Multicationic Quaternary Ammonium Compounds: A Framework for Combating Bacterial Resistance.
During previous stages of research, high biocidal activity toward microorganism archival strains has been used as the main indicator in the development of new antiseptic formulations. Although this factor remains one of the most important characteristics of biocide efficiency, the scale of antimicrobial resistance spread causes serious concern. Therefore, focus shifts toward the development of formulations with a stable effect even in the case of prolonged contact with pathogens. Here, we introduce an original isocyanuric acid alkylation method with the use of available alkyl dichlorides, which opened access to a wide panel of multi-QACs with alkyl chains of various lengths between the nitrogen atoms of triazine and pyridine cycles. We used a complex approach for the resulting series of 17 compounds, including their antibiofilm properties, bacterial tolerance development, and antimicrobial activity toward multiresistant pathogenic strains. As a result of these efforts, available compounds have shown higher levels of antibacterial activity against ESKAPE pathogens than widely used commercial QACs. Hit compounds possessed high activity toward clinical bacterial strains and have also demonstrated a long-term biocidal effect without significant development of microorganism tolerance. The overall results indicated a high level of antibacterial activity and the broad application prospects of multi-QACs based on isocyanuric acid against multiresistant bacterial strains.


The unfolding story of the second demographic transition.
This article presents a narrative of the unfolding of the Second Demographic Transition (SDT) since the theory was first formulated in 1986. The first part recapitulates the foundations of the theory, and documents the spread of the SDT to the point that it now covers most European populations. Also for Europe, it focuses on the relationship between the SDT and the growing heterogeneity in period fertility levels. It is shown that the current positive relationship between SDT and TFR levels is not a violation of the SDT theory, but the outcome of a "split correlation" with different sub-narratives concerning the onset of fertility postponement and the degree of subsequent recuperation in two parts of Europe. The second part of the article addresses the issue of whether the SDT has spread or is currently spreading in industrialized Asian countries. Evidence gathered for Japan, South Korea, Hong Kong, Singapore, and Taiwan is presented. That evidence pertains to both the macro-level (national trends in postponement of marriage and parenthood, rise of cohabitation) and the micro-level (connections between individual values orientations and postponement of parenthood). Strong similarities are found with SDT patterns in Southern Europe, except for the fact that parenthood is still very rare among Asian cohabiting partners.


Synergistic photomagnetic effects in coordination polymer heterostructure particles of Hofmann-like Fe(4-phenylpyridine)2[Ni(CN)4]·0.5H2O and K0.4Ni[Cr(CN)6]0.8·nH2O.
New nanometer scale heterostructure particles of the two-dimensional Hofmann-like Fe(ii) spin-crossover network, Fe(phpy)2[Ni(CN)4]·0.5H2O {phpy = 4-phenylpyridine}, and the Prussian blue analogue K0.4Ni1.0[Cr(CN)6]0.8·nH2O (NiCr-PBA) have been developed, exhibiting synergistic photomagnetic effects, whereby the LIESST (light-induced electron spin-state trapping) effect in the Hofmann-like material induces a magnetization change in the NiCr-PBA. A variety of microscopic and spectroscopic techniques demonstrate the heterogeneous growth of the NiCr-PBA on the Hofmann seed particles and show the Hofmann compound retains its thermal and photoinduced spin transition properties in the heterostructure. The photoinduced magnetization change in the NiCr-PBA network arises from coupling of the two lattices despite dissimilar structure types. Isothermal magnetization minor hysteresis loop studies at 5 K show light absorption leads to changes in the local anisotropy of NiCr-PBA magnetic domains, providing direct evidence for a general magnetomechanical mechanism of light-switchable magnetism in coordination polymer heterostructures combining a photoactive material with a magnet.


Dietary risk factors for ovarian cancer: the Adventist Health Study (United States).
Few prospective studies have reported dietary risk factors for ovarian cancer. A total of 71 histologically confirmed epithelial ovarian cancers occurred among 13,281 non-Hispanic white California Seventh-day Adventist women during follow-up. Participants were part of the Adventist Health Study (AHS) and had no history of cancer or hysterectomy at baseline in 1976 when they completed a detailed lifestyle questionnaire including a dietary assessment. The association of dietary variables with either all ovarian cancer cases or postmenopausal cases was tested using proportional hazards regression with adjustment for age and other covariates. The strongest hazardous risk factor associations among the food variables were found for meat intake with a risk ratio (RR) of 2.42 for intake > or = 1 time/week versus no meat (p for trend = 0.006), and cheese intake with a RR of 2.02 for intake of > 2 time/week versus < 1 per week (p for trend = 0.10), both of these being in postmenopausal cases. We found significantly reduced risk of all ovarian cancer with higher tomato consumption (RR = 0.32) comparing intakes > or = five times/week versus never to < 1 time/week (p for trend = 0.002), and also with higher fruit consumption (p < 0.01). A weak protective association was found with low fat, but not whole milk. Little confounding was observed between these foods.


Application of PAMAM dendrimers in optical sensing.
The need for an improved sensor performance is always encouraging us towards exploring new materials. Following the invention of dendrimers, the possibility was recognised of using them for improving optical sensor performance. Their more important aspects are their two main structural properties: three-dimensional structure and multiple terminal functional groups. In this review, firstly a brief introduction to dendrimers is provided with the focus on PAMAM dendrimers and optical sensors. Recent advances have been reported in those PAMAM dendrimer-based optical sensors, which are used for the detection of pH, cations, and other analyte.


Blood pressure-related hypoalgesia: a systematic review and meta-analysis.
Spontaneous or experimentally induced high blood pressure (BP) is associated with reduced pain perception, known as BP-related hypoalgesia. Despite its clinical implications, such as the interference with early detection of myocardial infarction in 'at risk' groups, the size of the association between high BP and pain has not yet been quantified. Moreover, the distinct association between high BP and physiological or psychological components of pain has not yet been considered so far. The aim of this study was to overcome this gap by performing separate meta-analyses on nociceptive response versus quantifiable perceptual measures of pain in relation to high BP. PubMed and Web of Knowledge databases were searched for English language studies conducted in humans. Fifty-nine studies were eligible for the analyses. Pooled effect sizes (Hedges' g) were compared. Random effect models were used. Results show that higher BP is significantly associated with lower nociceptive response (g = 0.38; k = 6) and reduced pain perception, assessed by quantifiable measures (g = 0.48; k = 59). The association between BP and pain perception, derived from highly heterogeneous studies, was characterized by significant publication bias. BP assessment, pain assessment, site of pain stimulation, percentage of female participants in the sample, and control for potential confounders were significant moderators. Current meta-analytic results confirm the presence of BP-related hypoalgesia and point towards the need for a better understanding of its underlying mechanisms.


Mi-1-mediated resistance to Meloidogyne incognita in tomato may not rely on ethylene but hormone perception through ETR3 participates in limiting nematode infection in a susceptible host.
Root-knot nematodes, Meloidogyne spp., are important pests of tomato (Solanum lycopersicum) and resistance to the three most prevalent species of this genus, including Meloidogyne incognita, is mediated by the Mi-1 gene. Mi-1 encodes a nucleotide binding (NB) leucine-rich repeat (LRR) resistance (R) protein. Ethylene (ET) is required for the resistance mediated by a subset of NB-LRR proteins and its role in Mi-1-mediated nematode resistance has not been characterized. Infection of tomato roots with M. incognita differentially induces ET biosynthetic genes in both compatible and incompatible interactions. Analyzing the expression of members of the ET biosynthetic gene families ACC synthase (ACS) and ACC oxidase (ACO), in both compatible and incompatible interactions, shows differences in amplitude and temporal expression of both ACS and ACO genes in these two interactions. Since ET can promote both resistance and susceptibility against microbial pathogens in tomato, we investigated the role of ET in Mi-1-mediated resistance to M. incognita using both genetic and pharmacological approaches. Impairing ET biosynthesis or perception using virus-induced gene silencing (VIGS), the ET-insensitive Never ripe (Nr) mutant, or 1-methylcyclopropene (MCP) treatment, did not attenuate Mi-1-mediated resistance to M. incognita. However, Nr plants compromised in ET perception showed enhanced susceptibility to M. incognita indicating a role for ETR3 in basal resistance to root-knot nematodes.


[Abnormal liver function in brucellosis].
We assessed the prevalence of impaired liver function in 47 patients suffering from brucellosis consecutively admitted to our department over the last five years. Parameters of liver function and ultrasound of the upper abdomen were performed at entry and at the end of treatment. On admission, mean transaminase values were elevated and significantly higher than at recovery (p 0.001): 38 percent and 53 percent of patients had elevated baseline values of GOT and GPT vs 13 and 19% at the end of treatment, respectively. Mean serum values of alkaline phosphatase (AP) were within normal limits on admission, although in 12 of them serum values were elevated. The same proportion was seen for gamma-glutamyltranspeptidase. Both transaminases and AP were elevated in 8 patients (17 percent). There were no significant differences in serum values of albumin and bilirubin before and after therapy. The platelet count slightly decreased, but not significantly, during the acute phase of disease. At ultrasound one third of the patients showed hepatomegaly with a hepatitis-like pattern and 40 percent of patients had splenomegaly. In conclusion, this study confirms data in the literature showing a high frequency of liver impairment during the course of brucellosis, which is usually mild-moderate.


Extracellular DNA release by undomesticated Bacillus subtilis is regulated by early competence.
Extracellular DNA (eDNA) release is a widespread capacity described in many microorganisms. We identified and characterized lysis-independent eDNA production in an undomesticated strain of Bacillus subtilis. DNA fragments are released during a short time in late-exponential phase. The released eDNA corresponds to whole genome DNA, and does not harbour mutations suggesting that is not the result of error prone DNA synthesis. The absence of eDNA was linked to a spread colony morphology, which allowed a visual screening of a transposon library to search for genes involved in its production. Transposon insertions in genes related to quorum sensing and competence (oppA, oppF and comXP) and to DNA metabolism (mfd and topA) were impaired in eDNA release. Mutants in early competence genes such as comA and srfAA were also defective in eDNA while in contrast mutations in late competence genes as those for the DNA uptake machinery had no effect. A subpopulation of cells containing more DNA is present in the eDNA producing strains but absent from the eDNA defective strain. Finally, competent B. subtilis cells can be transformed by eDNA suggesting it could be used in horizontal gene transfer and providing a rationale for the molecular link between eDNA release and early-competence in B. subtilis that we report.


Risk of surgical site infection, acute kidney injury, and Clostridium difficile infection following antibiotic prophylaxis with vancomycin plus a beta-lactam versus either drug alone: A national propensity-score-adjusted retrospective cohort study.
The optimal regimen for perioperative antimicrobial prophylaxis is controversial. Use of combination prophylaxis with a beta-lactam plus vancomycin is increasing; however, the relative risks and benefits associated with this strategy are unknown. Thus, we sought to compare postoperative outcomes following administration of 2 antimicrobials versus a single agent for the prevention of surgical site infections (SSIs). Potential harms associated with combination regimens, including acute kidney injury (AKI) and Clostridium difficile infection (CDI), were also considered. Using a multicenter, national Veterans Affairs (VA) cohort, all patients who underwent cardiac, orthopedic joint replacement, vascular, colorectal, and hysterectomy procedures during the period from 1 October 2008 to 30 September 2013 and who received planned manual review of perioperative antimicrobial prophylaxis regimen and manual review for the 30-day incidence of SSI were included. Using a propensity-adjusted log-binomial regression model stratified by type of surgical procedure, the association between receipt of 2 antimicrobials (vancomycin plus a beta-lactam) versus either single agent alone (vancomycin or a beta-lactam) and SSI was evaluated. Measures of association were adjusted for age, diabetes, smoking, American Society of Anesthesiologists score, preoperative methicillin-resistant Staphylococcus aureus (MRSA) status, and receipt of mupirocin. The 7-day incidence of postoperative AKI and 90-day incidence of CDI were also measured. In all, 70,101 procedures (52,504 beta-lactam only, 5,089 vancomycin only, and 12,508 combination) with 2,466 (3.5%) SSIs from 109 medical centers were included. Among cardiac surgery patients, combination prophylaxis was associated with a lower incidence of SSI (66/6,953, 0.95%) than single-agent prophylaxis (190/12,834, 1.48%; crude risk ratio [RR] 0.64, 95% CI 0.49, 0.85; adjusted RR 0.61, 95% CI 0.46, 0.83). After adjusting for SSI risk, no association between receipt of combination prophylaxis and SSI was found for the other types of surgeries evaluated, including orthopedic joint replacement procedures. In MRSA-colonized patients undergoing cardiac surgery, SSI occurred in 8/346 (2.3%) patients who received combination prophylaxis versus 4/100 (4.0%) patients who received vancomycin alone (crude RR 0.58, 95% CI 0.18, 1.88). Among MRSA-negative and -unknown cardiac surgery patients, SSIs occurred in 58/6,607 (0.9%) patients receiving combination prophylaxis versus 146/10,215 (1.4%) patients who received a beta-lactam alone (crude RR 0.61, 95% CI 0.45, 0.83). Based on these associations, the number needed to treat to prevent 1 SSI in MRSA-colonized patients is estimated to be 53, compared to 176 in non-MRSA patients. CDI incidence was similar in both exposure groups. Across all types of surgical procedures, risk of AKI was increased in the combination antimicrobial prophylaxis group (2,971/12,508 [23.8%] receiving combination versus 1,058/5,089 [20.8%] receiving vancomycin alone versus 7,314/52,504 [13.9%] receiving beta-lactam alone). We found a significant association between absolute risk of AKI and receipt of combination regimens across all types of procedures. If the observed association is causal, the number needed to harm for severe AKI following cardiac surgery would be 167. The major limitation of our investigation is that it is an observational study in a predominantly male population, which may limit generalizability and lead to unmeasured confounding. There are benefits but also unintended consequences of antimicrobial and infection prevention strategies aimed at "getting to zero" healthcare-associated infections. In our study, combination prophylaxis was associated with both benefits (reduction in SSIs following cardiac surgical procedures) and harms (increase in postoperative AKI). In cardiac surgery patients, the difference in risk-benefit profile by MRSA status suggests that MRSA-screening-directed prophylaxis may optimize benefits while minimizing harms in this selected population. More information about long-term outcomes and patient and societal preferences regarding risk of SSI versus risk of AKI is needed to improve clinical decision-making.


Mechanisms underlying phase lag between systemic arterial blood pressure and cerebral blood flow velocity.
To explore the mechanisms underlying the phase lag between oscillations in arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV), ABP and CBFV signals were recorded noninvasively from normal volunteers who lay quietly in a supine position. Mean ABP (MAP) and CBFV (MFV) were calculated beat-to-beat by means of integration. Cerebral vascular resistance (CVR) was calculated by dividing MAP with MFV. Frequency domain analysis of MAP, MFV and CVR signals revealed very-low frequency (VLF, 0.016-0.04 Hz), low-frequency (LF, 0.04-0.15 Hz), and high-frequency (HF, 0.15-0.4 Hz) components. The transfer phase of MAP-CVR coupling in the LF and HF range was frequency-dependent, which is equivalent to a time delay of 2 s. However, the transfer phase differed in the CVR-MFV coupling in that the phase was distributed around 180 degrees across the LF and HF ranges. Cross-correlation analysis revealed a positive relationship between MAP-CVR coupling, with MAP leading by 2 s, and a negative relationship between CVR-MFV coupling, with CVR leading by 0.3 s. We concluded that the phase lag between oscillations in ABP and CBFV was chiefly contributed to by the starting latency of cerebral autoregulation (i.e. cerebral vasomotion, revealed by MAP-CVR coupling). Moreover, the negative correlation of the CVR-MFV coupling could offer a different explanation for the physiologic significance of the phase lead of CBFV-ABP oscillations.


1,25-Dihydroxyvitamin D3 and the regulation of human cancer cell replication.
Several human and animal cancer cell lines have been shown to possess specific high affinity receptors for 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3). The replication of several of these cell types has also been shown to be regulated by this hormone, both in vitro and in vivo. To further understand the mechanisms of these actions, we have examined cancer cells in vitro and in vivo. The in vitro studies extend our previous reports on the treatment of human breast cancer cells (T 47D) with 10(-9) to 10(-6) M 1,25-(OH)2D3, which resulted in a dose- and time-dependent decrease in cell numbers over 6 days. Treatment with 10(-8) M 1,25-(OH)2D3, which reduced cell numbers to approximately one half of those found in control cultures at 6 days, was associated with a doubling of the proportion of cells in the G2 + M phase of the cell cycle and was accompanied by a significant decline in the proportion of G0/G1 cells. At higher concentrations there was a significant decline in S phase cells with accumulation of cells in both G0/G1 and G2 + M phases. The antiestrogen, tamoxifen, at a concentration which caused similar effects on cell number, resulted in proportional decreases in both S and G2 + M phase cells and accumulation of G0/G1 cells. The effects of 1,25-(OH)2D3 on T 47D cell proliferation were associated with time- and concentration-dependent reductions in epidermal growth factor receptor levels to a minimum level of about half that seen in control cultures. The in vivo experiments extend our previous studies, which demonstrated marked inhibition of the growth of human cancer xenografts in immunosuppressed mice by 1,25-(OH)2D3. Xenograft growth was inhibited with 1,25-(OH)2D3 (0.1 microgram ip three times per week) but growth was rapidly restored when the 1,25-(OH)2D3 was withdrawn. Thus, there are clear-cut time- and dose-dependent, yet reversible, effects of 1,25-(OH)2D3 on the replication of human cancer cells in vitro and in vivo, which are possibly mediated through changes in growth factor receptor levels. Further study of these effects may advance understanding of the hormonal control of cellular replication in human cancers.


Differential polymerase chain reaction: a technical comparison of three methods for the detection of CDK4 gene amplification in glioblastomas.
Among the different techniques used to detect oncogene amplification in tumor DNA, Southern blot and differential PCR have been the most frequently used. We report on a technical comparison of three different methods to detect gene amplification by differential PCR: ethidium bromide staining, silver staining (both after standard differential PCR), and fluorescent differential PCR. We explored the relative densitometric measure of a 119 bp fragment of the CDK4 gene versus an 82 bp fragment of the IFNG gene. In total agreement with previous studies carried out by Southern blot and differential PCR by other authors, we were able to detect CDK4 amplification in 3 of the 21 glioblastomas (14%), but only by the fluorescent differential PCR method. In conclusion, fluorescent differential PCR is more sensitive than standard differential PCR for detection oncogene amplification in tumor DNAs.


The Availability of Emergency Obstetric Care in Birthing Centres in Rural Nepal: A Cross-sectional Survey.
The purpose of this health system's study is to assess the availability of Emergency Obstetric Care (EmOC) services in birthing centres in Taplejung District of eastern Nepal. A cross-sectional survey was conducted in 2018 in all 16 public health facilities providing delivery services in the district. Data collection comprised: (1) quantitative data collected from health workers; (2) observation of key items; and (3) record data extracted from the health facility register. Descriptive statistics were used to calculate readiness scores using unweighted averages. Although key health personnel were available, EmOC services at the health facilities assessed were below the minimum coverage level recommended by the World Health Organisation. Only the district hospital provided the nine signal functions of Comprehensive EmOC. The other fifteen had only partially functioning Basic EmOC facilities, as they did not provide all of the seven signal functions. The essential equipment for performing certain EmOC functions was either missing or not functional in these health facilities. The Ministry of Health and Population and the federal government need to ensure that the full range of signal functions are available for safe deliveries in partially functioning EmOC health facilities by addressing the issues related to training, equipment, medicine, commodities and policy.


A noise control package for vibrating screens.
Hearing loss was the second-most common illness reported to the Mine Safety and Health Administration (MSHA) in 2009. Furthermore, between 2000 and 2010, 30% of all noise-related injury complaints reported to MSHA were for coal preparation plant employees. Previous National Institute for Occupational Safety and Health (NIOSH) studies have shown that vibrating screens are key noise sources to address in order to reduce coal preparation plant noise. In response, NIOSH researchers have developed a suite of noise controls for vibrating screens consisting of constrained layer damping (CLD) treatments, a tuned mechanism suspension, an acoustic enclosure, and spring inserts. Laboratory testing demonstrates that this noise control suite reduces the A-weighted sound power level of the vibrating screen by 6 dB. To provide a comparison to laboratory results and prove durability, field testing of two noise controls was performed on a vibrating screen in a working coal preparation plant. The spring inserts and CLD treatments were selected due to their ease of installation and practicability. Field testing of these controls yielded reductions that were comparable to laboratory results.


Designing an effective immunocontraceptive.
The immunological inhibition of fertilization is the goal of gamete immunocontraception. To achieve this goal a gamete-specific antigen target must be defined and the presentation of the immunogen to the immune system must be clearly understood in order to elicit a defined immune response which will target the native gamete molecule. Almost 20 years ago C.B. Metz suggested six studies which would answer the questions necessary for the development of a successful immunocontraceptive, and although much work has gone into answering each of these questions, none has been completed. Hyaluronidase is an example of a well studied sperm antigen whose native, membrane bound form (PH-20) is a successful immunocontraceptive in female guinea pigs. However, it remains to be demonstrated that a successful native antigen can be a successful synthetic or recombinant gamete immunocontraceptive (GAMICON). The problem of converting a successful native contraceptive antigen into an effective synthetic or recombinant GAMICON is at the heart of the problem of GAMICON design. If the epitopes of native and synthetic immunogens are not the same, then can a conversion ever be made? One approach to understanding how to make this conversion is to use defined, synthetic B- T-cell epitopes as specific B-cell epitopes on native antigens affect fertility.


Mimicry Embedding Facilitates Advanced Neural Network Training for Image-Based Pathogen Detection.
The use of deep neural networks (DNNs) for analysis of complex biomedical images shows great promise but is hampered by a lack of large verified data sets for rapid network evolution. Here, we present a novel strategy, termed "mimicry embedding," for rapid application of neural network architecture-based analysis of pathogen imaging data sets. Embedding of a novel host-pathogen data set, such that it mimics a verified data set, enables efficient deep learning using high expressive capacity architectures and seamless architecture switching. We applied this strategy across various microbiological phenotypes, from superresolved viruses to in vitro and in vivo parasitic infections. We demonstrate that mimicry embedding enables efficient and accurate analysis of two- and three-dimensional microscopy data sets. The results suggest that transfer learning from pretrained network data may be a powerful general strategy for analysis of heterogeneous pathogen fluorescence imaging data sets.IMPORTANCE In biology, the use of deep neural networks (DNNs) for analysis of pathogen infection is hampered by a lack of large verified data sets needed for rapid network evolution. Artificial neural networks detect handwritten digits with high precision thanks to large data sets, such as MNIST, that allow nearly unlimited training. Here, we developed a novel strategy we call mimicry embedding, which allows artificial intelligence (AI)-based analysis of variable pathogen-host data sets. We show that deep learning can be used to detect and classify single pathogens based on small differences.


Monitoring adverse events following immunisation in developing countries: experience from human papillomavirus vaccination demonstration projects.
Surveillance of adverse events following immunisation (AEFIs) is important for maintaining trust in vaccination. This paper discusses retrospective reports by parents and guardians of girls experiencing AEFIs during human papillomavirus (HPV) vaccine demonstration projects in Uganda and Vietnam. A secondary analysis of data from a population-based survey measuring HPV vaccine coverage of eligible girls and acceptability among parents and guardians was conducted. Survey data from parents were analysed for frequency and type of AEFI and actions taken. Of the 1700 eligible households contacted, all responded to the survey; of those, 1313 respondents had an eligible child who had received at least one dose of the HPV vaccine. Data were missing from 49 respondents, resulting in 1264 surveys. Twenty-five percent reported an AEFI, with fever (29.1%) and pain or swelling at the injection site (62.0%) being the most common. Events totalled 386 (10.5%) of the 3684 doses administered. Most parents reported that they took no action (63.9%) or cared for girls at home (16.1%) following an AEFI. Thirty-three parents sought advice from health workers or attended a clinic for 46 events (0.8% of all doses). Frequency of reporting varied by respondent identity, geographic location and vaccination location. AEFIs reported were similar to Phase III vaccine trials. Most parents reporting AEFIs took no action or treated the girl at home, suggesting that most AEFIs were not serious enough to contact the health system. AEFI reports were more frequent when solicited in surveys compared with reports from routine monitoring.


Structural organization of reconstituted human arterial smooth muscle tissue.
We used human arterial smooth muscle cells (SMCs) that had been reorganized three-dimensionally into aggregates, so-called spheroids, as a model system that might more closely correspond to arterial smooth muscle in vivo than do conventional monolayer cultures. After reaggregation the presence of serum in the culture medium strongly promoted the maintenance of spheroidal SMCs. With access to fresh serum, the spheroids developed into highly organized structures with an outer laminated shell of spindle-shaped SMCs and a more porous core of rounded or polygonal SMCs. After several weeks in culture, extracellular matrix components appeared and the tissue assumed features characteristic of maturing intimal repair tissue. Many cells had features of programmed cell death (apoptosis). This feature may be important because it may indicate that regression of arterial smooth muscle tissue may be a much more strongly controlled process than hitherto realized. Without access to fresh serum, the spheroidal tissue showed degenerative features, much like those in atherosclerotic lesions, ie, the presence of foam cells, cellular debris, and some cell death. It is possible that this situation in vitro resembles that of atherosclerotic tissue in vivo, in which retention of plasma constituents is a conspicuous feature. In some respects, therefore, the small sample of human arterial tissue represented by the spheroid may represent an in vitro analogue of the arterial wall, which may undergo maturation or degenerative atherosclerosis-like changes depending on exogenous factors. The spheroidal SMC system may therefore also be a suitable model for in vitro studies of atherogenesis.


Levetiracetam efficacy on frontal lobe dysfunctions and anger rumination in patients with epilepsy.
This study compared the frontal lobe functioning and anger rumination between patients with epilepsy and healthy individuals. The second objective was to examine the efficacy of levetiracetam therapy on frontal lobe dysfunctions and anger rumination in patients with epilepsy. Participants (50 patients with epilepsy and 50 healthy individuals) completed the Frontal Assessment Battery (FAB) and Anger Rumination Scale (ARS). The patients had two testing sessions: pre- and post-levetiracetam therapies. The results showed that patients with epilepsy had frontal lobe dysfunctions in contrast with healthy individuals. Patients with epilepsy had higher anger rumination than healthy individuals. Compared with baseline performance, frontal lobe dysfunctions and anger rumination were significantly reduced after three months of levetiracetam therapy in patients with epilepsy. It is concluded that levetiracetam therapy may be beneficial in improving frontal lobe functioning and anger rumination thought pattern in patients with epilepsy. However, further studies are required to confirm this evidence.


Expression of human CD46 and trans-complementation by murine adenovirus 1 fails to allow productive infection by a group B oncolytic adenovirus in murine cancer cells.
Oncolytic viruses are currently experiencing accelerated development in several laboratories worldwide, with some forty-seven clinical trials currently recruiting. Many oncolytic viruses combine targeted cytotoxicity to cancer cells with a proinflammatory cell lysis. Due to their additional potential to express immunomodulatory transgenes, they are also often known as oncolytic viral vaccines. However, several types of oncolytic viruses are human-specific and the lack of suitable immune-competent animal models complicates biologically relevant evaluation of their vaccine potential. This is a particular challenge for group B adenoviruses, which fail to infect even those immunocompetent animal model systems identified as semi-permissive for type 5 adenovirus. Here, we aim to develop a murine cell line capable of supporting replication of a group B oncolytic adenovirus, enadenotucirev (EnAd), for incorporation into a syngeneic immunocompetent animal model to explore the oncolytic vaccine potential of group B oncolytic viruses. Transgenic murine cell lines were infected with EnAd expressing GFP transgene under replication-independent or -dependent promoters. Virus mRNA expression, genome replication, and late protein expression were determined by qRT-PCR, qPCR, and immunoblotting, respectively. We also use Balb/c immune-competent mice to determine the tumourogenicity and infectivity of transgenic murine cell lines. Our results show that a broad range of human carcinoma cells will support EnAd replication, but not murine carcinoma cells. Murine cells can be readily modified to express surface human CD46, one of the receptors for group B adenoviruses, allowing receptor-mediated uptake of EnAd particles into the murine cells and expression of CMV promoter-driven transgenes. Although the early E1A mRNA was expressed in murine cells at levels similar to human cells, adenovirus E2B and Fibre mRNA expression levels were hampered and few virus genomes were produced. Unlike previous reports on group C adenoviruses, trans-complementation of group B adenoviruses by co-infection with mouse adenovirus 1 did not rescue replication. A panel of group B adenoviruses expressing individual mouse adenovirus 1 genes were also unable to rescue EnAd replication. Together, these results indicate that there may be major differences in the early stages of replication of group C and B adenoviruses in murine cells, and that the block to the life cycle of B adenoviruses in murine cells occurs in the early stage of virus replication, perhaps reflecting poor activity of Ad11p E1A in murine cells.


Evaluating the Interrater Agreement and Acceptability of a New Reference Tool for Assessing Respiratory Rate in Children under Five with Cough and/or Difficulty Breathing.
Manual assessment of respiratory rate (RR) in children is unreliable, but remains the main method to diagnose pneumonia in low-resource settings. While automated RR counters offer a potential solution, there is currently no gold standard to validate these diagnostic aids. A video-based reference tool is proposed that allows users to annotate breaths and distortions including movement periods, allowing the exclusion of distortions from the computation of RR measures similar to how new diagnostic aids account for distortions automatically. This study evaluated the interrater agreement and acceptability of the new reference tool. Annotations were based on previously recorded reference videos of children under five years old with cough and/or difficulty breathing (n = 50). Five randomly selected medical experts from a panel of ten annotated each video. RR measures (breaths per minute, bpm) were computed as the number of annotated certain breaths divided by the length of calm periods after removing annotated distorted periods. Reviewers showed good interrater agreement on continuous RR {standard error of measurement (SEM) [4.8 (95%CI 4.4-5.3)]} and substantial agreement on classification of fast breathing (Fleiss kappa, κ 0.71). Agreement was lowest in the youngest age group [< 2 months: SEM 6.2 (5.4-7.4) bpm, κ 0.48; 2-11 months: 4.7 (4.0-5.8) bpm, κ 0.84; 12-59 months: 2.6 (2.2-3.1) bpm, κ 0.8]. Reviewers found the functionalities of the tool helpful in annotating breaths, but remained uncertain about the validity of their annotations. Before the new tool can be considered a reference standard for RR assessments, interrater agreement in children younger than 2 months must be improved.


Control of DAF-7 TGF-(alpha) expression and neuronal process development by a receptor tyrosine kinase KIN-8 in Caenorhabditis elegans.
KIN-8 in C. elegans is highly homologous to human ROR-1 and 2 receptor tyrosine kinases of unknown functions. These kinases belong to a new subfamily related to the Trk subfamily. A kin-8 promoter::gfp fusion gene was expressed in ASI and many other neurons as well as in pharyngeal and head muscles. A kin-8 deletion mutant was isolated and showed constitutive dauer larva formation (Daf-c) phenotype: about half of the F(1) progeny became dauer larvae when they were cultivated on an old lawn of E. coli as food. Among the cells expressing kin-8::gfp, only ASI sensory neurons are known to express DAF-7 TGF-(beta), a key molecule preventing dauer larva formation. In the kin-8 deletion mutant, expression of daf-7::gfp in ASI was greatly reduced, dye-filling in ASI was specifically lost and ASI sensory processes did not completely extend into the amphid pore. The Daf-c phenotype was suppressed by daf-7 cDNA expression or a daf-3 null mutation. ASI-directed expression of kin-8 cDNA under the daf-7 promoter or expression by a heat shock promoter rescued the dye-filling defect, but not the Daf-c phenotype, of the kin-8 mutant. These results show that the kin-8 mutation causes the Daf-c phenotype through reduction of the daf-7 gene expression and that KIN-8 function is cell-autonomous for the dye-filling in ASI. KIN-8 is required for the process development of ASI, and also involved in promotion of daf-7 expression through a physiological or developmental function.


Effect of coadsorbent on the photovoltaic performance of squaraine sensitized nanocrystalline solar cells.
The effect of chenodeoxycholic acid as the coadsorbent with a squaraine sensitizer on TiO(2) nanocrystalline solar cells was investigated, and it was found that the coadsorbent prevents the squaraine sensitizer from aggregating on the TiO(2) nanoparticles but reduces dye loading leading to an interdependent photovoltaic performance. Analysis of the absorption spectra, and incident monochromatic photon-to-current conversion efficiency data showed that the load of squaraine sensitizer as well as the appearance of H-aggregates is strongly dependent on the molar concentration of chenodeoxycholic acid coadsorbent. The open circuit voltage of the solar cells with chenodeoxycholic acid increases due to the enhanced electron lifetime in the TiO(2) nanoparticles coupled with the band edge shift of TiO(2) to negative potentials.


A scoping review of the role of HIV-related stigma and discrimination in noncommunicable disease care.
People living with HIV are increasingly burdened by noncommunicable diseases (NCDs) as a result of the NCD susceptibility that accompanies increased life expectancy and the rising global prevalence of NCDs. Health systems are being strengthened and programs are being developed to address this burden, often building on HIV care strategies and infrastructure or through integrated care models. HIV remains a stigmatized condition and the role of HIV stigma in the provision of NCD care is not well understood. We conducted a scoping literature review of both peer reviewed and grey literature to identify evidence of the role of HIV stigma in the NCD-care continuum (prevention, diagnosis, care seeking, retention in care, and adherence to treatment of NCDs). We searched PsychInfo and Pubmed and conducted additional searches of programmatic reports and conference abstracts. Included studies were published in English within the past decade and examined HIV-related stigma as it relates to NCD-care or to integrated NCD-and HIV-care programs. Sixteen articles met the inclusion criteria. Findings suggest: fear of disclosure, internalized shame and embarrassment, and negative past experiences with or negative perceptions of health care providers negatively influence engagement with NCD care; HIV stigma can adversely affect not only people living with HIV in need of NCD care, but all NCD patients; some NCDs are stigmatized in their own right or because of their association with HIV; integrating NCD and HIV care can both reduce stigma for people living with HIV and a present a barrier to access for NCD care. Due to the dearth of available research and the variability in initial findings, further research on the role of HIV stigma in the NCD-care continuum for people living with HIV is necessary. Lessons from the field of HIV-stigma research can serve as a guide for these efforts.


Public perceptions and scientific evidence for perceived harms/risks of community water fluoridation: An examination of online comments pertaining to fluoridation cessation in Calgary in 2011.
To examine the perceived harms/risks of fluoridation as expressed in online forums relating to cessation and aftermath in Calgary, specifically, 1) which harms/risks are mentioned, 2) for those harms/risks, what kinds of evidence are cited, 3) to what extent is scientific literature cited, and what is its quality, and 4) for a subset of harms/risks, what is known from the broader scientific literature? Relevant online comments were identified through free-text Internet searches, and those explicitly discussing the harms/risks of water fluoridation were extracted. Types of evidence mentioned were identified, and the scientific papers cited were reviewed. Finally, the broader scientific literature on two of the harms/risks was reviewed and synthesized. We identified 17 distinct groups of harms/risks, which spanned human body systems, the environment and non-human organisms. Most often, no evidence was cited. When evidence was cited, types included individuals viewed as authorities and personal experiences. Reference to scientific articles was rare, and those papers (n = 9) had significant methodological concerns. Our review of scientific literature on fluoride and 1) thyroid functioning and 2) phytoplankton revealed some negative effects of fluoride at concentrations exceeding maximum recommended levels (>1.5 ppm). The findings have implications for communication with the public about fluoridation. First, to the extent that the public consults the scientific literature, it is essential that the methodological limitations of a study, as well as its relevance to community water fluoridation, be widely and promptly communicated. Second, scientific evidence is only one component of why some people support or do not support fluoridation, and communication strategies must accommodate that reality.


Reproducibility and repeatability of 99Tcm-HMPAO rCBF SPET in normal subjects at rest using brain atlas matching.
The aim of this study was to assess regional cerebral blood flow (rCBF) in normal subjects at rest using 99Tcm-HMPAO single photon emission tomography (SPET). Analysis of reproducibility and repeatability was performed both before and after normalization of flow data. Six healthy volunteers were examined, three times each, according to a routine rCBF protocol. A computerized brain atlas was used to evaluate flow data in eight selected regions. The overall reproducibility of rCBF was evaluated from two scans performed at an average interval of 3 months. Repeatability was evaluated from two scans, 3 h apart and without re-injection of 99Tcm-HMPAO. For the normalized (relative) flow data, the reproducibility was +/- 1.3% and the repeatability +/- 2.2% (i.e. methodological errors dominate). For the non-normalized flow data, the corresponding values were +/- 14.8% and +/- 5.9%. rCBF SPET with 99Tcm-HMPAO is highly reproducible provided that the flow data are normalized. The variation in flow between individuals at one point in time and 3 months later was less than +/- 5% for all brain regions.


Laminin-1 promotes differentiation of fetal mouse pancreatic beta-cells.
Extracellular factors that regulate the growth and differentiation of cell lineages in the pancreatic primordia are poorly understood. Identification of these factors for pancreatic islet beta-cells could open new avenues for the treatment of insulin-dependent diabetes. We developed a low cell density serum-free culture system for dissociated pancreatic cells from the 13.5-day mouse fetus and investigated the effects of extracellular matrix proteins on differentiation of islet cells. After 4 days in culture, total cell number decreased by two-thirds, but insulin-positive beta-cell number increased 10-fold. Both of collagens I and IV inhibited cell survival (by >50%), whereas fibronectin had no effect. In the presence of soluble laminin-1, however, the number of beta-cells increased linearly by 60-fold without an increase in the total cell number; glucagon-positive cell number was unchanged, and somatostatin and pancreatic polypeptide-positive cells were not detected. The effect of laminin-1 was completely blocked by a monoclonal rat anti-laminin-1 antibody. In the presence of laminin-1, the thymidine analogue, BrdU, was incorporated into only 2.5% of cells, which were mainly insulin-negative at days 1-3. Laminin-1 appeared, therefore, to induce differentiation of beta-cells from precursor cells in day-13.5 fetal pancreas. Laminin-1 was shown to be expressed in the epithelial basement membrane of the 13.5- to 17.5-day fetal pancreas. These findings provide the first evidence of a role for laminin-1 to promote differentiation of pancreatic beta-cells.


Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia: A Rare Case Report from Nephrology.
BACKGROUND Tumor lysis syndrome is common in hematological malignancy, but less frequent in chronic and solid tumors. Almost always it is observed after chemotherapy or radiotherapy initiation, but rarely occurs spontaneously. CASE REPORT A 89-year-old female with stable chronic lymphocytic leukemia was admitted to the hospital because of worsening dyspnea and dry cough. Her vital signs were normal, except for sinus tachycardia. On physical examination, she appeared distressed, dyspneic, sweaty but afebrile, anxious, but alert and well oriented. Lung examination revealed reduced air entry with bibasilar crackles. No peripheral edema was seen, pulses were normal, and no signs of deep vein thrombosis were observed. Laboratory analysis revealed leukocytosis; but normal hematological and biochemical parameters. Intravenous (IV) furosemide and antibiotics (IV ceftriaxone and orally azithromycin) were started along with steroid therapy (methylprednisolone 62.5 mg, IV). The treatment with steroids lasted for 1 day only, and in the following day, the patient was switched to prednisone (20 mg/day orally) for only 1 additional day. White blood cell count increased on day 1, 2 and 3 after admission, along development of hyperuricemia, hyperphosphatemia, hyperkalemia, acute renal failure and elevated troponin levels. Hemodiafiltration/hemodialysis was initiated, and the patient was discharged after serum concentrations of these electrolytes and kidney function were restored. One month after discharge, the patient denied any malaise and was at stable condition. CONCLUSIONS Herein, we present a case of a patient with stable chronic lymphocytic leukemia, who developed spontaneous tumor lysis syndrome after short low dose of steroid therapy. This case highlights the importance of including spontaneous tumor lysis syndrome in the differential diagnosis of any acute renal failure in the constellation of any malignancy.


Accuracy of the Radiographic Assessment of Lung Edema Score for the Diagnosis of ARDS.
Background: Bilateral opacities on chest radiographs are part of the Berlin Definition for Acute Respiratory Distress Syndrome (ARDS) but have poor interobserver reliability. The "Radiographic Assessment of Lung Edema" (RALE) score was recently proposed for evaluation of the extent and density of alveolar opacities on chest radiographs of ARDS patients. The current study determined the accuracy of the RALE score for the diagnosis and the prognosis of ARDS. Methods: Post-hoc analysis of a cohort of invasively ventilated intensive care unit (ICU) patients expected to need invasive ventilation for >24 h. The Berlin Definition was used as the gold standard. The RALE score was calculated for the first available chest radiograph after start of ventilation in the ICU. The primary endpoint was the diagnostic accuracy for ARDS of the RALE score. Secondary endpoints included the prognostic value of the RALE score for ICU and hospital mortality, and the association with ARDS severity, and the PaO2/FiO2. Receiver operating characteristic (ROC) curves were constructed, and the optimal cutoff was used to determine sensitivity, specificity and the negative and positive predictive value of the RALE score for ARDS. Results: The study included 131 patients, of whom 30 had ARDS (11 mild, 15 moderate, and 4 severe ARDS). The first available chest radiograph was obtained median 0 [0 to 1] days after start of invasive ventilation in ICU. Compared to patients without ARDS, a higher RALE score was found in patients with ARDS (24 [interquartile range (IQR) 16-30] vs. 6 [IQR 3-11]; P < 0.001), with RALE scores of 20 [IQR 14-24], 26 [IQR 16-32], and 32 [IQR 19-36] for mild, moderate and severe ARDS, respectively, (P = 0.166). The area under the ROC for ARDS was excellent (0.91 [0.86-0.96]). The best cutoff for ARDS diagnosis was 10 with 100% sensitivity, 71% specificity, 51% positive predictive value and 100% negative predictive value. The RALE score was not associated with ICU or hospital mortality, and weakly correlated with the PaO2/FiO2. Conclusion: In this cohort of invasively ventilated ICU patients, the RALE score had excellent diagnostic accuracy for ARDS.


The Mindfulness-Based Interventions: Teaching Assessment Criteria (MBI:TAC): reflections on implementation and development.
The Mindfulness-Based Interventions: Teaching Assessment Criteria (MBI:TAC) is a tool for supporting good practice in mindfulness-based teaching, training supervision and research contexts. It has been taken up in practice in teacher training organizations worldwide. The MBI:TAC sits within the wider consideration within research contexts of building methodological rigor by developing robust systems for ensuring intervention integrity. Research on the tool is at an early stage and needs development. The process of implementation needs careful attention to ensure reliability and good practice. Future research is needed on the tool's reliability, validity and sensitivity to change, and on the relationships between mindfulness-based teaching, participant outcomes and key contextual factors, including the influence of participant population, culture and context.


Quantitative Systems Pharmacology for Neuroscience Drug Discovery and Development: Current Status, Opportunities, and Challenges.
The substantial progress made in the basic sciences of the brain has yet to be adequately translated to successful clinical therapeutics to treat central nervous system (CNS) diseases. Possible explanations include the lack of quantitative and validated biomarkers, the subjective nature of many clinical endpoints, and complex pharmacokinetic/pharmacodynamic relationships, but also the possibility that highly selective drugs in the CNS do not reflect the complex interactions of different brain circuits. Although computational systems pharmacology modeling designed to capture essential components of complex biological systems has been increasingly accepted in pharmaceutical research and development for oncology, inflammation, and metabolic disorders, the uptake in the CNS field has been very modest. In this article, a cross-disciplinary group with representatives from academia, pharma, regulatory, and funding agencies make the case that the identification and exploitation of CNS therapeutic targets for drug discovery and development can benefit greatly from a system and network approach that can span the gap between molecular pathways and the neuronal circuits that ultimately regulate brain activity and behavior. The National Institute of Neurological Disorders and Stroke (NINDS), in collaboration with the National Institute on Aging (NIA), National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), and National Center for Advancing Translational Sciences (NCATS), convened a workshop to explore and evaluate the potential of a quantitative systems pharmacology (QSP) approach to CNS drug discovery and development. The objective of the workshop was to identify the challenges and opportunities of QSP as an approach to accelerate drug discovery and development in the field of CNS disorders. In particular, the workshop examined the potential for computational neuroscience to perform QSP-based interrogation of the mechanism of action for CNS diseases, along with a more accurate and comprehensive method for evaluating drug effects and optimizing the design of clinical trials. Following up on an earlier white paper on the use of QSP in general disease mechanism of action and drug discovery, this report focuses on new applications, opportunities, and the accompanying limitations of QSP as an approach to drug development in the CNS therapeutic area based on the discussions in the workshop with various stakeholders.


Total elbow arthroplasty after interposition arthroplasty for elbow arthritis.
Interposition arthroplasty is an option for the treatment of arthritis of the elbow. Conversion to a total elbow arthroplasty can be considered later, when the patient reaches a suitable age. We investigated the results of conversion of an interpositional elbow arthroplasty to a semiconstrained total elbow arthroplasty in a series of patients. The results of twelve consecutive linked semiconstrained total elbow arthroplasties in twelve patients who had had a prior interposition arthroplasty for the treatment of degenerative arthritis of the elbow were evaluated at an average of ten years postoperatively. The average age at the time of the total elbow arthroplasty was fifty years, and the average interval from the interposition arthroplasty to the total elbow arthroplasty was 9.9 years. Pain and elbow performance as measured with the Mayo Elbow Performance Score were assessed in a retrospective chart review and an evaluation of questionnaires, and postoperative radiographs were reviewed. At the time of the latest follow-up, postoperative pain was rated as mild or none in ten of the twelve patients, and the result was rated as subjectively satisfactory in ten patients. The average Mayo Elbow Performance Score improved from 32.1 points (range, 10 to 70 points) preoperatively to 80.4 points (range, 40 to 100 points) postoperatively (p < 0.001). According to these objective criteria, there were three excellent, six good, one fair, and two poor results. All of the elbows were stable following the arthroplasty. Radiographs demonstrated a well-fixed prosthesis in all but one patient who had extensive osteolysis at the site of the humeral component. One other patient had radiographic evidence of bushing wear. Both of these patients required revision procedures. Semiconstrained total elbow arthroplasty can be performed successfully in patients with a prior interposition arthroplasty. Reliable pain relief and a satisfactory result can be achieved in most patients.


The effectiveness of team-based learning on learning outcomes in health professions education: BEME Guide No. 30.
Team-Based Learning (TBL) is a student-centred active learning method, requiring less faculty time than other active learning methods. While TBL may have pedagogical value, individual studies present inconsistent findings. The aim of this systematic review was to assess the effectiveness of TBL on improving learning outcomes in health professions education. A peer-reviewed systematic review protocol was registered with the Best Evidence in Medical Education (BEME) organization. After comprehensive literature searching, title and full-text review were completed by two independent reviewers. Included studies assessed TBL and a valid comparator in health professions. Included studies were assessed for methodological quality by two independent reviewers. Studies were categorised by outcomes using the Kirkpatrick framework. Of 330 screened titles, 14 were included. Seven studies reported significant increase in knowledge scores for the TBL group, four reported no difference and three showed improvement but did not comment on statistical significance. Only one study reported significant improvement in learner reaction for the TBL group while another study reported a significant difference favouring the comparator. Despite improvement in knowledge scores, there was mixed learner reaction. This may reflect the increased demands on learners in this student-centred teaching strategy, although further study is needed.


Clusterin protein diversity in the primate eye.
The clusterin gene encodes a multi-functional protein that has been identified in different tissues, including a number of different eye tissues, primarily in the mouse and to a much lesser extent in humans. Clusterin has been implicated in a number of cellular processes such as lipid transport, membrane integrity, apoptosis, and neurodegeneration, all of which could be important to the biology of the eye. In the current communication, we provide data that confirms the expression of clusterin in a number of different human eye tissues and establishes the expression profile of this gene in monkey derived eye tissues. The issue that we sought to examine is whether a broad profile of clusterin expression in the eye is consistent in primates (monkey and human). The majority of our study was done using monkey eye tissues. Where possible, we have used human tissues in order to confirm published findings. Northern and western analysis was performed using tissues derived from monkey eyes. In situ hybridization and immunochemistry were carried out on human eye sections. Clusterin mRNA is expressed in primate lens, cornea, limbus, sclera, orbital muscle, ciliary body, retina, RPE/choroid, and RPE cells in culture. Western analysis revealed that two major groups of clusterin exist in the eye, a high molecular weight group (>100 kDa) and a second group consisting of at least five clusterin species that are all approximately 80 kDa. Analysis of conditioned media from RPE cells cultured on permeable supports suggests that different forms of clusterin display alternative patterns of secretion. Clusterin is expressed in a broad range of eye tissues in both human and monkey, suggesting that this is a characteristic feature in primates. We demonstrate for the first time that a diverse number of clusterin isoforms were observed in monkey eye tissues by western analysis. Meanwhile, the molecular size of clusterin mRNA detected in the array of tissues are identical in size, suggesting that the nature of the diversity in clusterin forms is due to post-translational modifications. In addition, new insights were made in defining clusterin expression in ciliary body, cornea, and the retinal pigment epithelium.


GUIRO: User-Guided Matrix Reordering.
Matrix representations are one of the main established and empirically proven to be effective visualization techniques for relational (or network) data. However, matrices-similar to node-link diagrams-are most effective if their layout reveals the underlying data topology. Given the many developed algorithms, a practical problem arises: "Which matrix reordering algorithm should I choose for my dataset at hand?" To make matters worse, different reordering algorithms applied to the same dataset may let significantly different visual matrix patterns emerge. This leads to the question of trustworthiness and explainability of these fully automated, often heuristic, black-box processes. We present GUIRO, a Visual Analytics system that helps novices, network analysts, and algorithm designers to open the black-box. Users can investigate the usefulness and expressiveness of 70 accessible matrix reordering algorithms. For network analysts, we introduce a novel model space representation and two interaction techniques for a user-guided reordering of rows or columns, and especially groups thereof (submatrix reordering). These novel techniques contribute to the understanding of the global and local dataset topology. We support algorithm designers by giving them access to 16 reordering quality metrics and visual exploration means for comparing reordering implementations on a row/column permutation level. We evaluated GUIRO in a guided explorative user study with 12 subjects, a case study demonstrating its usefulness in a real-world scenario, and through an expert study gathering feedback on our design decisions. We found that our proposed methods help even inexperienced users to understand matrix patterns and allow a user-guided steering of reordering algorithms. GUIRO helps to increase the transparency of matrix reordering algorithms, thus helping a broad range of users to get a better insight into the complex reordering process, in turn supporting data and reordering algorithm insights.


Alterations in epididymal proteomics and antioxidant activity of mice exposed to fluoride.
It is well known that high fluoride results in low fertility. Epididymis is the important place for spermatozoa maturation, which is essential for successful fertilization. In the previous studies, fluoride was reported to damage the epididymal structure of mouse and rabbit. However, the mechanism underlying sodium fluoride (NaF)-induced epididymal toxicity has not yet been well elucidated. The aim of this study is to explore the global protein alterations in epididymis of mice exposed to NaF using the iTRAQ technique. Results showed that 211 proteins were differentially expressed in both 25 and 100 mg/L NaF groups. Some of them have been proved to be important for reproduction, such as low-density lipoprotein receptor-related protein 2 (Lrp2), cytochrome c, testis-specific (Cyct), sorbitol dehydrogenase (Sord), glutathione S-transferases (GSTs), acrosin, beta-defensin 126, cysteine-rich secretory protein (Crisp) 1, and Crisp2. Gene ontology (GO) analysis suggested cellular process, organelle and catalytic activity account for high percent and number of differentially expressed proteins. 171 pathways were found after the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, among which the representative maps, such as ribosome, focal adhesion, and phagosome, were involved. Different functional categories post-translational modification, protein turnover, chaperones; translation, ribosomal structure and biogenesis; cytoskeleton; energy production and conversion are implicated in the Cluster of Orthologous Groups (COG) of proteins analysis. Subsequently, the effect of NaF on the antioxidant activity in epididymis, especially glutathione and glutathione-related enzymes, was evaluated. Results exhibited high fluoride caused low total antioxidant capacity (T-AOC), high methane dicarboxylic aldehyde (MDA), decreased reduced glutathione (GSH), and the glutathione-related enzymes [GSH peroxidase (GPx), GSH reductase (GR), and GSH S-transferase (GST)] changes in activity, protein, and mRNA expressions. In summary, NaF decreased the antioxidant activity of epididymis, especially glutathione and glutathione-related enzymes, as well as iTRAQ results, providing new explanations for the low sperm quality induced by fluoride.


Immunoassay-Amplified Responses Using a Functionalized MoS2-Based SPR Biosensor to Detect PAPP-A2 in Maternal Serum Samples to Screen for Fetal Down's Syndrome.
Due to educational, social and economic reasons, more and more women are delaying childbirth. However, advanced maternal age is associated with several adverse pregnancy outcomes, and in particular a high risk of Down's syndrome (DS). Hence, it is increasingly important to be able to detect fetal Down's syndrome (FDS). We developed an effective, highly sensitive, surface plasmon resonance (SPR) biosensor with biochemically amplified responses using carboxyl-molybdenum disulfide (MoS2) film. The use of carboxylic acid as a surface modifier of MoS2 promoted dispersion and formed specific three-dimensional coordination sites. The carboxylic acid immobilized unmodified antibodies in a way that enhanced the bioaffinity of MoS2 and preserved biorecognition properties of the SPR sensor surface. Complete antigen pregnancy-associated plasma protein-A2 (PAPP-A2) conjugated with the carboxyl-MoS2-modified gold chip to amplify the signal and improve detection sensitivity. This heterostructure interface had a high work function, and thus improved the efficiency of the electric field energy of the surface plasmon. These results provide evidence that the interface electric field improved performance of the SPR biosensor. The carboxyl-MoS2-based SPR biosensor was used successfully to evaluate PAPP-A2 level for fetal Down's syndrome screening in maternal serum samples. The detection limit was 0.05 pg/mL, and the linear working range was 0.1 to 1100 pg/mL. The women with an SPR angle >46.57 m° were more closely associated with fetal Down's syndrome. Once optimized for serum Down's syndrome screening, an average recovery of 95.2% and relative standard deviation of 8.5% were obtained. Our findings suggest that carboxyl-MoS2-based SPR technology may have advantages over conventional ELISA in certain situations. Carboxyl-MoS2-based SPR biosensors can be used as a new diagnostic technology to respond to the increasing need for fetal Down's syndrome screening in maternal serum samples. Our results demonstrated that the carboxyl-MoS2-based SPR biosensor was capable of determining PAPP-A2 levels with acceptable accuracy and recovery. We hope that this technology will be investigated in diverse clinical trials and in real case applications for screening and early diagnosis in the future.


Linking maternity data for England, 2005-06: methods and data quality.
Maternity Hospital Episode Statistics (HES) data were linked to birth registration and NHS Numbers for Babies (NN4B) data to bring together some key demographic and clinical data items not otherwise available at a national level. This project added to earlier work involving linkage of birth registration records to NN4B records. Birth registration and NN4B records were linked to Maternity HES delivery records and also Maternity HES baby records using the NHS Number or other indirect identifiers if NHS Number was missing.Data quality and completeness of Maternity HES were assessed in relation to birth registration data wherever possible. For information not collected at registration, NN4B data were used to validate quality of Maternity HES. Overall, 91 per cent of Maternity HES delivery records could be linked to the birth registration/NHS Numbers for Babies records and 84 per cent of Maternity HES baby records were linked.In 2005 only 3 per cent of Maternity HES records had mother's NHS number missing, compared with 30 per cent in the NN4B dataset. This did not reflect the extent to which Maternity HES data items were missing or discordant. Over a quarter of all linked Maternity HES records for singleton babies had one or more of the following data items missing: birthweight, gestational age, birth status, sex, and date of birth of the baby. On the other hand, for data items where information was stated such as birthweight, birth status, and sex for singleton babies, there was good agreement between Maternity HES and linked birth registration and NN4B data.Although NN4B records the ethnic category of the baby as defined by the mother, and Maternity HES records mother's ethnic category, 87 per cent of the linked records had the same ethnic group. Even though a good linkage rate was obtained, the method used will be simplified before data for 2007 are linked. To gain the maximum benefit from this linkage in future years, improvements are urgently needed in the quality and completeness of the data contained in Maternity HES.List of Tables, 55.


The UF family of reference hybrid phantoms for computational radiation dosimetry.
Computational human phantoms are computer models used to obtain dose distributions within the human body exposed to internal or external radiation sources. In addition, they are increasingly used to develop detector efficiencies for in vivo whole-body counters. Two classes of computational human phantoms have been widely utilized for dosimetry calculation: stylized and voxel phantoms that describe human anatomy through mathematical surface equations and 3D voxel matrices, respectively. Stylized phantoms are flexible in that changes to organ position and shape are possible given avoidance of region overlap, while voxel phantoms are typically fixed to a given patient anatomy, yet can be proportionally scaled to match individuals of larger or smaller stature, but of equivalent organ anatomy. Voxel phantoms provide much better anatomical realism as compared to stylized phantoms which are intrinsically limited by mathematical surface equations. To address the drawbacks of these phantoms, hybrid phantoms based on non-uniform rational B-spline (NURBS) surfaces have been introduced wherein anthropomorphic flexibility and anatomic realism are both preserved. Researchers at the University of Florida have introduced a series of hybrid phantoms representing the ICRP Publication 89 reference newborn, 15 year, and adult male and female. In this study, six additional phantoms are added to the UF family of hybrid phantoms-those of the reference 1 year, 5 year and 10 year child. Head and torso CT images of patients whose ages were close to the targeted ages were obtained under approved protocols. Major organs and tissues were segmented from these images using an image processing software, 3D-DOCTOR. NURBS and polygon mesh surfaces were then used to model individual organs and tissues after importing the segmented organ models to the 3D NURBS modeling software, Rhinoceros. The phantoms were matched to four reference datasets: (1) standard anthropometric data, (2) reference organ masses from ICRP Publication 89, (3) reference elemental compositions provided in ICRP 89 as well as ICRU Report 46, and (4) reference data on the alimentary tract organs given in ICRP Publications 89 and 100. Various adjustments and refinements to the organ systems of the previously described newborn, 15 year and adult phantoms are also presented. The UF series of hybrid phantoms retain the non-uniform scalability of stylized phantoms while maintaining the anatomical realism of patient-specific voxel phantoms with respect to organ shape, depth and inter-organ distance. While the final versions of these phantoms are in a voxelized format for radiation transport simulation, their primary format is given as NURBS and polygon mesh surfaces, thus permitting one to sculpt non-reference phantoms using the reference phantoms as an anatomic template.


SV40 Pseudovirion gene delivery of a toxin to treat human adenocarcinomas in mice.
SV40 vectors packaged in vitro (pseudovirions) are an efficient delivery system for plasmids up to 17.7 kb, with or without SV40 sequences. A truncated Pseudomonas exotoxin gene (PE38) was delivered into various human cells (HeLa, KB-3-1, human lymphoblastoids, and erythroleukemia cells), in vitro using pseudovirions. The number of viable cells was reduced significantly in the PE38-transduced cells. Human KB adenocarcinomas growing in mice were treated with intratumoral injection of PE38 packaged in vitro, and tumor size decreased significantly. Intraperitoneal treatments were as effective in reducing tumor size as intratumoral treatments. To check the viability of mock- or PE38-treated mice, every 4 days they were weighed, their blood was tested, and various tissues were screened for pathology. All parameters showed that the in vitro-packaged vectors, injected into tumors or intraperitoneally, caused no abnormalities in mice. The combined treatment of doxorubicin with in vitro-packaged PE38 reduced tumor size slightly more than each of the treatments separately. However, the combined treatment did not cause the weight loss seen with doxorubicin alone. These results indicate that SV40 in vitro packaging is an effective system for cancer gene delivery using two different routes of injection and in combination with chemotherapy.


Critical role of zinc finger protein 521 in the control of growth, clonogenicity and tumorigenic potential of medulloblastoma cells.
The stem cell-associated transcription co-factor ZNF521 has been implicated in the control of hematopoietic, osteo-adipogenic and neural progenitor cells. ZNF521 is highly expressed in cerebellum and in particular in the neonatal external granule layer that contains candidate medulloblastoma cells-of-origin, and in the majority of human medulloblastomas. Here we have explored its involvement in the control of human and murine medulloblastoma cells. The effect of ZNF521 on growth and tumorigenic potential of human medulloblastoma cell lines as well as primary Ptc1-/+ mouse medulloblastoma cells was investigated in a variety of in vitro and in vivo assays, by modulating its expression using lentiviral vectors carrying the ZNF521 cDNA, or shRNAs that silence its expression. Enforced overexpression of ZNF521 in DAOY medulloblastoma cells significantly increased their proliferation, growth as spheroids and ability to generate clones in single-cell cultures and semisolid media, and enhanced their migratory ability in wound-healing assays. Importantly, ZNF521-expressing cells displayed a greatly enhanced tumorigenic potential in nude mice. All these activities required the ZNF521 N-terminal motif that recruits the nucleosome remodeling and histone deacetylase complex, which might therefore represent an appealing therapeutic target. Conversely, silencing of ZNF521 in human UW228 medulloblastoma cells that display high baseline expression decreased their proliferation, clonogenicity, sphere formation and wound-healing ability. Similarly, Zfp521 silencing in mouse Ptc1-/+ medulloblastoma cells drastically reduced their growth and tumorigenic potential. Our data strongly support the notion that ZNF521, through the recruitment of the NuRD complex, contributes to the clonogenic growth, migration and tumorigenicity of medulloblastoma cells.


Following the publication of results of NLST (National Lung Screening Trial, USA) and ELCAP (Early Lung Cancer Action Project, USA), lung cancer screening with low-dose computed tomography (LDCT) in high-risk subjects has been recommended in North-America. Conversely, the European Community has been waiting for further evidence. The recently concluded Dutch-Belgian Lung Cancer Screening trial (NELSON) confirmed the efficacy of LDCT screening in reducing lung cancer mortality. Two recent studies in the USA and Italy showed positive results in occupational settings among workers formerly exposed to asbestos. The available evidence seems to suggest the need to implement lung cancer screening programs among heavy smokers and workers substantively exposed to occupational carcinogens.


A mixed-methods evaluation of health-related quality of life for male veterans with and without intestinal stomas.
Intestinal stomas have a major impact on Cases' lives. It is essential to better understand the areas in which interventions may help to minimize the negative consequences. This was a case-control survey study using validated instruments (City of Hope Quality of Life-Ostomy and Short Form 36 for Veterans). Cases were accrued from Veterans Affairs Medical Centers in Tucson, Indianapolis, and Los Angeles. Eligibility included a major intra-abdominal surgical procedure that led to an ostomy (cases), or a similar procedure that did not mandate a stoma (controls). Analysis included quantitative and qualitative responses. The response rate was 48 percent (511/1,063). Cases and controls had relatively similar demographic characteristics. Because of low numbers of female respondents (13 cases and 11 controls), only results for males are reported. Based on both the City of Hope Quality of Life-Ostomy and Short Form 36 for Veterans, cases reported significantly poorer scores on scales/domains reflecting psychologic and social functioning and well being. Additionally, cases reported poorer scores on Short Form 36 for Veterans scales reflecting physical functioning and significantly lower scores on multiple items in the social domain of the City of Hope Quality of Life-Ostomy compared with controls. Two-thirds of cases replied to an open-ended question on their "greatest challenge" related to their ostomy, which led to further clarification of major issues. Multiple health-related quality of life problems were reported by male veterans with intestinal stomas. The greatest differences between cases and controls were observed in the social and psychologic domains/scales. Findings from this study provide a greater understanding of the challenges faced by ostomates and will inform the development and evaluation of urgently needed intervention strategies.


The electrical and structural properties of n-type InAs nanowires grown from metal-organic precursors.
The electrical and structural properties of 111B-oriented InAs nanowires grown using metal-organic precursors have been studied. On the basis of electrical measurements it was found that the trends in carbon incorporation are similar to those observed in the layer growth, where an increased As/In precursor ratio and growth temperature result in a decrease in carbon-related impurities. Our results also show that the effect of non-intentional carbon doping is weaker in InAs nanowires compared to bulk, which may be explained by lower carbon incorporation in the nanowire core. We determine that differences in crystal quality, here quantified as the stacking fault density, are not the primary cause for variations in resistivity of the material studied. The effects of some n-dopant precursors (S, Se, Si, Sn) on InAs nanowire morphology, crystal structure and resistivity were also investigated. All precursors result in n-doped nanowires, but high precursor flows of Si and Sn also lead to enhanced radial overgrowth. Use of the Se precursor increases the stacking fault density in wurtzite nanowires, ultimately at high flows leading to a zinc blende crystal structure with strong overgrowth and very low resistivity.


Inhibition of heat shock protein 27 phosphorylation promotes sensitivity to 5-fluorouracil in colorectal cancer cells.
The aim of the present study was to investigate whether the inhibition of HSP27 phosphorylation, which affects certain cellular functions, modulates sensitivity to 5-fluorouracil (5-FU) in colorectal cancer cells. Exposure to 5-FU in HCT116 and HCT15 cells expressing high levels of HSP27 with a low 5-FU sensitivity caused a minimal change in HSP27 expression, but induced the upregulation of HSP27 phosphorylation, particularly at Ser78. By contrast, exposure to 5-FU in HT29 cells expressing a low level of HSP27 with a high 5-FU sensitivity marginally increased HSP27 expression, with minimal phosphorylation. Treatment with a selective inhibitor, p38 mitogen-activated protein kinase (MAPK; SB203580), caused the dose-dependent suppression of HSP27 phosphorylation, which was upregulated by 5-FU, reducing the half maximal inhibitory concentration values of 5-FU in the HCT116 and HCT15 cells. However, treatment with SB203580 exhibited no significant effect on cell growth or survival. In conclusion, this study indicated that the inhibition of HSP27 phosphorylation by a selective inhibitor of p38 MAPK promotes 5-FU sensitivity without causing cytotoxicity in colorectal cancer cells.


Diabetes topics associated with engagement on Twitter.
Social media are widely used by the general public and by public health and health care professionals. Emerging evidence suggests engagement with public health information on social media may influence health behavior. However, the volume of data accumulating daily on Twitter and other social media is a challenge for researchers with limited resources to further examine how social media influence health. To address this challenge, we used crowdsourcing to facilitate the examination of topics associated with engagement with diabetes information on Twitter. We took a random sample of 100 tweets that included the hashtag "#diabetes" from each day during a constructed week in May and June 2014. Crowdsourcing through Amazon's Mechanical Turk platform was used to classify tweets into 9 topic categories and their senders into 3 Twitter user categories. Descriptive statistics and Tweedie regression were used to identify tweet and Twitter user characteristics associated with 2 measures of engagement, "favoriting" and "retweeting." Classification was reliable for tweet topics and Twitter user type. The most common tweet topics were medical and nonmedical resources for diabetes. Tweets that included information about diabetes-related health problems were positively and significantly associated with engagement. Tweets about diabetes prevalence, nonmedical resources for diabetes, and jokes or sarcasm about diabetes were significantly negatively associated with engagement. Crowdsourcing is a reliable, quick, and economical option for classifying tweets. Public health practitioners aiming to engage constituents around diabetes may want to focus on topics positively associated with engagement.


Accelerated bone loss and increased post-fracture mortality in elderly women and men.
Bone loss, a fracture risk factor, may play a role in post-fracture mortality. We found accelerated bone loss (≥1.31 % bone loss/year for women and ≥1.35 % bone loss/year for men) associated with 44-77 % increased mortality. It remains unclear whether bone loss is a marker or plays a role in mortality. Osteoporotic fractures are associated with increased mortality although the cause is unknown. Bone loss, a risk factor for osteoporotic fracture is also associated with increased mortality, but its role in mortality risk post-fracture is unclear. This study aimed to examine post-fracture mortality risk according to levels of bone loss. Community-dwelling participants aged 60+ from Dubbo Osteoporosis Epidemiology Study with incident fractures were followed from 1989 to 2011. Kaplan-Meier survival curves were constructed according to bone loss quartiles. Cox proportional hazard models were used to determine the effect of bone loss on mortality. There were 341 women and 106 men with ≥2 BMD measurements. The rate of bone loss was similar for women and men (women mean -0.79 %/year, highest bone loss quartile -1.31 %/year; men mean -0.74 %/year, highest quartile -1.35 %/year). Survival was lowest for the highest quartile of bone loss for women (p < 0.005) and men (p = 0.05). When analysed by fracture type, the association of bone loss with mortality was observed for vertebral (highest vs lower 3 quartiles of bone loss, women p = 0.03 and men p = 0.02) and non-hip non-vertebral fractures in women (p < 0.0001). Bone loss did not play an additional role in mortality risk following hip fractures. Importantly, overall, rapid bone loss was associated with 44-77 % increased mortality risk after multiple variable adjustment. Rapid bone loss was an independent predictor of post-fracture mortality risk in both women and men. The association of bone loss and post-fracture mortality was predominantly observed following vertebral fracture in both women and men and non-hip non-vertebral fracture in women. It remains to be determined whether bone loss is a marker or plays a role in the mortality associated with fractures.


Fidelity and mutational spectrum of Pfu DNA polymerase on a human mitochondrial DNA sequence.
The study of rare genetic changes in human tissues requires specialized techniques. Point mutations at fractions at or below 10(-6) must be observed to discover even the most prominent features of the point mutational spectrum. PCR permits the increase in number of mutant copies but does so at the expense of creating many additional mutations or "PCR noise". Thus, each DNA sequence studied must be characterized with regard to the DNA polymerase and conditions used to avoid interpreting a PCR-generated mutation as one arising in human tissue. The thermostable DNA polymerase derived from Pyrococcus furiosus designated Pfu has the highest fidelity of any DNA thermostable polymerase studied to date, and this property recommends it for analyses of tissue mutational spectra. Here, we apply constant denaturant capillary electrophoresis (CDCE) to separate and isolate the products of DNA amplification. This new strategy permitted direct enumeration and identification of point mutations created by Pfu DNA polymerase in a 96-bp low melting domain of a human mitochondrial sequence despite the very low mutant fractions generated in the PCR process. This sequence, containing part of the tRNA glycine and NADH dehydrogenase subunit 3 genes, is the target of our studies of mitochondrial mutagenesis in human cells and tissues. Incorrectly synthesized sequences were separated from the wild type as mutant/wild-type heteroduplexes by sequential enrichment on CDCE. An artificially constructed mutant was used as an internal standard to permit calculation of the mutant fraction. Our study found that the average error rate (mutations per base pair duplication) of Pfu was 6.5 x 10(-7), and five of its more frequent mutations (hot spots) consisted of three transversions (GC-->TA, AT-->TA, and AT-->CG), one transition (AT-->GC), and one 1-bp deletion (in an AAAAAA sequence). To achieve an even higher sensitivity, the amount of Pfu-induced mutants must be reduced.


Health habit counseling amidst competing demands: effects of patient health habits and visit characteristics.
This study assesses the effects of competing demands, such as poor health habits or new medical problems, on health-habit counseling during a primary care visit. We surveyed a consecutive sample of 1,259 patients visiting primary care clinicians at an academic VA medical center. Before the visit, patients reported their health status, health habits, and sociodemographics; immediately after the visit, patients reported reasons for the visit and whether they had been counseled about specific health habits. We scored visit acuity ranging from visits for unscheduled walk-in care or new medical problems to scheduled visits for check-ups or old problems. We defined counseling "triggers" as clinical indications for counseling about particular health habits (e.g., smoking). We developed a logistic model predicting primary care provider counseling during a visit. Over two-thirds of patients (68.9%) received some health habit counseling. Controlling for other independent variables, patients with more triggers were more likely to report being counseled. Counseling rates went up as visit acuity went down; patients with the lowest visit acuity having 67% greater odds of being counseled than patients with the highest visit acuity. Physicians set priorities for health-habit counseling during a visit based on patients' health habit problems or triggers; whether the visit is scheduled or walk-in; and whether the patient has new or acute problems. Future research about primary care performance of health habit counseling should account for these patient and visit characteristics, and prevention-oriented health care organizations should ensure access to scheduled "check-up" visits.


Minos as a genetic and genomic tool in Drosophila melanogaster.
Much of the information about the function of D. melanogaster genes has come from P-element mutagenesis. The major drawback of the P element, however, is its strong bias for insertion into some genes (hotspots) and against insertion into others (coldspots). Within genes, 5'-UTRs are preferential targets. For the successful completion of the Drosophila Genome Disruption Project, the use of transposon vectors other than P will be necessary. We examined here the suitability of the Minos element from Drosophila hydei as a tool for Drosophila genomics. Previous work has shown that Minos, a member of the Tc1/mariner family of transposable elements, is active in diverse organisms and cultured cells; it produces stable integrants in the germ line of several insect species, in the mouse, and in human cells. We generated and analyzed 96 Minos integrations into the Drosophila genome and devised an efficient "jump-starting" scheme for production of single insertions. The ratio of insertions into genes vs. intergenic DNA is consistent with a random distribution. Within genes, there is a statistically significant preference for insertion into introns rather than into exons. About 30% of all insertions were in introns and approximately 55% of insertions were into or next to genes that have so far not been hit by the P element. The insertion sites exhibit, in contrast to other transposons, little sequence requirement beyond the TA dinucleotide insertion target. We further demonstrate that induced remobilization of Minos insertions can delete nearby sequences. Our results suggest that Minos is a useful tool complementing the P element for insertional mutagenesis and genomic analysis in Drosophila.


Evidence from action and fluorescence spectra that UV-induced violet-blue-green fluorescence enhances leaf photosynthesis.
We assessed the contribution of UV-induced violet-blue-green leaf fluorescence to photosynthesis in Poa annua, Sorghum halepense and Nerium oleander by measuring UV-induced fluorescence spectra (280-380 nm excitation, 400-550 nm emission) from leaf surfaces and determining the monochromatic UV action spectra for leaf photosynthetic O2-evolution. Peak fluorescence emission wavelengths from leaf surfaces ranged from violet (408 nm) to blue (448 nm), while excitation peaks for these maxima ranged from 333 to 344 nm. Action spectra were developed by supplementing monochromatic radiation from 280 to 440 nm, in 20 nm increments, to a visible nonsaturating background of 500 mumol m-2 s-1 photosynthetically active radiation and measuring photosynthetic O2-evolution rates. Photosynthetic rates tended to be higher with the 340 nm supplement than with higher or lower wavelength UV supplements. Comparing photosynthetic rates with the 340 nm supplement to those with the 400 nm supplement, the percentage enhancement in photosynthetic rates at 340 nm ranged from 7.8 to 9.8%. We suspect that 340 nm UV improves photosynthetic rates via fluorescence that provides violet-blue-green photons for photosynthetic energy conversion because (1) the peak excitation wavelength (340 nm) for violet-blue-green fluorescence from leaves was also the most effective UV wavelength at enhancing photosynthetic rates, and (2) the magnitude of photosynthetic enhancements attributable to supplemental 340 nm UV was well correlated (R2 = 0.90) with the apparent intensity of 340 nm UV-induced violet-blue-green fluorescence emission from leaves.


Harnessing genomics to improve outcomes for women with cancer in India: key priorities for research.
Cumulatively, breast, cervical, ovarian, and uterine cancer account for more than 70% of cancers in women in India. Distinct differences in the clinical presentation of women with cancer suggest underlying differences in cancer biology and genetics. The peak age of onset of breast and ovarian cancer appears to be a decade earlier in India (age 45-50 years) than in high-income countries (age >60 years). Understanding these differences through research to develop diagnosis, screening, prevention, and treatment frameworks that ar e specific to the Indian population are critical and essential to improving women's health in India. Since the sequencing of the human genome in 2001, applications of advanced technologies, such as massively parallel sequencing, have transformed the understanding of the genetic and environmental drivers of cancer. How can advanced technologies be harnessed to provide health-care solutions at a scale and to a budget suitable for a country of 1·2 billion people? What research programmes are necessary to answer questions specific to India, and to build capacity for innovative solutions using these technologies? In order to answer these questions, we convened a workshop with key stakeholders to address these issues. In this Series paper, we highlight challenges in tackling the growing cancer burden in India, discuss ongoing genomics research and developments in infrastructure, and suggest key priorities for future research in cancer in India.


Temporal dynamics of visuo-tactile extinction within and between hemispaces.
The ability to detect left-sided stimuli (visual or tactile) was studied in visual and tactile extinction (RBD) patients and in healthy (C) subjects. Stimuli were single or double; double stimuli were always cross-modal and could be released across the 2 hemispaces or within the same hemispace. Moreover, the stimuli could be either simultaneous or separated by 1 of 3 different asynchronies (105, 505, 905 ms). C subjects were perfect in all conditions. RBD patients omitted the contralesional tactile stimulus in bilateral trials (across space, classical extinction). They also omitted the tactile stimulus in unilateral left trials (within hemispace). Both effects showed the same temporal modulation with lower extinction rates at longer stimulus onset asynchronies. Results suggest that attentional processing of a visual stimulus inhibits processing of a tactile one, even if both are delivered in the same contralesional hemispace.


Mild traumatic brain injury and anxiety sequelae: a review of the literature.
There is scattered but significant psychological and neuropsychological evidence to suggest that mild traumatic brain injury (mild TBI) plays a notable role in the emergence and expression of anxiety. Conversely, there is also empirical evidence to indicate that anxiety may exert a pronounced impact on the prognosis and course of recovery of an individual who has sustained a mild TBI. Although the relationship between mild TBI and anxiety remains unclear, the present body of research attempts to elucidate a number of aspects regarding this topic. Overall, the mild TBI research is rife with inconsistencies concerning prevalence rates, the magnitude and implications of this issue and, in the case of PTSD, even whether certain diagnoses can exist at all. This review obviates the need for greater consistencies across studies, especially between varying disciplines, and calls for a shift from studies overly focused on categorical classification to those concerned with dimensional conceptualization.


Alternative splicing regulates the expression of G9A and SUV39H2 methyltransferases, and dramatically changes SUV39H2 functions.
Alternative splicing is the main source of proteome diversity. Here, we have investigated how alternative splicing affects the function of two human histone methyltransferases (HMTase): G9A and SUV39H2. We show that exon 10 in G9A and exon 3 in SUV39H2 are alternatively included in a variety of tissues and cell lines, as well as in a different species. The production of these variants is likely tightly regulated because both constitutive and alternative splicing factors control their splicing profiles. Based on this evidence, we have assessed the link between the inclusion of these exons and the activity of both enzymes. We document that these HMTase genes yield several protein isoforms, which are likely issued from alternative splicing regulation. We demonstrate that inclusion of SUV39H2 exon 3 is a determinant of the stability, the sub-nuclear localization, and the HMTase activity. Genome-wide expression analysis further revealed that alternative inclusion of SUV39H2 exon 3 differentially modulates the expression of target genes. Our data also suggest that a variant of G9A may display a function that is independent of H3K9 methylation. Our work emphasizes that expression and function of genes are not collinear; therefore alternative splicing must be taken into account in any functional study.


Direct measurement of cyclotron coherence times of high-mobility two-dimensional electron gases.
We have observed long-lived (approximately 30 ps) coherent oscillations of charge carriers due to cyclotron resonance (CR) in high-mobility two-dimensional electrons in GaAs in perpendicular magnetic fields using time-domain terahertz spectroscopy. The observed coherent oscillations were fitted well by sinusoids with exponentially-decaying amplitudes, through which we were able to provide direct and precise measures for the decay times and oscillation frequencies simultaneously. This method thus overcomes the CR saturation effect, which is known to prevent determination of true CR linewidths in high-mobility electron systems using Fourier-transform infrared spectroscopy.