Io: evidence for silicate volcanism in 1986.
Infrared observations of Io during the 1986 apparition of Jupiter indicate that a large eruptive event occurred on the leading side of Io on 7 August 1986, Universal Time. Measurements made at 4.8, 8.7, and 20 micrometers suggest that the source of the event was about 15 kilometers in radius with a model temperature of approximately 900 Kelvin. Together with previously reported events, these measurements indicate that high-temperature volcanic activity on the leading side of Io may be more frequent than previously thought. The inferred temperature is significantly above the boiling point of sulfur in a vacuum(715 Kelvin) and thus constitutes strong evidence for active silicate volcanism on the surface of Io.


Reading and math achievement profiles and longitudinal growth trajectories of children with an autism spectrum disorder.
This study examined the reading and math achievement profiles and longitudinal growth trajectories of a nationally representative sample of children ages 6 through 9 with an autism spectrum disorder. Four distinct achievement profiles were identified: higher-achieving (39%), hyperlexia (9%), hypercalculia (20%) and lower-achieving (32%). Children with hypercalculia and lower-achieving profiles were more likely to be from low socioeconomic families and had lower functional cognitive skills than the higher-achieving profile. All four profiles lost ground in passage comprehension over time. Slower improvement occurred for the higher-achieving group on letter-word identification, the hyperlexia group on conversation abilities and the hypercalculia group on calculation and functional cognitive skills relative to the lower-achieving group.


Glutamatergic neurons in rodent models respond to nanoscale particulate urban air pollutants in vivo and in vitro.
Inhalation of airborne particulate matter (PM) derived from urban traffic is associated with pathology in the arteries, heart, and lung; effects on brain are also indicated but are less documented. We evaluated rodent brain responses to urban nanoscale (< 200 nm) PM (nPM). Ambient nPM collected near an urban freeway was transferred to aqueous suspension and reaerosolized for 10-week inhalation exposure of mice or directly applied to rat brain cell cultures. Free radicals were detected by electron paramagnetic resonance in the nPM 30 days after initial collection. Chronic inhalation of reaerosolized nPM altered selected neuronal and glial activities in mice. The neuronal glutamate receptor subunit (GluA1) was decreased in hippocampus, whereas glia were activated and inflammatory cytokines were induced [interleukin-1α (IL-1α), tumor necrosis factor-α (TNFα)] in cerebral cortex. Two in vitro models showed effects of nPM suspensions within 24-48 hr of exposure that involved glutamatergic functions. In hippocampal slice cultures, nPM increased the neurotoxicity of NMDA (N-methyl-d-aspartic acid), a glutamatergic agonist, which was in turn blocked by the NMDA antagonist AP5 [(2R)-amino-5-phosphonopentanoate]. In embryonic neuron cultures, nPM impaired neurite outgrowth, also blocked by AP5. Induction of IL-1α and TNFα in mixed glia cultures required higher nPM concentrations than did neuronal effects. Because conditioned media from nPM-exposed glia also impaired outgrowth of embryonic neurites, nPM can act indirectly, as well as directly, on neurons in vitro. nPM can affect embryonic and adult neurons through glutamatergic mechanisms. The interactions of nPM with glutamatergic neuronal functions suggest that cerebral ischemia, which involves glutamatergic excitotoxicity, could be exacerbated by nPM.


Evaluation of nutritional availability and anti-tumor activity of selenium contained in selenium-enriched Kaiware radish sprouts.
We estimated the nutritional availability of selenium (Se) in Se-enriched Kaiware radish sprouts (SeRS) by the tissue Se deposition and glutathione peroxidase (GPX) activity of rats administered the sprouts, and examined the effect of SeRS on the formation of aberrant crypt foci (ACF) in the colon of mice administered 1,2-dimethylhydrazine (DMH) to evaluate anti-tumor activity. Male weanling Wistar rats were divided into seven groups and fed a Se-deficient basal diet or the basal diet supplemented with 0.05, 0.10, or 0.15 microg/g of Se as sodium selenite or SeRS for 28 d. Supplementation with Se dose-dependently increased serum and liver Se concentrations and GPX activities, and the selenite-supplemented groups showed a higher increase than the SeRS-supplemented groups. The nutritional availability of Se in SeRS was estimated to be 33 or 64% by slope ratio analysis. Male 4-week-old A/J mice were divided into seven groups and fed a low Se basal diet or the basal diet supplemented with selenite, SeRS, or selenite + non-Se-enriched radish sprouts (NonSeRS) at a level of 0.1 or 2.0 microg Se/g for 9 weeks. After 1 week of feeding, all mice were given six subcutaneous injections of DMH (20 mg/kg) at 1-week intervals. The average number of ACF formed in the colon of mice fed the basal diet was 4.3. At a supplementation level of 0.1 mug Se/g, only SeRS significantly inhibited ACF formation. At a supplementation level of 2.0 microg Se/g, both selenite and SeRS significantly inhibited ACF formation. The addition of NonSeRS to the selenite-supplemented diets tended to inhibit ACF formation, but this was not statistically significant. These results indicate that SeRS shows lower nutritional availability but higher anti-tumor activity than selenite.


Three novel approaches to structural identifiability analysis in mixed-effects models.
Structural identifiability is a concept that considers whether the structure of a model together with a set of input-output relations uniquely determines the model parameters. In the mathematical modelling of biological systems, structural identifiability is an important concept since biological interpretations are typically made from the parameter estimates. For a system defined by ordinary differential equations, several methods have been developed to analyse whether the model is structurally identifiable or otherwise. Another well-used modelling framework, which is particularly useful when the experimental data are sparsely sampled and the population variance is of interest, is mixed-effects modelling. However, established identifiability analysis techniques for ordinary differential equations are not directly applicable to such models. In this paper, we present and apply three different methods that can be used to study structural identifiability in mixed-effects models. The first method, called the repeated measurement approach, is based on applying a set of previously established statistical theorems. The second method, called the augmented system approach, is based on augmenting the mixed-effects model to an extended state-space form. The third method, called the Laplace transform mixed-effects extension, is based on considering the moment invariants of the systems transfer function as functions of random variables. To illustrate, compare and contrast the application of the three methods, they are applied to a set of mixed-effects models. Three structural identifiability analysis methods applicable to mixed-effects models have been presented in this paper. As method development of structural identifiability techniques for mixed-effects models has been given very little attention, despite mixed-effects models being widely used, the methods presented in this paper provides a way of handling structural identifiability in mixed-effects models previously not possible.


Comparative metabolomics in primates reveals the effects of diet and gene regulatory variation on metabolic divergence.
Human diets differ from those of non-human primates. Among few obvious differences, humans consume more meat than most non-human primates and regularly cook their food. It is hypothesized that a dietary shift during human evolution has been accompanied by molecular adaptations in metabolic pathways. Consistent with this notion, comparative studies of gene expression levels in primates have found that the regulation of genes with metabolic functions tend to evolve rapidly in the human lineage. The metabolic consequences of these regulatory differences, however, remained unknown. To address this gap, we performed a comparative study using a combination of gene expression and metabolomic profiling in livers from humans, chimpanzees, and rhesus macaques. We show that dietary differences between species have a strong effect on metabolic concentrations. In addition, we found that differences in metabolic concentration across species are correlated with inter-species differences in the expression of the corresponding enzymes, which control the same metabolic reaction. We identified a number of metabolic compounds with lineage-specific profiles, including examples of human-species metabolic differences that may be directly related to dietary differences.


Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) - United States, February 12-March 16, 2020.
Globally, approximately 170,000 confirmed cases of coronavirus disease 2019 (COVID-19) caused by the 2019 novel coronavirus (SARS-CoV-2) have been reported, including an estimated 7,000 deaths in approximately 150 countries (1). On March 11, 2020, the World Health Organization declared the COVID-19 outbreak a pandemic (2). Data from China have indicated that older adults, particularly those with serious underlying health conditions, are at higher risk for severe COVID-19-associated illness and death than are younger persons (3). Although the majority of reported COVID-19 cases in China were mild (81%), approximately 80% of deaths occurred among adults aged ≥60 years; only one (0.1%) death occurred in a person aged ≤19 years (3). In this report, COVID-19 cases in the United States that occurred during February 12-March 16, 2020 and severity of disease (hospitalization, admission to intensive care unit [ICU], and death) were analyzed by age group. As of March 16, a total of 4,226 COVID-19 cases in the United States had been reported to CDC, with multiple cases reported among older adults living in long-term care facilities (4). Overall, 31% of cases, 45% of hospitalizations, 53% of ICU admissions, and 80% of deaths associated with COVID-19 were among adults aged ≥65 years with the highest percentage of severe outcomes among persons aged ≥85 years. In contrast, no ICU admissions or deaths were reported among persons aged ≤19 years. Similar to reports from other countries, this finding suggests that the risk for serious disease and death from COVID-19 is higher in older age groups.


Responses of bovine lymphocytes to heat shock as modified by breed and antioxidant status.
We tested whether resistance of lymphocytes to heat stress is modified by breed, intracellular glutathione content, and extracellular antioxidants. In the first experiment, lymphocytes from Angus (Bos taurus, non-heat-tolerant), Brahman (B. indicus, heat-tolerant), and Senepol (B. taurus, heat-tolerant) heifers (12 heifers per breed) were cultured at 45 degrees C for 3 h to evaluate thermal killing, at 42 degrees C for 12 h in a 60-h phytohemagglutinin-induced proliferation test, and at 42 degrees C for 1 h to measure induction of heat shock protein 70 (HSP70). Killing at 45 degrees C was affected by breed x temperature (P < .01); the decrease in viability caused by a temperature of 45 degrees C was greater for Angus than for Brahman or Senepol. For phytohemagglutinin-stimulated lymphocytes, heating to 42 degrees C reduced [3H]thymidine incorporation equally for all breeds. Viability at the end of culture was affected (P < .001) by a breed x temperature interaction because the decrease in viability caused by culture at 42 degrees C was greatest for lymphocytes from Angus heifers. Heat shock for 1 h at 42 degrees C caused a two- to threefold increase in intracellular concentrations of HSP70, but there was no interaction of temperature with breed. In another experiment (with lymphocytes harvested from three Holstein cows), buthionine sulfoximine, a glutathione synthesis inhibitor, inhibited (P < .01) proliferation of phytohemagglutinin-stimulated lymphocytes at 38.5 and 42 degrees C. Addition of the antioxidants glutathione or thioredoxin to culture did not reduce the effects of heating to 42 degrees C on proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)


Possible involvement of the peripheral Mu-opioid system in antinociception induced by bergamot essential oil to allodynia after peripheral nerve injury.
The essential oil of bergamot (BEO) is one of the most common essential oils and is most familiar to the general public. The aims of this study were to investigate the effect of intraplantar (i.pl.) BEO on neuropathic allodynia induced by partial sciatic nerve ligation (PSNL) in mice and the opioid receptor subtypes involved in the antiallodynic effects of BEO. Our findings showed that a single dose of i.pl. administration of BEO significantly inhibited the PSNL-induced neuropathic pain using the von Frey test. The i.pl pretreatment with naloxone methiodide, a peripherally acting μ-opioid receptor preferring antagonist, β-funaltrexamine hydrochloride (β-FNA), a selective μ-opioid receptor antagonist, and β-endorphin antiserum significantly reversed the antiallodynic effect of BEO in the von Frey test, but not by naltrindole, the nonselective δ-opioid receptor antagonist and nor-binaltorphimine, the selective κ-opioid receptor antagonist. Furthermore, in the western blotting analysis, i.pl. administration of BEO resulted in a significant blockage of spinal extracellular signal-regulated protein kinase (ERK) activation induced by PSNL. Naloxone methiodide and β-FNA significantly reversed the blockage of spinal ERK activation induced by BEO. These results suggest that i.pl. injection of BEO-induced antiallodynic effect and blockage of spinal ERK activation may be triggered by activation of peripheral μ-opioid receptors.


Comparison of Near-Infrared Oximeters in a Liquid Optical Phantom with Varying Intralipid and Blood Content.
The interpretation of cerebral tissue oxygen saturation values (StO2) in clinical settings is currently complicated by the use of different near-infrared spectrophotometry (NIRS) devices producing different StO2 values for the same oxygenation due to differences in the algorithms and technical aspects. The aim was to investigate the effect of changes in scattering and absorption on the StO2 of different NIRS devices in a liquid optical phantom. We compared three continuous-wave (CW) with a frequency domain (FD) NIRS device. Responsiveness to oxygenation changes was only slightly altered by different intralipid (IL) concentrations. However, alterations in haematocrit (htc) showed a strong effect: increased htc led to a 20-35% increased response of all CW devices compared to the FD device, probably due to differences in algorithms regarding the water concentration.


Identification of helper T-cell epitopes that encompass or lie proximal to cytotoxic T-cell epitopes in the gp100 melanoma tumor antigen.
The melanocyte-associated antigen gp100 constitutes one of the most attractive targets for T-cell-based immunotherapy against malignant melanoma. Although several MHC class I-restricted epitopes have been identified for CTLs, thus far, only one MHC class II T helper epitope (restricted by HLA-DR4) has been described in the literature. Using an algorithm to identify promiscuous helper T-cell epitopes, here we describe three additional MHC class II-restricted epitopes from gp100. Whereas one T helper epitope, gp100(175-189), was restricted by the HLA-DR53 and DQw6 alleles, the T-cell responses to two other epitopes, gp100(74-89) and gp100(576-590), were restricted by HLA-DR7. Most interestingly, the newly identified helper T lymphocyte epitopes encompass or lie proximal to previously described CTL epitopes for this tumor-associated antigen. Together with the previously described HLA-DR4-restricted epitope, these T helper epitopes offer coverage for the majority of the human population. Moreover, the use of peptide vaccines containing both CTLs and T helper epitopes could offer therapeutic advantages over current approaches that focus solely on eliciting antitumor CTL responses.


Randomized trial of high-dose chemotherapy with autologous bone marrow support as adjuvant therapy for high-risk, multi-node-positive malignant melanoma.
Chemotherapy adjuvant to surgery in metastatic melanoma has been evaluated in only a few prospective randomized trials. In the treatment of metastatic melanoma, dacarbazine has response rates of 15%-25% and in several studies, when combined with other alkylating agents, has yielded even higher response rates. Among the highest response rates are those achieved by using high-dose chemotherapy regimens combined with autologous bone marrow support (transplantation). We conducted a prospective randomized clinical trial to test the efficacy of high-dose alkylating agents in combination with autologous bone marrow support given as adjuvant therapy for high-risk stage II (World Health Organization) melanoma. Thirty-nine patients with metastases involving five or more lymph nodes were randomly assigned to one of two treatment arms within 8 weeks of lymphadenectomy: immediate treatment or observation only. The immediate-treatment arm consisted of 19 patients who, immediately after random assignment, received high-dose chemotherapy with alkylating agents, followed 3 days later by reinfusion of autologous bone marrow. The observation arm consisted of 20 patients who were observed until relapse (confirmed by biopsy) and were then treated with the identical high-dose alkylating agent chemotherapy followed by reinfusion of autologous bone marrow. Bone marrow was harvested from the patients under general anesthesia 1-2 weeks prior to chemotherapy and was cryopreserved. Chemotherapy consisted of intravenous administration of cyclophosphamide (1875 mg/m2 as a 1-hour infusion daily for 3 days), cisplatin (55 mg/m2 per day by continuous infusion over the same 72-hour period), and carmustine (BCNU) (600 mg/m2) given immediately after cisplatin on the 4th day as a 2-hour infusion. The total doses of the three drugs were 5625, 165, and 600 mg/m2, respectively. All patients received medical evaluations every 6-12 weeks over the study period. Kaplan-Meier estimates were used to determine the time to disease progression on the basis of intent to treat. There was no statistically significant difference in overall survival or in time to disease progression between the two treatment arms. However, the median time to progression was 16 weeks in the observation arm and 35 weeks in the immediate-treatment arm. Immediate adjuvant high-dose chemotherapy with alkylating agents followed by autologous bone marrow support more than doubled the time to disease progression compared with observation alone, though the difference was not statistically significant. No differences in overall survival were noted.


Aphidicolin-resistant mutator strains of mouse teratocarcinoma.
From among a series of stable, aphidicolin-resistant mutant strains of mouse teratocarcinoma, derived from a multipotent parental line (PSA-1-80), three were selected for further study on the basis of their comparatively high degrees of resistance and elevated frequencies of spontaneous forward mutation to 6-thioguanine and ouabain resistance. Fluctuation tests confirmed that they were mutator strains. Since each of the three mutants was isolated after multiple rounds of selection, and since a variety of biochemical abnormalities were observed, it is likely that a number of mechanisms, probably consisting of overlapping subsets, determine the phenotypes. Abnormalities in the metabolism of the nucleotide substrates for polymerization are likely to be of major importance in mutants designated Aph-2 and Aph-3, as there were marked alterations in the dCTP and dATP pool sizes. The specific activity of DNA polymerase alpha was also increased. For the case of Aph-3, which exhibited the greatest (400-fold) increase in resistance to aphidicolin, a mutation in the structural gene for DNA polymerase alpha may be an additional important component, since in vitro assays revealed that the isolated enzyme was resistant to aphidicolin. For the case of Aph-1 however, only minor alterations in dNTP pools were observed, and there was no increase in the specific activity of DNA polymerase alpha or in the aphidicolin resistance of the isolated DNA polymerase alpha, suggesting yet another mechanism(s) underlying the aphidicolin resistance/mutator phenotype. All three mutants formed subcutaneous tumors in syngeneic mice; both Aph-1 and Aph-2 were multipotent; whereas Aph-3 was nullipotent.(ABSTRACT TRUNCATED AT 250 WORDS)


A Structured Transfer of Care Process Reduces Perioperative Complications in Cardiac Surgery Patients.
Serious complications are common during the intensive care of postoperative cardiac surgery patients. Some of these complications may be influenced by communication during the process of handover of care from the operating room to the intensive care unit (ICU) team. A structured transfer of care process may reduce the rate of communication errors and perioperative complications. We hypothesized that a collaborative, comprehensive, structured handover of care from the intraoperative team to the ICU team would reduce a specific set of postoperative complications. We tested this hypothesis by developing and introducing a comprehensive multidisciplinary transfer of care process. We measured patient outcomes before and after the intervention using a linkage between 2 care databases: an Anesthesia Information Management System and a critical care complication registry database. There were 1127 total postoperative cardiac surgery admissions during the study period, 550 before and 577 after the intervention. There was no statistical difference between overall complications before and after the intervention (P = .154). However, there was a statistically significant reduction in preventable complications after the intervention (P = .023). The main finding of this investigation is that the introduction of a collaborative, comprehensive transfer of care process from the operating room to the ICU was associated with patients suffering fewer preventable complications.


Decoupling the scholarly journal.
Although many observers have advocated the reform of the scholarly publishing system, improvements to functions like peer review have been adopted sluggishly. We argue that this is due to the tight coupling of the journal system: the system's essential functions of archiving, registration, dissemination, and certification are bundled together and siloed into tens of thousands of individual journals. This tight coupling makes it difficult to change any one aspect of the system, choking out innovation. We suggest that the solution is the "decoupled journal (DcJ)." In this system, the functions are unbundled and performed as services, able to compete for patronage and evolve in response to the market. For instance, a scholar might deposit an article in her institutional repository, have it copyedited and typeset by one company, indexed for search by several others, self-marketed over her own social networks, and peer reviewed by one or more stamping agencies that connect her paper to external reviewers. The DcJ brings publishing out of its current seventeenth-century paradigm, and creates a Web-like environment of loosely joined pieces-a marketplace of tools that, like the Web, evolves quickly in response to new technologies and users' needs. Importantly, this system is able to evolve from the current one, requiring only the continued development of bolt-on services external to the journal, particularly for peer review.


Impact of road network on the structure of a multifunctional forest landscape unit in southern Turkey.
Forest roads have many kinds of direct and indirect effects such as physical, ecological, and socio-economic effects in landscape scale. In this study the relationship between forest road network and the structure of a multifunctionally planned forest landscape, in the south of Turkey was examined. The aim of the study was to determine whether or not the correlation between road network and landscape structure across a gradient of road density categorical road/no road approach and landscape pattern data from the managed forest landscapes existed. It was concerned with three type polygons that were forest functioning patches, compartments, and stand patches and were associated with higher road density or existing of road network. To quantify the case, it was analyzed whether the spatial structure of forest patches adjacent to roads differs from the spatial structure of forest patches away from roads. GIS was used to integrate quantitative indices of landscape structure. There was little negatively significant relationship between road density and patch area/size, patch perimeter and shape index of patton index (PI) and no correlation with patch number and Fractal Dimension (FD). The forest road network modified spatial pattern of patch shape through PI values. The road network increased the number of patch and decreased mean patch size. The existence of road network was more effective than topography index appearing of PI and FD in the roaded areas. It was indicated to potential reverse impacts of road network on spatial structure of forest compartments in terms of shape index (FD). Highest proportions of harvestable forest areas fall into roaded areas. The results define that road networks are effective on the spatial structure of forest landscape. The forest road network of study area has all probable ecological impacts of forest roads mentioned in context.


Exploring mental status in Friedreich's ataxia: a combined neuropsychological, behavioral and neuroimaging study.
Despite much evidence of cognitive and affective disorders in Friedreich's ataxia (FRDA), the nature of mental status in FRDA has received little systematic attention. It has been proposed that the cerebellum may interfere indirectly with cognition through the cerebello-cortical loops, whereas the role of pathological changes in different areas of the central nervous system is still undetermined. In the present study, 13 patients with molecularly determined FRDA and a group of matched controls were evaluated by a comprehensive battery of neuropsychological tests and the Minnesota Multiphasic Personality Inventory. A repetitive task of simple visual-reaction times was used to investigate implicit learning in all subjects. Pathological changes in cortical areas were explored comparing cerebral activations of patients and controls during finger movements (functional MRI). The intelligence profile of FRDA patients is characterized by concrete thinking, poor capacity in concept formation and visuospatial reasoning. FRDA patients show reduced speed of information processing. The learning effect seen in controls was notably absent in patients with FRDA. The patients' personality is characterized by some pathological aspects and reduced defensiveness. Patterns of cortical activation during finger movements are heterogeneous in patients compared to controls. Cognitive impairment, mood disorders and motor deficits in FRDA patients may be the result of the cumulative damage caused by frataxin deficiency not only in the cerebellum and spinal cord but also in other brain areas.


Passive hyperthermia reduces voluntary activation and isometric force production.
It has been suggested that a critically high body core temperature may impair central neuromuscular activation and cause fatigue. We investigated the effects of passive hyperthermia on maximal isometric force production (MVC) and voluntary activation (VA) to determine the relative roles of skin (T(sk)) and body core temperature ( T(c)) on these factors. Twenty-two males [VO(2max)=64.2 (8.9) ml x kg(-1) min(-1), body fat=8.2 (3.9)%] were seated in a knee-extension myograph, then passively heated from 37.4 to 39.4 degrees C rectal temperature (T(re)) and then cooled back to 37.4(o)C using a liquid conditioning garment. Voluntary strength and VA (interpolated twitch) were examined during an isometric 10-s MVC at 0.5 degrees C intervals during both heating and cooling. Passive heating to a T(c) of 39.4(o)C reduced VA by 11 (11)% and MVC by 13 (18)% (P<0.05), but rapid skin cooling, with a concomitant reduction in cardiovascular strain [percentage heart rate reserve decreased from 64 (11)% to 29 (11)%] and psychophysical strain did not restore either of these measures to baseline. Only when cooling lowered T(c) back to normal did VA and MVC return to baseline (P<0.05). We conclude that an elevated T(c) reduces VA during isometric MVC, and neither T(sk) nor cardiovascular or psychophysical strain modulates this response. Results are given as mean (SD) unless otherwise stated.


Freeform lens design for a point source and far-field target.
The field of freeform illumination design has surged since the introduction of new fabrication techniques that allow for the production of non-axially symmetric surfaces. Freeform surfaces aim to efficiently control the redistribution of light from a particular source distribution to a target irradiance, but designing such surfaces is a challenging problem in the field of nonimaging optics. Optical design strategies have been developed in both academia and industry. In this paper, we consider the design of a single freeform lens that converts the light from an ideal (zero-étendue) point source into a far-field target. We present a mathematical approach and numerically solve the corresponding generalized Monge-Ampère equation of the optical system. We derive this equation using optimal transport theory and energy conservation. We use a generalized least-squares algorithm that can handle a non-quadratic cost function in the corresponding optimal transport problem. The algorithm first computes the optical map and subsequently constructs the optical surface. We demonstrate that the algorithm can generate a peanut-shaped lens for roadlighting purposes and a highly detailed lens that produces an image on a projection screen in the far field.


Viking magnetic properties investigation: further results.
The amounts of magnetic particles held on the reference test chart and backhoe magnets on lander 2 and lander 1 are comparable, indicating the presence of an estimated 3 to 7 percent by weight of relatively pure, strongly magnetic particles in the soil at the lander 2 sampling site. Preliminary spectrophotometric analysis of the material held on the backhoe magnets on lander 1 indicates that its reflectance characteristics are indistinguishable from material within a sampling trench with which it has been compared. The material on the RTC magnet shows a different spectrum, but it is suspected that the difference is the result of a reflectance contribution from the magnesium metal covering on the magnet. It is argued that the results indicate the presence, now or originally, of magnetite, which may be titaniferous.


Eccentric and concentric torque-velocity characteristics, torque output comparisons, and gravity effect torque corrections for the quadriceps and hamstring muscles in females.
The purpose of this study was to assess and compare eccentric (ECC) and concentric (CONC) torque output of the quadriceps and hamstring muscles and to analyze the effect of gravity effect torque (GET) correction on the calculation of the hamstring/quadriceps peak torque quotient (H/Q quotient). Twenty female subjects performed maximal voluntary CONC and ECC contractions of the quadriceps and hamstring muscles at five isokinetic lever arm velocities from 60 degrees/s to 360 degrees/s. Peak torque was measured and corrected for GET. Mean ECC torque did not significantly change with increasing ECC velocity for either the quadriceps or hamstring muscles (P greater than 0.05). Mean CONC torques were significantly lower than the corresponding ECC torques (P less than 0.05) and decreased with increasing CONC velocity. At each test velocity, the CONC H/Q quotient was significantly lower than the corresponding ECC H/Q quotient (P less than 0.05). Mean H/Q quotients did not significantly change with increasing velocity for either the CONC or ECC tests (means: 0.46 and 0.57; P greater than 0.05). Mean H/Q quotients not corrected for GET significantly increased with increasing velocity for the CONC (0.61 to 0.78; P less than 0.05), but not ECC tests (0.66 to 0.71; P greater than 0.05). The results indicate that the ECC torque-velocity curve is essentially level for both quadriceps and hamstring muscles. The present findings point strongly toward the necessity of correcting for GET when calculating both CONC and ECC H/Q quotients.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of hypertensive diseases in pregnancy on birthweight, gestational duration, and small-for-gestational-age births.
We measured the impact of hypertensive disorders in pregnancy (chronic hypertension, pregnancy-induced hypertension, and eclampsia) on birthweight, gestational duration, and small-for-gestational-age births. We employed a retrospective cohort design using North Carolina birth certificate data for the years 1988-1990, with the analyses based on nearly 300,000 pregnancies. Women noted to have eclampsia during pregnancy had a substantially greater risk of delivering very-low-birthweight infants (birthweight < or = 1,499 gm; risk difference (RD) = 6.7%) and moderately-low-birthweight infants (1,500-2,499 gm; RD = 14.6%), and very preterm (gestational age < 33 weeks; RD = 7.1%) and moderately preterm (33-36 weeks; RD = 9.3%) births, compared with women without hypertension. Corresponding risk differences for these outcomes were 1.9% and 5.1% for very low and moderately low birthweight, and 1.6% and 3.0% for very preterm and moderately preterm for women with chronic hypertension. Risk differences were of similar magnitude for women with pregnancy-induced hypertension for these outcomes. Hypertensive disorders in pregnancy were associated with small-for-gestational-age infants, with risk differences of 5.1%, 3.5%, and 9.2% for chronic hypertension, pregnancy-induced hypertension, and eclampsia, respectively. The patterns of risk were similar for preterm births due to spontaneous onset of labor and those due to other precipitating events. We observed similar patterns for black and white women. Control for confounders through multivariable logistic regression models did not alter the observed patterns. In spite of the limited data quality, we found that hypertensive disorders in pregnancy substantially increase the risk of low birthweight, preterm births, and small-for-gestational-age births.


Differential retention of pollen grains on clothing and the effectiveness of laboratory retrieval methods in forensic settings.
Forensic palynology has been important in criminal investigation since the 1950s and often provides evidence that is vital in identifying suspects and securing convictions. However, for such evidence to be used appropriately, it is necessary to understand the factors affecting taphonomic variability (i.e. the variability in the fate of pollen grains before they are found during forensic examination). Here, we test the relative amount of pollen retained on clothing after a period of simulated light or heavy wear based on pollen and fabric characteristics. We also test the efficiency of forensic laboratory protocols for retrieving pollen from fabrics for analysis. There was no statistically significant difference in retention of fresh or dried pollen on any fabric type. There was a substantial difference in pollen retention according to wear intensity, with considerably more pollen being retained after light wear than after heavy wear. Pollen from insect-pollinated species was retained at higher concentrations than pollen from wind-pollinated species. This pattern was consistent regardless of wear intensity but pollination type explained more of the variability in pollen retention after light wear. Fabric type was significantly related to pollen retention, but interacted strongly with plant species such that patterns were both complex and highly species-specific. The efficiency of removing pollen with the standard washing protocol differed substantially according to plant species, fabric type, and the interaction between these factors. The average efficiency was 67.7% but this ranged from 21% to 93%, demonstrating that previous assumptions on the reliability of the technique providing a representative sample for forensic use should be reviewed. This paper highlights the importance of understanding pollen and fabric characteristics when creating a pollen profile in criminal investigations and to ensure that evidence used in testimony is accurate and robust.


Association of cardiovascular risk factors with disease severity in cerebral cavernous malformation type 1 subjects with the common Hispanic mutation.
Cerebral cavernous malformations (CCM) are enlarged vascular lesions affecting 0.1-0.5% of the population worldwide and causing hemorrhagic strokes, seizures, and neurological deficits. Familial CCM type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and is characterized by multiple brain lesions whose number and size increase with age. The number of lesions varies widely for unknown reasons, even among carriers of similar ages with the same mutation. The purpose of this study was to investigate whether cardiovascular (CV) risk factors influence potential markers of familial CCM1 disease severity, such as lesion count and history of intracerebral hemorrhage. We analyzed baseline data from 185 Hispanic subjects, enrolled in the Brain Vascular Malformation Consortium study between June 2010 and March 2013. All subjects were carriers of the founder Q455X 'Common Hispanic Mutation' (CHM) in the KRIT1 gene, and had a clinical diagnosis of CCM or had an affected first- or second-degree relative with CCM. We performed a cross-sectional study, collecting detailed clinical information of CCM1-CHM subjects and cerebral susceptibility-weighted magnetic resonance imaging to assess lesion count. Linear or logistic regression analysis of log-lesion count or history of intracerebral hemorrhage and CV risk factors (age, gender, obesity, diabetes, hypertension, hyperlipidemia and smoking status) and related quantitative traits (body mass index, glycosylated hemoglobin levels, blood pressure, lipids levels and pack-years of cigarette smoking) was performed accommodating familial clustering. CCM1-CHM subjects were mainly female (63.8%) and symptomatic at presentation (63.2%). Lesion count was highly variable (mean ± SD: 57.7 ± 110.6; range: 0-713); 90% of CCM1-CHM subjects had multiple lesions at enrollment. Age (p < 0.001) was positively correlated with lesion count and male gender (p = 0.035) was associated with a greater number of lesions. Obesity (p = 0.001) and higher body mass index (p = 0.002) were associated with fewer lesions. No association with hypertension was detected, however, systolic blood pressure (p = 0.002) was associated with fewer lesions. No significant association with lesion count was observed for diabetes, hyperlipidemia, smoking status or for related quantitative traits. History of intracerebral hemorrhage was not significantly associated with any CV risk factors, however, we found borderline associations of hemorrhage with obesity (p = 0.062), systolic blood pressure (p = 0.083) and pack-years of cigarette smoking (p = 0.055). After correction for multiple testing, age and obesity remained significantly associated with lesion count in CCM1-CHM subjects. These results suggest that several CV risk factors explain some of the variability in lesion count in Hispanic CCM1-CHM subjects. Although age, gender, obesity, body mass index and systolic blood pressure may influence familial CCM1 disease severity, further longitudinal studies in larger sample sizes are essential to confirm these findings.


Inhibition of the host translation shutoff response by herpes simplex virus 1 triggers nuclear envelope-derived autophagy.
Macroautophagy is a cellular pathway that degrades intracellular pathogens and contributes to antigen presentation. Herpes simplex virus 1 (HSV-1) infection triggers both macroautophagy and an additional form of autophagy that uses the nuclear envelope as a source of membrane. The present study constitutes the first in-depth analysis of nuclear envelope-derived autophagy (NEDA). We established LC3a as a marker that allowed us to distinguish between NEDA and macroautophagy in both immunofluorescence and flow cytometry. NEDA was observed in many different cell types, indicating that it is a general response to HSV-1 infection. This autophagic pathway is known to depend on the viral protein γ34.5, which can inhibit macroautophagy via binding to beclin-1. Using mutant viruses, we were able to show that binding of beclin-1 by γ34.5 had no effect on NEDA, demonstrating that NEDA is regulated differently than macroautophagy. Instead, NEDA was triggered in response to γ34.5 binding to protein phosphatase 1α, an interaction used by the virus to prevent host cells from shutting off protein translation. NEDA was not triggered when late viral protein production was inhibited with acyclovir or hippuristanol, indicating that the accumulation of these proteins might stress infected cells. Interestingly, expression of the late viral protein gH was sufficient to rescue NEDA in the context of infection with a virus that otherwise does not support strong late viral protein expression. We argue that NEDA is a cellular stress response triggered late during HSV-1 infection and might compensate for the viral alteration of the macroautophagic response.


Population health and medicine: Policy and financial drivers.
The financial and policy levers of population health and potential opportunities for pharmacists are described. Three long-standing problems drive the focus on population health: (1) the United States suffers far worse population health outcomes compared with those of other developed nations that spend significantly less on healthcare, (2) the U.S. healthcare system's focus on "sick care" fails to address upstream prevention and population health improvement, and (3) financial incentives for healthcare delivery are poorly aligned with improvements in population health outcomes. The Patient Protection and Affordable Care Act of 2010 (ACA) was arguably the first major healthcare legislation since 1965 and had 3 main strategies for improving population health: expand health insurance coverage, control healthcare costs, and improve the healthcare delivery system. Federal and state legislation as well as Medicare and Medicaid financing strategies have designated mechanisms to reward advances in population outcomes since the passage of the ACA. States are responsible for many of the factors that affect population health, and a bipartisan effort that builds upon state and federal collaboration will likely be needed to implement the necessary health policy initiative. Population health issues affect productivity in the United States; conversely, improvements in population health may increase productivity, helping to offset the rising federal debt. Employers are in a position to improve population health and consequently help reduce the federal debt by addressing lifestyle, chronic disease, poverty, and inequality. National pharmacy organizations, regulatory bodies, and journal editors need to collectively agree to a threshold of quality and rigor for publication and endorsement. Knowledge of the policy and financial drivers of population health may both support pharmacists' efforts to improve population outcomes and identify opportunities for professional advancement.


Report on activities and attitudes of organizations active in the clinical practice guidelines field.
The organizing committee of a workshop on clinical practice guidelines (CPGs) surveyed invited organizations on their attitudes and activities related to five topics to be covered during the workshop sessions: organizational roles, priority setting, guidelines implementation, guidelines evaluation and development of a network of those active in the CPG field. Organizational roles: The national specialty societies were felt to have the largest role to play; the smallest roles were assigned to consumers, who were seen to have a role mainly in priority setting, and to industry and government, both of which were seen to have primarily a funding role. Many barriers to collaboration were identified, the solutions to all of which appeared to be better communication, establishment of common principles and clear role definitions. Priority setting: There was considerable agreement on the criteria that should be used to set priorities for CPG activities: the burden of disease on population health, the state of scientific knowledge, the cost of treatment and the economic burden of disease on society were seen as important factors, whereas the costs of guidelines development and practitioner interest in guidelines development were seen as less important. Organizations were unable to give much information on how they set priorities. Guidelines implementation: Most of the organizations surveyed did not actively try to ensure the implementation of guidelines, although a considerable minority devoted resources to implementation. The 38% of organizations that implemented guidelines actively listed a wide variety of activities, including training, use of local opinion leaders, information technology, local consensus processes and counter detailing. Guidelines evaluation: Formal evaluation of guidelines was undertaken by fewer than 13% of the responding organizations. All the evaluations incorporated assessments before and after guideline implementation, and some used primary patient data. Barriers to evaluation included lack of money, time, data or expertise. CPG Network: Most of the respondents felt that all organizations and individuals interested or involved in guidelines should form the membership of the network. The three most important functions of such a network were deemed to be (a) to facilitate collaboration among those involved in the CPG process, (b) to maintain an information centre on CPGs and (c) to provide expertise to the CPG process. It was felt that the network should have some formal structure and communicate through e-mail and print media.


Phylogeny of the main bacterial 16S rRNA sequences in Drentse A grassland soils (The Netherlands).
The main bacteria in peaty, acid grassland soils in the Netherlands were investigated by ribosome isolation, temperature gradient gel electrophoresis, hybridization, cloning, and sequencing. Instead of using only 16S rDNA to determine the sequences present, we focused on rRNA to classify and quantify the most active bacteria. After direct ribosome isolation from soil, a partial amplicon of bacterial 16S rRNA was generated by reverse transcription-PCR. The sequence-specific separation by temperature gradient gel electrophoresis yielded soil-specific fingerprints, which were compared to signals from a clone library of genes coding for 16S rRNA. Cloned 16S rDNA sequences matching with intense bands in the fingerprint were sequenced. The relationships of the sequences to those of cultured organisms of known phylogeny were determined. Most of the amplicons originated from organisms closely related to Bacillus species. Such sequences were also detected by direct dot blot hybridization on soil rRNA: a probe specific for Firmicutes with low G+C content counted for about 50% of all bacterial rRNA. The bacterial activity in Drentse A grassland soil could be estimated by direct dot blot hybridization and sequencing of clones; it was found that about 65% of all the bacterial ribosomes originated from Firmicutes. The most active bacteria apparently were Bacillus species, from which about half of the sequences derived. Other sequences similar to those of gram-positive bacteria were only remotely related to known Firmicutes with a high G+C content. Other sequences were related to Proteobacteria, mainly the alpha subclass.


Kinematic Correlates of Kinetic Outcomes Associated With Running-Related Injury.
High magnitudes and rates of loading have been implicated in the etiology of running-related injuries. Knowledge of kinematic variables that are predictive of kinetic outcomes could inform clinic-based gait retraining programs. Healthy novice female runners ran on a treadmill while 3-dimensional biomechanical data were collected. Kinetic outcomes consisted of vertical impact transient, average vertical loading rate, instantaneous vertical loading rate, and peak braking force. Kinematic outcomes included step length), hip flexion angle at initial contact, horizontal distance from heel to center of mass at initial contact, shank angle at initial contact, and foot strike angle. Stepwise multiple linear regression was used to evaluate the amount of variance in kinetic outcomes explained by kinematic outcomes. A moderate amount of variance in kinetic outcomes (vertical impact transient = 46%, average vertical loading rate = 37%, instantaneous vertical loading rate = 49%, peak braking force = 54%) was explained by several discrete kinematic variables-predominantly speed, horizontal distance from heel to center of mass, foot strike angle, and step length. Hip flexion angle and shank angle did not contribute to any models. Decreasing step length and transitioning from a rearfoot strike may reduce kinetic risk factors for running-related injuries. In contrast, clinical strategies such as modifying shank angle and hip flexion angle would not appear to contribute significantly to the variance of kinetic outcomes after accounting for other variables.


Severe infection with multidrug-resistant Salmonella choleraesuis in a young patient with primary sclerosing cholangitis.
Massive global spread of multidrug-resistant (MDR) Salmonella spp. expressing extended-spectrum beta-lactamase (ESBL) and additional resistance to fluoroquinolones has often been attributed to high international mobility as well as excessive use of oral antibiotics in livestock farming. However, MDR Salmonella spp. have not been mentioned as a widespread pathogen in clinical settings so far. We demonstrate the case of a 25-year-old male with primary sclerosing cholangitis who tested positive for MDR Salmonella enterica serotype Choleraesuis expressing ESBL and fluoroquinolone resistance. The pathogen was supposedly acquired during a trip to Thailand, causing severe fever, cholangitis and pancreatitis. To our knowledge, this is the first report of Salmonella enterica serotype Choleraesuis in Europe expressing such a multidrug resistance pattern. ESBL resistance of Salmonella enterica spp. should be considered in patients with obstructive biliary tract pathology and travel history in endemic countries.


The effects of subchronic exposure to terbuthylazine on zebrafish.
Terbuthylazine belongs to the group of symmetrical triazine herbicides used extensively in agriculture and non-agricultural sites, primarily to control broadleaf and some grassy weeds that have become ubiquitous contaminants of the environment. The aim of this study was to assess the impact of terbuthylazine in surface waters on fish under experimental conditions. The effects of subchronic exposure to terbuthylazine on fish growth and the development of histopathological changes in selected organs (gill, kidney, liver), and on the activity of some biochemical parameters - glutathione S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GPx) and on the concentration of thiobarbituric acid reactive substances (TBARS) in Danio rerio were investigated during a 28 day toxicity test. Juvenile growth tests were performed on Danio rerio according to OECD guideline No. 215. Fish at the age of 30 days were exposed for 28 days to a range of sublethal concentrations of terbuthylazine (0.55 - environmental concentration, 150, 400, 700 and 1000 μg/L). There were no significant differences (p<0.05) between the specific growth rates (r) of the test groups and control group. Histopathological examination revealed pathological changes only in the liver in fish exposed to terbuthylazine at concentrations of 700 and 1000 μg/L. Significant differences (p<0.05) in activities of biochemical markers were found in GST (400, 700 and 1000 μg/L), GR (700 and 1000 μg/L), significant differences (p<0.05) of TBARS concentration were found at 1000 μg/L. Based on the results of growth rate, the histopathological examination of selected organs, and the results of biochemical parameters, it was found that the environmental concentration of terbuthylazine did not have any effects on juvenile D. rerio. The values of NOEC and LOEC for terbuthylazine for juvenile D. rerio were 150 μg/L and 400 μg/L.


Best practice in diagnostic immunohistochemistry: prostate carcinoma and its mimics in needle core biopsies.
The unrelenting challenge encountered when differentiating limited-volume prostate carcinoma and sometimes subtle variants from its many morphologic mimics has increased the use of ancillary immunohistochemistry in routine prostate needle biopsies. The availability of prostate cancer-associated and basal cell-associated markers has been an invaluable addition to diagnostic surgical pathology. To review commonly used immunohistochemical stains, including innovative combinations, for confirmation or differential diagnosis of prostate carcinoma, and to propose appropriately constructed panels using morphologic patterns in prostate needle biopsies. These best practices are based on our experience with routine and consultative case sign-outs and on a review of the published English-language literature from 1987 through 2008. Basal cell-associated markers p63, high-molecular-weight cytokeratin 34 beta E12, cytokeratin 5/6 or a cocktail containing p63 and high-molecular-weight cytokeratin 34 beta E12 or cytokeratin 5/6 and prostate carcinoma-specific marker alpha-methylacyl coenzyme A (coA) racemase alone or in combination are useful adjuncts in confirming prostatic carcinoma that either lacks diagnostic, qualitative or quantitative features or that has an unusual morphologic pattern (eg, atrophic, pseudohyperplastic) or is in the setting of prior treatment. The combination of alpha-methylacyl coA racemase positivity with negative staining for basal cell-associated markers supports a malignant diagnosis in the appropriate morphologic context. Dual chromogen basal cell- associated markers (p63 [nuclear] and high-molecular-weight cytokeratin 34 beta E12/cytokeratin 5/6 [cytoplasmic]) and alpha-methylacyl coA racemase in an antibody cocktail provide greater sensitivity for the basal cell layer, easing evaluation and minimizing loss of representation of the focal area interest because the staining is performed on one slide. In the posttreatment setting, pancytokeratin facilitates detection of subtle-treated cancer cells. Prostate-specific antigen and prostatic acid phosphatase markers are helpful in excluding secondary malignancies involving the prostate, such as urothelial carcinoma, and occasionally in excluding nonprostatic benign mimickers, such as nephrogenic adenoma, mesonephric gland hyperplasia, and Cowper glands. There is no role for ordering immunohistochemistry prospectively in all cases of prostatic needle biopsies.


Synthesis and characterization of pH-sensitive, biotinylated MRI contrast agents and their conjugates with avidin.
Responsive or smart contrast agents (SCAs) provide new opportunities in magnetic resonance imaging (MRI) to examine a number of physiological and pathological events. However, their application in vivo remains challenging. Therefore, much research is focused on the optimization of their properties, to enable their use in additional imaging modalities, pre-targeted delivery, or to increase the local concentration of the agent. The key feature in the SCA synthetic modification is the retention of their physicochemical properties related to the specific MR response. Here, we report the preparation and characterization of pH sensitive SCAs appended with a phosphonate pendant arm and either an aliphatic (GdL(1)) or aromatic linker (GdL(2)). The longitudinal relaxivity of GdL(1) and GdL(2) increases by 146% and 31%, respectively, while the pH decreases from 9 to 5. These two SCAs were converted to the biotinylated systems GdL(3) and GdL(4) and their interaction with avidin was investigated. The binding affinity with avidin was assessed with a fluorescence displacement assay and with MRI phantom experiments in a 3T MRI scanner. The fluorometric assay and MRI E-titrations revealed a 3 : 1 binding mode of GdL(3-4) to avidin with the binding affinity as high as that of the parent avidin-biotin complex. The high binding affinity was confirmed with MRI by a competitive assay. The avidin-GdL(3-4) complexes thus obtained exhibit changes in both r(1) and r(2) that are pH dependent. The results reveal a new pathway for the modification and improvement of SCAs to make them more suitable for in vivo application.


Towards complete cofactor arrangement in the 3.0 A resolution structure of photosystem II.
Oxygenic photosynthesis in plants, algae and cyanobacteria is initiated at photosystem II, a homodimeric multisubunit protein-cofactor complex embedded in the thylakoid membrane. Photosystem II captures sunlight and powers the unique photo-induced oxidation of water to atmospheric oxygen. Crystallographic investigations of cyanobacterial photosystem II have provided several medium-resolution structures (3.8 to 3.2 A) that explain the general arrangement of the protein matrix and cofactors, but do not give a full picture of the complex. Here we describe the most complete cyanobacterial photosystem II structure obtained so far, showing locations of and interactions between 20 protein subunits and 77 cofactors per monomer. Assignment of 11 beta-carotenes yields insights into electron and energy transfer and photo-protection mechanisms in the reaction centre and antenna subunits. The high number of 14 integrally bound lipids reflects the structural and functional importance of these molecules for flexibility within and assembly of photosystem II. A lipophilic pathway is proposed for the diffusion of secondary plastoquinone that transfers redox equivalents from photosystem II to the photosynthetic chain. The structure provides information about the Mn4Ca cluster, where oxidation of water takes place. Our study uncovers near-atomic details necessary to understand the processes that convert light to chemical energy.


Janus scorpionates: supramolecular tectons for the directed assembly of hard-soft alkali metallopolymer chains.
A new scorpionate ligand [HB(mtda)3-] containing mercaptothiadiazolyl (mtda) heterocyclic rings with both hard nitrogen donors and soft sulfur donors has been prepared. This new ligand, the Janus scorpionate, is a hybrid of a tris(pyrazolyl)borate and a tris(mercaptoimidazolyl)borate. The differential hard/soft character of the dissimilar donor groups in this bridging ligand was exploited for the controlled solid-state organization of homometallic and heterometallic alkali metal coordination polymers. Remarkably, in the case of sodium, coordination polymers with both acentric (with NaS3N3H kernels) and centric (with alternating NaN6 and NaS6H2 kernels) chains are found in the same crystal (where the centricity is defined by the relative orientations of the B-H bonds of the ligands along the lattice). For the homometallic potassium congener, the larger cation size, compared to sodium, induced significant distortions and favored a polar arrangement of ligands in the resulting coordination polymer chain. An examination of the solid-state structure of the mixed alkali metal salt system revealed that synergistic binding of smaller sodium cations to the nitrogen portion and of the larger potassium cations to the sulfur portion of the ligand minimizes the ligand distortions relative to the homometallic coordination polymer counterparts, a design feature of the ligand that likely assists in thermodynamically driving the self-assembly of the heterometallic chains. The effect of alkali metal complexation on the solution properties of the ligand was studied by comparing NMR chemical shifts, B-H stretching frequencies, and electrochemical properties with those of the noncoordinating tetrabutylammonium salt of the scorpionate. The similarity of these data regardless of cation indicates that the salts are likely dissociated in solution rather than maintaining their solid-state polymeric structures. This data is augmented by the ESI(+/-) mass spectral data for a series of mixed alkali metal tris(mercaptothiadiazolyl)borates that also indicate that dissociation occurs in solution.


Comparison of blood values and health status of Floreana Mockingbirds (Mimus trifasciatus) on the islands of Champion and Gardner-by-Floreana, Galápagos Islands.
The Floreana Mockingbird (Mimus trifasciatus) is one of the rarest bird species in the world, with an estimated 550 individuals remaining on two rocky islets off the coast of Floreana, Galápagos, Ecuador, from which the main population was extirpated more than 100 yr ago. Because they have been listed in critical danger of extinction, a plan to reintroduce this species to Floreana has been initiated. Determining the health status of the source mockingbird populations is a top priority within the reintroduction plan. We report the health status, over the course of 4 yr, of 75 Floreana Mockingbirds on Champion Island and 160 Floreana Mockingbirds on Gardner-by-Floreana, based on physical examinations, hematology, hemolysis-hemagglutination assay, exposure to selected infectious disease agents, and ecto- and endoparasite counts. Birds on Gardner-by-Floreana had higher body condition index scores, packed cell volumes, total solids, and lymphocyte counts. Additionally, Gardner-by-Floreana birds had lower heterophil counts, eosinophil counts, and heterophil:lymphocyte ratios. No Chlamydophila psittaci DNA or antibodies to paramyxovirus-I, adenovirus-II, or Mycoplasma gallisepticum were found in any of the mockingbirds tested. Ectoparasites were present on birds from both islands, although species varied between islands. A coccidian species was found in eight of the 45 fecal samples from birds on Gardner-by-Floreana, but none of 33 birds examined from Champion. Birds on Gardner-by-Floreana were classified as healthier than those on Champion based on clinical and laboratory findings. These health data will be analyzed in conjunction with genetics, population structure, and disease presence on Floreana for developing recommendations for the Floreana Mockingbird reintroduction plan.


Evaluation of matrix-assisted laser desorption/ionization-time of flight mass spectrometry proteomic profiling: identification of alpha 2-HS glycoprotein B-chain as a biomarker of diet.
Biomarkers have the potential to impact a wide range of public health concerns, including early detection of diseases, drug discovery, and improved accuracy of monitoring effects of interventions. Given new technological developments, broad-based screening approaches will likely advance biomarker discovery at an accelerated pace. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) allows for the elucidation of individual protein masses from a complex mixture with high throughput. We have developed a method for identifying serum biomarkers using MALDI-TOF and statistical analysis. However, before applying this approach to screening of complex diseases, we evaluated the approach in a controlled dietary intervention study. In this study, MALDI-TOF spectra were generated using samples from a randomized controlled trial. During separate feeding periods, 38 participants ate a basal diet devoid of fruits and vegetables and a basal diet supplemented with cruciferous (broccoli) family vegetables. Serum samples were obtained at the end of each 7-day feeding period and treated to remove large, abundant proteins. MALDI-TOF spectra were analyzed using peak picking algorithms and logistic regression models. Our bioinformatics methods identified two significant peaks at m/z values of 2740 and 1847 that could classify participants based on diet (basal vs. cruciferous) with 76% accuracy. The 2740 m/z peak was identified as the B-chain of alpha 2-HS glycoprotein, a serum protein previously found to vary with diet and be involved in insulin resistance and immune function.


Discordant transmission of bacteria and viruses from mothers to babies at birth.
The earliest microbial colonizers of the human gut can have life-long consequences for their hosts. Precisely how the neonatal gut bacterial microbiome and virome are initially populated is not well understood. To better understand how the maternal gut microbiome influences acquisition of the infant gut microbiome, we studied the early life bacterial microbiomes and viromes of 28 infant twin pairs and their mothers. Infant bacterial and viral communities more closely resemble those of their related co-twin than unrelated infants. We found that 63% of an infant's bacterial microbiome can be traced to their mother's gut microbiota. In contrast, only 15% of their viral communities are acquired from their mother. Delivery route did not determine how much of the bacterial microbiome or virome was shared from mother to infant. However, bacteria-bacteriophage interactions were altered by delivery route. The maternal gut microbiome significantly influences infant gut microbiome acquisition. Vertical transmission of the bacterial microbiome is substantially higher compared to vertical transmission of the virome. However, the degree of similarity between the maternal and infant gut bacterial microbiome and virome did not vary by delivery route. The greater similarity of the bacterial microbiome and virome between twin pairs than unrelated twins may reflect a shared environmental exposure. Thus, differences of the inter-generation transmissibility at birth between the major kingdoms of microbes indicate that the foundation of these microbial communities are shaped by different rules. Video Abstract.


Preformulation investigation and challenges; salt formation, salt disproportionation and hepatic recirculation.
A compound, which is a selective peroxisome proliferator activated receptor (PPAR) agonist, was investigated. The aim of the presented studies was to evaluate the potential of the further development of the compound. Fundamental physicochemical properties and stability of the compound were characterized in solution by liquid chromatography and NMR and in solid-state by various techniques. The drug itself is a lipophilic acid with tendency to form aggregates in solution. The neutral form was only obtained in amorphous form with a glass-transition temperature of approximately 0°C. The intrinsic solubility at room temperature was determined to 0.03mg/mL. Chemical stability studies of the compound in aqueous solutions showed good stability for at least two weeks at room temperature, except at pH1, where a slight degradation was already observed after one day. The chemical stability in the amorphous solid-state was investigated during a period of three months. At 25°C/60% relative humidity (RH) and 40°C/75% RH no significant degradation was observed. At 80°C, however, some degradation was observed after four weeks and approximately 3% after three months. In an accelerated photostability study, degradation of approximately 4% was observed. Attempts to identify a crystalline form of the neutral compound were unsuccessful, however, salt formation with tert-butylamine, resulted in crystalline material. Results from stability tests of the presented crystalline salt form indicated improved chemical stability at conditions whereas the amorphous neutral form degraded. However, the salt form of the drug dissociated under certain conditions. The drug was administered both per oral and intravenously, as amorphous nanoparticles, to conscious dogs. Plasma profiles showed curves with secondary absorption peaks, indicating hepatic recirculation following both administration routes. A similar behavior was observed in rats after oral administration of a pH-adjusted solution. The observed double peaks in plasma exposure and the dissociation tendency of the salt form, were properties that contributed to make further development of the candidate drug challenging. Options for development of solid dosage forms of both amorphous and crystalline material of the compound are discussed.


Surgical treatment of anterior urethral stricture diseases: brief overview.
We performed an up-to-date review of the surgical techniques suggested for the treatment of anterior urethral strictures. References for this review were identified by searching PubMed and MEDLINE using the search terms "urethral stricture" or "urethroplasty" from 1995 to 2006. Descriptive statistics of the articles were provided. Meta-analyses or other multivariate designs were not employed. Out of 327 articles, 50 (15%) were determined to be germane to this review. Eight abstracts were referenced as the authors of this review attended the meetings where the abstract results were presented, thus it was possible to collect additional information on such abstracts. Urethrotomy continues to be the most commonly used technique, but it does have a high failure rate and many patients progress to surgical repair. Buccal mucosa has become the most popular substitute material in urethroplasty; however, the skin appears to have a longer follow-up. Free grafts have been making a comeback, with fewer surgeons using genital flaps. Short bulbar strictures are amenable using primary anastomosis, with a high success rate. Longer strictures are repaired using ventral or dorsal graft urethroplasty, with the same success rate. New tools such as fibrin glue or engineered material will become a standard in future treatment. In reconstructive urethral surgery, the superiority of one approach over another is not yet clearly defined. The surgeon must be competent in the use of various techniques to deal with any condition of the urethra presented at the time of surgery.


Organized outpatient care: stroke prevention clinic referrals are associated with reduced mortality after transient ischemic attack and ischemic stroke.
Organized inpatient stroke care decreases mortality and morbidity irrespective of patient age, stroke severity, or stroke subtype. Limited information is available on whether organized outpatient care models such as stroke prevention clinics (SPC) improve outcomes after a transient ischemic attack or ischemic stroke. We compared 1-year mortality and stroke readmission in patients with transient ischemic attack or ischemic stroke referred versus not referred to an SPC. This was a retrospective cohort study including 16,468 consecutive patients with ischemic stroke or transient ischemic attack who were seen in the emergency department or admitted to a hospital between July 1, 2003 and March 31, 2008 at registry stroke centers (n=12) in the province of Ontario. Cox proportional hazards models and propensity score-matched analyses were used to evaluate 1-year mortality and readmission. One-year mortality rates were lower in those referred to SPCs compared with those not referred, even after adjustment for age, sex, ethnic origin, income, comorbid conditions, stroke symptoms and severity, receipt of thrombolysis, stroke unit care, discharge destination, and functional status at discharge (adjusted hazard ratio [HR], 0.67; 95% CI, 0.60-0.75). Survival analysis after propensity matching showed a 26% reduction in 1-year mortality (HR, 0.74; 95% CI, 0.65-0.84). There were no significant differences in 1-year readmission rates in those referred versus not referred to SPCs. Referral to an SPC is associated with a one-quarter reduction in mortality after ischemic stroke or transient ischemic attack. This supports the argument that outpatient stroke units may prove as effective as their inpatient counterparts.


Suppression of adipocyte differentiation by low-intensity pulsed ultrasound via inhibition of insulin signaling and promotion of CCN family protein 2.
Adipocyte differentiation is regulated by several transcription factors such as the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor-γ (PPARγ). Here, we demonstrate that low-intensity pulsed ultrasound (LIPUS) suppressed differentiation into mature adipocytes via multiple signaling pathways. When C3H10T1/2, a mesenchymal stem cell line, was treated with LIPUS (3.0 MHz, 60 mW/cm2 ) for 20 minutes once a day for 4 days during adipogenesis, and both the number of lipid droplets and the gene expression of PPARγ and C/EBPα were significantly decreased. Furthermore, LIPUS treatment decreased the phosphorylation of the insulin receptor and also that of Akt and ERK1/2, which are located downstream of this receptor. Next, we showed that LIPUS suppressed the gene expression of angiotensinogen (AGT), which is an adipokine produced by mature adipocytes, as well as that of angiotensin-converting enzyme 1 (ACE1) and angiotensin receptor type 1 (AT1 R) during adipogenesis of pre-adipogenic 3T3-L1 cells. Next, the translocation of Yes-associated protein (YAP) into the nucleus of 3T3-L1 cells was promoted by LIPUS, leading to upregulation of CCN family protein 2 (CCN2), a cellular communication network factor. Moreover, forced expression of CCN2 in 3T3-L1 cells decreased PPARγ gene expression, but it did not increase alkaline phosphatase and osterix gene expression. Finally, gene silencing of CCN2 in C3H10T1/2 cells diminished the effect of LIPUS on the gene expression of PPARγ and C/EBPα. These findings suggest that LIPUS suppressed adipogenesis through inhibition of insulin signaling and decreased PPARγ expression via increased CCN2 production, resulting in a possible decrease of mature adipocytes.


Natriuretic peptide-guided management in heart failure.
Heart failure is a clinical syndrome that manifests from various cardiac and noncardiac abnormalities. Accordingly, rapid and readily accessible methods for diagnosis and risk stratification are invaluable for providing clinical care, deciding allocation of scare resources, and designing selection criteria for clinical trials. Natriuretic peptides represent one of the most important diagnostic and prognostic tools available for the care of heart failure patients. Natriuretic peptide testing has the distinct advantage of objectivity, reproducibility, and widespread availability.The concept of tailoring heart failure management to achieve a target value of natriuretic peptides has been tested in various clinical trials and may be considered as an effective method for longitudinal biomonitoring and guiding escalation of heart failure therapies with overall favorable results.Although heart failure trials support efficacy and safety of natriuretic peptide-guided therapy as compared with usual care, the relationship between natriuretic peptide trajectory and clinical benefit has not been uniform across the trials, and certain subgroups have not shown robust benefit. Furthermore, the precise natriuretic peptide value ranges and time intervals of testing are still under investigation. If natriuretic peptides fail to decrease following intensification of therapy, further work is needed to clarify the optimal pharmacologic approach. Despite decreasing natriuretic peptide levels, some patients may present with other high-risk features (e.g. elevated troponin). A multimarker panel investigating multiple pathological processes will likely be an optimal alternative, but this will require prospective validation.Future research will be needed to clarify the type and magnitude of the target natriuretic peptide therapeutic response, as well as the duration of natriuretic peptide-guided therapy in heart failure patients.


Left ventricular end diastolic pressure and contrast-induced acute kidney injury in patients with acute coronary syndrome undergoing percutaneous coronary intervention.
Left ventricular end-diastolic pressure (LVEDP) reflects ventricular performance and volume status. We sought to analyze the relationship between LVEDP and the incidence of contrast-induced acute kidney injury (AKI) in patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI). Between January 2006 and December 2008, a total of 254 patients presenting with an acute coronary syndrome had the LVEDP assessed prior to the intervention. Contrast-induced AKI was defined as an increase in serum creatinine ≥25% from baseline or an absolute increase of >0.5 mg/dL from baseline. Patients were divided into three groups according to baseline LVEDP (<12 mmHg, 12-20 mmHg and > 20 mmHg). Baseline clinical, angiographic and procedural characteristics, as well as serum creatinine and estimated glomerular filtration rate (eGFR) at baseline and at 24, 48 and 72 h were retrospectively collected. Baseline clinical characteristics were similar in all three groups with the exception of lower left ventricular ejection fraction in patients with elevated LVEDP (p = 0.02). Among the 17 patients with an LVEDP < 12 mmHg, only one (5.9%) developed AKI; among the 82 patients with an LVEDP = 12-20 mmHg, 15 (18.3%) developed AKI; and among the 155 patients with an LVEDP > 20 mmHg, only 22 developed AKI (13.6%). There was no correlation between LVEDP and the change in GFR at 24 h and at 48 h. Further comparison between the group of patients that developed contrast induced AKI versus those that did not, showed a that there was a significantly lower baseline left ventricular ejection fraction (LVEF) among patients that developed contrast induced AKI compared to those that did not (41.4% vs. 48.3%, p = 0.045, respectively). In patients with acute coronary syndrome undergoing PCI, baseline LVEDP was not associated with contrast-induced AKI. However patients with reduced ejection fraction seemed to be at a higher risk of developing AKI. More studies are needed to assess the relationship between LVEDP, LVEF and the risk of developing contrast induced AKI.


Best practices recommendations in the application of immunohistochemistry in the prostate: report from the International Society of Urologic Pathology consensus conference.
The following are the International Society of Urological Pathology (ISUP) recommendations for the use of immunohistochemistry (IHC) in prostate specimens. Either high-molecular weight cytokeratin (34βE12 or CK5/6 or others) or p63 or a combination of the 2 with AMACR either in a double or triple cocktail is recommended for the workup of small foci of atypical glands suspicious for adenocarcinoma of the prostate (PCa). ERG is optional as it is present in only 40% to 50% of prostate cancers and also positive in high-grade prostatic intraepithelial neoplasia. In the setting of obvious carcinoma or benign glands, there is no justification to do basal cell stains and AMACR. If there is a Gleason score of 3+4=7 or a higher-grade cancer on at least 1 part, the workup of other parts with an atypical focus suspicious for Gleason score 3+3=6 cancer is not recommended. In the setting of Gleason score 4+3 or 4+4=8 cancer on at least 1 part, the extent of high-grade cancer could affect clinical treatment such that workup of other atypical possible high-grade cancer foci is justified. In the setting of Gleason score 4+3 or higher-grade cancer on at least 1 part, given that intraductal carcinoma in the vast majority of cases is considered extension of high-grade cancer into prostatic ducts and acini, it is not recommended in the setting of definitive invasive high-grade cancer that workup of additional cribriform lesions be pursued. In the setting of Gleason score 3+3 on at least 1 part, the number of positive cores and/or their location could possibly affect subsequent therapy in terms of suitability for active surveillance or focal therapy, such that unless one knows with certainty that it would not affect therapy, it is justified to perform an IHC workup of additional atypical foci. In the differential diagnosis of high-grade PCa versus urothelial carcinoma (UC), the primary option is to use prostate-specific antigen (PSA) as a first test to identify PCa and GATA3 to identify UC. If GATA3 is not available, then HMWCK and p63 can be used. If the tumor is PSA positive with intense staining and HMWCK and p63 negative, the findings are diagnostic of PCa. If the tumor is equivocal/weak/negative for PSA and negative/focal for p63 and HMWCK, then one needs to perform staining for P501S, NKX3.1, and GATA3. Some experts also include PAP in this second round of staining. If the tumor is negative for PSA and diffusely strongly positive for p63 and HMWCK, the findings are diagnostic of UC. If the tumor is negative for PSA and moderately to strongly positive for GATA3, it is diagnostic of UC. Laboratories should be encouraged to use GATA3 for UC and add P501S and NKX3.1 as prostate markers in addition to PSA, p63, and HMWCK. If GATA3, p501S, and NKX3.1 are not available in equivocal cases, the case should be sent out for consultation to laboratories with these antibodies. The article also covers the use of IHC in: (1) high-grade PCa versus bladder adenocarcinoma; (2) prostatic small cell carcinoma versus high-grade PCa; (3) metastatic carcinoma of unknown primary: rule out PCa; (4) nonspecific granulomatous prostatitis/xanthoma versus high-grade PCa; (5) adult prostate sarcoma versus sarcomatoid PCa; (6) colorectal adenocarcinoma versus high-grade PCa; and (7) prognostic IHC markers.


Fundamental limits of target detection performance in passive polarization imaging.
We quantitatively determine the target detection performance of different passive polarization imaging architectures perturbed by signal-independent detection noise or signal-dependent Poisson shot noise. We compare the fully adaptive polarimetric imager and the best channel of a static polarimetric imager, and in each case, we compare the use of a polarizer and a polarizing beam splitter as the polarization analyzing device. For all these configurations, we derive a closed-form expression of the target/background separability and quantify the performance gain brought by polarization imaging compared to standard intensity imaging. We show in particular that all the considered polarimetric imaging configurations but one require a minimum value of the polarimetric contrast in order to outperform intensity imaging. The only configuration that always performs better than intensity imaging uses a polarizing beam splitter in the presence of background shot noise. These results are useful in evaluating the fundamental limits of the gain brought by polarization imaging and determining, in practice, which type of imaging architecture is preferable for a given application.


Quantitative analysis of bayberry juice acidity based on visible and near-infrared spectroscopy.
Visible and near-infrared (Vis/NIR) reflectance spectroscopy has been investigated for its ability to nondestructively detect acidity in bayberry juice. What we believe to be a new, better mathematic model is put forward, which we have named principal component analysis-stepwise regression analysis-backpropagation neural network (PCA-SRA-BPNN), to build a correlation between the spectral reflectivity data and the acidity of bayberry juice. In this model, the optimum network parameters, such as the number of input nodes, hidden nodes, learning rate, and momentum, are chosen by the value of root-mean-square (rms) error. The results show that its prediction statistical parameters are correlation coefficient (r) of 0.9451 and root-mean-square error of prediction (RMSEP) of 0.1168. Partial least-squares (PLS) regression is also established to compare with this model. Before doing this, the influences of various spectral pretreatments (standard normal variate, multiplicative scatter correction, S. Golay first derivative, and wavelet package transform) are compared. The PLS approach with wavelet package transform preprocessing spectra is found to provide the best results, and its prediction statistical parameters are correlation coefficient (r) of 0.9061 and RMSEP of 0.1564. Hence, these two models are both desirable to analyze the data from Vis/NIR spectroscopy and to solve the problem of the acidity prediction of bayberry juice. This supplies basal research to ultimately realize the online measurements of the juice's internal quality through this Vis/NIR spectroscopy technique.


Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement.
The cytochrome P450 (CYP) 2C19 isoenzyme plays an important role in clopidogrel metabolization. A recently explored CYP2C19*17 allelic variant has been linked to increased transcriptional activity, resulting in extensive metabolization of CYP2C19 substrates, which may lead to an enhanced platelet response to clopidogrel treatment. The aim of this study was to assess the impact of CYP2C19*17 on ADP-induced platelet aggregation, the risk of bleeding, and stent thrombosis in clopidogrel-treated patients undergoing percutaneous coronary intervention. The study population included 1524 patients undergoing percutaneous coronary intervention after pretreatment with 600 mg clopidogrel. Genotypes were determined with a TaqMan assay. ADP-induced platelet aggregation was assessed on a Multiplate analyzer. The primary clinical safety end point was the 30-day incidence of bleeding defined according to Thrombolysis in Myocardial Infarction criteria, and the primary clinical efficacy end point was the 30-day incidence of stent thrombosis. For both heterozygous (*wt/*17; n=546) and homozygous (*17/*17; n=76) allele carriers, significantly lower ADP-induced platelet aggregation values were found compared with wild-type homozygotes (*wt/*wt; n=902; P=0.039 and P=0.008, respectively). CYP2C19*17 allele carriage was significantly associated with an increased risk of bleeding; the highest risk was observed for CYP2C19*17 homozygous patients (P=0.01, chi(2) test for trend). Multivariate analysis confirmed the independent association of CYP2C19*17 allele carriage with platelet aggregation values (P<0.001) and the occurrence of bleeding (P=0.006). No significant influence of CYP2C19*17 on the occurrence of stent thrombosis was found (P=0.79). CYP2C19*17 carrier status is significantly associated with enhanced response to clopidogrel and an increased risk of bleeding.


Blind image deconvolution using the zero-lag slice of higher-order statistics.
A novel algorithm for blind image deconvolution using the zero-lag slice (ZLS) of higher-order statistics only is presented. This method first estimates the point-spread function (PSF) using the ZLS of its third-order moment (TOM) and then uses it with one of the known classical image deconvolution methods. The proposed method has simple computations for PSF estimation because it solves a nonlinear problem by using an iterative method with fast convergence. In each iteration, one need only calculate the ZLS of the TOM and estimate the PSF using simple two-dimensional operations. Furthermore, the method presented achieves good results, since the ZLS estimate obtained from the degraded image exhibits high reliability. The good performance of the proposed algorithm is demonstrated by applying it to synthetic and real data sets.


The incidence of fatal breast cancer measures the increased effectiveness of therapy in women participating in mammography screening.
Women and their health care providers need a reliable answer to this important question: If a woman chooses to participate in regular mammography screening, then how much will this choice improve her chances of avoiding a death from breast cancer compared with women who choose not to participate? To answer this question, we used comprehensive registries for population, screening history, breast cancer incidence, and disease-specific death data in a defined population in Dalarna County, Sweden. The annual incidence of breast cancer was calculated along with the annual incidence of breast cancers that were fatal within 10 and within 11 to 20 years of diagnosis among women aged 40 to 69 years who either did or did not participate in mammography screening during a 39-year period (1977-2015). For an additional comparison, corresponding data are presented from 19 years of the prescreening period (1958-1976). All patients received stage-specific therapy according to the latest national guidelines, irrespective of the mode of detection. The benefit for women who chose to participate in an organized breast cancer screening program was a 60% lower risk of dying from breast cancer within 10 years after diagnosis (relative risk, 0.40; 95% confidence interval, 0.34-0.48) and a 47% lower risk of dying from breast cancer within 20 years after diagnosis (relative risk, 0.53; 95% confidence interval, 0.44-0.63) compared with the corresponding risks for nonparticipants. Although all patients with breast cancer stand to benefit from advances in breast cancer therapy, the current results demonstrate that women who have participated in mammography screening obtain a significantly greater benefit from the therapy available at the time of diagnosis than do those who have not participated.


Genetic dissection defines the roles of elsinochrome Phytotoxin for fungal pathogenesis and conidiation of the citrus pathogen Elsinoë fawcettii.
Elsinochrome pigments produced by many phytopathogenic Elsinoë spp. are nonhost-selective toxins which react with oxygen molecules after light activation to produce highly toxic reactive oxygen species. The structures and chemical properties of four derivatives are well known. However, the biological roles of elsinochromes in fungal pathogenesis are poorly understood. Many isolates of Elsinoë fawcettii causing citrus scab are able to produce elsinochromes under axenic conditions. In this article, we report the cloning, expression, and functional characterization of the polyketide synthase-encoding gene, EfPKS1, which we show is required for the production of elsinochromes and fungal pathogenesis. Targeted disruption of EfPKS1 in E.fawcettii completely abrogated elsinochrome production, drastically reduced conidiation, and significantly decreased lesion formation on rough lemon leaves. All mutant phenotypes were restored to the wild type in fungal strains expressing a functional copy of EfPKS1. Accumulation of the EfPKS1 transcript and elsinochromes by a wild-type strain appears to be coordinately regulated by light, nutrients, and pH. The results indicate that the product of EfPKS1 is involved in the biosynthesis of elsinochromes via a fungal polyketide pathway, and that elsinochromes play an important role in fungal pathogenesis.


Structural analysis of Musashi-RNA complex on the basis of long-range structural information.
Musashi protein is supposed to be involved in the regulation of differentiation of neural stem cells. Musashi binds to 3' untranslated region of target mRNA and represses the translation of mRNA. Musashi has two tandem RNA-binding domains (RBDs), RBD1 and RBD2. Both RBDs cooperatively bind to the target mRNA. Here, we determined the structure of RBD1-RBD2 in complex with target RNA. First, the structures of two RBDs in the complex were determined on the basis of short-range distance restrains derived from NOEs. However, the relative position of two RBDs was not determined due to the lack of long-range distance restraints across two RBDs. In order to overcome the situation, we introduced the paramagnetic center into Musashi by attaching MTSL carrying the NO radical. The long-range distance restraints (ca. 20-40 A) between two RBDs were derived from paramagnetic relaxation enhancement (PRE) caused by the paramagnetic center. The relative position of two RBDs was successfully determined on the basis of these long-range distance restraints. The change in the relative position of two RBDs on binding to the target RNA was also detected by PRE. The determined structure of RBD1-RBD2 in the complex has suggested how Musashi recognizes its target mRNA.


Engineering DNA nanoparticles as immunomodulatory reagents that activate regulatory T cells.
Nanoparticles containing DNA complexed with the cationic polymer polyethylenimine are efficient vehicles to transduce DNA into cells and organisms. DNA/polyethylenimine nanoparticles (DNPs) also elicit rapid and systemic release of proinflammatory cytokines that promote antitumor immunity. In this study, we report that DNPs possess previously unrecognized immunomodulatory attributes due to rapid upregulation of IDO enzyme activity in lymphoid tissues of mice. IDO induction in response to DNP treatment caused dendritic cells and regulatory T cells (Tregs) to acquire potent regulatory phenotypes. As expected, DNP treatment stimulated rapid increase in serum levels of IFN type I (IFN-αβ) and II (IFN-γ), which are both potent IDO inducers. IDO-mediated Treg activation was dependent on IFN type I receptor signaling, whereas IFN-γ receptor signaling was not essential for this response. Moreover, systemic IFN-γ release was caused by TLR9-dependent activation of NK cells, whereas TLR9 signaling was not required for IFN-αβ release. Accordingly, DNPs lacking immunostimulatory TLR9 ligands in DNA stimulated IFN-αβ production, induced IDO, and promoted regulatory outcomes, but did not stimulate potentially toxic, systemic release of IFN-γ. DNP treatment to induce IDO and activate Tregs blocked Ag-specific T cell responses elicited in vivo following immunization and suppressed joint pathology in a model of immune-mediated arthritis. Thus, DNPs lacking TLR9 ligands may be safe and effective reagents to protect healthy tissues from immune-mediated destruction in clinical hyperimmune syndromes.


MEK-ERK signaling is a therapeutic target in metastatic castration resistant prostate cancer.
Metastatic castration resistant prostate cancer (mCRPC) is incurable and progression after drugs that target the androgen receptor-signaling axis is inevitable. Thus, there is an urgent need to develop more effective treatments beyond hormonal manipulation. We sought to identify activated kinases in mCRPC as therapeutic targets for existing, approved agents, with the goal of identifying candidate drugs for rapid translation into proof of concept Phase II trials in mCRPC. To identify evidence of activation of druggable kinases in these patients, we compared mRNA expression from metastatic biopsies of patients with mCRPC (n = 101) to mRNA expression in localized prostate from TCGA and used this analysis to infer differential kinase activity. In addition, we assessed the differential phosphorylation levels for key MAPK pathway kinases between mCRPC and localized prostate cancers. Transcriptomic profiling of 101 patients with mCRPC as compared to patients with localized prostate cancer identified evidence of hyperactive ERK1, and whole genome sequencing revealed frequent amplifications of members of the MAPK pathway in 32% of this cohort. Next, we confirmed elevated levels of phosphorylated ERK1/2 in castration resistant prostate cancer as compared to untreated primary prostate cancer. We observed that the presence of detectable phosphorylated ERK1/2 in the primary tumor is associated with biochemical failure after radical prostatectomy independent of clinicopathologic features. ERK1 is the immediate downstream target of MEK1/2, which is druggable with trametinib, an approved therapeutic for melanoma. Trametinib elicited a profound biochemical and clinical response in a patient who had failed multiple prior treatments for mCRPC. We conclude that pharmacologic targeting of the MEK/ERK pathway may be a viable treatment strategy for patients with refractory metastatic prostate cancer. An ongoing Phase II trial tests this hypothesis.


Trends in high-risk sexual behaviors among general population groups in China: a systematic review.
The objective of this review was to investigate whether Chinese population groups that do not belong to classical high risk groups show an increasing trend of engaging in high-risk sexual behaviors. We systematically searched the English and Chinese literature on sexual risk behaviors published between January 1980 and March 2012 in PubMed and the China National Knowledge Infrastructure (CNKI). We included observational studies that focused on population groups other than commercial sex workers (CSWs) and their clients, and men who have sex with men (MSM) and quantitatively reported one of the following indicators of recent high-risk sexual behavior: premarital sex, commercial sex, multiple sex partners, condom use or sexually transmitted infections (STIs). We used generalized linear mixed model to examine the time trend in engaging in high-risk sexual behaviors. We included 174 observational studies involving 932,931 participants: 55 studies reported on floating populations, 73 on college students and 46 on other groups (i.e. out-of-school youth, rural residents, and subjects from gynecological or obstetric clinics and premarital check-up centers). From the generalized linear mixed model, no significant trends in engaging in high-risk sexual behaviors were identified in the three population groups. Sexual risk behaviors among certain general population groups have not increased substantially. These groups are therefore unlikely to incite a STI/HIV epidemic among the general Chinese population. Because the studied population groups are not necessarily representative of the general population, the outcomes found may not reflect those of the general population.