[Health-related out-of-pocket expenses in older peruvian adults: analysis of the national household survey on living conditions and poverty 2017].
. To estimate out-of-pocket spending on health (GBS) and identify its associated factors in Peruvian older adults. Analytical cross-sectional study of the National Household Survey on Living Conditions and Poverty (ENAHO) 2017. Older adults were considered to be all individuals aged 60 and over and the GBS was considered the main study variable. Prevalence ratios (PR) and adjusted prevalence ratios (PRa) were estimated for each of the factors associated with GBS. GBS means were estimated using a generalized linear model with gamma distribution and log binding function. All confidence intervals (95%) of the estimators were calculated by bootstrapping with the normal-based method. . Eighteen 386 older adults were included, of which 56.5% reported GBS. The mean and median GBS is S/. 140.8 (USD 43.2) and S/. 34.5 (USD 10.6), respectively. Factors such as urban origin, a higher level of education, chronic diseases and higher per capita expenses increase the probability of GBS by up to 1.6 times. In those affiliated to the Integral Health Insurance (SIS), the GBS is reduced by 63.0 soles (USD 19.3) compared to those without any health insurance. . Six out of ten older Peruvian adults reported GBS to attend to their health needs. This generates an access inequity in terms of health services, mainly for socially-vulnerable groups. We suggest researching into the economic impact of health insurance and the preventive-promotional approach to chronic diseases, in order to reduce GBS and improve the efficiency of the Peruvian health system.


Cardiovascular issues in respiratory care.
The hemodynamic effects of ventilation are complex but can be grouped under four clinically relevant concepts. First, spontaneous ventilation is exercise, and critically ill patients may not withstand the increased work of breathing. Initiation of mechanical ventilatory support will improve oxygen delivery to the remainder of the body by decreasing oxygen consumption. To the extent that mixed venous oxygen also increases, Pao(2) will increase without any improvement in gas exchange. Similarly, weaning from mechanical ventilatory support is a cardiovascular stress test. Patients who fail to wean also manifest cardiovascular insufficiency during the failed weaning attempts. Improving cardiovascular reserve or supplementing support with inotropic therapy may allow patients to wean from mechanical ventilation. Second, changes in lung volume alter autonomic tone and pulmonary vascular resistance (PVR), and at high lung volumes compress the heart in the cardiac fossa. Hyperinflation increases PVR and pulmonary artery pressure, impeding right ventricular ejection. Decreases in lung volume induce alveolar collapse and hypoxia, stimulating an increased pulmonary vasomotor tone by the process of hypoxic pulmonary vasoconstriction. Recruitment maneuvers, positive end-expiratory pressure, and continuous positive airway pressure may reverse hypoxic pulmonary vasoconstriction and reduce pulmonary artery pressure. Third, spontaneous inspiration and spontaneous inspiratory efforts decrease intrathoracic pressure (ITP). Since diaphragmatic descent increases intra-abdominal pressure, these combined effects cause right atrial pressure inside the thorax to decrease but venous pressure in the abdomen to increase, markedly increasing the pressure gradient for systemic venous return. Furthermore, the greater the decrease in ITP, the greater the increase in left ventricular (LV) afterload for a constant arterial pressure. Mechanical ventilation, by abolishing the negative swings in ITP, will selectively decrease LV afterload, as long as the increases in lung volume and ITP are small. Finally, positive-pressure ventilation increases ITP. Since diaphragmatic descent increases intra-abdominal pressure, the decrease in the pressure gradient for venous return is less than would otherwise occur if the only change were an increase in right atrial pressure. However, in hypovolemic states, positive-pressure ventilation can induce profound decreases in venous return. Increases in ITP decrease LV afterload and will augment LV ejection. In patients with hypervolemic heart failure, this afterload reducing effect can result in improved LV ejection, increased cardiac output, and reduced myocardial oxygen demand.


mTOR inhibition and BMP signaling act synergistically to reduce muscle fibrosis and improve myofiber regeneration.
Muscle trauma is highly morbid due to intramuscular scarring, or fibrosis, and muscle atrophy. Studies have shown that bone morphogenetic proteins (BMPs) reduce muscle atrophy. However, increased BMP signaling at muscle injury sites causes heterotopic ossification, as seen in patients with fibrodysplasia ossificans progressiva (FOP), or patients with surgically placed BMP implants for bone healing. We use a genetic mouse model of hyperactive BMP signaling to show the development of intramuscular fibrosis surrounding areas of ectopic bone following muscle injury. Rapamycin, which we have previously shown to eliminate ectopic ossification in this model, also eliminates fibrosis without reducing osteogenic differentiation, suggesting clinical value for patients with FOP and with BMP implants. Finally, we use reporter mice to show that BMP signaling is positively associated with myofiber cross-sectional area. These findings underscore an approach in which 2 therapeutics (rapamycin and BMP ligand) can offset each other, leading to an improved outcome.


A visual analysis of gender bias in contemporary anatomy textbooks.
Empirical research has linked gender bias in medical education with negative attitudes and behaviors in healthcare providers. Yet it has been more than 20 years since research has considered the degree to which women and men are equally represented in anatomy textbooks. Furthermore, previous research has not explored beyond quantity of representation to also examine visual gender stereotypes and, in light of theoretical advancements in the area of intersectional research, the relationship between representations of gender and representations of ethnicity, body type, health, and age. This study aimed to determine the existence and representation of gender bias in the major anatomy textbooks used at Australian Medical Schools. A systematic visual content analysis was conducted on 6044 images in which sex/gender could be identified, sourced from 17 major anatomy textbooks published from 2008 to 2013. Further content analysis was performed on the 521 narrative images, which represent an unfolding story, found within the same textbooks. Results indicate that the representation of gender in images from anatomy textbooks remain predominantly male except within sex-specific sections. Further, other forms of bias were found to exist in: the visualization of stereotypical gendered emotions, roles and settings; the lack of ethnic, age, and body type diversity; and in the almost complete adherence to a sex/gender binary. Despite increased attention to gender issues in medicine, the visual representation of gender in medical curricula continues to be biased. The biased construction of gender in anatomy textbooks designed for medical education provides future healthcare providers with inadequate and unrealistic information about patients.


Wireless multi-level terahertz amplitude modulator using active metamaterial-based spatial light modulation.
The ever increasing demand for bandwidth in wireless communication systems will inevitably lead to the extension of operating frequencies toward the terahertz (THz) band known as the 'THz gap'. Towards closing this gap, we present a multi-level amplitude shift keying (ASK) terahertz wireless communication system using terahertz spatial light modulators (SLM) instead of traditional voltage mode modulation, achieving higher spectral efficiency for high speed communication. The fundamental principle behind this higher efficiency is the conversion of a noisy voltage domain signal to a noise-free binary spatial pattern for effective amplitude modulation of a free-space THz carrier wave. Spatial modulation is achieved using an an active metamaterial array embedded with pseudomorphic high-electron mobility (pHEMT) designed in a consumer-grade galium-arsenide (GaAs) integrated circuit process which enables electronic control of its THz transmissivity. Each array is assembled as individually controllable tiles for transmissive terahertz spatial modulation. Using the experimental data from our metamaterial based modulator, we show that a four-level ASK digital communication system has two orders of magnitude improvement in symbol error rate (SER) for a degradation of 20 dB in transmit signal-to-noise ratio (SNR) using spatial light modulation compared to voltage controlled modulation.


Insensitivity of Tree-Ring Growth to Temperature and Precipitation Sharpens the Puzzle of Enhanced Pre-Eruption NDVI on Mt. Etna (Italy).
On Mt. Etna (Italy), an enhanced Normalized Difference in Vegetation Index (NDVI) signature was detected in the summers of 2001 and 2002 along a distinct line where, in November 2002, a flank eruption subsequently occurred. These observations suggest that pre-eruptive volcanic activity may have enhanced photosynthesis along the future eruptive fissure. If a direct relation between NDVI and future volcanic eruptions could be established, it would provide a straightforward and low-cost method for early detection of upcoming eruptions. However, it is unclear if, or to what extent, the observed enhancement of NDVI can be attributed to volcanic activity prior to the subsequent eruption. We consequently aimed at determining whether an increase in ambient temperature or additional water availability owing to the rise of magma and degassing of water vapour prior to the eruption could have increased photosynthesis of Mt. Etna's trees. Using dendro-climatic analyses we quantified the sensitivity of tree ring widths to temperature and precipitation at high elevation stands on Mt. Etna. Our findings suggest that tree growth at high elevation on Mt. Etna is weakly influenced by climate, and that neither an increase in water availability nor an increase in temperature induced by pre-eruptive activity is a plausible mechanism for enhanced photosynthesis before the 2002/2003 flank eruption. Our findings thus imply that other, yet unknown, factors must be sought as causes of the pre-eruption enhancement of NDVI on Mt. Etna.


Measured luminance and visual appearance of multi-color persistent phosphors.
In the past decade, several persistent phosphors were intensively studied, such as CaAl(2)O(4):Eu,Nd (blue) and SrAl(2)O(4):Eu,Dy (green). Yellow-to-red emitting persistent phosphors have also been identified. All these phosphors are normally evaluated by measuring their afterglow as a function of time in photometric units. However, the eye sensitivity curve shifts from photopic vision to scotopic vision upon decreasing light intensity, with a corresponding decrease in red-sensitivity. Performance of red-emitting persistent phosphors thus cannot be described with usual photometry. An alternative description is presented, based on recent vision research in the intermediate (mesopic) region and using a unified system of photometry. It turns out that this effect seriously compromises the development of red-emitting persistent phosphors. This is illustrated on a number of commercially available persistent phosphors.


Ginkgo biloba exocarp extracts induces apoptosis in Lewis lung cancer cells involving MAPK signaling pathways.
A fruit of Ginkgo biloba L. is known as Ginkgo nuts. It is an edible traditional Chinese medicine, and could be used for the treatment of cancer thousands of years ago in China. The extracts prepared from the exocarp of Ginkgo biloba (Ginkgo biloba exocarp extracts, GBEE) has the effects of anti-cancer, immune promotion, anti-aging and etc. To study the effects of GBEE inducing apoptosis in Lewis lung cancer (LLC) cells and the role of Mitogen-activated protein kinase(MAPK) signaling pathways in it. The LLC solid tumor model was established in C57BL/6J mice. The tumor-bearing mice were randomly divided into 5 groups. A normal control group without tumor cells was established additionally. There were 10 mice in each group, and they were dosed 24h after inoculation. The GBEE (50, 100, 200mg/kg b.w.) groups were dosed by intragastric gavage (i.g.). The mice in positive control group were intraperitoneal (i.p.) injected with cyclophosphamide (CPA) at a dose of 20mg/kg (b.w.). The model control group and the normal control group were both given normal saline (NS) by i.g.. All the groups were dosed at a volume of 0.1mL/10g (b.w.), once a day for 18d. The day after the last administration, the transplanted tumors was stripped and weighed, and the inhibition rate was calculated. In vitro experiments, MTT method was applied to detect the effects of GBEE on LLC cells and primary cultured mouse lung cells. Annexin V-FITC/PI method was used to detect the apoptosis rate of LLC cells. Rhodamine 123 method was used to detect the Mitochondrial transmembrane potential (MTP). Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect the levels of Fas mRNA. Western Blot was used to detect the expression of Bax, Bcl-2, Cyt C, cleaved Caspase-3 and MAPK proteins in the corresponding parts of LLC cells. GBEE (50-200mg/kg) inhibited the growth of LLC transplanted tumors with a dose-effect relationship. GBEE (5-160µg/mL) inhibited the proliferation of LLC cells in vitro with the half maximal inhibitory concentration (IC50) value of 162.43µg/mL, while it had no significant inhibitory effects on the primary cultured mouse lung cells. After GBEE (10, 20 and 40µg/mL) acted on the LLC cells, the apoptosis rate was increased and the MTP was decreased. The ratio of Bax/Bcl-2 was increased in the cells. Meanwhile, it also promoted the translocation of Bax/Bcl-2 in mitochondrial membrane and the release of Cyt C from mitochondria to cytosol. In addition, it up-regulated the cleaved-Caspase-3 protein expression. The mRNA levels of Fas and the protein levels of Fas, FasL and p-p38 in the cells were both increased. The levels of p-ERK1/2 and p-JNK1/2 protein were down-regulated but the p38, ERK1/2 and JNK1/2 were not significantly changed. GBEE induces apoptosis in LLC cells via mitochondrial-mediated intrinsic pathway and death receptor-mediated extrinsic pathway, which may be closely relevant to the regulation of MAPK signaling pathways.


A multiphase system bone implant for regenerating the calvaria.
The regeneration of bone with a biodegradable, biocompatible carrier and osteo-regenerative proteins may be possible if the carrier has the appropriate architecture to support osteoconduction and prevent soft-tissue prolapse into ablated bone segments. Using radiomorphometry and histomorphometry, our group assessed individually and combined the components of a multiphase system bone implant (MSI) in rabbit cranial defects (critical-size defects: CSDs): two disks of biodegradable polymer (PLG) and demineralized bone matrix (DBM), a recognized osteo-regenerative material. We used 48 rabbits evenly divided between four treatment groups and two time periods. Six weeks after treatment, both DBM and PLG had significant positive effects on bone regeneration (based on a three-factor analysis of variance, p < 0.05). These effects were synergistic when the components were combined (MSI). Defects treated with DBM or PLG alone continued to regenerate bone through 12 weeks. By this time, bone within the defects treated with MSI appeared to be maturing and consolidating. We conclude that the concept of placing osteo-regenerative factors between two biodegradable disks for regenerating segments of calvaria is viable.


Small molecule ambient mass spectrometry imaging by infrared laser ablation metastable-induced chemical ionization.
Presented here is a novel ambient ion source termed infrared laser ablation metastable-induced chemical ionization (IR-LAMICI). IR-LAMICI integrates IR laser ablation and direct analysis in real time (DART)-type metastable-induced chemical ionization for open air mass spectrometry (MS) ionization. The ion generation in the IR-LAMICI source is a two step process. First, IR laser pulses impinge the sample surface ablating surface material. Second, a portion of ablated material reacts with the metastable reactive plume facilitating gas-phase chemical ionization of analyte molecules generating protonated or deprotonated species in positive and negative ion modes, respectively. The successful coupling of IR-laser ablation with metastable-induced chemical ionization resulted in an ambient plasma-based spatially resolved small molecule imaging platform for mass spectrometry (MS). The analytical capabilities of IR-LAMICI are explored by imaging pharmaceutical tablets, screening counterfeit drugs, and probing algal tissue surfaces for natural products. The resolution of a chemical image is determined by the crater size produced with each laser pulse but not by the size of the metastable gas jet. The detection limits for an active pharmaceutical ingredient (acetaminophen) using the IR-LAMICI source is calculated to be low picograms. Furthermore, three-dimensional computational fluid dynamic simulations showed improvements in the IR-LAMICI ion source are possible.


Antitumor effect of insulin-like growth factor-1 receptor inhibition in head and neck squamous cell carcinoma.
The insulin-like growth factor-1 receptor (IGF1R) has been implicated in therapeutic resistance in head and neck squamous cell carcinoma (HNSCC), and small molecule tyrosine kinase inhibitors (TKIs) of IGF1R activity may have anticancer activity. Therefore, the relationship between survival and IGF1R expression was assessed for oral cavity (OC) cancer, and the antitumor effects of two IGF1R-TKIs, OSI-906 and BMS-754807, were evaluated in HNSCC cell lines in vitro. Clinical outcome data and tissue microarray immunohistochemistry were used to generate IGF1R expression-specific survival curves. Immunoblot, alamarBlue proliferation assay, trypan blue exclusion viability test, clonogenic assay, flow cytometry, and reverse phase protein array (RPPA) were used to evaluate in vitro responses to IGF1R-TKIs. For patients with stage III/IV OCSCC, higher IGF1R expression was associated with poorer overall 5-year survival (P = 0.029). Both BMS-754807 and OSI-906 caused dose-dependent inhibition of IGF1R and Akt phosphorylation and inhibited proliferation; BMS-754807 was more potent than OSI-906. Both drugs reduced HNSCC cell viability; only OSI-906 was able to eliminate all viable cells at 10 μM. The two drugs similarly inhibited clonogenic cell survival. At 1 μM, only BMS-754807 caused a fourfold increase in the basal apoptotic rate. RPPA demonstrated broad effects of both drugs on canonical IGF1R signaling pathways and also inhibition of human epidermal growth factor receptor-3 (HER3), Src, paxillin, and ezrin phosphorylation. OSI-906 and BMS-754807 inhibit IGF1R activity in HNSCC cell lines with reduction in prosurvival and proliferative signaling and with concomitant antiproliferative and proapoptotic effects. Such antagonists may have utility as adjuvants to existing therapies for HNSCC. NA Laryngoscope, 130:1470-1478, 2020.


Development and usage of protein microarrays for the quantitative measurement of Panton-Valentine leukocidin.
Staphylococcus aureus is a human pathogen that can harbour several genes encoding exotoxins including leukocidins. A clinically most relevant factor is Panton-Valentine leukocidin (PVL) because of its association with chronic, recurrent or severe skin and soft tissue infections. In this study an antibody array was designed and used to obtain an overview about the in vitro PVL expression levels of 266 clinical isolates of MRSA as well as of MSSA belonging to a wide variety of clonal complexes. For that purpose, a novel precipitation based method was used. Unknown PVL concentrations were determined by mapping the signal intensities for spotted monoclonal antibodies to calibration curves that resulted from experiments with known concentrations of recombinant LukF-PV. In most cases, isolates belonging to one clonal complex (CC) showed similar PVL expressions. However, there were also CCs with widely varying PVL concentrations. First analyses, based on in vitro PVL measurements, showed low PVL concentrations in isolates from severe and fatal conditions that are not associated with PVL, such as sepsis, while isolates from skin and soft tissue infections yielded higher concentrations. Agr-group I and IV isolates generally produced more PVL than isolates from agr-groups II and III. The few isolates harbouring the gene encoding toxic shock syndrome toxin (tst1) were particularly low level PVL producers. However, these issues warrant further studies. The method described herein allows rapid quantification of expressed proteins such as PVL in collections of clinical isolates in order to correlate with clinical or genotypic data with a potential for further parallelisation.


High prevalence of a missense mutation of the glucokinase gene in gestational diabetic patients due to a founder-effect in a local population.
A high proportion of the female patients who are members of maturity onset diabetes of the young (MODY) pedigrees, and whose diabetes mellitus is due to a glucokinase mutation, originally presented with gestational diabetes. To establish whether glucokinase mutations could be a common cause of gestational diabetes, we studied 50 subjects who presented with gestational diabetes and on follow-up had hyperglycaemia (5.5-10.0 mmol/l). Screening for glucokinase mutations using single-stranded conformational polymorphism (SSCP) analysis detected a missense mutation at position 299 (Gly299-->Arg) in three subjects. As two pedigrees in the Oxford area had the same glucokinase mutation, we suspected the role of a founder-effect, and carried out pedigree extension, haplotype construction (using microsatellite markers GCK1 and GCK2) and mutation screening of at-risk subjects from the same geographical area. One of the gestational diabetic subjects was found to be related to one of the previous pedigrees via her paternal grandmother. Subjects with the mutation were found to have the Z + 4/2 (GCK1/ GCK2) haplotype, suggesting that the observed high prevalence of the Gly299-->Arg glucokinase mutation in the Oxford region was due to a founder-effect. Since glucokinase mutations predominantly induce subclinical hyperglycaemia, it is likely that in the locality of other pedigrees there will be undiagnosed subjects with the same glucokinase mutation, which remains undetected unless pregnancy occurs.


Sediment quality assessment in tidal salt marshes in northern California, USA: an evaluation of multiple lines of evidence approach.
The objective of this study was to evaluate the efficacy of integrating a traditional sediment quality triad approach with selected sublethal chronic indicators in resident species in assessing sediment quality in four salt marshes in northern California, USA. These included the highly contaminated (Stege Marsh) and relatively clean (China Camp) marshes in San Francisco Bay and two reference marshes in Tomales Bay. Toxicity potential of contaminants and benthic macroinvertebrate survey showed significant differences between contaminated and reference marshes. Sublethal responses (e.g., apoptotic DNA fragmentation, lipid accumulation, and glycogen depletion) in livers of longjaw mudsucker (Gillichthys mirabilis) and embryo abnormality in lined shore crab (Pachygrapsus crassipes) also clearly distinguished contaminated and reference marshes, while other responses (e.g., cytochrome P450, metallothionein) did not. This study demonstrates that additional chronic sublethal responses in resident species under field exposure conditions can be readily combined with sediment quality triads for an expanded multiple lines of evidence approach. This confirmatory step may be warranted in environments like salt marshes in which natural variables may affect interpretation of toxicity test data. Qualitative and quantitative integration of the portfolio of responses in resident species and traditional approach can support a more comprehensive and informative sediment quality assessment in salt marshes and possibly other habitat types as well.


A computerised third molar surgery simulator--results of supervision by different professionals.
The purpose of the study was to investigate which supervisory approach afforded the most efficient learning method for undergraduate students in oral and maxillofacial surgery (OMS) using a computerised third molar surgery simulator. Fifth year dental students participated voluntarily in a randomised experimental study using the simulator. The amount of time required and the number of trials used by each student were evaluated as a measure of skills development. Students had the opportunity to practise the procedure until no further visible improvements were achieved. The study assessed four different types of supervision to guide the students. The first group was where they were supported by a teacher/specialist in OMS, the second by a teaching assistant, the third group practised without any supervision and the fourth received help from a simulator technician/engineer. A protocol describing assessment criteria was designed for this purpose, and a questionnaire was completed by all participating students after the study. The average number of attempts required to virtually remove a third molar tooth in the simulator was 1.44 times for the group supervised by an OMS teacher; 1.5 times for those supervised by a teaching assistant; 2.8 times for those who had no supervision; and 3.6 times when support was provided only by a simulator technician. The results showed that the most efficient experience of the students was when they were helped by an OMS teacher or a teaching assistant. In a time and cost-effective perspective, supervision by a teaching assistant for a third molar surgery simulator would be the optimal choice.


Drift-balanced random stimuli: a general basis for studying non-Fourier motion perception.
To some degree, all current models of visual motion-perception mechanisms depend on the power of the visual signal in various spatiotemporal-frequency bands. Here we show how to construct counterexamples: visual stimuli that are consistently perceived as obviously moving in a fixed direction yet for which Fourier-domain power analysis yields no systematic motion components in any given direction. We provide a general theoretical framework for investigating non-Fourier motion-perception mechanisms; central are the concepts of drift-balanced and microbalanced random stimuli. A random stimulus S is drift balanced if its expected power in the frequency domain is symmetric with respect to temporal frequency, that is, if the expected power in S of every drifting sinusoidal component is equal to the expected power of the sinusoid of the same spatial frequency, drifting at the same rate in the opposite direction. Additionally, S is microbalanced if the result WS of windowing S by any space-time-separable function W is drift balanced. We prove that (i) any space-time-separable random (or nonrandom) stimulus is microbalanced; (ii) any linear combination of pairwise independent microbalanced (respectively, drift-balanced) random stimuli is microbalanced and drift balanced if the expectation of each component is uniformly zero; (iii) the convolution of independent microbalanced and drift-balanced random stimuli is microbalanced and drift balanced; (iv) the product of independent microbalanced random stimuli is microbalanced; and (v) the expected response of any Reichardt detector to any microbalanced random stimulus is zero at every instant in time. Examples are provided of classes of microbalanced random stimuli that display consistent and compelling motion in one direction. All the results and examples from the domain of motion perception are transposable to the space-domain problem of detecting orientation in a texture pattern.


Wide and fast wavelength-tunable mode-locked fiber laser based on dispersion tuning.
We demonstrate a wide and fast wavelength-tunable modelocked fiber laser based on tuning the mode-locking frequency. The laser is in a sigma-laser configuration, and a wideband semiconductor optical amplifier (SOA) at 1.3 mum wavelength region is used as a gain medium. Mode locking is achieved by direct modulation of the injection current to the SOA, and a dispersion compensation fiber (DCF) is used to provide desired intracavity dispersion. By tuning the modulation frequency, a wide tuning range over 100 nm is achieved. Lasing wavelength is measured to be linearly in proportion to the RF frequency applied to the SOA. The sweep rate over the entire wavelength range (100 nm) can be raised to be as high as 200 kHz.


Hemodynamic response to ketamine and diazepam in dogs with acute cardiac tamponade.
Induction of anesthesia may produce a significant hazard to patients with critical cardiovascular status. Ketamine has been advocated as the drug of choice for maintaining cardiovascular performance during induction of anesthesia in high-risk surgical patients. There is no detailed information on the use of ketamine in patients with acute cardiac tamponade. The purpose of this study was to assess the safety of ketamine in acute cardiac tamponade in dogs. Sixteen dogs were studied and a Swan-Ganz catheter was inserted through the right external jugular vein to measure hemodynamic parameters. Data obtained before tamponade was used as the control, then, tamponade was accomplished by infusing a mixture of saline and blood from the same dog through a catheter into the pericardial sac. Ketamine, 2 mg/kg intravenously resulted in an improvement of cardiac output from 1.2 +/- 0.5 L/min to 2.2 +/- 0.3 L/min (p less than 0.05). The addition of diazepam 0.3-0.5 mg/kg blunted the ketamine-induced cardiostimulation and resulted in a fall in cardiac output from 2.2 +/- 0.3 L/min to 1.7 +/- 0.2 L/min (p less than 0.05). Five dogs with intrapericardial pressure above 10 mmHg did not respond to ketamine. Diazepam did not blunt any more to these decompensated dogs. This study demonstrated that ketamine plays a beneficial role in acute cardiac tamponade as a safe induction agent. Limitation still existed when using ketamine in dogs with high intrapericardial pressure because they showed only negative inotropic effect during decompensation. Diazepam inhibited the cardiostimulant effects of ketamine in dogs with tamponade, but could not elicit a negative inotropic effect during decompensation. The practical application of ketamine and diazepam in patients with acute cardiac tamponade could be determined by evaluation of intrapericardial pressure through a needle-transducer kit.


Bortezomib induces apoptosis in primitive chronic myeloid leukemia cells including LTC-IC and NOD/SCID repopulating cells.
Chronic myeloid leukemia (CML) is treated effectively with tyrosine kinase inhibitors (TKIs); however, 2 key problems remain-the insensitivity of CML stem and progenitor cells to TKIs and the emergence of TKI-resistant BCR-ABL mutations. BCR-ABL activity is associated with increased proteasome activity and proteasome inhibitors (PIs) are cytotoxic against CML cell lines. We demonstrate that bortezomib is antiproliferative and induces apoptosis in chronic phase (CP) CD34+ CML cells at clinically achievable concentrations. We also show that bortezomib targets primitive CML cells, with effects on CD34+38(-), long-term culture-initiating (LTC-IC) and nonobese diabetic/severe combined immunodeficient (NOD/SCID) repopulating cells. Bortezomib is not selective for CML cells and induces apoptosis in normal CD34+38(-) cells. The effects against CML cells are seen when bortezomib is used alone and in combination with dasatinib. Bortezomib causes proteasome but not BCR-ABL inhibition and is also effective in inhibiting proteasome activity and inducing apoptosis in cell lines expressing BCR-ABL mutations, including T315I. By targeting both TKI-insensitive stem and progenitor cells and TKI-resistant BCR-ABL mutations, we believe that bortezomib offers a potential therapeutic option in CML. Because of known toxicities, including myelosuppression, the likely initial clinical application of bortezomib in CML would be in resistant and advanced disease.


Does the application site of spinal manipulative therapy alter spinal tissues loading?
Previous studies found that the intervertebral disc (IVD) experiences the greatest loads during spinal manipulation therapy (SMT). Based on that, this study aimed to determine if loads experienced by spinal tissues are significantly altered when the application site of SMT is changed. A biomechanical robotic serial dissection study. Thirteen porcine cadaveric motion segments. Forces experienced by lumbar spinal tissues. A servo-controlled linear actuator provided standardized 300 N SMT simulations to six different cutaneous locations of the porcine lumbar spine: L2-L3 and L3-L4 facet joints (FJ), L3 and L4 transverse processes (TVP), and the space between the FJs and the TVPs (BTW). Vertebral kinematics were tracked optically using indwelling bone pins; the motion segment was removed and mounted in a parallel robot equipped with a six-axis load cell. Movements of each SMT application at each site were replayed by the robot with the intact specimen and following the sequential removal of spinal ligaments, FJs and IVD. Forces induced by SMT were recorded, and specific axes were analyzed using linear mixed models. Analyses yielded a significant difference (p<.05) in spinal structures loads as a function of the application site. Spinal manipulative therapy application at the L3 vertebra caused vertebral movements and forces between L3 and L4 spinal segment in the opposite direction to when SMT was applied at L4 vertebra. Additionally, SMT applications over the soft tissue between adjacent vertebrae significantly decreased spinal structure loads. Applying SMT with a constant force at different spinal levels creates different relative kinetics of the spinal segments and load spinal tissues in significantly different magnitudes.


Exon definition may facilitate splice site selection in RNAs with multiple exons.
Interactions at the 3' end of the intron initiate spliceosome assembly and splice site selection in vertebrate pre-mRNAs. Multiple factors, including U1 small nuclear ribonucleoproteins (snRNPs), are involved in initial recognition at the 3' end of the intron. Experiments were designed to test the possibility that U1 snRNP interaction at the 3' end of the intron during early assembly functions to recognize and define the downstream exon and its resident 5' splice site. Splicing precursor RNAs constructed to have elongated second exons lacking 5' splice sites were deficient in spliceosome assembly and splicing activity in vitro. Similar substrates including a 5' splice site at the end of exon 2 assembled and spliced normally as long as the second exon was less than 300 nucleotides long. U2 snRNPs were required for protection of the 5' splice site terminating exon 2, suggesting direct communication during early assembly between factors binding the 3' and 5' splice sites bordering an exon. We suggest that exons are recognized and defined as units during early assembly by binding of factors to the 3' end of the intron, followed by a search for a downstream 5' splice site. In this view, only the presence of both a 3' and a 5' splice site in the correct orientation and within 300 nucleotides of one another will stable exon complexes be formed. Concerted recognition of exons may help explain the 300-nucleotide-length maximum of vertebrate internal exons, the mechanism whereby the splicing machinery ignores cryptic sites within introns, the mechanism whereby exon skipping is normally avoided, and the phenotypes of 5' splice site mutations that inhibit splicing of neighboring introns.


Battlefield Extracorporeal Cardiopulmonary Resuscitation for Out-of-Hospital Cardiac Arrest: A Feasibility Study During Military Exercises.
To evaluate the feasibility of prehospital extracorporeal cardiopulmonary resuscitation (E-CPR) in the military exercise setting. Three 40kg Sus scrofa (wild swine) underwent controlled 35% blood loss and administration of potassium chloride to achieve cardiac arrest (CA). During CPR, initiated 1 minute after CA, the animals were transported to Role 1. Femoral vessels were cannulated, followed by E-CPR using a portable perfusion device. Crystalloid and blood transfusions were initiated, followed by tactical evacuation to Role 2 and 4-hour observation. All animals developed sustained asystole. Chest compressions supported effective but gradually deteriorating blood circulation. Two animals underwent successful E-CPR, with restoration of perfusion pressure to 80mmHg (70-90mmHg) 25 and 23 minutes after the induction of CA. After transportation to Role 2, one animal developed abdominal compartment syndrome as a result of extensive (9L) fluid replacement. The other animal received a lower volume of crystalloids (4L), and no complications occurred. In the third animal, multiple attempts to cannulate arteries were unsuccessful because of spasm and hypotension. Open aortic cannulation enabled the circuit to commence. No return of spontaneous circulation was ultimately achieved in either of the remaining animals. Our study demonstrates both the potential feasibility of battlefield E-CPR and the evolving capability in the care of severey injured combat casualties.


Azelastine and fluticasone nasal spray: any advantage?
Allergic rhinitis affects over 20% of the UK population. It can have a significant impact on quality of life and interferes with both attendance and performance at school and at work.1 Intranasal corticosteroids are widely recognised as the most effective symptomatic treatment available, but oral or intranasal new generation antihistamines are usually offered as first-line treatment for intermittent symptoms.1,2 Patients with moderate to severe allergic rhinitis may require a combination of drugs, and many patients only achieve limited control of their symptoms.3 Dymista is described as a novel intranasal formulation combining the antihistamine azelastine hydrochloride with the corticosteroid fluticasone propionate.3 It is licensed for the relief of symptoms of moderate to severe seasonal and perennial allergic rhinitis in adults and adolescents if monotherapy with either intranasal antihistamine or glucocorticoid is not considered sufficient.4 The manufacturer claims that compared with fluticasone or azelastine alone, Dymista is twice as effective (when placebo effect is excluded) in providing relief from both nasal and ocular symptoms, and leads to greater overall relief from nasal symptoms. It also claims that Dymista controls nasal symptoms up to 6 days faster than fluticasone.5 Here we consider the evidence for Dymista and whether it represents a significant advantage in the management of patients with allergic rhinitis.


CRITICA: coding region identification tool invoking comparative analysis.
Gene recognition is essential to understanding existing and future DNA sequence data. CRITICA (Coding Region Identification Tool Invoking Comparative Analysis) is a suite of programs for identifying likely protein-coding sequences in DNA by combining comparative analysis of DNA sequences with more common noncomparative methods. In the comparative component of the analysis, regions of DNA are aligned with related sequences from the DNA databases; if the translation of the aligned sequences has greater amino acid identity than expected for the observed percentage nucleotide identity, this is interpreted as evidence for coding. CRITICA also incorporates noncomparative information derived from the relative frequencies of hexanucleotides in coding frames versus other contexts (i.e., dicodon bias). The dicodon usage information is derived by iterative analysis of the data, such that CRITICA is not dependent on the existence or accuracy of coding sequence annotations in the databases. This independence makes the method particularly well suited for the analysis of novel genomes. CRITICA was tested by analyzing the available Salmonella typhimurium DNA sequences. Its predictions were compared with the DNA sequence annotations and with the predictions of GenMark. CRITICA proved to be more accurate than GenMark, and moreover, many of its predictions that would seem to be errors instead reflect problems in the sequence databases. The source code of CRITICA is freely available by anonymous FTP (rdp.life.uiuc.edu in/pub/critica) and on the World Wide Web (http:/(/)rdpwww.life.uiuc.edu).


Effectiveness of cognitive-behavioral therapy for smokers with histories of alcohol dependence and depression.
Alcohol dependence and major depression have been associated with heavy cigarette use and poor smoking-treatment outcomes. This preliminary study examined the efficacy of a mood management intervention for smoking cessation in abstinent alcoholics with a history of major depression. Participants were 29 (15 female, 14 male) heavy smokers (mean cigs/day = 30.2), with an average of 6.8 years of continuous abstinence from alcohol and drugs, randomized to behavioral counseling (BC) (n = 16) or behavioral counseling + cognitive-behavioral mood management (CBT) (n = 13). A 2 x 5 repeated measures design was used to evaluate the effectiveness of the interventions on smoking outcome at baseline, posttreatment and at 1-, 3- and 12-month-follow-up. Self-reported smoking status was verified with biochemical (COa) and informant report. Verified self-report indicated that significantly more smokers in CBT quit by posttreatment (69.2%; 9 of 13) than in BC (31.3%; 5 of 16) (chi2 = 4.14, 1 df, p = .04). These abstinence rates remained unchanged at 1-month follow-up. At 3-month follow-up, differences in smoking abstinence rates were nonsignificant between CBT (46.2%; 6 of 13) and BC (25.0%; 4 of 16) conditions. However, at 12-month follow-up, significantly more participants in CBT were abstinent from smoking (46.2%; 6 of 13) than in BC (12.5%; 2 of 16) (chi2 = 4.07, 1 df, p = .04). The results suggest that interventions focused on managing negative mood may benefit these high-risk, comorbid smokers.


Validation of the Care-Related Quality of Life Instrument in different study settings: findings from The Older Persons and Informal Caregivers Survey Minimum DataSet (TOPICS-MDS).
Validity is a contextual aspect of a scale which may differ across sample populations and study protocols. The objective of our study was to validate the Care-Related Quality of Life Instrument (CarerQol) across two different study design features, sampling framework (general population vs. different care settings) and survey mode (interview vs. written questionnaire). Data were extracted from The Older Persons and Informal Caregivers Minimum DataSet (TOPICS-MDS, www.topics-mds.eu ), a pooled public-access data set with information on >3,000 informal caregivers throughout the Netherlands. Meta-correlations and linear mixed models between the CarerQol's seven dimensions (CarerQol-7D) and caregiver's level of happiness (CarerQol-VAS) and self-rated burden (SRB) were performed. The CarerQol-7D dimensions were correlated to the CarerQol-VAS and SRB in the pooled data set and the subgroups. The strength of correlations between CarerQol-7D dimensions and SRB was weaker among caregivers who were interviewed versus those who completed a written questionnaire. The directionality of associations between the CarerQol-VAS, SRB and the CarerQol-7D dimensions in the multivariate model supported the construct validity of the CarerQol in the pooled population. Significant interaction terms were observed in several dimensions of the CarerQol-7D across sampling frame and survey mode, suggesting meaningful differences in reporting levels. Although good scientific practice emphasises the importance of re-evaluating instrument properties in individual research studies, our findings support the validity and applicability of the CarerQol instrument in a variety of settings. Due to minor differential reporting, pooling CarerQol data collected using mixed administration modes should be interpreted with caution; for TOPICS-MDS, meta-analytic techniques may be warranted.


MicroRNA-150 protects the mouse heart from ischaemic injury by regulating cell death.
Cardiac injury is accompanied by dynamic changes in the expression of microRNAs (miRs). For example, miR-150 is down-regulated in patients with acute myocardial infarction, atrial fibrillation, dilated and ischaemic cardiomyopathy as well as in various mouse heart failure (HF) models. Circulating miR-150 has been recently proposed as a better biomarker of HF than traditional clinical markers such as brain natriuretic peptide. We recently showed using the β-arrestin-biased β-blocker, carvedilol that β-arrestin1-biased β1-adrenergic receptor cardioprotective signalling stimulates the processing of miR-150 in the heart. However, the potential role of miR-150 in ischaemic injury and HF is unknown. Here, we show that genetic deletion of miR-150 in mice causes abnormalities in cardiac structural and functional remodelling after MI. The cardioprotective roles of miR-150 during ischaemic injury were in part attributed to direct repression of the pro-apoptotic genes egr2 (zinc-binding transcription factor induced by ischaemia) and p2x7r (pro-inflammatory ATP receptor) in cardiomyocytes. These findings reveal a pivotal role for miR-150 as a regulator of cardiomyocyte survival during cardiac injury.


Gut microbiota in health and disease.
Gut microbiota is an assortment of microorganisms inhabiting the length and width of the mammalian gastrointestinal tract. The composition of this microbial community is host specific, evolving throughout an individual's lifetime and susceptible to both exogenous and endogenous modifications. Recent renewed interest in the structure and function of this "organ" has illuminated its central position in health and disease. The microbiota is intimately involved in numerous aspects of normal host physiology, from nutritional status to behavior and stress response. Additionally, they can be a central or a contributing cause of many diseases, affecting both near and far organ systems. The overall balance in the composition of the gut microbial community, as well as the presence or absence of key species capable of effecting specific responses, is important in ensuring homeostasis or lack thereof at the intestinal mucosa and beyond. The mechanisms through which microbiota exerts its beneficial or detrimental influences remain largely undefined, but include elaboration of signaling molecules and recognition of bacterial epitopes by both intestinal epithelial and mucosal immune cells. The advances in modeling and analysis of gut microbiota will further our knowledge of their role in health and disease, allowing customization of existing and future therapeutic and prophylactic modalities.


Peax: Interactive Visual Pattern Search in Sequential Data Using Unsupervised Deep Representation Learning.
We present Peax, a novel feature-based technique for interactive visual pattern search in sequential data, like time series or data mapped to a genome sequence. Visually searching for patterns by similarity is often challenging because of the large search space, the visual complexity of patterns, and the user's perception of similarity. For example, in genomics, researchers try to link patterns in multivariate sequential data to cellular or pathogenic processes, but a lack of ground truth and high variance makes automatic pattern detection unreliable. We have developed a convolutional autoencoder for unsupervised representation learning of regions in sequential data that can capture more visual details of complex patterns compared to existing similarity measures. Using this learned representation as features of the sequential data, our accompanying visual query system enables interactive feedback-driven adjustments of the pattern search to adapt to the users' perceived similarity. Using an active learning sampling strategy, Peax collects user-generated binary relevance feedback. This feedback is used to train a model for binary classification, to ultimately find other regions that exhibit patterns similar to the search target. We demonstrate Peax's features through a case study in genomics and report on a user study with eight domain experts to assess the usability and usefulness of Peax. Moreover, we evaluate the effectiveness of the learned feature representation for visual similarity search in two additional user studies. We find that our models retrieve significantly more similar patterns than other commonly used techniques.


Fruit and vegetable consumption and risk of distal gastric cancer in the Shanghai Women's and Men's Health studies.
Results from case-control and cohort studies of the association between fruit and vegetable consumption and gastric cancer risk have been inconsistent. Cases for the current study consisted of incident distal gastric cancers identified between 1996 and 2007 among members of the Shanghai Women's Health Study (n = 206) and the Shanghai Men's Health Study (n = 132). Intakes of fruits, vegetables, and select micronutrients were assessed on the basis of validated food frequency questionnaires. Multivariate-adjusted hazards ratios and 95% confidence intervals were calculated by Cox proportional hazards regression. For women, no associations were found between gastric cancer risk and the highest intake of fruits (hazard ratio (HR) = 1.02, 95% confidence interval (CI): 0.68, 1.54; P(trend) = 0.87) or vegetables (HR = 0.89, 95% CI: 0.60, 1.31; P(trend) = 0.32). For men, increased fruit intake was associated with decreased risk of distal gastric cancer (for the highest quartile of intake, HR = 0.50, 95% CI: 0.29, 0.84; P(trend) = 0.004), but no association was seen with increased intake of vegetables (HR = 1.00, 95% CI: 0.59, 1.68; P(trend) = 0.87). The inverse association with fruit intake for men was more evident among ever smokers (P(trend) = 0.001) than never smokers (P(trend) = 0.67). No associations between dietary intakes of select antioxidant micronutrients were seen for men or women. Fruit intake is inversely associated with distal gastric cancer risk among men in Shanghai, China.


Molecular and phylogenetic analysis of pyridoxal phosphate-dependent acyltransferase of Exiguobacterium acetylicum.
The pyridoxal-5'-phosphate (PLP)-dependent family of enzymes is a very diverse group of proteins that metabolize small molecules like amino acids and sugars, and synthesize cofactors for other metabolic pathways through transamination, decarboxylation, racemization, and substitution reactions. In this study we employed degenerated primer-based PCR amplification, using genomic DNA isolated from the soil bacterium Exiguobacterium acetylicum strain SN as template. We revealed the presence of a PLP-dependent family of enzymes, such as PLP-dependent acyltransferase, and similarity to 8-amino-7-oxononoate synthase. Sequencing analysis and multiple alignment of the thymidine-adenine-cloned PCR amplicon revealed PLP-dependent family enzymes with specific confering codes and consensus amino acid residues specific to this group of functional proteins. Amino acid residues common to the majority of PLP-dependent enzymes were also revealed by the Lasergene MegAlign software. A phylogenetic tree was constructed. Its analysis revealed a close relationship of E. acetylicum to other bacteria isolated from extreme environments suggesting similarities in anabolic adaptability and evolutionary development.


Pervasive iron limitation at subsurface chlorophyll maxima of the California Current.
Subsurface chlorophyll maximum layers (SCMLs) are nearly ubiquitous in stratified water columns and exist at horizontal scales ranging from the submesoscale to the extent of oligotrophic gyres. These layers of heightened chlorophyll and/or phytoplankton concentrations are generally thought to be a consequence of a balance between light energy from above and a limiting nutrient flux from below, typically nitrate (NO3). Here we present multiple lines of evidence demonstrating that iron (Fe) limits or with light colimits phytoplankton communities in SCMLs along a primary productivity gradient from coastal to oligotrophic offshore waters in the southern California Current ecosystem. SCML phytoplankton responded markedly to added Fe or Fe/light in experimental incubations and transcripts of diatom and picoeukaryote Fe stress genes were strikingly abundant in SCML metatranscriptomes. Using a biogeochemical proxy with data from a 40-y time series, we find that diatoms growing in California Current SCMLs are persistently Fe deficient during the spring and summer growing season. We also find that the spatial extent of Fe deficiency within California Current SCMLs has significantly increased over the last 25 y in line with a regional climate index. Finally, we show that diatom Fe deficiency may be common in the subsurface of major upwelling zones worldwide. Our results have important implications for our understanding of the biogeochemical consequences of marine SCML formation and maintenance.


A secondary metabolite acting as a signalling molecule controls Pseudomonas entomophila virulence.
Pseudomonas entomophila is an entomopathogenic bacterium that is lethal to Drosophila melanogaster within 1-2 days of ingestion of high doses. Flies orally infected with P. entomophila rapidly succumb despite the induction of both local and systemic immune responses. Recent studies suggest that its virulence relies on its ability to cause irreversible damages to the intestinal epithelium, in contrast to what is observed with milder pathogenic bacteria such as Erwinia carotovora carotovora Ecc15 or Pseudomonas aeruginosa PA14. The GacS/GacA two-component system plays a key role in P. entomophila pathogenicity. Here, we report the identification of the pvf genes, whose products are involved in production of a secondary metabolite involved in P. entomophila virulence. A pvf mutant is impaired in its ability to persist within the gut, to trigger the fly immune responses and to inflict gut damages. The expression of several genes is affected in a pvf mutant, independently of the Gac system. Moreover, growing a pvf mutant in medium supplemented with supernatant extracts from either the wild-type strain or a gacA mutant restore its pathogenicity. Collectively, our results indicate that we identified genes involved in the synthesis of a signalling molecule that controls P. entomophila virulence independently from the Gac system.


Assessing the virulence of Cryptococcus neoformans causing meningitis in HIV infected and uninfected patients in Vietnam.
We previously observed a substantial burden of cryptococcal meningitis in Vietnam atypically arising in individuals who are uninfected with human immunodeficiency virus (HIV). This disease was associated with a single genotype of Cryptococcus neoformans (sequence type [ST]5), which was significantly less common in HIV-infected individuals. Aiming to compare the phenotypic characteristics of ST5 and non-ST5 C. neoformans, we selected 30 representative Vietnamese isolates and compared their in vitro pathogenic potential and in vivo virulence. ST5 and non-ST5 organisms exhibited comparable characteristics with respect to in vitro virulence markers including melanin production, replication at 37°C, and growth in cerebrospinal fluid. However, the ST5 isolates had significantly increased variability in cellular and capsular sizing compared with non-ST5 organisms (P < .001). Counterintuitively, mice infected with ST5 isolates had significantly longer survival with lower fungal burdens at day 7 than non-ST5 isolates. Notably, ST5 isolates induced significantly greater initial inflammatory responses than non-ST5 strains, measured by TNF-α concentrations (P < .001). Despite being generally less virulent in the mouse model, we hypothesize that the significant within strain variation seen in ST5 isolates in the tested phenotypes may represent an evolutionary advantage enabling adaptation to novel niches including apparently immunocompetent human hosts.


Selective vulnerability in α-synucleinopathies.
Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy are neurodegenerative disorders resulting in progressive motor/cognitive deficits among other symptoms. They are characterised by stereotypical brain cell loss accompanied by the formation of proteinaceous aggregations of the protein α-synuclein (α-syn), being, therefore, termed α-synucleinopathies. Although the presence of α-syn inclusions is a common hallmark of these disorders, the exact nature of the deposited protein is specific to each disease. Different neuroanatomical regions and cellular populations manifest a differential vulnerability to the appearance of protein deposits, cell dysfunction, and cell death, leading to phenotypic diversity. The present review describes the multiple factors that contribute to the selective vulnerability in α-synucleinopathies. We explore the intrinsic cellular properties in the affected regions, including the physiological and pathophysiological roles of endogenous α-syn, the metabolic and genetic build-up of the cells and their connectivity. These factors converge with the variability of the α-syn conformational strains and their spreading capacity to dictate the phenotypic diversity and regional vulnerability of each disease. Finally, we describe the exogenous and environmental factors that potentially contribute by igniting and modulating the differential pathology in α-synucleinopathies. In conclusion, we think that it is the confluence of this disruption of the cellular metabolic state and α-syn structural equilibrium through the anatomical connectivity which appears to initiate cascades of pathological processes triggered by genetic, environmental, or stochastic events that result in the "death by a thousand cuts" profile of α-synucleinopathies.


Effect of dehydrozingerone, a half analog of curcumin on dexamethasone-delayed wound healing in albino rats.
Oxidative stress is triggered by the wound which results in the production of reactive oxygen species (ROS), thereby delaying normal wound repair. Therefore, it is important to reduce the level of ROS to improve healing. A known antioxidant, dehydrozingerone (DHZ) was synthesized and selected for the study. The authors aimed to investigate the wound healing action of topical (100 mg/wound) and systemic (100 mg/kg, p. o.). DHZ on different wound models in normal and dexamethasone (DEX)-suppressed healing. Topical DHZ showed a significant (P < 0.05) rise in tensile strength when compared to control in normal healing. Significant (P < 0.05) wound closure was observed from 3 to 9 days in DHZ oral and gel treated groups. There was a significant (P < 0.05) rise in hydroxyproline content with the DHZ treated groups when compared to control. Systemic DHZ exhibited a significant (P < 0.05) increase in lysyl oxidase (LO) levels of 3.73 ± 0.15 nmol of H(2)O(2) when compared to control. In DEX-suppressed healing, showed good pro-healing activity with respect to the parameters mentioned above. DHZ treatment exhibited a parabolic dose response of ROS inhibition with a plateau effect at 75 μM. There was a steady and constant increase in the % NO inhibition with increasing doses of DHZ. Oral DHZ is effective in accelerating the healing process in both normal and dexamethasone-suppressed wounds. Our study suggests that DHZ (half analog of curcumin) supplementation reduces the steroid-induced delay in wound healing.


Bordetella bronchialis sp. nov., Bordetella flabilis sp. nov. and Bordetella sputigena sp. nov., isolated from human respiratory specimens, and reclassification of Achromobacter sediminum Zhang et al. 2014 as Verticia sediminum gen. nov., comb. nov.
The phenotypic and genotypic characteristics of four Bordetella hinzii-like strains from human respiratory specimens and representing nrdA gene sequence based genogroups 3, 14 and 15 were examined. In a 16S rRNA gene sequence based phylogenetic tree, the four strains consistently formed a single coherent lineage but their assignment to the genus Bordetella was equivocal. The respiratory quinone, polar lipid and fatty acid profiles generally conformed to those of species of the genus Bordetella and were characterized by the presence of ubiquinone 8, of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and several aminolipids, and of high percentages of C16 : 0, cyclo-C17 : 0 and summed feature 2, as major chemotaxonomic marker molecules, respectively. The DNA G+C content was about 66 mol%, which corresponded with that of the high-percentage DNA G+C content genera of the family Alcaligenaceae including the genus Bordetella. DNA–DNA hybridization experiments revealed the presence of three distinct genomospecies and thus confirmed phenotypic differences as revealed by means of extensive biochemical characterization. We therefore propose to formally classify Bordetella genogroups 3, 14 and 15 as Bordetella bronchialis sp. nov. (type strain LMG 28640T = AU3182T = CCUG 56828T), Bordetella sputigena sp. nov. (type strain LMG 28641T = CCUG 56478T) and Bordetella flabilis sp. nov. (type strain LMG 28642T = AU10664T = CCUG 56827T). In addition, we propose to reclassify Achromobacter sediminum into the novel genus Verticia, as Verticia sediminum, gen. nov., comb. nov., on the basis of its unique phylogenetic position, its marine origin and its distinctive phenotypic, fatty acid and polar lipid profile.


Dynamic Changes in Metabolite Accumulation and the Transcriptome during Leaf Growth and Development in Eucommia ulmoides.
Eucommia ulmoides Oliver is widely distributed in China. This species has been used mainly in medicine due to the high concentration of chlorogenic acid (CGA), flavonoids, lignans, and other compounds in the leaves and barks. However, the categories of metabolites, dynamic changes in metabolite accumulation and overall molecular mechanisms involved in metabolite biosynthesis during E. ulmoides leaf growth and development remain unknown. Here, a total of 515 analytes, including 127 flavonoids, 46 organic acids, 44 amino acid derivatives, 9 phenolamides, and 16 vitamins, were identified from four E. ulmoides samples using ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) (for widely targeted metabolites). The accumulation of most flavonoids peaked in growing leaves, followed by old leaves. UPLC-MS analysis indicated that CGA accumulation increased steadily to a high concentration during leaf growth and development, and rutin showed a high accumulation level in leaf buds and growing leaves. Based on single-molecule long-read sequencing technology, 69,020 transcripts and 2880 novel loci were identified in E. ulmoides. Expression analysis indicated that isoforms in the flavonoid biosynthetic pathway and flavonoid metabolic pathway were highly expressed in growing leaves and old leaves. Co-expression network analysis suggested a potential direct link between the flavonoid and phenylpropanoid biosynthetic pathways via the regulation of transcription factors, including MYB (v-myb avian myeloblastosis viral oncogene homolog) and bHLH (basic/helix-loop-helix). Our study predicts dynamic metabolic models during leaf growth and development and will support further molecular biological studies of metabolite biosynthesis in E. ulmoides. In addition, our results significantly improve the annotation of the E. ulmoides genome.


A homoallelic FECH mutation in a patient with both erythropoietic protoporphyria and palmar keratoderma.
Erythropoietic protoporphyria (EPP) is a hereditary disorder caused by the deficiency of ferrochelatase (FECH) in the haem biosynthetic pathway. In the majority of families, EPP is transmitted as a pseudodominant trait. Autosomal recessive form of EPP is found in only about 3% of the families. In this study, we describe a 6-year-old boy who suffered from both EPP and palmar keratoderma. A novel homoallelic missense mutation (p.Ser318Tyr) was identified in the FECH gene. In addition, a region of homozygosity of approximately 6.8 Mb was observed in chromosome 18 of the patient by both microsatellite and SNP array. The parents of the patient, both of Palestinian (Jordanian) origin, were heterozygous for the S318Y mutation, although no history of consanguinity was known. Microsatellite genotyping identified a partial haplotype from each parent that corresponds to the region of homozygosity in the patient. Assuming S318Y is a founder mutation, the number of generations separating the two parents from their common ancestor from whom they inherited S318Y was estimated as 21.7 (95% CI 3.42–69.7). EPP was therefore inherited as an autosomal recessive trait in the family. This study confirms the association between palmar keratoderma and autosomal recessive EPP.


Iron Content in Deep Gray Matter as a Function of Age Using Quantitative Susceptibility Mapping: A Multicenter Study.
To evaluate the effect of resolution on iron content using quantitative susceptibility mapping (QSM); to verify the consistency of QSM across field strengths and manufacturers in evaluating the iron content of deep gray matter (DGM) of the human brain using subjects from multiple sites; and to establish a susceptibility baseline as a function of age for each DGM structure using both a global and regional iron analysis. Data from 623 healthy adults, ranging from 20 to 90 years old, were collected across 3 sites using gradient echo imaging on one 1.5 Tesla and two 3.0 Tesla MR scanners. Eight subcortical gray matter nuclei were semi-automatically segmented using a full-width half maximum threshold-based analysis of the QSM data. Mean susceptibility, volume and total iron content with age correlations were evaluated for each measured structure for both the whole-region and RII (high iron content regions) analysis. For the purpose of studying the effect of resolution on QSM, a digitized model of the brain was applied. The mean susceptibilities of the caudate nucleus (CN), globus pallidus (GP) and putamen (PUT) were not significantly affected by changing the slice thickness from 0.5 to 3 mm. But for small structures, the susceptibility was reduced by 10% for 2 mm thick slices. For global analysis, the mean susceptibility correlated positively with age for the CN, PUT, red nucleus (RN), substantia nigra (SN), and dentate nucleus (DN). There was a negative correlation with age in the thalamus (THA). The volumes of most nuclei were negatively correlated with age. Apart from the GP, THA, and pulvinar thalamus (PT), all the other structures showed an increasing total iron content despite the reductions in volume with age. For the RII regional high iron content analysis, mean susceptibility in most of the structures was moderately to strongly correlated with age. Similar to the global analysis, apart from the GP, THA, and PT, all structures showed an increasing total iron content. A reasonable estimate for age-related iron behavior can be obtained from a large cross site, cross manufacturer set of data when high enough resolutions are used. These estimates can be used for correcting for age related iron changes when studying diseases like Parkinson's disease, Alzheimer's disease, and other iron related neurodegenerative diseases.


Mechanisms of exercise-induced delayed onset muscular soreness: a brief review.
Delayed-onset muscular soreness (DOMS), the sensation of pain and stiffness in the muscles that occurs from 1 to 5 d following unaccustomed exercise, can adversely affect muscular performance, both from voluntary reduction of effort and from inherent loss of capacity of the muscles to produce force. This reduction in performance is temporary; permanent impairment does not occur. A number of clinical correlates are associated with DOMS, including elevations in plasma enzymes, myoglobinemia, and abnormal muscle histology and ultrastructure; exertional rhabdomyolysis appears to be the extreme form of DOMS. Presently, the best treatment for DOMS appears to be muscular activity, although the sensation again returns following the exercise. Training for the specific contractile activity that causes DOMS reduces the soreness response. The etiology and cellular mechanisms of DOMS are not known, but a number of hypotheses exist to explain the phenomenon. The following model may be proposed: 1) high tensions (particularly those associated with eccentric exercise) in the contractile/elastic system of the muscle result in structural damage; 2) cell membrane damage leads to disruption of Ca++ homeostasis in the injured fibers, resulting in necrosis that peaks about 2 d post-exercise; and 3) products of macrophage activity and intracellular contents accumulate in the interstitium, which in turn stimulate free nerve endings of group-IV sensory neurons in the muscles leading to the sensation of DOMS.


Signaling within a coactivator complex: methylation of SRC-3/AIB1 is a molecular switch for complex disassembly.
Recent studies indicate that steroid receptor-mediated transcriptional initiation is a cyclical process involving multiple rounds of coactivator assembly and disassembly. Steroid receptor coactivator 3 (SRC-3) coactivator phosphorylation has been shown to regulate coactivator complex assembly, but the mechanisms by which coactivator disassembly is triggered are not well understood. In this study, we provide in vitro and in vivo evidence that members of the SRC coactivator family serve as substrates for the enzymatic coactivator coactivator-associated arginine methyltransferase 1 (CARM1). Methylation of SRC-3 was localized to an arginine in its CARM1 binding region and correlated with decreased estrogen receptor alpha-mediated transcription, as seen with both cell-based and in vitro transcription assays. Consistent with this finding, we demonstrated that methylation promotes dissociation of the SRC-3/CARM1 coactivator complex. Methylation of SRC-3 is regulated by estrogen signaling in MCF7 cells and serves as a molecular switch for disassembly of the SRC-3 transcriptional coactivator complex. We propose that CARM1 is a dual-function coactivator, as it not only activates transcription by modifying core histone tails but also terminates hormone signaling by disassembly of the coactivator complex.


Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma.
Melanoma is the most dangerous form of skin cancer with the majority of deaths arising from metastatic disease. Evidence implicates Rho-activated gene transcription in melanoma metastasis mediated by the nuclear localization of the transcriptional coactivator, myocardin-related transcription factor (MRTF). Here, we highlight a role for Rho and MRTF signaling and its reversal by pharmacologic inhibition using in vitro and in vivo models of human melanoma growth and metastasis. Using two cellular models of melanoma, we clearly show that one cell type, SK-Mel-147, is highly metastatic, has high RhoC expression, and MRTF nuclear localization and activity. Conversely, SK-Mel-19 melanoma cells have low RhoC expression, and decreased levels of MRTF-regulated genes. To probe the dependence of melanoma aggressiveness to MRTF transcription, we use a previously developed small-molecule inhibitor, CCG-203971, which at low micromolar concentrations blocks nuclear localization and activity of MRTF-A. In SK-Mel-147 cells, CCG-203971 inhibits cellular migration and invasion, and decreases MRTF target gene expression. In addition, CCG-203971-mediated inhibition of the Rho/MRTF pathway significantly reduces cell growth and clonogenicity and causes G1 cell-cycle arrest. In an experimental model of melanoma lung metastasis, the RhoC-overexpressing melanoma cells (SK-Mel-147) exhibited pronounced lung colonization compared with the low RhoC-expressing SK-Mel-19. Furthermore, pharmacologic inhibition of the MRTF pathway reduced both the number and size of lung metastasis resulting in a marked reduction of total lung tumor burden. These data link Rho and MRTF-mediated signaling with aggressive phenotypes and support targeting the MRTF transcriptional pathway as a novel approach to melanoma therapeutics. Mol Cancer Ther; 16(1); 193-204. ©2016 AACR.


Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults.
Mortality resulting from coronary heart disease (CHD), cardiovascular disease (CVD), and all causes in persons with diabetes and pre-existing CVD is high; however, these risks compared with those with metabolic syndrome (MetS) are unclear. We examined the impact of MetS on CHD, CVD, and overall mortality among US adults. In a prospective cohort study, 6255 subjects 30 to 75 years of age (54% female) (representative of 64 million adults in the United States) from the Second National Health and Nutrition Examination Survey were followed for a mean+/-SD of 13.3+/-3.8 years. MetS was defined by modified National Cholesterol Education Program criteria. From sample-weighted multivariable Cox proportional-hazards regression, compared with those with neither MetS nor prior CVD, age-, gender-, and risk factor-adjusted hazard ratios (HRs) for CHD mortality were 2.02 (95% CI, 1.42 to 2.89) for those with MetS and 4.19 (95% CI, 3.04 to 5.79) for those with pre-existing CVD. For CVD mortality, HRs were 1.82 (95% CI, 1.40 to 2.37) and 3.14 (95% CI, 2.49 to 3.96), respectively; for overall mortality, HRs were 1.40 (95% CI, 1.19 to 1.66) and 1.87 (95% CI, 1.60 to 2.17), respectively. In persons with MetS but without diabetes, risks of CHD and CVD mortality remained elevated. Diabetes predicted all mortality end points. Those with even 1 to 2 MetS risk factors were at increased risk for mortality from CHD and CVD. Moreover, MetS more strongly predicts CHD, CVD, and total mortality than its individual components. CHD, CVD, and total mortality are significantly higher in US adults with than in those without MetS.


Impact of a resident's sex on intraoperative entrustment of surgery trainees.
Optimizing intraoperative education is critical for development of autonomous residents. Faculty decisions concerning intraoperative entrustment determine the degree to which a resident gains intraoperative responsibility. Accordingly, residents exhibit entrustable behaviors that further faculty entrustment in the operating room. Little empiric evidence exists evaluating how the sex of a resident influences faculty-resident decisions of entrustment. Studies involving perception-based measurements of autonomy report inequities for women residents. We sought to assess faculty behaviors in entrustment in relation to resident sex using OpTrust, a third-party objective measurement tool. From September 2015 to June 2017 at the University of Michigan, surgical cases were observed and entrustment behaviors were rated using OpTrust. Critical case sampling was used to generate variation in operation type, case difficulty, faculty-resident pairings, faculty experience, and the level of the resident's training. Independent sample t-tests were conducted to compare faculty entrustment scores, as well as resident entrustability scores. A total of 56 faculty and 73 residents were observed across 223 surgical cases from 4 surgical specialties: general, plastic, thoracic, and vascular. There was no difference in faculty entrustment or entrustability scores between women and men (2.54 vs 2.35, P = .117 and 2.32 vs 2.22, P = .393, respectively). Using OpTrust scores, we found that a resident's sex does not appear to influence faculty entrustment in the OR. Faculty entrustment scores for women and men residents are similar across cases. This observation suggests that during the intraoperative interaction, faculty are not extending entrustment or opportunities for autonomy differently to women or men. Future research is needed to identify and measure perioperative elements that inform resident autonomy, which may contribute to inequities for women residents.


Unique oxidative mechanisms for the reactive nitrogen oxide species, nitroxyl anion.
The nitroxyl anion (NO-) is a highly reactive molecule that may be involved in pathophysiological actions associated with increased formation of reactive nitrogen oxide species. Angeli's salt (Na2N2O3; AS) is a NO- donor that has been shown to exert marked cytotoxicity. However, its decomposition intermediates have not been well characterized. In this study, the chemical reactivity of AS was examined and compared with that of peroxynitrite (ONOO-) and NO/N2O3. Under aerobic conditions, AS and ONOO- exhibited similar and considerably higher affinities for dihydrorhodamine (DHR) than NO/N2O3. Quenching of DHR oxidation by azide and nitrosation of diaminonaphthalene were exclusively observed with NO/N2O3. Additional comparison of ONOO- and AS chemistry demonstrated that ONOO- was a far more potent one-electron oxidant and nitrating agent of hydroxyphenylacetic acid than was AS. However, AS was more effective at hydroxylating benzoic acid than was ONOO-. Taken together, these data indicate that neither NO/N2O3 nor ONOO- is an intermediate of AS decomposition. Evaluation of the stoichiometry of AS decomposition and O2 consumption revealed a 1:1 molar ratio. Indeed, oxidation of DHR mediated by AS proved to be oxygen-dependent. Analysis of the end products of AS decomposition demonstrated formation of NO2- and NO3- in approximately stoichiometric ratios. Several mechanisms are proposed for O2 adduct formation followed by decomposition to NO3- or by oxidation of an HN2O3- molecule to form NO2-. Given that the cytotoxicity of AS is far greater than that of either NO/N2O3 or NO + O2, this study provides important new insights into the implications of the potential endogenous formation of NO- under inflammatory conditions in vivo.


Gold-nanocrystal-enhanced bioluminescent nanocapsules.
Metal-enhanced bioluminescence presents a great opportunity to achieve ultrasensitive analysis and imaging with low bioluminescent background and enhanced luminescence. We hereby report metal-enhanced bioluminescence based on bioluminescent protein nanocapsules conjugated with gold nanocrystals. Such gold-nanocapsule complexes exhibit near 10-fold enhancement in bioluminescent intensity and are effectively delivered into the cells with outstanding stability. This work offers a class of bioluminescent nanoparticles for imaging and other applications.


Cryo-EM structure and rRNA model of a translating eukaryotic 80S ribosome at 5.5-A resolution.
Protein biosynthesis, the translation of the genetic code into polypeptides, occurs on ribonucleoprotein particles called ribosomes. Although X-ray structures of bacterial ribosomes are available, high-resolution structures of eukaryotic 80S ribosomes are lacking. Using cryoelectron microscopy and single-particle reconstruction, we have determined the structure of a translating plant (Triticum aestivum) 80S ribosome at 5.5-Å resolution. This map, together with a 6.1-Å map of a Saccharomyces cerevisiae 80S ribosome, has enabled us to model ∼98% of the rRNA. Accurate assignment of the rRNA expansion segments (ES) and variable regions has revealed unique ES-ES and r-protein-ES interactions, providing insight into the structure and evolution of the eukaryotic ribosome.


Parents' personality and parenting stress in families of children with spina bifida.
Spina bifida (SB) can place parents at risk for increased levels of parenting stress. Little is known, however, about the role of parents' intrapersonal resources. Therefore, based on ideas of the Disability-Stress-Coping Model, relations between the severity of SB, parents' personality traits and parenting stress were examined. Forty-six mothers and 37 fathers of children with SB (6-14 years) participated. Severity of SB (physical dysfunctions and cognitive functions), parental personality (Big Five) and parenting stress (Parenting Stress Index) were measured. Multiple regression analyses were performed. The severity of the child's physical dysfunctions was positively associated with parenting stress. Extraversion (mothers only), emotional stability and agreeableness (fathers only) were negatively related to parenting stress. In the final model, 64% of the variance in mothers' and 67% of the variance in fathers' levels of parenting stress was explained. Parents' personality traits explained the largest proportions of variance in parenting stress. Mobility, bladder and bowel dysfunctions in school-aged children with SB represent ongoing stressors for parents. Parents' intrapersonal resources of positive affectivity, however, are more important determinants of parental adjustment to SB than the child's physical dysfunctions.


Selection for longer lived sperm within ejaculate reduces reproductive ageing in offspring.
Males produce numerous sperm in a single ejaculate that greatly outnumber their potential egg targets. Recent studies found that phenotypic and genotypic variation among sperm in a single ejaculate of a male affects the fitness and performance of the resulting offspring. Specifically, within-ejaculate sperm selection for sperm longevity increased the performance of the resulting offspring in several key life-history traits in early life. Because increased early-life reproductive performance often correlates with rapid ageing, it is possible that within-ejaculate sperm selection increases early-life fitness at the cost of accelerated senescence. Alternatively, within-ejaculate sperm selection could improve offspring quality throughout the life cycle, including reduced age-specific deterioration. We tested the two alternative hypotheses in an experimental setup using zebrafish Danio rerio. We found that within-ejaculate sperm selection for sperm longevity reduced age-specific deterioration of fecundity and offspring survival but had no effect on fertilization success in males. Remarkably, we found an opposing effect of within-ejaculate sperm selection on female fecundity, where selection for sperm longevity resulted in increased early-life performance followed by a slow decline, while females sired by unselected sperm started low but increased their fecundity with age. Intriguingly, within-ejaculate sperm selection also reduced the age-specific decline in fertilization success in females, suggesting that selection for sperm longevity improves at least some aspects of female reproductive ageing. These results demonstrate that within-ejaculate variation in sperm phenotype contributes to individual variation in animal life histories in the two sexes and may have important implications for assisted fertilization programs in livestock and humans.


Antibodies targeting sialyl Lewis A mediate tumor clearance through distinct effector pathways.
Sialyl Lewis A (sLeA, also known as CA19-9), a tetrasaccharide selectively and highly expressed on advanced adenocarcinomas including colon, stomach, and pancreatic cancers, has long been considered as an attractive target for active and passive vaccination. While progress in antibodies targeting tumor-associated protein antigens resulted in an impressive array of therapeutics for cancer treatment, similar progress in exploiting tumor-associated carbohydrate antigens, such as sLeA, has been hampered by the lack of a detailed understanding of the singular characteristics of these antigens. We have addressed this issue by analyzing antibodies derived from patients immunized with an sLeA/KLH vaccine. These antibodies were engineered to mediate tumor clearance in vivo in preclinical models through Fc-FcγR interactions. However, in contrast to protein antigens in which hFcγRIIIA engagement was both necessary and sufficient to mediate tumor clearance in both preclinical and clinical settings, a similar selective dependence was not seen for anti-sLeA antibodies. Thus, re-engineering the Fc portion of sLeA-targeting antibodies to broadly enhance their affinity for activating FcγRs led to an enhanced therapeutic effect. These findings will facilitate the development of more efficient anticancer therapies and further advance this promising class of therapeutic antibodies into clinical use.


Effects of Sacubitril/Valsartan Versus Irbesartan in Patients With Chronic Kidney Disease.
Sacubitril/valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction, but its effects on kidney function and cardiac biomarkers in people with moderate to severe chronic kidney disease are unknown. The UK HARP-III trial (United Kingdom Heart and Renal Protection-III), a randomized double-blind trial, included 414 participants with an estimated glomerular filtration rate (GFR) 20 to 60 mL/min/1.73 m2 who were randomly assigned to sacubitril/valsartan 97/103 mg twice daily versus irbesartan 300 mg once daily. The primary outcome was measured GFR at 12 months using ANCOVA with adjustment for each individual's baseline measured GFR. All analyses were by intention to treat. In total, 207 participants were assigned to sacubitril/valsartan and 207 to irbesartan. Baseline measured GFR was 34.0 (SE, 0.8) and 34.7 (SE, 0.8) mL/min/1.73 m2, respectively. At 12 months, there was no difference in measured GFR: 29.8 (SE 0.5) among those assigned sacubitril/valsartan versus 29.9 (SE, 0.5) mL/min/1.73 m2 among those assigned irbesartan; difference, -0.1 (0.7) mL/min/1.73 m2. Effects were similar in all prespecified subgroups. There was also no significant difference in estimated GFR at 3, 6, 9, or 12 months and no clear difference in urinary albumin:creatinine ratio between treatment arms (study average difference, -9%; 95% CI, -18 to 1). However, compared with irbesartan, allocation to sacubitril/valsartan reduced study average systolic and diastolic blood pressure by 5.4 (95% CI, 3.4-7.4) and 2.1 (95% CI, 1.0-3.3) mm Hg and levels of troponin I and N terminal of prohormone brain natriuretic peptide (tertiary end points) by 16% (95% CI, 8-23) and 18% (95% CI, 11-25), respectively. The incidence of serious adverse events (29.5% versus 28.5%; rate ratio, 1.07; 95% CI, 0.75-1.53), nonserious adverse reactions (36.7% versus 28.0%; rate ratio, 1.35; 95% CI, 0.96-1.90), and potassium ≥5.5 mmol/L (32% versus 24%, P=0.10) was not significantly different between randomized groups. Over 12 months, sacubitril/valsartan has similar effects on kidney function and albuminuria to irbesartan, but it has the additional effect of lowering blood pressure and cardiac biomarkers in people with chronic kidney disease. URL: http://www.isrctn.com . Unique identifier: ISRCTN11958993.


Comparative analysis of proteome changes induced by the two spotted spider mite Tetranychus urticae and methyl jasmonate in citrus leaves.
Citrus plants are currently facing biotic and abiotic stresses. Therefore, the characterization of molecular traits involved in the response mechanisms to stress could facilitate selection of resistant varieties. Although large cDNA microarray profiling has been generated in citrus tissues, the available protein expression data are scarce. In this study, to identify differentially expressed proteins in Citrus clementina leaves after infestation by the two-spotted spider mite Tetranychus urticae, a proteome comparison was undertaken using two-dimensional gel electrophoresis. The citrus leaf proteome profile was also compared with that of leaves treated over 0-72h with methyl jasmonate, a compound playing a key role in the defense mechanisms of plants to insect/arthropod attack. Significant variations were observed for 110 protein spots after spider mite infestation and 67 protein spots after MeJA treatments. Of these, 50 proteins were successfully identified by liquid chromatography-mass spectrometry-tandem mass spectrometry. The majority constituted photosynthesis- and metabolism-related proteins. Five were oxidative stress associated enzymes, including phospholipid glutathione peroxidase, a salt stressed associated protein, ascorbate peroxidase and Mn-superoxide dismutase. Seven were defense-related proteins, such as the pathogenesis-related acidic chitinase, the protease inhibitor miraculin-like protein, and a lectin-like protein. This is the first report of differentially regulated proteins after T. urticae attack and exogenous MeJA application in citrus leaves.


Healthy-lifestyle behaviors associated with overweight and obesity in US rural children.
There are disproportionately higher rates of overweight and obesity in poor rural communities but studies exploring children's health-related behaviors that may assist in designing effective interventions are limited. We examined the association between overweight and obesity prevalence of 401 ethnically/racially diverse, rural school-aged children and healthy-lifestyle behaviors: improving diet quality, obtaining adequate sleep, limiting screen-time viewing, and consulting a physician about a child's weight. A cross-sectional analysis was conducted on a sample of school-aged children (6-11 years) in rural regions of California, Kentucky, Mississippi, and South Carolina participating in CHANGE (Creating Healthy, Active, and Nurturing Growing-up Environments) Program, created by Save the Children, an independent organization that works with communities to improve overall child health, with the objective to reduce unhealthy weight gain in these school-aged children (grades 1-6) in rural America. After measuring children's height and weight, we17 assessed overweight and obesity (BMI ≥ 85th percentile) associations with these behaviors: improving diet quality18 (≥ 2 servings of fruits and vegetables/day), reducing whole milk, sweetened beverage consumption/day; obtaining19 adequate night-time sleep on weekdays (≥ 10 hours/night); limiting screen-time (i.e., television, video, computer,20 videogame) viewing on weekdays (≤ 2 hours/day); and consulting a physician about weight. Analyses were adjusted 21 for state of residence, children's race/ethnicity, gender, age, and government assistance. Overweight or obesity prevalence was 37 percent in Mississippi and nearly 60 percent in Kentucky. Adjusting for covariates, obese children were twice as likely to eat ≥ 2 servings of vegetables per day (OR=2.0,95% CI 1.1-3.4), less likely to consume whole milk (OR=0.4,95% CI 0.2-0.70), Their parents are more likely to be told by their doctor that their child was obese (OR=108.0,95% CI 21.9-541.6), and less likely to report talking to their child about fruits and vegetables a lot/sometimes vs. not very much/never (OR=0.4, 95%CI 0.2-0.98) compared to the parents of healthy-weight children. Rural children are not meeting recommendations to improve diet, reduce screen time and obtain adequate sleep. Although we expected obese children to be more likely to engage in unhealthy behaviors, we found the opposite to be true. It is possible that these groups of respondent parents were highly aware of their weight status and have been advised to change their children's health behaviors. Perhaps given the opportunity to participate in an intervention study in combination with a physician recommendation could have resulted in actual behavior change.


Effect of age, breast density, and family history on the sensitivity of first screening mammography.
To determine factors that influence the sensitivity of modern first screening mammography. Cross-sectional. Nine counties in northern California. A total of 28 271 women aged 30 years and older referred for first screening mammography to the Mobile Mammography Screening Program of the University of California, San Francisco, from April 1985 to March 1992, of whom 238 were subsequently diagnosed as having breast cancer. Breast cancer risk profile, 2 standard mammographic views per breast, breast density, and follow-up of abnormal and normal mammography by contacting women's physicians and by linkage to the regional Surveillance, Epidemiology, and End Results tumor registry to determine the occurrence of any invasive cancer or ductal carcinoma in situ. For women aged 50 years and older, the sensitivity of first screening mammography was relatively high and decreased slightly with increasing length of follow-up after mammography: 98.5% for 7 months of follow-up, 93.2% for 13 months, and 85.7% for 25 months. Sensitivity was higher among women aged 50 years and older when breast density was primarily fatty rather than primarily dense (98.4% vs 83.7%; P < .01). For women younger than 50 years, the sensitivity of first screening mammography also decreased with increasing length of follow-up but was significantly lower than for older women: 87.5% for 7 months of follow-up, 83.6% for 13 months, and 71.4% for 25 months. For women younger than 50 years, breast density did not affect the sensitivity of mammography (81.8% for those with primarily fatty breasts vs 85.4% for those with primarily dense breasts) and was lower among those with a family history of breast cancer (68.8%). The sensitivity of modern mammography is highest among women aged 50 years and older who have primarily fatty breast density. Sensitivity is lowest among women younger than 50 years and particularly low when the time between screenings is about 2 years or when women have a family history of breast cancer, possibly because of rapid tumor growth.


Determinants of VLDL-triglycerides production.
Plasma free fatty acids (FFA) are major substrates for hepatic VLDL-triglycerides (VLDL-TG) production. In addition, it is a common belief that VLDL-TG production is a substrate driven process primarily determined by systemic FFA delivery. This review summarizes recent research of our understanding of the regulation of VLDL-TG production. Recent studies have shown that increasing FFA flux is not inevitably associated with increased VLDL-TG production. Exercise induced increase in FFA flux resulting in unchanged VLDL-TG production in lean patients as well as in obese patients with increased hepatic fat despite exercise reduced hepatic fat content. With respect to the other inseparable conditions of insulin resistance and hyperinsulinemia, recent studies demonstrate that increased hepatic VLDL-TG production precedes the insulin resistance-associated impairment of the regulation of hepatic glucose production, whereas isolated chronic hyperinsulinemia (insulinoma) was not associated with increased VLDL-TG production. Insulin has been shown to have acute potent temporary suppressing effect on VLDL-TG production and new data demonstrates that increased glucagon reduces VLDL-TG production. Finally, recent studies indicate that sex hormones, oestrogen and testosterone, have no or very modest impact on VLDL-TG production. Regulation of hepatic VLDL-TG production involves interplay between systemic FFA delivery, hormonal, and nutritional factors that act in concert with hepatic fatty acid handling to regulate short-term and long-term VLDL-TG production. The results of recent studies underscore that our current understanding of these relationships is complex and needs further research.


Checking the Dark Matter Origin of a 3.53 keV Line with the Milky Way Center.
We detect a line at 3.539±0.011 keV in the deep exposure data set of the Galactic center region, observed with the x-ray multi-mirror mission Newton. The dark matter interpretation of the signal observed in the Perseus galaxy cluster, the Andromeda galaxy [A. Boyarsky et al., Phys. Rev. Lett. 113, 251301 (2014)], and in the stacked spectra of galaxy clusters [E. Bulbul et al., Astrophys. J. 789, 13 (2014)], together with nonobservation of the line in blank-sky data, put both lower and upper limits on the possible intensity of the line in the Galactic center data. Our result is consistent with these constraints for a class of Milky Way mass models, presented previously by observers, and would correspond to the radiative decay dark matter lifetime, τDM∼6-8×10(27) sec. Although it is hard to exclude an astrophysical origin of this line based on the Galactic center data alone, this is an important consistency check of the hypothesis that encourages us to check it with more observational data that are expected by the end of 2015.


YAP and TAZ are required for the postnatal development and the maintenance of the structural integrity of the oviduct.
The development of the Müllerian ducts into the female reproductive tract requires the coordination of multiple signaling pathways that regulate proliferation, apoptosis and differentiation. The Hippo pathway has been reported to interact with several pathways with established roles in Müllerian duct development; yet, its potential roles in reproductive tract development and function remain mostly uncharacterized. The objective of this study was therefore to characterize the roles of the Hippo transcriptional coactivators YAP and TAZ in the female reproductive tract using transgenic mouse models. This report shows that the concomitant conditional inactivation of Yap and Taz in the mouse Müllerian duct mesenchyme results in postnatal developmental defects of the oviduct. Most notably, discontinuities in the myosalpinx layer lead to the progressive formation of cystic dilations of the isthmus. These defects prevented embryo transport and subsequent implantation in older animals, causing infertility. The loss of YAP/TAZ did not appear to affect other biological processes known to be required for the maintenance of oviductal wall integrity, such as TGF-β/SMAD and Notch signaling and the biogenesis of miRNA, suggesting that the Hippo pathway acts independently of these processes to direct oviduct development. Taken together, these results suggest redundant and essential roles for YAP and TAZ in the postnatal development of the oviduct and the maintenance of its structural integrity.