphasic approach. Using AFLP fingerprinting, amplified rDNA restriction analysis and phenotypic characterization, the strains were classified into two phenetically coherent groups (comprising 15 and 9 strains) that were distinct from each other and from all known Acinetobacter species. Confirmation that these groups formed two separate lineages within the genus Acinetobacter was obtained from comparative analysis of partial sequences of the gene encoding the beta-subunit of RNA polymerase in all strains and also from 16S rRNA gene sequence analysis of representative strains. Previously published DNA-DNA reassociation data for some of the strains used also supported the species rank for both groups, for which the names Acinetobacter beijerinckii sp. nov. and Acinetobacter gyllenbergii sp. nov. are proposed. The strains of A. beijerinckii sp. nov. originated from human and animal specimens and from various environmental sources, whereas those of A. gyllenbergii sp. nov. were isolated exclusively from human clinical specimens. The phenotypic characteristics most useful for the differentiation of these species from other Acinetobacter species that comprise haemolytic strains were the inability of A. beijerinckii sp. nov. to grow on l-arginine and the ability of A. gyllenbergii sp. nov. to grow on azelate. The type strain of A. beijerinckii sp. nov. is NIPH 838T (=LUH 4759T=CCUG 51249T=CCM 7266T=58aT) and the type strain of A. gyllenbergii sp. nov. is NIPH 2150T (=RUH 422T=CCUG 51248T=CCM 7267T=1271T).


In-utero and perinatal influences on suicide risk: a systematic review and meta-analysis.
Adverse in-utero and perinatal conditions might contribute to an increased suicide risk throughout the lifespan; however, existing evidence is sparse and contradictory. We aimed to investigate in-utero and perinatal exposures associated with suicide, suicide attempt, and suicidal ideation. We did a systematic review and meta-analysis and searched MEDLINE, Embase, and PsycINFO from inception to Jan 24, 2019, for population-based prospective studies that investigated the association between in-utero and perinatal factors and suicide, suicide attempt, and suicidal ideation. Only papers published in English in peer-reviewed journals were considered. Two researchers independently extracted formal information (eg, country, year, duration of follow-up) and number of cases and non-cases exposed and non-exposed to each risk factor. We calculated pooled odds ratios (ORs) with 95% CIs using random-effects models and used meta-regression to investigate heterogeneity. This study was registered with PROSPERO, number CRD42018091205. We identified 42 eligible studies; they had a low risk of bias (median quality score 9/9 [IQR 8-9]). Family or parental characteristics, such as high birth order (eg, for fourth-born or later-born vs first-born, pooled OR 1·51 [95% CIs 1·21-1·88]), teenage mothers (1·80 [1·52-2·14]), single mothers (1·57 [1·31-1·89]); indices of socioeconomic position, such as low maternal (1·36 [1·28-1·46]) and paternal (1·38 [1·27-1·51]) education; and fetal growth (eg, low birthweight 1·30 [1·09-1·55] and small for gestational age 1·18 [1·00-1·40]) were associated with higher suicide risk. Father's age, low gestational age, obstetric characteristics (eg, caesarean section), and condition or exposure during pregnancy (eg, maternal smoking or hypertensive disease) were not associated with higher suicide risk. Similar patterns of associations were observed for suicide attempt and suicidal ideation; however, these results were based on a lower number of studies. In meta-regression, differences in length of follow-up explained most between-study heterogeneity (inital I2 ranged from 0 to 79·5). These findings suggest that prenatal and perinatal characteristics are associated with increased suicide risk during the life course, supporting the developmental origin of health and diseases hypothesis for suicide. The low number of studies for some risk factors, especially for suicide attempt and ideation, leaves gaps in knowledge that need to be addressed. The mechanisms underlying the reported associations and their causal nature still remain unclear. Horizon 2020 (EU).


Expression of aquaporin-4 water channels in rat cholangiocytes.
We recently reported that secretin induces the exocytic insertion of functional aquaporin-1 water channels (AQP1) into the apical membrane of cholangiocytes and proposed that this was a key process in ductal bile secretion. Because AQP1 is present on the basolateral cholangiocyte membrane in low amounts, we hypothesized that another AQP must be expressed at this domain to facilitate transbasolateral water movement. Thus, we investigated the expression, subcellular localization, possible regulation by secretin, and functional activity of AQP4, a mercury-insensitive water channel expressed in other fluid transporting epithelia. Using reverse transcription-polymerase chain reaction (RT-PCR) on RNA prepared from purified rat cholangiocytes, we amplified a product of 311 bp that was 100% homologous to the reported AQP4 sequence. RNase protection assay confirmed the presence of an appropriate size transcript for AQP4 in cholangiocytes. Immunoblotting detected a band of approximately 31 kd corresponding to AQP4 in basolateral but not apical membranes of cholangiocytes. Secretin did not alter the amount of plasma membrane AQP4 but, as expected, induced AQP1 redistribution from intracellular to apical plasma membranes. Functional studies showed that AQP4 accounts for about 15% of total cholangiocyte membrane water permeability. Our results indicate that: (1) cholangiocytes express AQP4 messenger RNA (mRNA) and protein and (2) in contrast to AQP1, which is targeted to the apical cholangiocyte membrane by secretin, AQP4 is constitutively expressed on the basolateral cholangiocyte membrane and is secretin unresponsive. The data suggest that AQP4 facilitates the basolateral transport of water in cholangiocytes, a process that could be relevant to ductal bile formation.


Effects of Screening Compliance on Long-term Reductions in All-Cause and Colorectal Cancer Mortality.
Randomized trials have shown that biennial fecal occult blood test (FOBT) screening reduces mortality from colorectal cancer (CRC), but not overall mortality. Differences in benefit for men vs women, and by age, are unknown. We sought to evaluate long-term reduction in all-cause and CRC-specific mortality in men and women who comply with offered screening, and in different age groups, using individual participant data from 2 large randomized trials of biennial FOBT screening, compared with an intention to treat analysis. We updated the CRC and all-cause mortality from the Danish CRC screening trial (n = 61,933) through 30 years of follow up and pooled individual participant data with individual 30-year follow-up data from the Minnesota Colon Cancer Control trial (n = 46,551). We compared the biennial screening groups to usual care (controls) in individuals 50-80 years old using Kaplan Meier estimates of relative risks and risk differences, adjusted for study differences in age, sex, and compliance. Through 30 years of follow up, there were 33,478 (71.9%) and 33,479 (72.2%) total deaths and 1023 (2.2%) and 1146 (2.5%) CRC deaths in the biennial screening (n = 46,553) and control groups (n = 46,358), respectively. Among compliers, biennial FOBT screening significantly reduced CRC mortality by 16% (relative risk [RR], 0.84; 95% CI, 0.74-0.96) and all-cause mortality by 2% (RR, 0.98; 95% CI, 0.97-0.99). Among compliers, the reduction in CRC mortality was larger for men (RR, 0.75; 95% CI, 0.62-0.90) than women (RR, 0.91; 95% CI, 0.75-1.09). The largest reduction in CRC mortality was in compliant men 60-69 years old (RR, 0.59; 95% CI, 0.42-0.81) and women 70 years and older (RR, 0.53; 95% CI, 0.30-0.94). Long-term CRC mortality outcomes of screening among compliers using biennial FOBT are sustained, with a statistically significant reduction in all-cause mortality. The reduction in CRC mortality is greater in men than women-the benefit in women lags that of men by about 10 years.


Extrapyramidal symptoms with selective serotonin reuptake inhibitors.
Several case reports in the literature suggest that selective serotonin reuptake inhibitors can produce extrapyramidal symptoms. Computerised literature searches were used to identify reports on extrapyramidal symptoms and serotonin reuptake inhibitors. Subsequently, manual searches were made for articles in which there was any indication of the mechanisms responsible for these extrapyramidal symptoms. Only a few reports could be identified in which serotonin reuptake inhibitors were implicated in extrapyramidal symptoms in some patients. Evidence is discussed from preclinical and clinical studies suggesting the interaction between serotoninergic and dopaminergic neurotransmitter system, as a possible mechanism for production of extrapyramidal symptoms.


Nalmefene: A Novel Drug for an Old Disorder.
Alcoholism is an increasing problem all over the world, and nowadays especially amongst teenagers. Although several drug treatments have been proposed for this condition, only a few have demonstrated a significant efficacy. Nalmefene, a novel compound that combines opioids mu-receptors antagonism and kappa-receptors partial agonism, was recently approved by the European Medicine Agency for the treatment of alcoholism. This drug can be very helpful in reducing the alcohol intake, and, as such, it can be considered one of the first and fundamental steps towards alcohol abstinence. The aim of this review is to discuss and comment on the available literature on nalmefene, as well as on novel treatment strategies of this condition (and perhaps of other addictions) opened by this latest pharmacological approach.


Perceiving animacy purely from visual motion cues involves intraparietal sulcus.
Distinguishing animate from inanimate objects is fundamental for social perception in humans and animals. Visual motion cues indicative of self-propelled object motion are useful for animacy perception: they can be detected over a wide expanse of visual field, at distance and in low visibility conditions, can attract attention and provide clues about object behaviour. However, the neural correlates of animacy perception evoked exclusively by visual motion cues, i.e. not relying on form, background or visual context, are unclear. We aimed to address this question in four psychophysical experiments in humans, two of which performed during neuroimaging. The stimulus was a single dot with constant form that moved on a blank background and evoked controlled degrees of perceived animacy through parametric variations of self-propelled motion cues. BOLD signals reflecting perceived animacy in a graded manner irrespective of eye movements were found in one intraparietal region. Additional whole-brain and region-of-interest analyses revealed no comparable effects in brain regions associated with social processing or other areas. Our study shows that animacy perception evoked solely by visual motion cues, a basic perceptual process in social cognition, engages brain regions not primarily associated with social cognition.


Polytene Chromosomes - A Portrait of Functional Organization of the Drosophila Genome.
This mini-review is devoted to the problem genetic meaning of main polytene chromosome structures - bands and interbands. Generally, densely packed chromatin forms black bands, moderately condensed regions form grey loose bands, whereas decondensed regions of the genome appear as interbands. Recent progress in the annotation of the Drosophila genome and epigenome has made it possible to compare the banding pattern and the structural organization of genes, as well as their activity. This was greatly aided by our ability to establish the borders of bands and interbands on the physical map, which allowed to perform comprehensive side-by-side comparisons of cytology, genetic and epigenetic maps and to uncover the association between the morphological structures and the functional domains of the genome. These studies largely conclude that interbands 5'-ends of housekeeping genes that are active across all cell types. Interbands are enriched with proteins involved in transcription and nucleosome remodeling, as well as with active histone modifications. Notably, most of the replication origins map to interband regions. As for grey loose bands adjacent to interbands, they typically host the bodies of house-keeping genes. Thus, the bipartite structure composed of an interband and an adjacent grey band functions as a standalone genetic unit. Finally, black bands harbor tissue-specific genes with narrow temporal and tissue expression profiles. Thus, the uniform and permanent activity of interbands combined with the inactivity of genes in bands forms the basis of the universal banding pattern observed in various Drosophila tissues.