Geometric interpretation of the Pancharatnam connection and non-cyclic polarization changes.
If the state of polarization of a monochromatic light beam is changed in a cyclical manner, the beam acquires-in addition to the usual dynamic phase-a geometric phase. This geometric or Pancharatnam-Berry phase equals half the solid angle of the contour traced out on the Poincaré sphere. We show that such a geometric interpretation also exists for the Pancharatnam connection, the criterion according to which two beams with different polarization states are said to be in phase. This interpretation offers what is to our knowledge a new and intuitive method to calculate the geometric phase that accompanies non-cyclic polarization changes.


Chloroquine and COVID-19 - a potential game changer?
The novel coronavirus SARS-CoV-2, causing the disease COVID-19, first emerged in Wuhan, China in December 2019 and has now spread to 203 countries or territories, infected over 2 million people and caused over 133,000 deaths. There is an urgent need for specific treatments. One potential treatment is chloroquine and its derivatives, including hydroxychloroquine, which have both antiviral and anti-inflammatory effects. These compounds are effective against SARS-CoV-2 in vitro, but in vivo data are lacking. Although some encouraging outcomes have been reported, and these results have been received enthusiastically, we recommend careful and critical evaluation of current evidence only when all methods and data are available for peer review. Chloroquine is safe and cheap. However, further evidence from coordinated multicentre trials is required before it can be confidently said whether it is effective against the current pandemic.


The adult spinal cord injury without radiographic abnormalities syndrome: magnetic resonance imaging and clinical findings in adults with spinal cord injuries having normal radiographs and computed tomography studies.
Spinal cord injury without radiographic abnormalities (SCIWORA) is thought to represent mostly a pediatric entity and its incidence in adults is rather underreported. Some authors have also proposed the term spinal cord injury without radiologic evidence of trauma, as more precisely describing the condition of adult SCIWORA in the setting of cervical spondylosis. The purpose of the present study was to evaluate adult patients with cervical spine injuries and radiological-clinical examination discrepancy, and to discuss their characteristics and current management. During a 16-year period, 166 patients with a cervical spine injury were admitted in our institution (Level I trauma center). Upper cervical spine injuries (occiput to C2, 54 patients) were treated mainly by a Halo vest, whereas lower cervical spine injuries (C3-T1, 112 patients) were treated surgically either with an anterior, or posterior procedure, or both. Seven of these 166 patients (4.2%) had a radiologic-clinical mismatch, i.e., they presented with frank spinal cord injury with no signs of trauma, and were included in the study. Magnetic resonance imaging was available for 6 of 7 patients, showing intramedullary signal changes in 5 of 6 patients with varying degrees of compression from the disc and/or the ligamentum flavum, whereas the remaining patient had only traumatic herniation of the intervertebral disc and ligamentum flavum bulging. Follow-up period was 6.4 years on average (1-10 years). This retrospective chart review provides information on adult patients with cervical spinal cord injuries whose radiographs and computed tomography studies were normal. It furthers reinforces the pathologic background of SCIWORA in an adult population, when evaluated by magnetic resonance imaging. Particularly for patients with cervical spondylosis, special attention should be paid with regard to vascular compromise by predisposing factors such as smoking or vascular disease, since they probably contribute in the development of SCIWORA.


Absolute frequencies of lipopolysaccharide-reactive B cells producing A5A idiotype in unprimed, streptococcal A carbohydrate-primed, anti-A5A idiotype-sensitized and anti-A5A idiotype-suppressed A/J mice.
The absolute frequencies of B cells-producing A5A idiotype have been determined in vitro by limiting dilution analysis in a culture system in which every LPS-reactive B cell grows into a clone of IgM-secreting cells. Spleen cells from normal A/J mice contain 1 A5A-idiotype-producing B-cell precursor in 2.5 X 10(3) LPS-reactive B cells. Approximately a 10-20-fold increase in frequencies of precursor cells from antigen priming with Strep A-CHO (1 in 2.8 X 10(2)) or from sensitization with IgG1 anti-A5A idiotype (1 in 1.3 X 10(2)). Injection of IgG2 anti-A5A idiotype which has been shown to suppress A5A idiotype in vivo results in only a marginal and maybe insignificant decrease in precursor frequencies (1 in 6.7 X 10(3)). On the other hand, priming does not result in a detectable qualitative difference in the specific precursor cells, since each clone of B cells secretes 30 ng of A5A-bearing Ig within 8 days of culture, regardless of being unprimed or primed. Nearly half of all A5A idiotype-producing clones, both from unprimed as well as from primed mice, show antigen specificity in binding A-CHO. Priming by antigen, therefore, also results in a 10-fold increase in the frequency of idiotype positive B cells without antigen specificity. This result is a prediction of the network hypothesis.


Combinatorial optimization of PEG architecture and hydrophobic content improves ternary siRNA polyplex stability, pharmacokinetics, and potency in vivo.
A rationally-designed library of ternary siRNA polyplexes was developed and screened for gene silencing efficacy in vitro and in vivo with the goal of overcoming both cell-level and systemic delivery barriers. [2-(dimethylamino)ethyl methacrylate] (DMAEMA) was homopolymerized or copolymerized (50mol% each) with butyl methacrylate (BMA) from a reversible addition - fragmentation chain transfer (RAFT) chain transfer agent, with and without pre-conjugation to polyethylene glycol (PEG). Both single block polymers were tested as core-forming units, and both PEGylated, diblock polymers were screened as corona-forming units. Ternary siRNA polyplexes were assembled with varied amounts and ratios of core-forming polymers to PEGylated corona-forming polymers. The impact of polymer composition/ratio, hydrophobe (BMA) placement, and surface PEGylation density was correlated to important outcomes such as polyplex size, stability, pH-dependent membrane disruptive activity, biocompatibility, and gene silencing efficiency. The lead formulation, DB4-PDB12, was optimally PEGylated not only to ensure colloidal stability (no change in size by DLS between 0 and 24h) and neutral surface charge (0.139mV) but also to maintain higher cell uptake (>90% positive cells) than the most densely PEGylated particles. The DB4-PDB12 polyplexes also incorporated BMA in both the polyplex core- and corona-forming polymers, resulting in robust endosomolysis and in vitro siRNA silencing (~85% protein level knockdown) of the model gene luciferase across multiple cell types. Further, the DB4-PDB12 polyplexes exhibited greater stability, increased blood circulation time, reduced renal clearance, increased tumor biodistribution, and greater silencing of luciferase compared to our previously-optimized, binary parent formulation following intravenous (i.v.) delivery. This polyplex library approach enabled concomitant optimization of the composition and ratio of core- and corona-forming polymers (indirectly tuning PEGylation density) and identification of a ternary nanomedicine optimized to overcome important siRNA delivery barriers in vitro and in vivo.


Response time models separate single- and dual-process accounts of memory-based decisions.
Human decisions often deviate from economic rationality and are influenced by cognitive biases. One such bias is the memory bias according to which people prefer choice options they have a better memory of-even when the options' utilities are comparatively low. Although this phenomenon is well supported empirically, its cognitive foundation remains elusive. Here we test two conceivable computational accounts of the memory bias against each other. On the one hand, a single-process account explains the memory bias by assuming a single biased evidence-accumulation process in favor of remembered options. On the contrary, a dual-process account posits that some decisions are driven by a purely memory-driven process and others by a utility-maximizing one. We show that both accounts are indistinguishable based on choices alone as they make similar predictions with respect to the memory bias. However, they make qualitatively different predictions about response times. We tested the qualitative and quantitative predictions of both accounts on behavioral data from a memory-based decision-making task. Our results show that a single-process account provides a better account of the data, both qualitatively and quantitatively. In addition to deepening our understanding of memory-based decision-making, our study provides an example of how to rigorously compare single- versus dual-process models using empirical data and hierarchical Bayesian parameter estimation methods.


Precarious hope: Ethical considerations for offering experimental fetal therapies outside of research after initial studies in humans.
Risks and benefits of experimental fetal therapies can remain uncertain after initial clinical studies, especially long-term effects. Nevertheless, pregnant individuals may request them, hoping to benefit their future child. Guidance about offering experimental fetal therapies outside research (as "innovative therapy") is limited, despite their ethical complexity. We propose points for clinicians and reviewers to consider when deciding whether and how to offer experimental fetal therapies as innovative therapies after initial clinical studies. We used conceptual analysis and a current case to develop points for consideration, grounded in broader debates on innovative therapy and the unique challenges associated with experimental fetal therapies. Clinicians should evaluate whether offering experimental fetal therapies as innovative therapy is appropriate for a pregnant individual and their fetus. The anticipated risk-benefit ratio for the fetus should be favorable. For the pregnant individual, risks may outweigh benefits, within reasonable limits. Medical resources should be sufficient to ensure appropriate care. Clinicians should support pregnant individuals in making informed choices. Clinicians offering innovative therapies with more than minimal risk should collect and report data on outcomes. Independent review should take place. Considering these points may advance the interests of fetuses, future children, and their families.


Detection of vaccine-derived rotavirus strains in nonimmunocompromised children up to 3-6 months after RotaTeq® vaccination.
We conducted a survey on the presence of RotaTeq vaccine viruses in infants hospitalized with respiratory infection, and detected shedding in 17% of children (<2 years of age) who had ever received the vaccine. The latest detection was at the age of 8 months. We conclude that asymptomatic long-time shedding of RotaTeq viruses is not uncommon, and is particularly associated with genotype G1.


Expression of an engineered granule-bound Escherichia coli glycogen branching enzyme in potato results in severe morphological changes in starch granules.
The Escherichia coli glycogen branching enzyme (GLGB) was fused to either the C- or N-terminus of a starch-binding domain (SBD) and expressed in two potato genetic backgrounds: the amylose-free mutant (amf) and an amylose-containing line (Kardal). Regardless of background or construct used, a large amount of GLGB/SBD fusion protein was accumulated inside the starch granules, however, without an increase in branching. The presence of GLGB/SBD fusion proteins resulted in altered morphology of the starch granules in both genetic backgrounds. In the amf genetic background, the starch granules showed both amalgamated granules and porous starch granules, whereas in Kardal background, the starch granules showed an irregular rough surface. The altered starch granules in both amf and Kardal backgrounds were visible from the initial stage of potato tuber development. High-throughput transcriptomic analysis showed that expression of GLGB/SBD fusion protein in potato tubers did not affect the expression level of most genes directly involved in the starch biosynthesis except for the up-regulation of a beta-amylase gene in Kardal background. The beta-amylase protein could be responsible for the degradation of the extra branches potentially introduced by GLGB.


The auxin responsive AP2/ERF transcription factor CROWN ROOTLESS5 is involved in crown root initiation in rice through the induction of OsRR1, a type-A response regulator of cytokinin signaling.
Cytokinin is known to have negative effects on de novo auxin-induced root formation. However, the regulatory mechanisms of root initiation by both cytokinin and auxin are poorly understood. In this study, we characterized a rice mutant, termed crown rootless5 (crl5), which produced fewer crown roots and displayed impaired initiation of crown root primordia. The expression of CRL5, which encodes a member of the large AP2/ERF transcription factor family protein, was observed in the stem region where crown root initiation occurs. Exogenous auxin treatment induced CRL5 expression without de novo protein biosynthesis, which also required the degradation of AUX/IAA proteins. A putative auxin response element in the CRL5 promoter region specifically interacted with a rice ARF, demonstrating that CRL5 may be a direct target of an ARF, similar to CRL1/ADVENTITIOUS ROOTLESS1 (ARL1) that also regulates crown root initiation. A crl1 crl5 double mutant displayed an additive phenotype, indicating that these two genes function in different genetic pathways for crown root initiation. In addition, ProACT:CRL5/WT showed a cytokinin-resistant phenotype for crown root initiation, and also up-regulated the expression of two negative regulators of cytokinin signaling, OsRR1 and OsRR2, which were downregulated in crl5. Transgenic plants that over-expressed OsRR1 under the control of the CRL5 promoter in a crl5 mutant background produced a higher number of crown roots than the crl5 plant. Taken together, these results indicate that auxin-induced CRL5 promotes crown root initiation through repression of cytokinin signaling by positively regulating type-A RR, OsRR1.


Use of complementary and alternative medicine in Europe: Health-related and sociodemographic determinants.
The aim of this research was to study health-related and sociodemographic determinants of the use of different complementary and alternative medicine (CAM) treatments in Europe and differences in CAM use in various European countries. The study was based on a design-based logistic regression analysis of the European Social Survey (ESS), Round 7. We distinguished four CAM modalities: manual therapies, alternative medicinal systems, traditional Asian medical systems and mind-body therapies. In total, 25.9% of the general population had used CAM during the last 12 months. Typically, only one CAM treatment had been used, and it was used more often as complementary rather than alternative treatment. The use of CAM varied greatly by country, from 10% in Hungary to almost 40% in Germany. Compared to those in good health, the use of CAM was two to fourfold greater among those with health problems. The health profiles of users of different CAM modalities varied. For example, back or neck pain was associated with all types of CAM, whereas depression was associated only with the use of mind-body therapies. Individuals with difficult to diagnose health conditions were more inclined to utilize CAM, and CAM use was more common among women and those with a higher education. Lower income was associated with the use of mind-body therapies, whereas the other three CAM modalities were associated with higher income. Help-seeking differed according to the health problem, something that should be acknowledged by clinical professionals to ensure safe care. The findings also point towards possible socioeconomic inequalities in health service use.


Classic high lateral tension and triangular resection methods to prevent dog ear and elongation scar in patients undergoing abdominoplasty: A comparative open-label clinical trial.
One of the most common operations in the plastic surgery curse is abdominoplasty. Several methods were recommended for achieving better results. In the present study, efficacy of a new method compared with classical high lateral tension on preventing dog ear and elongation scar was evaluated. in an open-label, randomized clinical trial, seventy patients who were candidates for abdominoplasty were selected and randomly divided into two groups. The first group was operated by classic high lateral method and the second group was operated by a new method concentrating on changing incision line and angle. Dog ear prevention, length of scar, improvement, and postoperative complications were compared between the two groups. The mean ± standard deviation (SD) length of scar in treated patients with classical and new abdominoplasty surgical methods was 53.68 ± 6.34 and 41.71 ± 1.78 cm, respectively, and the length of scar in the group treated with the new method was significantly shorter (P < 0.001). The mean ± SD distance between two anterior superior iliac spine in group treated by new method was significantly decreased after surgery (31.3 ± 1.3 cm) compared to before intervention (36.7 ± 3.9 cm) (P < 0.01). The new method is more likely to be successful in patients with high lateral tension abdominoplasty. However, according to the lack of similar studies in this regard and the fact that this method was introduced for the first time, it is recommended that further studies in this area are needed and patients in term of complications after surgery need a longer period of follow-up.


High-performance bioassisted nanophotocatalyst for hydrogen production.
Nanophotocatalysis is one of the potentially efficient ways of capturing and storing solar energy. Biological energy systems that are intrinsically nanoscaled can be employed as building blocks for engineering nanobio-photocatalysts with tunable properties. Here, we report upon the application of light harvesting proton pump bacteriorhodopsin (bR) assembled on Pt/TiO2 nanocatalyst for visible light-driven hydrogen generation. The hybrid system produces 5275 μmole of H2 (μmole protein)(-1) h(-1) at pH 7 in the presence of methanol as a sacrificial electron donor under white light. Photoelectrochemical and transient absorption studies indicate efficient charge transfer between bR protein molecules and TiO2 nanoparticles.


Evaluation of a cholecystokinin 2 receptor-targeted near-infrared dye for fluorescence-guided surgery of cancer.
Surgical resection of malignant disease remains one of the most effective tools for treating cancer. Tumor-targeted near-infrared dyes have the potential to improve contrast between normal and malignant tissues, thereby enabling surgeons to more quantitatively resect malignant disease. Because the cholecystokinin 2 receptor (CCK2R and its tumor-specific splice variant CCK2i4svR) is overexpressed in cancers of the lungs, colon, thyroid, pancreas, and stomach, but absent or inaccessible to parenterally administered drugs in most normal tissues, we have undertaken to design a targeting ligand that can deliver attached near-infrared dyes to CCK2R+ tumors. We report here the synthesis and biological characterization of a CCK2R-targeted conjugate of the near-infrared dye, LS-288 (CRL-LS288). We demonstrate that CRL-LS288 binds selectively to CCK2R+ cancer cells with low nanomolar affinity (Kd = 7 × 10(-9) M). We further show that CRL-LS288 localizes primarily to CCK2R-expressing HEK 293 murine tumor xenografts and that dye uptake in these xenografts is significantly reduced when CCK2R are blocked by preinjection of excess ligand (CRL) or when mice are implanted with CCK2R-negative tumors. Because CRL-LS288 is also found to reveal the locations of distant tumor metastases, we suggest that CRL-LS288 has the potential to facilitate intraoperative identification of malignant disease during a variety of cancer debulking surgeries.


Clinical experience with (18)F-fluorodeoxyglucose positron emission tomography and (123)I-metaiodobenzylguanine scintigraphy in pediatric neuroblastoma: complementary roles in follow-up of patients.
To evaluate the potential utility of (123)I-metaiodobenzylguanine ((123)I-MIBG) scintigraphy and (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) for the detection of primary and metastatic lesions in pediatric neuroblastoma (NBL) patients, and to determine whether (18)F-FDG PET is as beneficial as (123)I-MIBG imaging. We selected 8 NBL patients with significant residual mass after operation and who had paired (123)I-MIBG and (18)F-FDG PET images that were obtained during the follow-up. We retrospectively reviewed the clinical charts and the findings of 45 paired scans. Both scans correlated relatively well with the disease status as determined by standard imaging modalities during follow-up; the overall concordance rates were 32/45 (71.1%) for primary tumor sites and 33/45 (73.3%) for bone-bone marrow (BM) metastatic sites. In detecting primary tumor sites, (123)I-MIBG might be superior to (18)F-FDG PET. The sensitivity of (123)I-MIBG and (18)F-FDG PET were 96.7% and 70.9%, respectively, and their specificity were 85.7% and 92.8%, respectively. (18)F-FDG PET failed to detect 9 true NBL lesions in 45 follow-up scans (false negative rate, 29%) with positive (123)I-MIBG. For bone-BM metastatic sites, the sensitivity of (123)I-MIBG and (18)F-FDG PET were 72.7% and 81.8%, respectively, and the specificity were 79.1% and 100%, respectively. (123)I-MIBG scan showed higher false positivity (20.8%) than (18)F-FDG PET (0%). (123)I-MIBG is superior for delineating primary tumor sites, and (18)F-FDG PET could aid in discriminating inconclusive findings on bony metastatic NBL. Both scans can be complementarily used to clearly determine discrepancies or inconclusive findings on primary or bone-BM metastatic NBL during follow-up.


Establishing tobacco origin from pollen identification: an approach to resolving the debate.
Previous research into pollen content of tobacco resulted in a debate. We address this debate and determine that pollen analysis may be able to assist with identifying geographical origin of tobacco. However, the value of any results should be assessed on a case-by-case regional basis until sufficient database information is available for an objective interpretation to be undertaken on a global basis. As a first step toward developing comparative data for South America, we analyzed a tobacco sample from Brazil in an effort to identify signature taxa from the state of Minas Gerais. We also assessed the role of honey additives to tobacco to assess this issue. Comparing the data to previously published data, we conclude that pollen signatures can distinguish broad geographic areas. We conclude that this forensic interpretation framework needs to be developed in context of the National Academy of Sciences recommendations for tightening methods in forensic science.


Use of an experimental language acquisition paradigm for standardized neuropsychological assessment of learning: A pilot study in young and older adults.
Introduction: Despite the numerous episodic memory tasks used in neuropsychological assessment, relatively few learning tasks are available, with methods lacking the complexity and sophistication to capture very subtle changes in information acquisition.Method: We adapted a previously validated associative learning task for use within an online framework, utilizing real-world stimuli, in which learning of audio-visual pairs of Chinese characters and English words occurs over 5 days. The aim of this study was to validate our adaptation to the task, provide estimates of rates of learning in both young and older adults, as well as provide a methodological framework for further adaptation and development of the paradigm. A total of 30 young adults and 30 older adults completed 5 days of the Chinese Characters Learning Task (CCLT).Results: Results indicated that rates of learning on the adapted task were comparable to the original paradigm and consistent across variations to testing frequency and duration. Our results also indicate the presence of a significant age-related impairment in the rate and accuracy of learning, with young adults aged 18-45 years performing significantly better than older adults aged 65-85 years, that was not due to differences in reaction time.Conclusions: These findings suggest that daily measurement of cognition via an online platform can detect age-related impairments in learning and is therefore applicable for use within the context of age-related disorders of memory and learning.


Early onset of lipofuscin accumulation in dystrophin-deficient skeletal muscles of DMD patients and mdx mice.
Lipofuscin, the so-called ageing pigment, is formed by the oxidative degradation of cellular macromolecules by oxygen-derived free radicals and redox-active metal ions. Usually it accumulates in post-mitotic, long-lived cells such as neurons and cardiac muscle cells. In contrast, it is rarely seen in either normal or diseased skeletal muscle fibres. In this paper, we report that lipofuscin accumulates at an early age in both human and murine dystrophic muscles. Autofluorescent lipofuscin granules were localized, using confocal laser scanning microscopy and electron microscopy, in dystrophin-deficient skeletal muscles of X chromosome-linked young Duchenne muscular dystrophy (DMD) patients and of mdx mice at various ages after birth. Age-matched normal controls were studied similarly. Autofluorescent lipofuscin granules were observed in dystrophic biceps brachii muscles of 2-7-year-old DMD patients where degeneration and regeneration of myofibres are active, but they were rarely seen in age-matched normal controls. In normal mice, lipofuscin first appears in diaphragm muscles nearly 20 weeks after birth but in mdx muscles it occurs much earlier, 4 weeks after birth, when the primary degeneration of dystrophin-deficient myofibres is at a peak. Lipofuscin accumulation increases with age in both mdx and normal controls and is always higher in dystrophic muscles than in age-matched normal controls. At the electron microscopical level, it was confirmed that the localisation of autofluorescent granules observed by light microscopy in dystrophin-deficient skeletal muscles coincided with lipofuscin granules in myofibres and myosatellite cells, and in macrophages accumulating around myofibres and in interstitial connective tissue. Our results agree with previous biochemical and histochemical data implying increased oxidative damages in DMD and mdx muscles. They indicate that dystrophin-deficient myofibres are either more susceptible to oxidative stress, or are subjected to higher intra- or extracellular oxidative stress than normal controls, or both.


Differential impact of the Canadian point-of-sale tobacco display bans on quit attempts and smoking cessation outcomes by sex, income and education: longitudinal findings from the ITC Canada Survey.
This study examines the differential effects of Canadian point-of-sale (POS) tobacco display bans across provinces on quit attempts and smoking cessation, by sex, education and income. We analysed survey data from five waves (waves 4-8) of the International Tobacco Control Canada Survey, a population-based, longitudinal survey, where provinces implemented display bans between 2004 and 2010. Primary outcomes were quit attempts and successful cessation. We used generalised estimating equation Poisson regression models to estimate associations between living in a province with or without a POS ban (with a 24-month threshold) and smoking outcomes. We tested whether these associations varied by sex, education and income by including interaction terms. Across survey waves, the percentage of participants in provinces with POS bans established for more than 24 months increased from 5.0% to 95.8%. There was no association between POS bans and quit attempts for provinces with bans in place for 0-24 months or more than 24 months, respectively (adjusted relative risk (aRR)=0.99, 95% CI: 0.89 to 1.10; 1.03, 95% CI: 0.88 to 1.20). However, we found a differential impact of POS bans on quit attempts by sex, whereby bans were more effective for women than men for bans of 0-24 months. Participants living in a province with a POS ban for at least 24 months had a higher chance of successful cessation (aRR=1.49; 95% CI: 1.08 to 2.05) compared with those in a province without a ban. We found no differences in the association between POS bans and quit attempts or cessation by education or income, and no differences by sex for cessation. POS bans are associated with increased smoking cessation overall and more quit attempts among women than men.


Cinnabarinic Acid-Induced Stanniocalcin 2 Confers Cytoprotection against Alcohol-Induced Liver Injury.
We recently identified upregulation of a novel aryl hydrocarbon receptor (AhR) target gene, stanniocalcin 2 (STC2), by an endogenous AhR agonist, cinnabarinic acid (CA). STC2 is a disulfide-linked homodimeric secreted glycoprotein that plays a role in various physiologic processes, including cell metabolism, inflammation, endoplasmic reticulum (ER) and oxidative stress, calcium regulation, cell proliferation, and apoptosis. Our previous studies have confirmed that CA-induced AhR-dependent STC2 expression was able to confer cytoprotection both in vitro and in vivo in response to injury induced by variety of ER/oxidative insults. Here, we used mouse models of chronic and acute ethanol feeding and demonstrated that upregulation of STC2 by CA was critical for cytoprotection. In STC2 knockout mice (STC2-/-), CA failed to protect against both acute as well as chronic-plus-binge ethanol-induced liver injury, whereas re-expression of STC2 in the liver using in vivo gene delivery restored cytoprotection against injury based on measures of apoptosis and serum levels of liver enzymes, underlining STC2's indispensable function in cell survival. In conclusion, the identification of STC2 as an AhR target gene receptive to CA-mediated endogenous AhR signaling and STC2's role in providing cytoprotection against liver injury represents a key finding with potentially significant therapeutic implications. SIGNIFICANCE STATEMENT: We recently identified stanniocalcin 2 (STC2) as a novel aryl hydrocarbon receptor (AhR) target gene regulated by endogenous AhR agonist and tryptophan metabolite, cinnabarinic acid (CA). Here, we showed that CA-induced STC2 expression conferred cytoprotection against apoptosis, steatosis, and liver injury in chronic as well as acute models of ethanol feeding. Therefore, this study will prove instrumental in developing CA as a promising lead compound for future drug development against hepatic diseases.


Measurement of the spin asymmetry in the photoproduction of pairs of high- p(T) hadrons at HERMES
We present a measurement of the longitudinal spin asymmetry A(||) in photoproduction of pairs of hadrons with high transverse momentum p(T). Data were accumulated by the HERMES experiment using a 27.5 GeV polarized positron beam and a polarized hydrogen target internal to the HERA storage ring. For h(+)h(-) pairs with p(h(1))(T)>1.5 GeV/c and p(h(2))(T)>1.0 GeV/c, the measured asymmetry is A(||) = -0. 28+/-0.12(stat)+/-0.02(syst). This negative value is in contrast to the positive asymmetries typically measured in deep inelastic scattering from protons, and is interpreted to arise from a positive gluon polarization.


The Anti-Inflammatory Effects of Adipose Tissue Mesenchymal Stem Cell Exosomes in a Mouse Model of Inflammatory Bowel Disease.
Inflammatory bowel disease (IBD) is a group of chronic, relapsing inflammatory disorders that affect the gastrointestinal tract, with the primary subtypes being ulcerative colitis (UC) and Crohn's disease (CD). We aimed to evaluate the therapeutic potential of extracellular vesicles released by adipose-tissue-derived mesenchymal stem cells, which we, in this manuscript, call "exosomes" (ASC-EXOs), in a mouse model of IBD. We specifically aimed to determine the effectiveness of different treatment protocols and compare the effects with that of anti-IL-12 p40 monoclonal antibody. The addition of dextran sulfate sodium (DSS) to drinking water induced multiple signs of IBD, including weight loss, soft stool, and bloody feces. ASC-EXOs given by either intraperitoneal (IP) or intravenous (IV) routes resulted in moderate improvement in these signs of IBD. IV ASC-EXOs resulted in significantly reduced body weight loss, improved histopathological scoring, and suppressed the disease activity index (DAI) compared to the IBD control group. Also, a reduction in PCR for pro-inflammatory cytokines was observed. IV ASC treatment resulted in dose-related reduction in IBD signs, including weight loss. An increasing number of injections with ASC-EXOs reduced histopathological scores as well as DAI. Co-administration of ASC-EXOs with anti-IL-12 p40 significantly decreased DAI scores in the ASC-EXO + anti-IL-12 p40 group. In conclusion, ASC-EXOs have potential as a therapeutic agent for IBD, but the route of administration, number of injections, and dosage need to be considered to optimize the effects of ASC-EXO treatment. This study also highlights the potential benefits of combination therapies of ASC-EXOs and anti-IL-12. Our findings pave the way for further studies to unravel the underlying therapeutic mechanisms of ASC-EXOs in IBD treatment.


Friction and Wear in Nanoscratching of Single Crystals: Effect of Adhesion and Plasticity.
Friction and wear are two main tribological behaviors that are quite different for contact surfaces of distinct properties. Conventional studies generally focus on a specific material (e.g., copper or iron) such that the tribological result is not applicable to the other contact systems. In this paper, using a group of virtual materials characterized by coarse-grained potentials, we studied the effect of interfacial adhesion and material plasticity on friction and wear by scratching a rigid tip over an atomic smooth surface. Due to the combined effects of adhesion and plasticity on the nanoscratch process, the following findings are revealed: (1) For shallow contact where interfacial adhesion dominates friction, both friction coefficient and wear rate increase as the adhesion increases to a critical value. For deep contact where plasticity prevails, the variation of friction coefficient and wear rate is limited as the adhesion varies. (2) For weak and strong interfacial adhesions, the friction coefficient exhibits different dependence on the scratch depth, whereas the wear rate becomes higher as the scratch depth increases. (3) As the material hardness increases, both the friction coefficient and wear rate decrease in shallow and deep contacts.


Studies on the rosette inhibition assay. Improvement of the method and correlation with monkey skin graft prolongation.
The rosette inhibition assay for immunosuppressive activity of antilymphocyte globulin or plasma has been studied in an effort to improve its reliability. Important changes include the elimination of calcium and magnesium ions from salt solutions used in the assay, the use of deoxyribonuclease to prevent lymphocyte clumping, and pretreatment of plasma samples (heating at 63 C for 10 min followed by acrinol precipitation) to prevent nonspecific inhibition of rosette formation. The use of a graded dose response potency assay against a house standard is discussed. A significant correlation was established between the in vitro activity of several series of antilymphocyte globulin or antithymocyte globulin preparations and their ability to prolong skin graft survival in primates. The best correlation was achieved using a potency estimate relative to a house standard, rather than the conventional titer estimate.


Crystal structure of human dehydroepiandrosterone sulphotransferase in complex with substrate.
Dehydroepiandrosterone sulphotransferase (DHEA-ST) is an enzyme that converts dehydroepiandrosterone (DHEA), and some other steroids, into their sulphonated forms. The enzyme catalyses the sulphonation of DHEA on the 3alpha-oxygen, with 3'-phosphoadenosine-5'-phosphosulphate contributing the sulphate. The structure of human DHEA-ST in complex with its preferred substrate DHEA has been solved here to 1.99 A using molecular replacement with oestradiol sulphotransferase (37% sequence identity) as a model. Two alternative substrate-binding orientations have been identified. The primary, catalytic, orientation has the DHEA 3alpha-oxygen and the highly conserved catalytic histidine in nearly identical positions as are seen for the related oestradiol sulphotransferase. The substrate, however, shows rotations of up to 30 degrees, and there is a corresponding rearrangement of the protein loops contributing to the active site. This may also reflect the low identity between the two enzymes. The second orientation penetrates further into the active site and can form a potential hydrogen bond with the desulphonated cofactor 3',5'-phosphoadenosine (PAP). This second site contains more van der Waal interactions with hydrophobic residues than the catalytic site and may also reflect the substrate-inhibition site. The PAP position was obtained from the previously solved structure of DHEA-ST co-crystallized with PAP. This latter structure, due to the arrangement of loops within the active site and monomer interactions, cannot bind substrate. The results presented here describe details of substrate binding to DHEA-ST and the potential relationship to substrate inhibition.


[Mental disorders in men enlisted into military service and in soldiers (clinico-epidemiological study)].
A total clinical epidemiologic survey was performed in one of Moscow regions in 1985-1990. On the first stage 2660 medical records of the individuals unfitted for military service were picked out. 42.8% of them had mental diseases. From 2102 medical records of the soldiers and sailors there were 66 of the discharged from the army. 45.5% of them were dismissed because of mental disease. On the second stage, 30 men dismissed because of mental disease and 299 men called for military service but discharged because of mental disease were examined. The duration of the follow-up was from 2 to 8 years. The most frequent reason both for the discharge from the army and for unfittness because of medical indications were borderline mental diseases (56.6% in the group of the discharged from the army and 40.9% in the group of men called up for military service). Endogenic diseases (schizophrenia, manic-depressive psychosis) made up only 16.6 and 15.8%, respectively. It was found that personal peculiarities and structure of mental diseases as well as risk factors of microsocial and biological nature were the most important indices for fitness for military service and for rehabilitative-prophylactic work in soldiers during the first 6 months of the service.


Role of cytoskeleton network in anisosmotic volume changes of intact and permeabilized A549 cells.
Recently we found that cytoplasm of permeabilized mammalian cells behaves as a hydrogel displaying intrinsic osmosensitivity. This study examined the role of microfilaments and microtubules in the regulation of hydrogel osmosensitivity, volume-sensitive ion transporters, and their contribution to volume modulation of intact cells. We found that intact and digitonin-permeabilized A549 cells displayed similar rate of shrinkage triggered by hyperosmotic medium. It was significantly slowed-down in both cell preparations after disruption of actin microfilaments by cytochalasin B, suggesting that rapid water release by intact cytoplasmic hydrogel contributes to hyperosmotic shrinkage. In hyposmotic swelling experiments, disruption of microtubules by vinblastine attenuated the maximal amplitude of swelling in intact cells and completely abolished it in permeabilized cells. The swelling of intact cells also triggered ~10-fold elevation of furosemide-resistant (86)Rb+ (K+) permeability and the regulatory volume decrease (RVD), both of which were abolished by Ba2+. Interestingly, RVD and K+ permeability remained unaffected in cytocholasin/vinblastine treated cells demonstrating that cytoskeleton disruption has no direct impact on Ba2+-sensitive K+-channels involved in RVD. Our results show, for the first time, that the cytoskeleton network contributes directly to passive cell volume adjustments in anisosmotic media via the modulation of the water retained by the cytoplasmic hydrogel.


Transcutaneous electric nerve stimulation (TENS) in dentistry- A review.
Transcutaneous electric nerve stimulation (TENS) is a non-pharmacological method which is widely used by medical and paramedical professionals for the management of acute and chronic pain in a variety of conditions. Similarly, it can be utilized for the management of pain during various dental procedures as well as pain due to various conditions affecting maxillofacial region. This review aims to provide an insight into clinical research evidence available for the analgesic and non analgesic uses of TENS in pediatric as well as adult patients related to the field of dentistry. Also, an attempt is made to briefly discuss history of therapeutic electricity, mechanism of action of TENS, components of TENs equipment, types, techniques of administration, advantages and contradictions of TENS. With this we hope to raise awareness among dental fraternity regarding its dental applications thereby increasing its use in dentistry. Key words:Dentistry, pain, TENS.


Factors associated with employment among a cohort of injection drug users.
One of the most substantial costs of drug use is lost productivity and social functioning, including holding of a regular job. However, little is known about employment patterns of injection drug users (IDU). We sought to identify factors that were associated with legal employment among IDU. We describe the employment patterns of participants of a longitudinal cohort study of IDU in Vancouver, Canada. We then use generalised estimating equations (GEE) to determine statistical associations between legal employment and various intrinsic, acquired, behavioural and circumstantial factors. From 1 June 1999 to 30 November 2003, 330 (27.7%) of 1190 participants reported having a job at some point during follow up. Employment rates remain somewhat stable throughout the study period (9-12.4%). Factors positively and significantly associated with legal employment in multivariate analysis were male gender (adjusted odds ratio [AOR] = 2.78) and living outside the Downtown Eastside (AOR = 1.85). Factors negatively and significantly associated with legal employment included older age (AOR = 0.97); Aboriginal ethnicity (AOR = 0.72); HIV-positive serostatus (AOR = 0.32); HCV-positive serostatus (AOR = 0.46); daily heroin injection (AOR = 0.73); daily crack use (AOR = 0.77); public injecting (AOR = 0.50); sex trade involvement (AOR = 0.49); recent incarceration (AOR = 0.56); and unstable housing (AOR = 0.57). Our results suggest a stabilising effect of employment for IDU and socio-demographic, drug use and risk-related barriers to employment. There is a strong case to address these barriers and to develop innovative employment programming for high-risk drug users.


Recruitment and Lessons Learned from a Community-Based Intervention Program: The Learning Families Project in Hong Kong.
Recruitment is central to any research project, and recruitment itself should be well documented and researched. We describe our recruitment efforts for a community-based research project-entitled the Learning Families Project-conducted in Hong Kong. In collaboration with community stakeholders, residents from a public housing estate were recruited to participate in family programs aimed at enhancing family well-being. Various recruitment strategies were employed including the distribution of 19,200 leaflets, 688 posters, a banner, a kick-off ceremony, 10 promotion activities, 1,000 direct calls, word of mouth, 51 mobile counters, and 10 door-to-door visits. Drawing on field notes, research logs, short questionnaires, and focus group conducted with our community partners and residents, we describe and discuss our recruitment strategies, challenges, and lessons learned. Over a 9-month period, 980 participants were recruited and participated in our study, exceeding our recruitment goal (860 participants). Several observations were made including active recruitment strategies (i.e., door-to-door and mobile counter) being more effective than passive strategies (i.e., posters and leaflets); the importance of raising project awareness to facilitate recruitment; and the challenges encountered (i.e., burn-out and loss of motivation of staff, decreased community capacity in collaborating in research projects). The lessons learned include the importance of engaging Chinese communities, utilizing a positive outreach approach, and setting realistic expectations. Although similar recruitment strategies have been reported the West, a number of cultural differences should be taken into account when working with Chinese population. Further research is needed to examine the effectiveness of tailoring recruitment strategies to various populations.


Neuropathy associated with monoclonal gammopathies of undetermined significance.
Monoclonal proteins (IgM, IgG, and IgA) in the serum or urine of patients with neuropathy may provide a marker for amyloidosis, myeloma, lymphoma, leukemia, Waldenström's macroglobulinemia, or monoclonal gammopathy of undetermined significance (MGUS). The clinical characteristics, course, and electromyographic features among neuropathies associated with monoclonal IgM (IgM-MGUS, 31 patients), monoclonal IgG (IgG-MGUS, 24 patients), and monoclonal IgA (IgA-MGUS, 10 patients) evaluated between 1980 and 1986 were compared. Four statistically significant differences set IgM-MGUS neuropathies apart from IgG-MGUS and IgA-MGUS neuropathies: (1) higher frequency of sensory loss and ataxia, (2) higher frequency of nerve conduction abnormality--10 attributes were significantly worse (none were significantly better), (3) higher frequency of dispersion of the compound muscle action potential, and (4) higher frequency of IgM-MGUS in the MGUS neuropathy cohort than is characteristic of MGUS without neuropathy seen at our institution or than is encountered in epidemiological surveys. These differences were not thought to be due to selection or severity biases. Neither the amount of IgM nor the estimated size of the monoclonal peak was associated with severity of neuropathy. The type and severity of IgM-MGUS neuropathies with anti-myelin-associated glycoprotein antibodies were not significantly different from those without anti-myelin-associated glycoprotein antibodies. A simple relationship between the presence and amount of IgM-MGUS or anti-myelin-associated glycoprotein antibodies and neuropathy cannot be assumed.


Contributions of GABAA receptors and GABAC receptors to acetylcholine release and directional selectivity in the rabbit retina.
GABA is a major inhibitory neurotransmitter in the mammalian retina and it acts at many different sites via a variety of postsynaptic receptors. These include GABAA receptors and bicuculline-resistant GABAC receptors. The release of acetylcholine (ACh) is inhibited by GABA and strongly potentiated by GABA antagonists. In addition, GABA appears to mediate the null inhibition which is responsible for the mechanism of directional selectivity in certain ganglion cells. We have used these two well-known examples of GABA inhibition to compare three GABA antagonists and assess the contributions of GABAA and GABAC receptors. All three GABA antagonists stimulated ACh release by as much as ten-fold. By this measure, the ED50s for SR-95531, bicuculline, and picrotoxin were 0.8, 7.0, and 14 microM, respectively. Muscimol, a potent GABAA agonist, blocked the effects of SR-95531 and bicuculline, but not picrotoxin. This indicates that SR-95531 and bicuculline are competitive antagonists at the GABAA receptor, while picrotoxin blocks GABAA responses by acting at a different, nonreceptor site such as the chloride channel. In the presence of a saturating dose of SR-95531 to completely block GABAA receptors, picrotoxin caused a further increase in the release of ACh. This indicates that picrotoxin potentiates ACh release by a mechanism in addition to the block of GABAA responses, possibly by also blocking GABAC receptors, which have been associated with bipolar cells. All three GABA antagonists abolished directionally selective responses from ON/OFF directional-selective (DS) ganglion cells. In this system, the ED50S for SR-95531, bicuculline, and picrotoxin were 0.7 microM, 8 microM, and 94.6 microM, respectively. The results with SR-95531 and bicuculline indicate that GABAA receptors mediate the inhibition responsible for directional selectivity. The addition of picrotoxin to a high dose of SR-95531 caused no further increase in firing rate. The comparatively high dose required for picrotoxin also suggests that GABAC receptors do not contribute to directional selectivity. This in turn suggests that feedforward GABAA inhibition, as opposed to feedback at bipolar terminals, is responsible for the null inhibition underlying directional selectivity.


Increased phosphorylation of Ca(2+) handling proteins as a proarrhythmic mechanism in myocarditis.
Because fatal arrhythmia is an important cause of death in patients with myocarditis, we investigated the proarrhythmic mechanisms of experimental autoimmune myocarditis. METHODS AND RESULTS: Myocarditis was induced by injection of 2 mg porcine cardiac myosin into the footpads of adult Lewis rats on days 1 and 8 (Myo, n=15) and the results compared with Control rats (Control, n=15). In an additional 15 rats, 6 mg/kg prednisolone was injected into the gluteus muscle before the injection of porcine cardiac myosin on days 1 and 8 (MyoS, n=15). Hearts with myocarditis had longer action potential duration (APD), slower conduction velocity (CV; P<0.01 vs. Control), higher CV heterogeneity, greater fibrosis, higher levels of immunoblotting of high-mobility group protein B1, interleukin 6 and tumor necrosis factor-α proteins. Steroid treatment partially reversed the translations for myocarditis, CV heterogeneity, reduced APD at 90% recovery to baseline, increased CV (P<0.01), and reversed fibrosis (P<0.05). Programmed stimulation triggered sustained ventricular tachycardia in Myo rats (n=4/5), but not in controls (n=0/5) or Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor (KN93) treated Myo rats (n=0/5, P=0.01). CaMKII autophosphorylation at Thr287 (201%), and RyR2 phosphorylation at Ser2808 (protein kinase A/CaMKII site, 126%) and Ser2814 (CaMKII site, 21%) were increased in rats with myocarditis and reversed by steroid. The myocarditis group had an increased incidence of arrhythmia caused by increased phosphorylation of Ca(2+)handling proteins. These changes were partially reversed by an antiinflammatory treatment and CaMKII inhibition.


Determination of the hemodynamic significance of iliac artery stenosis by noninvasive Doppler ultrasonography.
The ability of common femoral artery Doppler blood flow velocity waveforms to predict the hemodynamic significance of aortoiliac artery stenosis was determined by comparing intraoperative pressure gradient and flow measurements with two noninvasive nondimensional Doppler velocity waveform indices. The Doppler velocity waveforms of 63 common femoral arteries were recorded preoperatively, and iliac artery pressure gradients and blood flows were measured intraoperatively in 48 nonoccluded arterial segments. The mean iliac artery pressure gradient at double resting flow was calculated for comparisons between patients. Two Nondimensional Doppler velocity waveform indices were calculated: the minimum to maximum velocity amplitude ratio and the maximum to mean velocity amplitude ratio. Both Doppler velocity ratios successfully distinguish arteries with minimal or no hemodynamically significant stenosis from arteries with hemodynamically significant stenosis (mean pressure gradient at double resting flow resting flow greater than 6 mm Hg). A minimum to maximum Doppler velocity ratio of less than 0.185 or a maximum to mean Doppler velocity ratio greater than 2.10 indicates hemodynamically significant aortoiliac stenosis. Superficial femoral artery occlusion was indistinguishable from mild iliac stenosis by the two Doppler velocity waveform ratios but was clearly distinct from significant iliac stenosis.


[Pyruvate decarboxylase: mechanistic model of paracatalytic interactions].
The recent data from literature concerning mechanisms of nonenzymic and enzymic thiamine diphosphate-dependent catalysis have been analyzed. The application of model nonenzymic quinone, molecular oxygen and ferricyanide oxidation of 2-(l-hydroxyethyl)- and 2-(l-hydroxybenzyl)thiazole ions to catalysis by thiamin diphosphate-dependent enzymes especially pyruvate decarboxylase are summarized in this review. Mechanisms of paracatalytic interactions of pyruvate decarboxylase and possibility of biocatalyst design to change reaction specificity of the enzyme have been discussed.


Proteome profiling of wild type and lumican-deficient mouse corneas.
To elucidate how the deficiency of a major corneal proteoglycan, lumican, affects corneal homeostasis, we used mass spectrometry to derive the proteome profile of the lumican-deficient and the heterozygous mouse corneas and compared these to the wild type corneal proteome. 2108 proteins were quantified in the mouse cornea. Selected proteins and transcripts were investigated by Western blot and quantitative RT-PCR, respectively. We observed major changes in the composition of the stromal extracellular matrix (ECM) proteins in the lumican-deficient mice. Lumican deficiency altered cellular proteins in the stroma and the corneal epithelium. The ECM changes included increases in fibril forming collagen type I, Collagen type VI, fibromodulin, perlecan, laminin β₂, collagen type IV, nidogen/entactin and anchoring collagen type VII in the Lum⁺/⁻ and the Lum⁻/⁻ mouse corneas, while the stromal proteoglycans decorin, biglycan and keratocan were decreased in the Lum⁻/⁻( corneas. Cellular protein changes included increases in alcohol dehydrogenase, superoxide dismutase and decreases in epithelial cytokeratins 8 and 14. We also detected proteins that are novel to the cornea. The proteomes will provide an insight into the lumican-deficient corneal phenotype of stromal thinning and loss of transparency and a better understanding of pathogenic changes in corneal and ocular dystrophies.


Supplementation with cumulus cell masses improves the in vitro meiotic competence of porcine cumulus-oocytes complexes derived from small follicles.
The present study was conducted to examine the supplemented effect of cumulus cell masses (CCMs) derived from middle follicle (MF; 3-6 mm diameter) on the morphology and the meiotic or developmental competence of oocytes from small follicles (SF; 1-2 mm diameter). The number of cumulus cells surrounding oocytes just after collection was also lower in cumulus-oocyte complexes (COCs) from SF than MF. The ooplasmic diameter of oocytes was significantly smaller in SF-derived oocytes than MF-derived ones before and after in vitro maturation (IVM), whereas the diameter significantly increased during the culture. Co-culture of SF-derived COCs with MF-derived CCMs during IVM significantly improved the meiotic competence of the oocytes to the metaphase-II stage. Furthermore, the ooplasmic diameter of SF-derived COCs during IVM was increased to the similar size of MF-derived those in the presence of MF-derived CCMs. The abilities of oocytes to be penetrated, to form male pronuclear formation and to cleave or develop to the blastocyst stage were not affected by the co-culture with CCMs. Electrophoretic analysis of CCM secretions clearly showed the presence of more protein(s) approximately 27.6 kDa in the conditioned medium when supplemented with MF-derived CCMs. In conclusion, we demonstrate that supplementation with MF-derived CCMs improves the ooplasmic diameter and meiotic competence of SF-derived oocytes.


Measuring tidal volume and functional residual capacity change in sleeping infants using a volume displacement plethysmograph.
The noninvasive measurement of infant lung function during unsedated sleep in infants has been a long-standing objective in paediatric respiratory medicine. This note reports on the design and performance of a head-out volume-displacement plethysmograph (VDP) that overcomes some of the limitations of traditional lung function apparatus. The VDP comprises a rigid acrylic box with an integral water-sealed spirometer and a novel neck seal. The bilayer neck seal is of variable compliance and is comfortable and simple to use. The spirometer permits volume resolution of 1.5 mL and a dynamic range in excess of 100 mL. The frequency response extends from 0-7 Hz. Spirometer inertance was measured as 0.0015 kPa.L(-1).s(-2), resistance 0.021 kPa.L(-1).s(-1) and box capacitance 0.18L.kPa(-1). Tidal volume, respiratory rate and changes in functional residual capacity can be recorded during unsedated rapid eye movement and nonrapid eye movement whilst monitoring with conventional polysomnographic methods. The head-out configuration allows additional instrumentation to be implemented with ease, avoids facial stimulation and allows unimpeded access to the upper airway. A polysomnograph illustrating the limitations of respiratory inductance plethysmography signals and typical changes in functional residual capacity are shown.


NO2, as a marker of air pollution, and recurrent wheezing in children: a nested case-control study within the BAMSE birth cohort.
To investigate the association between air pollution, including with NO2, and recurrent wheezing during the first two years of life. A birth cohort (BAMSE) comprised 4089 children, for whom information on exposures, symptoms, and diseases was available from parental questionnaires at ages 2 months, and 1 and 2 years. NO2 was measured during four weeks in and outside the dwellings of children with recurrent wheezing and two age matched controls, in a nested case-control study (540 children). Conditional logistic regression showed an OR of 1.60 (95% CI 0.78 to 3.26) among children in the highest quartile of outdoor NO2 exposure in relation to those in the lowest quartile, adjusted for potential confounders. The corresponding OR for indoor NO2 was 1.51 (95% CI 0.81 to 2.82). An interaction with environmental tobacco smoke (ETS) was indicated with an OR of 3.10 (95% CI 1.32 to 7.30) among children exposed to the highest quartile of indoor NO2 and ETS. The association between NO2 and recurrent wheezing appeared stronger in children who did not fulfil the criteria for recurrent wheezing until their second year. Although the odds of increased recurrent wheezing are not statistically significantly different from one, results suggest that exposure to air pollution including NO2, particularly in combination with exposure to ETS, increases the risk of recurrent wheezing in children.


Long- and short-range signals control the dynamic expression of an animal hemisphere-specific gene in Xenopus.
Little is known of the control of gene expression in the animal hemisphere of the Xenopus embryo. Here we show that expression of FoxI1e, a gene essential for normal ectoderm formation, is expressed regionally within the animal hemisphere, in a highly dynamic fashion. In situ hybridization shows that FoxI1e is expressed in a wave-like fashion that is initiated on the dorsal side of the animal hemisphere, extends across to the ventral side by the mid-gastrula stage, and is then turned off in the dorsal ectoderm, the neural plate, at the neurula stage. It is confined to the inner layers of cells in the animal cap, and is expressed in a mosaic fashion throughout. We show that this dynamic pattern of expression is controlled by both short- and long-range signals. Notch signaling controls both the mosaic, and dorsal/ventral changes in expression, and is controlled, in turn, by Vg1 signaling from the vegetal mass. FoxI1e expression is also regulated by nodal signaling downstream of VegT. Canonical Wnt signaling contributes only to late changes in the FoxI1e expression pattern. These results provide new insights into the roles of vegetally localized mRNAs in controlling zygotic genes expressed in the animal hemisphere by long-range signaling. They also provide novel insights into the role of Notch signaling at the earliest stages of vertebrate development.


Chromosome-scale genome assembly of sweet tea (Lithocarpus polystachyus Rehder).
Lithocarpus, with >320 species, is the second largest genus of Fagaceae. However, the lack of a reference genome limits the molecular biology and functional study of Lithocarpus species. Here, we report the chromosome-scale genome assembly of sweet tea (Lithocarpus polystachyus Rehder), the first Lithocarpus species to be sequenced to date. Sweet tea has a 952-Mb genome, with a 21.4-Mb contig N50 value and 98.6% complete BUSCO score. In addition, the per-base consensus accuracy and completeness of the genome were estimated at 60.6 and 81.4, respectively. Genome annotation predicted 37,396 protein-coding genes, with repetitive sequences accounting for 64.2% of the genome. The genome did not undergo whole-genome duplication after the gamma (γ) hexaploidy event. Phylogenetic analysis showed that sweet tea diverged from the genus Quercus approximately at 59 million years ago. The high-quality genome assembly and gene annotation resources enrich the genomics of sweet tea, and will facilitate functional genomic studies in sweet tea and other Fagaceae species.


Characterization of multi-drug tolerant persister cells in Streptococcus suis.
Persister cells constitute a subpopulation of dormant cells within a microbial population which are genetically identical but phenotypically different to regular cells. Notably, persister cells show an elevated tolerance to antimicrobial agents. Thus, they are considered to represent a microbial 'bet-hedging' strategy and are of particular importance in pathogenic bacteria. We studied the ability of the zoonotic pathogen Streptococcus (S.) suis to form multi-drug tolerant variants and identified persister cells dependent on the initial bacterial growth phase. We observed lower numbers of persisters in exponential phase cultures than in stationary growth phase populations. S. suis persister cells showed a high tolerance to a variety of antibiotics, and the phenotype was not inherited as tested with four passages of S. suis populations. Furthermore, we provide evidence that the persister phenotype is related to expression of genes involved in general metabolic pathways since we found higher numbers of persister cells in a mutant strain defective in the catabolic arginine deiminase system as compared to its parental wild type strain. Finally, we observed persister cell formation also in other S. suis strains and pathogenic streptococcal species. Taken together, this is the first study that reports multi-drug tolerant persister cells in the zoonotic pathogen S. suis.


GABAA receptor-expressing neurons promote consumption in Drosophila melanogaster.
Feeding decisions are highly plastic and bidirectionally regulated by neurons that either promote or inhibit feeding. In Drosophila melanogaster, recent studies have identified four GABAergic interneurons that act as critical brakes to prevent incessant feeding. These GABAergic neurons may inhibit target neurons that drive consumption. Here, we tested this hypothesis by examining GABA receptors and neurons that promote consumption. We find that Resistance to dieldrin (RDL), a GABAA type receptor, is required for proper control of ingestion. Knockdown of Rdl in a subset of neurons causes overconsumption of tastants. Acute activation of these neurons is sufficient to drive consumption of appetitive substances and non-appetitive substances and acute silencing of these neurons decreases consumption. Taken together, these studies identify GABAA receptor-expressing neurons that promote Drosophila ingestive behavior and provide insight into feeding regulation.


HIV outcomes among migrants from low-income and middle-income countries living in high-income countries: a review of recent evidence.
Migrants living in high-income countries are disproportionately affected by HIV infection and frequently have characteristics associated with poor HIV clinical outcomes. HIV epidemiology among migrants is influenced by changes in migration patterns and variations in transmission risk behaviors. Here we review the recently published literature on known HIV outcomes among migrants from low-income and middle-income countries living in high-income countries. High proportions of migrants acquire HIV after migration, and this group frequently presents to care late. Once established in care, migrants are often more likely to experience worse HIV treatment outcomes compared with native populations. Multiple individual and structural factors influence HIV diagnosis and treatment outcomes among migrants, including disruption of social networks, increased sexual risk behaviors, communication barriers, limited access to care, and stigma. Few studies have examined interventions targeted at improving HIV outcomes among migrants. Stigma and limited access to care appear to be primary drivers of poor HIV outcomes among migrants in high-income countries. Addressing these disparities is limited by difficulties in identifying and monitoring this population as well as a lack of evidence regarding appropriate interventions for migrants living with HIV. Improving outcomes for this group requires interventions that are specifically targeted at this marginalized and growing population.


Detection by PCR of the nim genes encoding 5-nitroimidazole resistance in Bacteroides spp.
A PCR method was developed for detection of the nim genes encoding 5-nitrolmidazole resistance in Bacteroides spp. Two PCR primers specific for nim genes were designed. They allowed amplification of a 458-bp fragment from all characterized plasmid- and chromosome-borne metronidazole resistance genes. The specificity of the method was tested with DNA from metronidazole-sensitive Bacteroides spp. strains and from other strains of unrelated species. Each DNA preparation was analyzed with and without an internal positive control to verify that the absence of PCR amplification product was not due to inhibition of the Taq polymerase inhibitors. By this technique, two newly discovered metronidazole-resistant clinical strains of Bacteroides fragilis were shown to harbor resistance genes undetectable by Southern blotting. In spite of the sequence divergence of the nim genes, the PCR method is thus suitable for epidemiological investigations. The amplification method also revealed that nim-related resistance genes were not present in either Streptomyces strain S6670, a natural producer of 2-nitroimidazole, or in Enterococcus faecalis strains, which have been suggested to possess metronidazole-inactivating enzyme.


DMDM: domain mapping of disease mutations.
Domain mapping of disease mutations (DMDM) is a database in which each disease mutation can be displayed by its gene, protein or domain location. DMDM provides a unique domain-level view where all human coding mutations are mapped on the protein domain. To build DMDM, all human proteins were aligned to a database of conserved protein domains using a Hidden Markov Model-based sequence alignment tool (HMMer). The resulting protein-domain alignments were used to provide a domain location for all available human disease mutations and polymorphisms. The number of disease mutations and polymorphisms in each domain position are displayed alongside other relevant functional information (e.g. the binding and catalytic activity of the site and the conservation of that domain location). DMDM's protein domain view highlights molecular relationships among mutations from different diseases that might not be clearly observed with traditional gene-centric visualization tools. Freely available at http://bioinf.umbc.edu/dmdm.


SCSsim: an integrated tool for simulating single-cell genome sequencing data.
Allele dropout (ADO) and unbalanced amplification of alleles are main technical issues of single-cell sequencing (SCS), and effectively emulating these issues is necessary for reliably benchmarking SCS-based bioinformatics tools. Unfortunately, currently available sequencing simulators are free of whole-genome amplification involved in SCS technique and therefore not suited for generating SCS datasets. We develop a new software package (SCSsim) that can efficiently simulate SCS datasets in a parallel fashion with minimal user intervention. SCSsim first constructs the genome sequence of single cell by mimicking a complement of genomic variations under user-controlled manner, and then amplifies the genome according to MALBAC technique and finally yields sequencing reads from the amplified products based on inferred sequencing profiles. Comprehensive evaluation in simulating different ADO rates, variation detection efficiency and genome coverage demonstrates that SCSsim is a very useful tool in mimicking single-cell sequencing data with high efficiency. SCSsim is freely available at https://github.com/qasimyu/scssim. Supplementary data are available at Bioinformatics online.


Transesophageal pacing for prognostic evaluation of preexcitation syndrome and assessment of protective therapy.
An esophageal lead was used to perform decremental atrial pacing and elective induction of atrial fibrillation (AF) in 5 patients with the Wolff-Parkinson-White (W-P-W) syndrome before and after amiodarone therapy. In the control state, 1:1 atrioventricular (AV) conduction over the accessory pathway ranged from 220 to 260 ms (mean 232). The shortest R-R interval during AF ranged from 190 to 210 ms (mean 198). The ventricular rate ranged from 175 to 212 beats/min (mean 196). After amiodarone therapy, the shortest cycle length with 1:1 AV conduction increased in all patients, ranging from 290 to 540 ms (mean 370); during AF, no preexcited beat was present in 2 patients, whereas the minimal preexcited R-R interval in the remaining 3 was 290, 240, and 370 ms, respectively. The ventricular response during AF decreased in all patients. Thus, esophageal pacing is a useful method for identifying patients at risk with the W-P-W syndrome and for assessing appropriate management in individual patients. Amiodarone provides protection against life-threatening arrhythmias in these patients.


Phylogenomics from Whole Genome Sequences Using aTRAM.
Novel sequencing technologies are rapidly expanding the size of data sets that can be applied to phylogenetic studies. Currently the most commonly used phylogenomic approaches involve some form of genome reduction. While these approaches make assembling phylogenomic data sets more economical for organisms with large genomes, they reduce the genomic coverage and thereby the long-term utility of the data. Currently, for organisms with moderate to small genomes ($<$1000 Mbp) it is feasible to sequence the entire genome at modest coverage ($10-30\times$). Computational challenges for handling these large data sets can be alleviated by assembling targeted reads, rather than assembling the entire genome, to produce a phylogenomic data matrix. Here we demonstrate the use of automated Target Restricted Assembly Method (aTRAM) to assemble 1107 single-copy ortholog genes from whole genome sequencing of sucking lice (Anoplura) and out-groups. We developed a pipeline to extract exon sequences from the aTRAM assemblies by annotating them with respect to the original target protein. We aligned these protein sequences with the inferred amino acids and then performed phylogenetic analyses on both the concatenated matrix of genes and on each gene separately in a coalescent analysis. Finally, we tested the limits of successful assembly in aTRAM by assembling 100 genes from close- to distantly related taxa at high to low levels of coverage.Both the concatenated analysis and the coalescent-based analysis produced the same tree topology, which was consistent with previously published results and resolved weakly supported nodes. These results demonstrate that this approach is successful at developing phylogenomic data sets from raw genome sequencing reads. Further, we found that with coverages above $5-10\times$, aTRAM was successful at assembling 80-90% of the contigs for both close and distantly related taxa. As sequencing costs continue to decline, we expect full genome sequencing will become more feasible for a wider array of organisms, and aTRAM will enable mining of these genomic data sets for an extensive variety of applications, including phylogenomics. [aTRAM; gene assembly; genome sequencing; phylogenomics.].


Single molecule in vivo analysis of toll-like receptor 9 and CpG DNA interaction.
Toll-like receptor 9 (TLR9) activates the innate immune system in response to oligonucleotides rich in CpG whereas DNA lacking CpG could inhibit its activation. However, the mechanism of how TLR9 interacts with nucleic acid and becomes activated in live cells is not well understood. Here, we report on the successful implementation of single molecule tools, constituting fluorescence correlation/cross-correlation spectroscopy (FCS and FCCS) and photon count histogram (PCH) with fluorescence lifetime imaging (FLIM) to study the interaction of TLR9-GFP with Cy5 labeled oligonucleotide containing CpG or lacking CpG in live HEK 293 cells. Our findings show that i) TLR9 predominantly forms homodimers (80%) before binding to a ligand and further addition of CpG or non CpG DNA does not necessarily increase the proportion of TLR9 dimers, ii) CpG DNA has a lower dissociation constant (62 nM±9 nM) compared to non CpG DNA (153 nM±26 nM) upon binding to TLR9, suggesting that a motif specific binding affinity of TLR9 could be an important factor in instituting a conformational change-dependant activation, and iii) both CpG and non CpG DNA binds to TLR9 with a 1∶2 stoichiometry in vivo. Collectively, through our findings we establish an in vivo model of TLR9 binding and activation by CpG DNA using single molecule fluorescence techniques for single cell studies.


Why has HIV stabilized in South Africa, yet not declined further? Age and sexual behavior patterns among youth.
To understand the stabilization in HIV prevalence in South Africa, and why HIV prevalence has not declined further, despite behavior change and apparently moderate risk behaviors. HIV prevalence and 4 HIV-related sexual behaviors in 15- to 24-year old South Africans and Ugandans were compared, before and during HIV prevalence stabilization and decrease, respectively. According to standard indicators, 15- to 24-year-old South Africans have shown behavior change and have moderate risk behaviors. Yet, the HIV prevalence of South African youth is more than twice the prevalence among Ugandan youth, despite 2 times greater reported condom use and an increase in secondary abstinence among young females. We observed inconsistent use of condoms and an extended age distribution of risk together with age and partner mixing. These increase the cumulative risk beyond indicators which are based on sexual behavior in the last year and condom use at last sexual act. In addition, the extended age distribution of risk together with age and partner mixing, increase the cumulative risk beyond standard indicators which are based on sexual behavior in the last year and condom use at last sexual act. Comprehensive HIV prevention in South Africa needs to be intensified beyond individual age groups for example youth, clearly promote consistent condom use and reduction in sexual partners, and focus on the transmission dynamics including older age groups. This should be based on careful behavioral analysis of the epidemic, which goes beyond standard indicators. This study shows the significant risks beyond apparently improving behavioral indicators in Southern Africa, and helps explains the seriousness of the epidemics in this region.


Transfer of an indigenous plasmid of Rhizobium loti to other rhizobia and Agrobacterium tumefaciens.
Rhizobium loti strains NZP2037 and NZP2213 were each found to contain a single large plasmid: pRlo2037a (240 MDal) and pRlo2213a (120 MDal), respectively. Plasmid DNA present in crude cell lysates of each strain and purified pRlo2037a DNA did not hybridize with pID1, a recombinant plasmid containing part of the nitrogen fixation (nif) region of R. meliloti, indicating that nif genes were not present on these plasmids. The transposon Tn5 was inserted into pRlo2037a and this plasmid was then transferred into R. leguminosarum, R. meliloti and Agrobacterium tumefaciens. All transconjugants failed to nodulate Lotus pedunculatus, suggesting that the ability to nodulate this legume was also not carried on pRlo2037a. Transfer of pRlo2037a to R. loti strain NZP2213 did not alter the Nod+ Fix- phenotype of this strain for L. pedunculatus. Determinants for flavolan resistance, believed to be necessary for effective nodulation of L. pedunculatus, were not carried on pRlo2037a. These data suggest that nodulation, nitrogen fixation and flavolan resistance genes are not present on the large plasmid in R. loti strain NZP2037.


Study protocol of the Edinburgh and Lothian Virus Intervention Study in Kids: a randomised controlled trial of hypertonic saline nose drops in children with upper respiratory tract infections (ELVIS Kids).
Edinburgh and Lothians' Viral Intervention Study Kids is a parallel, open-label, randomised controlled trial of hypertonic saline (HS) nose drops (~2.6% sodium chloride) vs standard care in children <7 years of age with symptoms of an upper respiratory tract infection (URTI). Children are recruited prior to URTI or within 48 hours of developing URTI symptoms by advertising in areas such as local schools/nurseries, health centres/hospitals, recreational facilities, public events, workplaces, local/social media. Willing parents/guardians, of children <7 years of age will be asked to contact the research team at their local site. Children will be randomised to either a control arm (standard symptomatic care), or intervention arm (three drops/nostril of HS, at least four times a day, until 24 hours after asymptomatic or a maximum of 28 days). All participants are requested to provide a nasal swab at the start of the study (intervention arm: before HS drops) and then daily for four more days. Parent/guardian complete a validated daily diary, an end of illness diary, a satisfaction questionnaire and a wheeze questionnaire (day 28). The parent/guardian of a child in the intervention arm is taught to prepare HS nose drops. Parent/guardian of children asymptomatic at recruitment are requested to inform the research team within 48 hours of their child developing an URTI and follow the instructions already provided. The day 28 questionnaire determines if the child experienced a wheeze following illness. Participation in the study ends on day 28. The study has been approved by the West of Scotland Research Ethics Service (18/WS/0080). It is cosponsored by Academic and Clinical Central Office for Research and Development-a partnership between the University of Edinburgh and National Health Service Lothian Health Board. The findings will be disseminated through peer-reviewed publications, conference presentations and via the study website. NCT03463694.


Word frequency has similar effects in picture naming and gender decision: A failure to replicate Jescheniak and Levelt (1994).
Word frequency plays a key role in theories of lexical access, which assume that the word frequency effect (WFE, faster access to high-frequency than low-frequency words) occurs as a result of differences in the representation and processing of the words. In a seminal paper, Jescheniak and Levelt (1994) proposed that the WFE arises during the retrieval of word forms, rather than the retrieval of their syntactic representations (their lemmas) or articulatory commands. An important part of Jescheniak and Levelt's argument was that they found a stable WFE in a picture naming task, which requires complete lexical access, but not in a gender decision task, which only requires access to the words' lemmas and not their word forms. We report two attempts to replicate this pattern, one with new materials, and one with Jescheniak and Levelt's orginal pictures. In both studies we found a strong WFE when the pictures were shown for the first time, but much weaker effects on their second and third presentation. Importantly these patterns were seen in both the picture naming and the gender decision tasks, suggesting that either word frequency does not exclusively affect word form retrieval, or that the gender decision task does not exclusively tap lemma access.


[The advantages of dynamic evaluation of measurement quality in clinical diagnostic laboratory].
The national standard of laboratory quality control is based on a assumption about normal distribution of random error. The data of procedure of quality control get from analyzer Flexor XL during three months period were examined. The distributions of random error were non-Gauss ones in almost half of all examined tests by reason of both abnormal asymmetry and excess. To prevent possible clinical mistakes the actual level of quality is to be evaluated using dynamic values of bias, variation coefficient and o-metrics based on simple consecutive means. The most appropriate time of averaging consisted about 10 days and had no dependencies of type of test. The actual standard cab y easily improved taking into account the discovered advantages and simplicity of proposed approach.


Preliminary results of an open label study of heart rate variability biofeedback for the treatment of major depression.
Major depressive disorder (MDD) is a common mood disorder that can result in significant discomfort as well as interpersonal and functional disability. A growing body of research indicates that autonomic function is altered in depression, as evidenced by impaired baroreflex sensitivity, changes in heart rate, and reduced heart rate variability (HRV). Decreased vagal activity and increased sympathetic arousal have been proposed as major contributors to the increased risk of cardiovascular mortality in participants with MDD, and baroreflex gain is decreased. To assess the feasibility of using HRV biofeedback to treat major depression. This was an open-label study in which all eleven participants received the treatment condition. Participants attended 10 weekly sessions. Questionnaires and physiological data were collected in an orientation (baseline) session and Treatment Sessions 1, 4, 7 and 10. Significant improvements were noted in the Hamilton Depression Scale (HAM-D) and the Beck Depression Inventory (BDI-II) by Session 4, with concurrent increases in SDNN, standard deviation of normal cardiac interbeat intervals) an electrocardiographic estimate of overall measure of adaptability. SDNN decreased to baseline levels at the end of treatment and at follow-up, but clinically and statistically significant improvement in depression persisted. Main effects for task and session occurred for low frequency range (LF) and SDNN. Increases in these variables also occurred during breathing at one's resonant frequency, which targets baroreflex function and vagus nerve activity, showing that subjects performed the task correctly. HRV biofeedback appears to be a useful adjunctive treatment for the treatment of MDD, associated with large acute increases in HRV and some chronic increases, suggesting increased cardiovagal activity. It is possible that regular exercise of homeostatic reflexes helps depression even when changes in baseline HRV are smaller. A randomized controlled trial is warranted.


Parastomal Hernia Repair with a 3D Funnel Intraperitoneal Mesh Device and Same-Sided Stoma Relocation: Results of 56 Cases.
Parastomal hernias (PSHs) are a common and challenging issue. In previous studies, three-dimensional (3D) funnel mesh devices have been used successfully for the repair of PSHs. We performed an analysis of prospectively collected data of patients who underwent a same-sided stoma reposition with 3D funnel-shaped mesh augmentation in intraperitoneal (IPOM) position at our department between the years of 2012 and 2015. Primary outcome parameters were intra- and postoperative surgical complications and recurrence rate during the follow-up period. Fifty-six patients could be included in this analysis. PSH repair was performed in 89.3% as elective surgery and in 73% in laparoscopic technique. A concomitant incisional hernia (EHS type 2 and 4) was found in 50% and repaired in a single-step procedure with PSH. Major postoperative complications requiring redo surgery (Clavien-Dindo ≥3b) were identified in 8.9% (5/56). Overall recurrence rate was 12.5% (7/56). Median follow-up time was 38 months, and a 1-year follow-up rate of 96.4% was reached. PSH repair with 3D funnel mesh in IPOM technique is safe, efficient and easy to perform in laparoscopic and open surgical approaches providing advantageous results compared to other techniques. Furthermore, simultaneous detection and treatment of concomitant incisional hernias has shown favorable. However, the mesh funnel distends and becomes shortened encasing a bulky bowel mesentery and further shrinkage happens eccentric. Changing mesh construction according to lengthening the funnel could possibly lead to reduction in recurrence.


Structural basis of cargo recognitions for class V myosins.
Class V myosins (MyoV), the most studied unconventional myosins, recognize numerous cargos mainly via the motor's globular tail domain (GTD). Little is known regarding how MyoV-GTD recognizes such a diverse array of cargos specifically. Here, we solved the crystal structures of MyoVa-GTD in its apo-form and in complex with two distinct cargos, melanophilin and Rab interacting lysosomal protein-like 2. The apo-MyoVa-GTD structure indicates that most mutations found in patients with Griscelli syndrome, microvillus inclusion disease, or cancers or in "dilute" rodents likely impair the folding of GTD. The MyoVa-GTD/cargo complex structure reveals two distinct cargo-binding surfaces, one primarily via charge-charge interaction and the other mainly via hydrophobic interactions. Structural and biochemical analysis reveal the specific cargo-binding specificities of various isoforms of mammalian MyoV as well as very different cargo recognition mechanisms of MyoV between yeast and higher eukaryotes. The MyoVa-GTD structures resolved here provide a framework for future functional studies of vertebrate class V myosins.


A computational model to predict bone metastasis in breast cancer by integrating the dysregulated pathways.
Although there are a lot of researches focusing on cancer prognosis or prediction of cancer metastases, it is still a big challenge to predict the risks of cancer metastasizing to a specific organ such as bone. In fact, little work has been published for such a purpose nowadays. In this work, we propose a Dysregulated Pathway Based prediction Model (DPBM) built on a merged data set with 855 samples. First, we use bootstrapping strategy to select bone metastasis related genes. Based on the selected genes, we then detect out the dysregulated pathways involved in the process of bone metastasis via enrichment analysis. And then we use the discriminative genes in each dysregulated pathway, called as dysregulated genes, to construct a sub-model to forecast the risk of bone metastasis. Finally we combine all sub-models as an ensemble model (DPBM) to predict the risk of bone metastasis. We have validated DPBM on the training, test and independent sets separately, and the results show that DPBM can significantly distinguish the bone metastases risks of patients (with p-values of 3.82E-10, 0.00007 and 0.0003 on three sets respectively). Moreover, the dysregulated genes are generally with higher topological coefficients (degree and betweenness centrality) in the PPI network, which means that they may play critical roles in the biological functions. Further functional analysis of these genes demonstrates that the immune system seems to play an important role in bone-specific metastasis of breast cancer. Each of the dysregulated pathways that are enriched with bone metastasis related genes may uncover one critical aspect of influencing the bone metastasis of breast cancer, thus the ensemble strategy can help to describe the comprehensive view of bone metastasis mechanism. Therefore, the constructed DPBM is robust and able to significantly distinguish the bone metastases risks of patients in both test set and independent set. Moreover, the dysregulated genes in the dysregulated pathways tend to play critical roles in the biological process of bone metastasis of breast cancer.


Detection of links between Ebola nucleocapsid and virulence using disorder analysis.
The underlying reasons for the differences in the virulence of various types of Ebola virus (EBOV) remain unknown. Comparison of the percentage of disorder (PID) in nucleocapsid proteins VP30 and NP reveals high correlation between nucleocapsid PIDs and the case-fatality rates of EBOV. The higher disorder of these proteins is likely to be needed for more efficient multiplication of virus copies via more efficient viral RNA transcription and more promiscuous protein binding potential. This is important for the more efficient assistance of nucleocapsid in viral particle budding and of the assembly and mobility of viral proteins across the host membrane and within the cytoplasm. A more comprehensive knowledge of the molecular mechanisms of EBOV virulence would also lead to new and more effective strategies in vaccine development.


Finding axes of symmetry from potential fields.
This paper addresses the problem of detecting axes of bilateral symmetry in images. In order to achieve robustness to variation in illumination, only edge-gradient information is used. To overcome the problem of edge breaks, a potential field is developed from the edge map which spreads the information in the image plane. Pairs of points in the image plane are made to vote for their axes of symmetry with some confidence values. To make the method robust to overlapping objects, only local features in the form of Taylor coefficients are used for quantifying symmetry. We define an axis of symmetry histogram, which is used to accumulate the weighted votes for all possible axes of symmetry. To reduce the computational complexity of voting, a hashing scheme is proposed, wherein pairs of points, whose potential fields are too asymmetric, are pruned by not being counted for the vote. Experimental results indicate that the proposed method is fairly robust to edge breaks and is able to detect symmetries even when only 0.05% of the possible pairs are used for voting.


Clinical outcome of patients with the Brugada type 1 electrocardiogram without prophylactic implantable cardioverter defibrillator in primary prevention: a cumulative analysis of seven large prospective studies.
Patients with the Brugada type 1 ECG (Br type 1) without previous aborted sudden death (aSD) who do not have a prophylactic ICD constitute a very large population whose outcome is little known. The objective of this study was to evaluate the risk of SD or aborted SD (aSD) in these patients. We conducted a meta-analysis and cumulative analysis of seven large prospective studies involving 1568 patients who had not received a prophylactic ICD in primary prevention. Patients proved to be heterogeneous. Many were theoretically at low risk, in that they had a drug-induced Br type 1 (48%) and/or were asymptomatic (87%), Others, in contrast, had one or more risk factors. During a mean/median follow-up ranging from 30 to 48 months, 23 patients suffered SD and 1 had aSD. The annual incidence of SD/aSD was 0.5% in the total population, 0.9% in patients with spontaneous Br type 1 and 0.08% in those with drug-induced Br type 1 (P = 0.0001). The paper by Brugada et al. reported an incidence of SD more than six times higher than the other studies, probably as a result of selection bias. On excluding this paper, the annual incidence of SD/aSD in the remaining 1198 patients fell to 0.22% in the total population and to 0.38 and 0.06% in spontaneous and drug-induced Br type 1, respectively. Of the 24 patients with SD/aSD, 96% were males, the mean age was 39 ± 15 years, 92% had spontaneous Br type 1, 61% had familial SD (f-SD), and only 18.2% had a previous syncope; 43% had a positive electrophysiological study. Multiple meta-analysis of individual trials showed that spontaneous Br type 1, f-SD, and previous syncope increased the risk of SD/aSD (RR 2.83, 2.49, and 3.03, respectively). However, each of these three risk factors had a very low positive predictive value (PPV) (1.9-3.3%), while negative predictive values (NPV) were high (98.5-99.7%). The incidence of SD/aSD was only slightly higher in patients with syncope than in asymptomatic patients (2% vs. 1.5%, P = 0.6124). Patients with SD/aSD when compared with the others had a mean of 1.74 vs. 0.95 risk factors (P = 0.026). (i) In patients with Br type 1 ECG without an ICD in primary prevention, the risk of SD/aSD is low, particularly in those with drug-induced Br type 1; (ii) spontaneous Br type 1, f-SD, and syncope increase the risk. However, each of these risk factors individually has limited clinical usefulness, owing to their very low PPV; (iii) patients at highest risk are those with more than one risk factor.


An expanded role for the TWN1 gene in embryogenesis: defects in cotyledon pattern and morphology in the twn1 mutant of Arabidopsis (Brassicaceae).
The suspensor is a specialized basal structure that differentiates early in plant embryogenesis to support development of the embryo proper. Suspensor differentiation in Arabidopsis is maintained in part by the TWIN1 (TWN1) gene, which suppresses embryogenic development in suspensor cells: twn1 mutants produce supernumerary embryos via suspensor transformation. To better understand mechanisms of suspensor development and further investigate the function of TWN1, we have characterized late-embryo and post-embryonic development in the twn1 mutant, using seedling culture, microscopy, and genetics. We report here that the twn1 mutation disrupts cotyledon number, arrangement, and morphology and occasionally causes partial conversion of cotyledons into leaves. These defects are not a consequence of suspensor transformation. Thus, in addition to its basal role in suspensor differentiation, TWN1 influences apical pattern and morphology in the embryo proper. To determine whether other genes can similarly affect both suspensor and cotyledon development, we looked for twinning in Arabidopsis mutants previously identified by their abnormal cotyledon phenotypes. One such mutant, amp1, produced a low frequency of twin embryos by suspensor transformation. Our results suggest that mechanisms that maintain suspensor identity also function later in development to influence organ formation at the embryonic shoot apex. We propose that TWN1 functions in cell communication pathways that convey local positional information in both the apical and basal regions of the Arabidopsis embryo.


A modified technique for intralesional injection of collagenase Clostridium histolyticum for Peyronie's disease results in reduced procedural morbidity using a standardized hematoma classification rubric.
Early clinical trials of injectable collagenase Clostridium histolyticum (CCh) for Peyronie's disease (PD) demonstrated safety and efficacy. Since then, modified injection protocols have been proposed. Adverse events-such as bruising, swelling, hematoma, and corporal rupture-exceed 50% in many studies, but lack of standardization of hematoma severity limits conclusions about the relative safety of protocols. We propose a modification of the standard injection technique that aims to decrease the rates of adverse events. We further describe a hematoma classification rubric that may standardize safety assessment. A modified injection procedure, termed the "fan" technique, was employed in the treatment of PD. All men receiving CCh from January 2016 through January 2019 at a single institution were included in an institutional review board (IRB) approved database. Treatment outcomes and adverse events were retrospectively assessed. A three-tiered hematoma classification rubric was devised to standardize reporting of hematoma, which was defined as concurrent bruising and swelling at the site of injection without loss of erection. Using the fan technique, 152 patients received 1323 injections. Eight hematomas (5.3% of all patients, 0.6% of all injections) were observed. The number of grade I, grade II, and grade III hematomas were 3, 2, and 3, respectively. Bruising or swelling not meeting the definition of hematoma was seen in 54.6% and 27.0% of patients, respectively. There were zero corporal ruptures. A modified injection technique results in reduced procedural morbidity. A hematoma classification system provides clarity and standardization to the assessment of safety in PD treatment. Further clinical studies with control arms are required to verify these findings.