The fusidic acid stimulon of Staphylococcus aureus.
Fusidic acid interferes with the release of elongation factor G (EF-G) after the translocation step of protein synthesis. The objective of this study was to characterize the fusidic acid stimulon of a fusidic acid-susceptible strain of Staphylococcus aureus (SH1000). S. aureus microarrays and real-time PCR determined transcriptome alterations occurring in SH1000 grown with fusidic acid. The Staphylococcus aureus microarray meta-database (SAMMD) compared and contrasted the SH1000 fusidic stimulon with 89 other S. aureus transcriptional datasets. Fusidic acid gradient analyses with mutant-parent strain pairs were used to identify genes required for intrinsic fusidic acid susceptibility identified during transcriptional analysis. Many genes altered by fusidic acid challenge are associated with protein synthesis. SAMMD analysis determined that the fusidic acid stimulon has the greatest overlap with the S. aureus cold shock and stringent responses. Six out of nine peptidoglycan hydrolase genes making up the two component YycFG regulon were also up-regulated by fusidic acid, as were a carboxylesterase gene (est) and two putative drug efflux pump genes (emr-qac1 and macA). Genes down-regulated by fusidic acid induction encoded a putative secreted acid phosphatase and a number of protease genes. Roles for the agr operon, the peptidoglycan hydrolase gene isaA and two proteases (htrA1 and htrA2) in the expression of fusidic acid susceptibility were revealed. The SH1000 fusidic acid stimulon includes genes involved with two stress responses, YycFG-regulated cell wall metabolism, drug efflux, and protein synthesis and turnover.


Mode of action of hydrogen peroxide and other oxidizing agents: differences between liquid and gas forms.
Antimicrobials such as chlorine dioxide, peracetic acid and hydrogen peroxide (H(2)O(2)) share a basic mechanism of action (chemical oxidation of cellular components), but profound differences arise in their efficacy against microorganisms. Optimization of activity requires an understanding of their interaction with microbial targets and a clear differentiation between the chemical efficacies of each oxidative biocide. This study aimed to elucidate the biochemical mechanisms of action of oxidizing biocides at a macromolecular level, using amino acids, protein and an enzyme as model substrates for the action of each biocide. The interactions of a number of oxidising agents (liquid and gaseous H(2)O(2), ClO(2), peracetic acid formulations) with amino acids, proteins (bovine serum albumin and aldolase) and enzymes were investigated by spectrophotometry, SDS-PAGE and alkaline phosphatase activity measurements. Biocide reactions yielded different types of oxidative structural change and different degrees of oxidation to amino acids and proteins, and differences in activity against a microbial enzyme. In particular there was a marked difference in the interactions of liquid H(2)O(2) and gaseous H(2)O(2) with the macromolecules, the latter causing greater oxidation; these results explain the dramatic differences in antimicrobial efficacy between liquid and gas peroxide. These results provide a comprehensive understanding of the differences in interactions between a number of oxidizing agents and macromolecules commonly found in microbial cells. Biochemical mechanistic differences between these oxidative biocides do exist and lead to differential effects on macromolecules. This in turn could provide an explanation as to their differences in biocidal activity, particularly between liquid and gas peroxide.


Three dimensional shape comparison of flexible proteins using the local-diameter descriptor.
Techniques for inferring the functions of the protein by comparing their shape similarity have been receiving a lot of attention. Proteins are functional units and their shape flexibility occupies an essential role in various biological processes. Several shape descriptors have demonstrated the capability of protein shape comparison by treating them as rigid bodies. But this may give rise to an incorrect comparison of flexible protein shapes. We introduce an efficient approach for comparing flexible protein shapes by adapting a local diameter (LD) descriptor. The LD descriptor, developed recently to handle skeleton based shape deformations 1, is adapted in this work to capture the invariant properties of shape deformations caused by the motion of the protein backbone. Every sampled point on the protein surface is assigned a value measuring the diameter of the 3D shape in the neighborhood of that point. The LD descriptor is built in the form of a one dimensional histogram from the distribution of the diameter values. The histogram based shape representation reduces the shape comparison problem of the flexible protein to a simple distance calculation between 1D feature vectors. Experimental results indicate how the LD descriptor accurately treats the protein shape deformation. In addition, we use the LD descriptor for protein shape retrieval and compare it to the effectiveness of conventional shape descriptors. A sensitivity-specificity plot shows that the LD descriptor performs much better than the conventional shape descriptors in terms of consistency over a family of proteins and discernibility across families of different proteins. Our study provides an effective technique for comparing the shape of flexible proteins. The experimental results demonstrate the insensitivity of the LD descriptor to protein shape deformation. The proposed method will be potentially useful for molecule retrieval with similar shapes and rapid structure retrieval for proteins. The demos and supplemental materials are available on https://engineering.purdue.edu/PRECISE/LDD.


Home food preparation techniques impacted the availability of natural antioxidants and bioactivities in kale and broccoli.
This study evaluated the effects of grinding and chopping with/without microwaving on the health-beneficial components, and antioxidant, anti-inflammation and anti-proliferation capacities of commercial kale and broccoli samples. The availability of indole-3-carbinol (I3C) was evaluated using high-performance liquid chromatography. The total phenolic contents, the scavenging activities against DPPH, oxygen, hydroxyl and ABTS cation radicals, and cell-based antioxidant activities were determined for the antioxidant capacities. The results indicated that chopping released the least nutraceutical components and antioxidant compounds. Microwaving had no effect on the I3C release from kale, but resulted in an elevated (more than 2-fold) release of I3C from broccoli. In addition, the choice of a blender affected the availability of the anti-proliferative compounds from the vegetables, while it had no effect on the availability of their anti-inflammatory compounds. In summary, different food preparation methods could strongly impact the availability of bioactive factors in the selected vegetables. These findings suggest that choosing an appropriate food processing method for each vegetable might be critical to obtain desirable health-beneficial effects.


Cognitive Decline and Hearing Health Care for Older Adults.
The purpose of this article is to consider the implications of age-related cognitive decline for hearing health care. Recent research and current thinking about age-related declines in cognition and the links between auditory and cognitive aging are reviewed briefly. Implications of this research for improving prevention, assessment, and intervention in audiologic practice and for enhancing interprofessional teamwork are highlighted. Given the important connection between auditory and cognitive aging and given the high prevalence of both hearing and cognitive impairments in the oldest older adults, health care services could be improved by taking into account how both the ear and the brain change over the life span. By incorporating cognitive factors into audiologic prevention, assessment, and intervention, hearing health care can contribute to better hearing and communication as well as to healthy aging.


Using variance information in magnetoencephalography measures of functional connectivity.
The use of magnetoencephalography (MEG) to assess long range functional connectivity across large scale distributed brain networks is gaining popularity. Recent work has shown that electrodynamic networks can be assessed using both seed based correlation or independent component analysis (ICA) applied to MEG data and further that such metrics agree with fMRI studies. To date, techniques for MEG connectivity assessment have typically used a variance normalised approach, either through the use of Pearson correlation coefficients or via variance normalisation of envelope timecourses prior to ICA. Here, we show that the use of variance information (i.e. data that have not been variance normalised) in source space projected Hilbert envelope time series yields important spatial information, and is of significant functional relevance. Further, we show that employing this information in functional connectivity analyses improves the spatial delineation of network nodes using both seed based and ICA approaches. The use of variance is particularly important in MEG since the non-independence of source space voxels (brought about by the ill-posed MEG inverse problem) means that spurious signals can exist in areas of low signal variance. We therefore suggest that this approach be incorporated into future studies.


Crystallographic and modeling studies of RNase III suggest a mechanism for double-stranded RNA cleavage.
Aquifex aeolicus Ribonuclease III (Aa-RNase III) belongs to the family of Mg(2+)-dependent endonucleases that show specificity for double-stranded RNA (dsRNA). RNase III is conserved in all known bacteria and eukaryotes and has 1-2 copies of a 9-residue consensus sequence, known as the RNase III signature motif. The bacterial RNase III proteins are the simplest, consisting of two domains: an N-terminal endonuclease domain, followed by a double-stranded RNA binding domain (dsRBD). The three-dimensional structure of the dsRBD in Escherichia coli RNase III has been elucidated; no structural information is available for the endonuclease domain of any RNase III. We present the crystal structures of the Aa-RNase III endonuclease domain in its ligand-free form and in complex with Mn(2+). The structures reveal a novel protein fold and suggest a mechanism for dsRNA cleavage. On the basis of structural, genetic, and biological data, we have constructed a hypothetical model of Aa-RNase III in complex with dsRNA and Mg(2+) ion, which provides the first glimpse of RNase III in action. The functional Aa-RNase III dimer is formed via mainly hydrophobic interactions, including a "ball-and-socket" junction that ensures accurate alignment of the two monomers. The fold of the polypeptide chain and its dimerization create a valley with two compound active centers at each end of the valley. The valley can accommodate a dsRNA substrate. Mn(2+) binding has significant impact on crystal packing, intermolecular interactions, thermal stability, and the formation of two RNA-cutting sites within each compound active center.


Structural and functional characterization of a putative polysaccharide deacetylase of the human parasite Encephalitozoon cuniculi.
The microsporidian Encephalitozoon cuniculi is an intracellular eukaryotic parasite considered to be an emerging opportunistic human pathogen. The infectious stage of this parasite is a unicellular spore that is surrounded by a chitin containing endospore layer and an external proteinaceous exospore. A putative chitin deacetylase (ECU11_0510) localizes to the interface between the plasma membrane and the endospore. Chitin deacetylases are family 4 carbohydrate esterases in the CAZY classification, and several bacterial members of this family are involved in evading lysis by host glycosidases, through partial de-N-acetylation of cell wall peptidoglycan. Similarly, ECU11_0510 could be important for E. cuniculi survival in the host, by protecting the chitin layer from hydrolysis by human chitinases. Here, we describe the biochemical, structural, and glycan binding properties of the protein. Enzymatic analyses showed that the putative deacetylase is unable to deacetylate chitooligosaccharides or crystalline beta-chitin. Furthermore, carbohydrate microarray analysis revealed that the protein bound neither chitooligosaccharides nor any of a wide range of other glycans or chitin. The high resolution crystal structure revealed dramatic rearrangements in the positions of catalytic and substrate binding residues, which explain the loss of deacetylase activity, adding to the unusual structural plasticity observed in other members of this esterase family. Thus, it appears that the ECU11_0510 protein is not a carbohydrate deacetylase and may fulfill an as yet undiscovered role in the E. cuniculi parasite.


Characteristics and potential functions of human milk adiponectin.
Adiponectin is a protein hormone produced by adipose tissue, whose circulating levels are inversely related to adiposity and inflammation. Adiponectin circulates as oligomers, from the low-molecular-weight trimer to the high-molecular-weight octodecamer (18 mer). Each oligomer has distinct biological activities, which include enhancement of insulin sensitivity and metabolic control and suppression of inflammation. Adiponectin occurs in human milk at higher concentrations than leptin. The adiponectin in human milk is almost entirely of the high-molecular-weight form, the form with the highest activity in controlling many types of metabolic processes. Human adiponectin fed to infant mice is transported across the intestinal mucosa into the serum. An inverse relationship between adiponectin levels in milk and adiposity (weight-for-height) of the breast-fed infant was observed and could be due to modulation of infant metabolism by milk adiponectin and may be related to the observed protection against obesity by breast-feeding. Human milk may be a medium whereby the hormonal milieu (in response to internal factors and the environment) of the mother can be used to communicate with the breast-fed infant to modify infant metabolic processes. Transmission of information from mother to infant through milk may allow adaptation to fluctuating environmental conditions.


Screening for frailty in primary care: Accuracy of gait speed and hand-grip strength.
To examine the accuracy of individual Fried frailty phenotype measures in identifying the Fried frailty phenotype in primary care. Retrospective chart review. A community-based primary care practice in Kitchener, Ont. A total of 516 patients 75 years of age and older who underwent frailty screening. Using modified Fried frailty phenotype measures, frailty criteria included gait speed, hand-grip strength as measured by a dynamometer, and self-reported exhaustion, low physical activity, and unintended weight loss. Sensitivity, specificity, accuracy, and precision were calculated for single-trait and dual-trait markers. Complete frailty screening data were available for 383 patients. The overall prevalence of frailty based on the presence of 3 or more frailty criteria was 6.5%. The overall prevalence of individual Fried frailty phenotype markers ranged from 2.1% to 19.6%. The individual criteria all showed sensitivity and specificity of more than 80%, with the exception of weight loss (8.3% and 97.4%, respectively). The positive predictive value of the single-item criteria in predicting the Fried frailty phenotype ranged from 12.5% to 52.5%. When gait speed and hand-grip strength were combined as a dual measure, the positive predictive value increased to 87.5%. There is a need for frailty measures that are psychometrically sound and feasible to administer in primary care. While use of gait speed or grip strength alone was found to be sensitive and specific as a proxy for the Fried frailty phenotype, use of both measures together was found to be accurate, precise, specific, and more sensitive than other possible combinations. Assessing both measures is feasible within primary care.


Crystal structures of thrombin complexed to a novel series of synthetic inhibitors containing a 5,5-trans-lactone template.
The binding modes of four active site-directed, acylating inhibitors of human alpha-thrombin have been determined using X-ray crystallography. These inhibitors (GR157368, GR166081, GR167088, and GR179849) are representatives of a series utilizing a novel 5, 5-trans-lactone template to specifically acylate Ser195 of thrombin, resulting in an acyl complex. In each case the crystal structure of the complex reveals a binding mode which is consistent with the formation of a covalent bond between the ring-opened lactone of the inhibitor and residue Ser195. Improvements in potency and selectivity of these inhibitors for thrombin are rationalized on the basis of the observed protein/inhibitor interactions identified in these complexes. Occupation of the thrombin S2 and S3 pockets is shown to be directly correlated with improved binding and a degree of selectivity. The binding mode of GR179849 to thrombin is compared with the thrombin/PPACK complex [Bode, W., Turk, D., and Karshikov, A. (1992) Protein Sci. 1, 426-471] as this represents the archetypal binding mode for a thrombin inhibitor. This series of crystal structures is the first to be reported of synthetic, nonpeptidic acylating inhibitors bound to thrombin and provides details of the molecular recognition features that resulted in nanomolar potency.


Hybrid Imaging in Ischemic Heart Disease.
Hybrid imaging for ischemic heart disease refers to the fusion of information from a single or usually from multiple cardiovascular imaging modalities enabling synergistic assessment of the presence, the extent, and the severity of coronary atherosclerotic disease along with the hemodynamic significance of lesions and/or with evaluation of the myocardial function. A combination of coronary computed tomography angiography with myocardial perfusion imaging, such as single-photon emission computed tomography and positron emission tomography, has been adopted in several centers and implemented in international coronary artery disease management guidelines. Interest has increased in novel hybrid methods including coronary computed tomography angiography-derived fractional flow reserve and computed tomography perfusion and these techniques hold promise for the imminent diagnostic and management approaches of patients with coronary artery disease. In this review, we discuss the currently available hybrid noninvasive imaging modalities used in clinical practice, research approaches, and exciting potential future technological developments.


Heritability of haemodynamics in the ascending aorta.
Blood flow in the vasculature can be characterised by dimensionless numbers commonly used to define the level of instabilities in the flow, for example the Reynolds number, Re. Haemodynamics play a key role in cardiovascular disease (CVD) progression. Genetic studies have identified mechanosensitive genes with causal roles in CVD. Given that CVD is highly heritable and abnormal blood flow may increase risk, we investigated the heritability of fluid metrics in the ascending aorta calculated using patient-specific data from cardiac magnetic resonance (CMR) imaging. 341 participants from 108 British Caucasian families were phenotyped by CMR and genotyped for 557,124 SNPs. Flow metrics were derived from the CMR images to provide some local information about blood flow in the ascending aorta, based on maximum values at systole at a single location, denoted max, and a 'peak mean' value averaged over the area of the cross section, denoted pm. Heritability was estimated using pedigree-based (QTDT) and SNP-based (GCTA-GREML) methods. Estimates of Reynolds number based on spatially averaged local flow during systole showed substantial heritability ([Formula: see text], [Formula: see text]), while the estimated heritability for Reynolds number calculated using the absolute local maximum velocity was not statistically significant (12-13%; [Formula: see text]). Heritability estimates of the geometric quantities alone; e.g. aortic diameter ([Formula: see text], [Formula: see text]), were also substantially heritable, as described previously. These findings indicate the potential for the discovery of genetic factors influencing haemodynamic traits in large-scale genotyped and phenotyped cohorts where local spatial averaging is used, rather than instantaneous values. Future Mendelian randomisation studies of aortic haemodynamic estimates, which are swift to derive in a clinical setting, will allow for the investigation of causality of abnormal blood flow in CVD.


Deep hierarchies in the primate visual cortex: what can we learn for computer vision?
Computational modeling of the primate visual system yields insights of potential relevance to some of the challenges that computer vision is facing, such as object recognition and categorization, motion detection and activity recognition, or vision-based navigation and manipulation. This paper reviews some functional principles and structures that are generally thought to underlie the primate visual cortex, and attempts to extract biological principles that could further advance computer vision research. Organized for a computer vision audience, we present functional principles of the processing hierarchies present in the primate visual system considering recent discoveries in neurophysiology. The hierarchical processing in the primate visual system is characterized by a sequence of different levels of processing (on the order of 10) that constitute a deep hierarchy in contrast to the flat vision architectures predominantly used in today's mainstream computer vision. We hope that the functional description of the deep hierarchies realized in the primate visual system provides valuable insights for the design of computer vision algorithms, fostering increasingly productive interaction between biological and computer vision research.


Inhibition of photosynthetic CO₂ fixation in the coral Pocillopora damicornis and its relationship to thermal bleaching.
Two inhibitors of the Calvin-Benson cycle [glycolaldehyde (GA) and potassium cyanide (KCN)] were used in cultured Symbiodinium cells and in nubbins of the coral Pocillopora damicornis to test the hypothesis that inhibition of the Calvin-Benson cycle triggers coral bleaching. Inhibitor concentration range-finding trials aimed to determine the appropriate concentration to generate inhibition of the Calvin-Benson cycle, but avoid other metabolic impacts to the symbiont and the animal host. Both 3 mmol l(-1) GA and 20 μmol l(-1) KCN caused minimal inhibition of host respiration, but did induce photosynthetic impairment, measured by a loss of photosystem II function and oxygen production. GA did not affect the severity of bleaching, nor induce bleaching in the absence of thermal stress, suggesting inhibition of the Calvin-Benson cycle by GA does not initiate bleaching in P. damicornis. In contrast, KCN did activate a bleaching response through symbiont expulsion, which occurred in the presence and absence of thermal stress. While KCN is an inhibitor of the Calvin-Benson cycle, it also promotes reactive oxygen species formation, and it is likely that this was the principal agent in the coral bleaching process. These findings do not support the hypothesis that temperature-induced inhibition of the Calvin-Benson cycle alone induces coral bleaching.


Weekly primaquine for radical cure of patients with Plasmodium vivax malaria and glucose-6-phosphate dehydrogenase deficiency.
The World Health Organization recommends that primaquine should be given once weekly for 8-weeks to patients with Plasmodium vivax malaria and glucose-6-phosphate dehydrogenase (G6PD) deficiency, but data on its antirelapse efficacy and safety are limited. Within the context of a multicentre, randomised clinical trial of two primaquine regimens in P. vivax malaria, patients with G6PD deficiency were excluded and enrolled into a separate 12-month observational study. They were treated with a weekly dose of 0.75 mg/kg primaquine for 8 weeks (PQ8W) plus dihydroartemisinin piperaquine (Indonesia) or chloroquine (Afghanistan, Ethiopia, Vietnam). G6PD status was diagnosed using the fluorescent spot test and confirmed by genotyping for locally prevalent G6PD variants. The risk of P. vivax recurrence following PQ8W and the consequent haematological recovery were characterized in all patients and in patients with genotypically confirmed G6PD variants, and compared with the patients enrolled in the main randomised control trial. Between July 2014 and November 2017, 42 male and 8 female patients were enrolled in Afghanistan (6), Ethiopia (5), Indonesia (19), and Vietnam (20). G6PD deficiency was confirmed by genotyping in 31 patients: Viangchan (14), Mediterranean (4), 357A-G (3), Canton (2), Kaiping (2), and one each for A-, Chatham, Gaohe, Ludhiana, Orissa, and Vanua Lava. Two patients had recurrent P. vivax parasitaemia (days 68 and 207). The overall 12-month cumulative risk of recurrent P. vivax malaria was 5.1% (95% CI: 1.3-18.9) and the incidence rate of recurrence was 46.8 per 1000 person-years (95% CI: 11.7-187.1). The risk of P. vivax recurrence was lower in G6PD deficient patients treated with PQ8W compared to G6PD normal patients in all treatment arms of the randomised controlled trial. Two of the 26 confirmed hemizygous males had a significant fall in haemoglobin (>5g/dl) after the first dose but were able to complete their 8 week regimen. PQ8W was highly effective in preventing P. vivax recurrences. Whilst PQ8W was well tolerated in most patients across a range of different G6PD variants, significant falls in haemoglobin may occur after the first dose and require clinical monitoring. This trial is registered at ClinicalTrials.gov (NCT01814683).


Risk factors for the between-herd spread of Mycobacterium bovis in Canadian cattle and cervids between 1985 and 1994.
Microorganisms of the genus Mycobacterium cause tuberculosis in many animal species including humans. Generally, Mycobacterium bovis (M. bovis) infects cattle and cervids, but it has the potential to infect virtually all species of mammals. This study examined and analysed the data from the nine outbreaks of tuberculosis in Canadian cattle and cervids from 1985 to 1994. For the purposes of this study, a positive herd was one with at least one culture-positive animal. A reactor herd had at least one animal which was positive or suspicious on a mid-cervical, comparative cervical, or gross or histopathologic test for tuberculosis. Herd classification was either reactor/positive or negative. Data for the study were collected from the outbreak records in the Regional or District offices of Agriculture and Agri-Food Canada. Logistic regression was used to study spread of tuberculosis between herds. Two risk factors were identified: increasing herd size; and, the reason why a herd was investigated as part of the outbreak. This latter factor was interpreted as a surrogate measure for the nature of contact between the study herd and other potentially infected herds in the outbreak. Increasing herd size was associated with an increased risk of being positive for tuberculosis with herds of 16-35, 36-80, and >80 animals having odds ratios of 2.9, 5.8, and 9.3, respectively, when compared to a herd size of <16 animals (p < 0.001). When compared to perimeter testing (i.e. testing herds within a specified radius of an infected herd), all other reasons for investigation had higher odds ratios (p < 0.001). These odds ratios were 57.8 for traceout herds (i.e. herds which had purchased animal(s) from a reactor/positive herd), 31.8 for herds with pasture or fence-line contact with a reactor/positive herd, and 14.9 for traceback herds (i.e. herds which had been a source of animals for reactor/positive herd(s)).


Gluteal muscle fatty atrophy is not associated with elevated blood metal ions or pseudotumors in patients with a unilateral metal-on-metal hip replacement.
There are no international guidelines to define adverse reaction to metal debris (ARMD). Muscle fatty atrophy has been reported to be common in patients with failing metal-on-metal (MoM) hip replacements. We assessed whether gluteal muscle fatty atrophy is associated with elevated blood metal ion levels and pseudotumors. 263 consecutive patients with unilateral ASR XL total hip replacement using a posterior approach and with an unoperated contralateral hip were included in the study. All patients had undergone a standard screening program at our institution, including MRI and blood metal ion measurement. Muscle fatty atrophy was graded as being absent, mild, moderate, or severe in each of the gluteal muscles. The prevalence of moderate-to-severe gluteal muscle atrophy was low (12% for gluteus minimus, 10% for gluteus medius, and 2% for gluteus maximus). Muscle atrophy was neither associated with elevated blood metal ion levels (> 5 ppb) nor with the presence of a clear (solid- or mixed-type) pseudotumor seen in MRI. A combination of moderate-to-severe atrophy in MRI, elevated blood metal ion levels, and MRI-confirmed mixed or solid pseudotumor was rare. Multivariable regression revealed that "preoperative diagnosis other than osteoarthrosis" was the strongest predictor of the presence of fatty atrophy. Gluteal muscle atrophy may be a clinically significant finding with influence on hip muscle strength in patients with MoM hip replacement. However, our results suggest that gluteal muscle atrophy seen in MRI is not associated with either the presence or severity of ARMD, at least not in patients who have been operated on using the posterior approach.


People are averse to machines making moral decisions.
Do people want autonomous machines making moral decisions? Nine studies suggest that that the answer is 'no'-in part because machines lack a complete mind. Studies 1-6 find that people are averse to machines making morally-relevant driving, legal, medical, and military decisions, and that this aversion is mediated by the perception that machines can neither fully think nor feel. Studies 5-6 find that this aversion exists even when moral decisions have positive outcomes. Studies 7-9 briefly investigate three potential routes to increasing the acceptability of machine moral decision-making: limiting the machine to an advisory role (Study 7), increasing machines' perceived experience (Study 8), and increasing machines' perceived expertise (Study 9). Although some of these routes show promise, the aversion to machine moral decision-making is difficult to eliminate. This aversion may prove challenging for the integration of autonomous technology in moral domains including medicine, the law, the military, and self-driving vehicles.


Species Cross-Reactivity of Antibodies Used to Treat Ophthalmic Conditions.
The species cross-reactivity of the monoclonal antibodies infliximab, bevacizumab, and an anti-VEGF-B antibody, 2H10, in humans and rodents was determined. The binding of infliximab to human, mouse, and rat TNF-α, of bevacizumab to human, mouse, and rat VEGF-A, and of the 2H10 antibody to human, mouse, and rat VEGF-B was evaluated by ELISA. The sequence of human, mouse, and rat TNF-α and VEGF-A at the binding sites for infliximab and bevacizumab were compared. Infliximab bound to human TNF-α, but no binding to mouse or rat TNF-α was detected between 10 pg/mL and 10 μg/ml. Sequence comparison of the binding site revealed four changes in mouse and five in rat TNF-α compared with human. Bevacizumab bound strongly to human VEGF-A, but showed 5-log weaker binding to both mouse and rat VEGF-A. There was a single amino acid substitution in mouse and rat VEGF-A at the bevacizumab binding site. The 2H10 antibody displayed a similar binding profile to human, mouse, and rat VEGF-B. The species cross-reactivity of monoclonal antibodies should be determined prior to their use in preclinical animal models. The 2H10 antibody binds to human, mouse, and rat VEGF-B making it suitable for testing in rodent models of human disease.


Photodynamic Therapy and Multi-Modality Imaging of Up-Conversion Nanomaterial Doped with AuNPs.
Two key concerns exist in contemporary cancer chemotherapy in clinic: limited therapeutic efficiency and substantial side effects in patients. In recent years, researchers have been investigating a revolutionary cancer treatment technique, and photodynamic therapy (PDT) has been proposed by many scholars. A drug for photodynamic cancer treatment was synthesized using the hydrothermal method, which has a high efficiency to release reactive oxygen species (ROS). It may also be utilized as a clear multi-modality bioimaging platform for photoacoustic imaging (PAI) due to its photothermal effect, computed tomography (CT), and magnetic resonance imaging (MRI). When compared to single-modality imaging, multi-modality imaging delivers far more thorough and precise details for cancer diagnosis. Furthermore, Au-doped up-conversion nanoparticles (UCNPs) have an exceptionally high luminous intensity. The Au-doped UCNPs, in particular, are non-toxic to tissues without laser at an 808 nm wavelength, endowing the as-prepared medications with outstanding therapeutic efficacy but exceptionally low side effects. These findings may encourage fresh effective imaging-guided approaches to meet the goal of photodynamic cancer therapy to be created.


Shotgun proteomics of Methanococcus jannaschii and insights into methanogenesis.
Methanococcus jannaschii is an autotrophic hyperthermophilic archaeon isolated from an oceanic hydrothermal vent. Its primary pathway for energy production is methanogenesis from H2 and CO2. High-throughput Multidimensional Protein Identification Technology based on microcapillary LC/LC/ MS/MS was used to investigate the proteome of M. jannaschii and the methanogenesis pathway in cells grown in complex medium with high H2 supply. A total of 963 proteins have been unambiguously identified. The identified proteins represent approximately 54% of the whole genome of M. jannaschii. About 44% of the identified proteins are either conserved hypothetical or hypothetical proteins. We identified 83-95% of the proteins predicted to be involved in amino acid biosynthesis, cellular processes, central intermediary metabolism, energy metabolism, protein synthesis, transcription, and purine, pyridine, nucleoside, and nucleotide synthesis. Over 40% of these proteins have better than 50% sequence coverage. Approximately 90% of the predicted methanogenesis proteins were detected. In contrast, only 27-37% of predicted hypothetical proteins, proteins involved in transport and binding, and proteins with regulatory functions were identified. High peptide number, spectrum count, and sequence coverage have been used as indicators of high expression levels and are in good agreement with codon bias analysis. Predicted intein peptides were detected in MJ1043 (DNA-directed RNA polymerase, subunit A"), MJ0542 (phosphoenolpyruvate synthase), MJ0782 (transcription initiation factor IIB), and MJ1422 (putative replication factor C subunit). New peptides created by protein splicing were detected in MJ0885 (DNA dependent DNA polymerase), MJ0542, and MJ0782. The methanogenesis pathway and the enzymes involved are also discussed.


Phonological, visual, and semantic coding strategies and children's short-term picture memory span.
Three experiments addressed controversies in the previous literature on the development of phonological and other forms of short-term memory coding in children, using assessments of picture memory span that ruled out potentially confounding effects of verbal input and output. Picture materials were varied in terms of phonological similarity, visual similarity, semantic similarity, and word length. Older children (6/8-year-olds), but not younger children (4/5-year-olds), demonstrated robust and consistent phonological similarity and word length effects, indicating that they were using phonological coding strategies. This confirmed findings initially reported by Conrad (1971), but subsequently questioned by other authors. However, in contrast to some previous research, little evidence was found for a distinct visual coding stage at 4 years, casting doubt on assumptions that this is a developmental stage that consistently precedes phonological coding. There was some evidence for a dual visual and phonological coding stage prior to exclusive use of phonological coding at around 5-6 years. Evidence for semantic similarity effects was limited, suggesting that semantic coding is not a key method by which young children recall lists of pictures.


Extracellular Vesicles: An Emerging Mechanism Governing the Secretion and Biological Roles of Tenascin-C.
ECM composition and architecture are tightly regulated for tissue homeostasis. Different disorders have been associated to alterations in the levels of proteins such as collagens, fibronectin (FN) or tenascin-C (TnC). TnC emerges as a key regulator of multiple inflammatory processes, both during physiological tissue repair as well as pathological conditions ranging from tumor progression to cardiovascular disease. Importantly, our current understanding as to how TnC and other non-collagen ECM components are secreted has remained elusive. Extracellular vesicles (EVs) are small membrane-bound particles released to the extracellular space by most cell types, playing a key role in cell-cell communication. A broad range of cellular components can be transported by EVs (e.g. nucleic acids, lipids, signalling molecules and proteins). These cargoes can be transferred to target cells, potentially modulating their function. Recently, several extracellular matrix (ECM) proteins have been characterized as bona fide EV cargoes, exosomal secretion being particularly critical for TnC. EV-dependent ECM secretion might underpin diseases where ECM integrity is altered, establishing novel concepts in the field such as ECM nucleation over long distances, and highlighting novel opportunities for diagnostics and therapeutic intervention. Here, we review recent findings and standing questions on the molecular mechanisms governing EV-dependent ECM secretion and its potential relevance for disease, with a focus on TnC.


High Resolution Mass Profile of Bufadienolides and Peptides Combing with Anti-Tumor Cell Screening and Multivariate Analysis for the Quality Evaluation of Bufonis Venenum.
In order to evaluate the quality of Bufonis Venenum commercial herbs, a three-step qualitative and quantitative research study was performed. Firstly, we tried to identify small molecules and peptides in Bufonis Venenum using pre-fractionation chromatography and high-resolution mass spectrometry. The database search of the small molecules and peptides of Bufonis Venenum revealed that the dried venom consisted of free/conjugated-type bufadienolides and peptides with a mass range of 0.4-2 kDa. Secondly, we used partial least squares (PLS) multivariate statistical analysis to screen bufadienolides markers (VIP > 1.5) responsible for the anti-tumor cell activity of Bufonis Venenum, including 21 identified bufadienolides and 7 unknown compounds. It is noticeable that these bufadienolide markers could not be recognized by traditional HPLC-UV based spectrum-effect relationship analysis (correlation coefficient ranging from -0.24 to 0.40). Finally, we proposed a weight coefficient-based corrected total contents of 9 bufadienolides as a quality evaluation indicator, which had good correlation with inhibitory effects on tumor cells of commercial Bufonis Venenum. The correlation coefficient increased from 0.4 to 0.6. Thus, our pre-fractionation chromatography and mass spectrometry strategy had significant advancement over the traditional spectrum-effect relationship method for chemical marker identification. These results could be crucial and helpful in the development of a quality evaluation method that could reflect the pharmacological activity of Bufonis Venenum.


Functional characterization of UvrD helicases from Haemophilus influenzae and Helicobacter pylori.
Haemophilus influenzae and Helicobacter pylori are major bacterial pathogens that face high levels of genotoxic stress within their host. UvrD, a ubiquitous bacterial helicase that plays important roles in multiple DNA metabolic pathways, is essential for genome stability and might, therefore, be crucial in bacterial physiology and pathogenesis. In this study, the functional characterization of UvrD helicase from Haemophilus influenzae and Helicobacter pylori is reported. UvrD from Haemophilus influenzae (HiUvrD) and Helicobacter pylori (HpUvrD) exhibit strong single-stranded DNA-specific ATPase and 3'-5' helicase activities. Mutation of highly conserved arginine (R288) in HiUvrD and glutamate (E206) in HpUvrD abrogated their activities. Both the proteins were able to bind and unwind a variety of DNA structures including duplexes with strand discontinuities and branches, three- and four-way junctions that underpin their role in DNA replication, repair and recombination. HiUvrD required a minimum of 12 nucleotides, whereas HpUvrD preferred 20 or more nucleotides of 3'-single-stranded DNA tail for efficient unwinding of duplex DNA. Interestingly, HpUvrD was able to hydrolyze and utilize GTP for its helicase activity although not as effectively as ATP, which has not been reported to date for UvrD characterized from other organisms. HiUvrD and HpUvrD were found to exist predominantly as monomers in solution together with multimeric forms. Noticeably, deletion of distal C-terminal 48 amino acid residues disrupted the oligomerization of HiUvrD, whereas deletion of 63 amino acids from C-terminus of HpUvrD had no effect on its oligomerization. This study presents the characteristic features and comparative analysis of Haemophilus influenzae and Helicobacter pylori UvrD, and constitutes the basis for understanding the role of UvrD in the biology and virulence of these pathogens.


Electronic medication packaging devices and medication adherence: a systematic review.
Medication nonadherence, which has been estimated to affect 28% to 31% of US patients with hypertension, hyperlipidemia, and diabetes, may be improved by electronic medication packaging (EMP) devices (adherence-monitoring devices incorporated into the packaging of a prescription medication). To investigate whether EMP devices are associated with improved adherence and to identify and describe common features of EMP devices. Systematic review of peer-reviewed studies testing the effectiveness of EMP systems in the MEDLINE, EMBASE, PsycINFO, CINAHL, International Pharmaceutical Abstracts, and Sociological Abstracts databases from searches conducted to June 13, 2014, with extraction of associations between the interventions and adherence, as well as other key findings. Each study was assessed for bias using the Cochrane Handbook for Systematic Reviews of Interventions; features of EMP devices and interventions were qualitatively assessed. Thirty-seven studies (32 randomized and 5 nonrandomized) including 4326 patients met inclusion criteria (10 patient interface-only "simple" interventions and 29 "complex" interventions integrated into the health care system [2 qualified for both categories]). Overall, the effect estimates for differences in mean adherence ranged from a decrease of 2.9% to an increase of 34.0%, and the those for differences in the proportion of patients defined as adherent ranged from a decrease of 8.0% to an increase of 49.5%. We identified 5 common EMP characteristics: recorded dosing events and stored records of adherence, audiovisual reminders to cue dosing, digital displays, real-time monitoring, and feedback on adherence performance. Many varieties of EMP devices exist. However, data supporting their use are limited, with variability in the quality of studies testing EMP devices. Devices integrated into the care delivery system and designed to record dosing events are most frequently associated with improved adherence, compared with other devices. Higher-quality evidence is needed to determine the effect, if any, of these low-cost interventions on medication nonadherence and to identify their most useful components.


Diversity and biotic homogenization of urban land-snail faunas in relation to habitat types and macroclimate in 32 central European cities.
The effects of non-native species invasions on community diversity and biotic homogenization have been described for various taxa in urban environments, but not for land snails. Here we relate the diversity of native and non-native land-snail urban faunas to urban habitat types and macroclimate, and analyse homogenization effects of non-native species across cities and within the main urban habitat types. Land-snail species were recorded in seven 1-ha plots in 32 cities of ten countries of Central Europe and Benelux (224 plots in total). Each plot represented one urban habitat type characterized by different management and a specific disturbance regime. For each plot, we obtained January, July and mean annual temperature and annual precipitation. Snail species were classified into either native or non-native. The effects of habitat type and macroclimate on the number of native and non-native species were analysed using generalized estimating equations; the homogenization effect of non-native species based on the Jaccard similarity index and homogenization index. We recorded 67 native and 20 non-native species. Besides being more numerous, native species also had much higher beta diversity than non-natives. There were significant differences between the studied habitat types in the numbers of native and non-native species, both of which decreased from less to heavily urbanized habitats. Macroclimate was more important for the number of non-native than native species; however in both cases the effect of climate on diversity was overridden by the effect of urban habitat type. This is the first study on urban land snails documenting that non-native land-snail species significantly contribute to homogenization among whole cities, but both the homogenization and diversification effects occur when individual habitat types are compared among cities. This indicates that the spread of non-native snail species may cause biotic homogenization, but it depends on scale and habitat type.


Health promotion: the impact of beliefs of health benefits, social relations and enjoyment on exercise continuation.
The aim of this study was to explore how and why participants in structured exercise intervention programs continue or stop exercising after the program is finished. We conducted four focus group interviews with four groups of middle-aged and elderly men (total n = 28) who had participated in exercise interventions involving playing either a team sport (football) or a more individually focused activity (spinning and crossfit). Our results show that different social, organizational and material structures inherent in the different activities shape the subjects' enjoyment of exercise participation, as well as their intention and ability to continue being active. In conclusion, team sport activities seem to be intrinsically motivating to the participants through positive social interaction and play. They are therefore more likely to result in exercise continuation than activities that rely primarily on extrinsic motivation such as the expectation of improved health and well-being.


Fluorescent CRISPR Adaptation Reporter for rapid quantification of spacer acquisition.
CRISPR-Cas systems are adaptive prokaryotic immune systems protecting against horizontally transferred DNA or RNA such as viruses and other mobile genetic elements. Memory of past invaders is stored as spacers in CRISPR loci in a process called adaptation. Here we developed a novel assay where spacer integration results in fluorescence, enabling detection of memory formation in single cells and quantification of as few as 0.05% cells with expanded CRISPR arrays in a bacterial population. Using this fluorescent CRISPR Adaptation Reporter (f-CAR), we quantified adaptation of the two CRISPR arrays of the type I-E CRISPR-Cas system in Escherichia coli, and confirmed that more integration events are targeted to CRISPR-II than to CRISPR-I. The f-CAR conveniently analyzes and compares many samples, allowing new insights into adaptation. For instance, we show that in an E. coli culture the majority of acquisition events occur in late exponential phase.


Hypotonic induction of SGK1 and Na+ transport in A6 cells.
Serum and glucocorticoid-regulated kinase-1 (SGK1) is a serine-threonine kinase that is regulated at the transcriptional level by numerous regulatory inputs, including mineralocorticoids, glucocorticoids, follicle-stimulating hormone, and osmotic stress. In the distal nephron, SGK1 is induced by aldosterone and regulates epithelial Na+ channel-mediated transepithelial Na+ transport. In other tissues, including liver and shark rectal gland, SGK1 is regulated by hypertonic stress and is thought to modulate epithelial Na+ channel- and Na+-K+-2Cl- cotransporter-mediated Na+ transport. In this report, we examined the regulation of SGK1 mRNA and protein expression and Na+ currents in response to osmotic stress in A6 cells, a cultured cell line derived from Xenopus laevis distal nephron. We found that in contrast to hepatocytes and rectal gland cells, hypotonic conditions stimulated SGK1 expression and Na+ transport in A6 cells. Moreover, a correlation was found between SGK1 induction and the later phase of activation of Na+ transport in response to hypotonic treatment. When A6 cells were pretreated with an inhibitor of phosphatidylinositol 3-kinase (PI3K), Na+ transport was blunted and only inactive forms of SGK1 were expressed. Surprisingly, these results demonstrate that both hypertonic and hypotonic stimuli can induce SGK1 gene expression in a cell type-dependent fashion. Moreover, these data lend support to the view that SGK1 contributes to the defense of extracellular fluid volume and tonicity in amphibia by mediating a component of the hypotonic induction of distal nephron Na+ transport.


Race and ethnicity, obesity, metabolic health, and risk of cardiovascular disease in postmenopausal women.
It is unclear whether obesity unaccompanied by metabolic abnormalities is associated with increased cardiovascular disease risk across racial and ethnic subgroups. We identified 14 364 postmenopausal women from the Women's Health Initiative who had data on fasting serum lipids and serum glucose and no history of cardiovascular disease or diabetes at baseline. We categorized women by body mass index (in kg/m(2)) as normal weight (body mass index 18.5 to <25), overweight (body mass index 25 to <30), or obese (body mass index ≥30) and by metabolic health, defined first as the metabolic syndrome (metabolically unhealthy: ≥3 metabolic abnormalities) and second as the number of metabolic abnormalities. We used Cox proportional hazards regression to assess associations between baseline characteristics and cardiovascular risk. Over 13 years of follow-up, 1101 women had a first cardiovascular disease event (coronary heart disease or ischemic stroke). Among black women without metabolic syndrome, overweight women had higher adjusted cardiovascular risk than normal weight women (hazard ratio [HR] 1.49), whereas among white women without metabolic syndrome, overweight women had similar risk to normal weight women (HR 0.92, interaction P=0.05). Obese black women without metabolic syndrome had higher adjusted risk (HR 1.95) than obese white women (HR 1.07; interaction P=0.02). Among women with only 2 metabolic abnormalities, cardiovascular risk was increased in black women who were overweight (HR 1.77) or obese (HR 2.17) but not in white women who were overweight (HR 0.98) or obese (HR 1.06). Overweight and obese women with ≤1 metabolic abnormality did not have increased cardiovascular risk, regardless of race or ethnicity. Metabolic abnormalities appeared to convey more cardiovascular risk among black women.


[Anthropologic study of the population of Peloponnesus with special reference to the Arwanites and Tsakones].
A total of 1582 individuals of the indigenous population of the Peloponnesus was investigated anthropologically. 1465 of these individuals are males, 117 females in the age between 20 and 60 years. The mean age of the males is 40 years, that of the females 30 years. Altogether 19 metric and 42 morphognostic characters could be considered. In order to study the geographical variability of these characters 90 distribution maps were drawn. Furthermore, multivariate statistical analysis was done, using Hiernaux's distance method, which allows to consider metric and morphognostic characters simultaneously. According to the distribution pattern of the anthropological characters under study and the results of Hiernaux's distance method two anthropological types can be discerned. The first of these two types covers the largest part of the country and is found mainly in the Western and Southern parts of the Peloponnesus, whereas the other one is dominating in Northeastern and Central Peloponnesus. The Western-Southern type is characterized by a relatively dark skin, straight nose, brown-grey eyes, marked eye-brows, and a marked torus supraorbitalis as compared to the Northeastern-Central type. An ethnohistorical interpretation of these differences is not yet possible.


The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin.
Tetherin (CD317/BST2) is an interferon-induced membrane protein that inhibits the release of diverse enveloped viral particles. Several mammalian viruses have evolved countermeasures that inactivate tetherin, with the prototype being the HIV-1 Vpu protein. Here we show that the human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is sensitive to tetherin restriction and its activity is counteracted by the KSHV encoded RING-CH E3 ubiquitin ligase K5. Tetherin expression in KSHV-infected cells inhibits viral particle release, as does depletion of K5 protein using RNA interference. K5 induces a species-specific downregulation of human tetherin from the cell surface followed by its endosomal degradation. We show that K5 targets a single lysine (K18) in the cytoplasmic tail of tetherin for ubiquitination, leading to relocalization of tetherin to CD63-positive endosomal compartments. Tetherin degradation is dependent on ESCRT-mediated endosomal sorting, but does not require a tyrosine-based sorting signal in the tetherin cytoplasmic tail. Importantly, we also show that the ability of K5 to substitute for Vpu in HIV-1 release is entirely dependent on K18 and the RING-CH domain of K5. By contrast, while Vpu induces ubiquitination of tetherin cytoplasmic tail lysine residues, mutation of these positions has no effect on its antagonism of tetherin function, and residual tetherin is associated with the trans-Golgi network (TGN) in Vpu-expressing cells. Taken together our results demonstrate that K5 is a mechanistically distinct viral countermeasure to tetherin-mediated restriction, and that herpesvirus particle release is sensitive to this mode of antiviral inhibition.


Determinants of demand for total hip and knee arthroplasty: a systematic literature review.
Documented age, gender, race and socio-economic disparities in total joint arthroplasty (TJA), suggest that those who need the surgery may not receive it, and present a challenge to explain the causes of unmet need. It is not clear whether doctors limit treatment opportunities to patients, nor is it known the effect that patient beliefs and expectations about the operation, including their paid work status and retirement plans, have on the decision to undergo TJA. Identifying socio-economic and other determinants of demand would inform the design of effective and efficient health policy. This review was conducted to identify the factors that lead patients in need to undergo TJA. An electronic search of the Embase and Medline (Ovid) bibliographic databases conducted in September 2011 identified studies in the English language that reported on factors driving patients in need of hip or knee replacement to undergo surgery. The review included reports of elective surgery rates in eligible patients or, controlling for disease severity, in general subjects, and stated clinical experts' and patients' opinions on suitability for or willingness to undergo TJA. Quantitative and qualitative studies were reviewed, but quantitative studies involving fewer than 20 subjects were excluded. The quality of individual studies was assessed on the basis of study design (i.e., prospective versus retrospective), reporting of attrition, adjustment for and report of confounding effects, and reported measures of need (self-reported versus doctor-assessed). Reported estimates of effect on the probability of surgery from analyses adjusting for confounders were summarised in narrative form and synthesised in odds ratio (OR) forest plots for individual determinants. The review included 26 quantitative studies-23 on individuals' decisions or views on having the operation and three about health professionals' opinions-and 10 qualitative studies. Ethnic and racial disparities in TJA use are associated with socio-economic access factors and expectations about the process and outcomes of surgery. In the United States, health insurance coverage affects demand, including that from the Medicare population, for whom having supplemental Medicaid coverage increases the likelihood of undergoing TJA. Patients with post-secondary education are more likely to demand hip or knee surgery than those without it (range of OR 0.87-2.38). Women are as willing to undergo surgery as men, but they are less likely to be offered surgery by specialists than men with the same need. There is considerable variation in patient demand with age, with distinct patterns for hip and knee. Paid employment appears to increase the chances of undergoing surgery, but no study was found that investigated the relationship between retirement plans and demand for TJA. There is evidence of substantial geographical variation in access to joint replacement within the territory covered by a public national health system, which is unlikely to be explained by differences in preference or unmeasured need alone. The literature tends to focus on associations, rather than testing of causal relationships, and is insufficient to assess the relative importance of determinants. Patients' use of hip and knee replacement is a function of their socio-economic circumstances, which reinforce disparities by gender and race originating in the doctor-patient interaction. Willingness to undergo surgery declines steeply after the age of retirement, at the time some eligible patients may lower their expectations of health status achievement. There is some evidence that paid employment independently increases the likelihood of operation. The relative contribution of variations in surgical decision making to differential access across regions within countries deserves further research that controls for clinical need and patient lifestyle preferences, including retirement decisions. Evidence on this question will become increasingly relevant for service planning and policy design in societies with ageing populations.


Characterizing grassland fire activity in the Flint Hills region and air quality using satellite and routine surface monitor data.
Prescribed grassland fires in the Flint Hills region of central Kansas and northern Oklahoma are a common tool for land management. Local to regional scale impacts on air quality from grassland fires in this region are not well understood, which is important as these types of prescribed fires may increase in the future to preserve broader areas of native grasses in the central U.S. Routine air quality and deposition measurements from sites in and near the Flint Hills were examined for coincident increases during periods of increased prescribed grassland fires. Prescribed fire activity in this region was quantified using satellite detections and multiple publicly available data products of area burned information. March and April comprise over half (41 to 93%) of all annual fire detections in the Flint Hills region seen from satellites between 2007 and 2018 excluding drought years. Annual total fire detections in this region range between 1 and 12 thousand and account for approximately 3% of all fire detections in the contiguous U.S. Annual acres burned ranged from 0.2 to 2 million acres based on U.S. EPA's National Emission Inventory, which accounts for 4 to 38% of grasslands in the area. A comparison of weekly standardized anomalies suggests a relationship between periods of increased grassland fire activity and elevated levels of PM2.5 organic carbon, elemental carbon, and potassium. Daily 1-hr maximum ozone (O3), ammonia (NH3), sulfur dioxide (SO2), and oxidized nitrogen gases measured at Konza Prairie also had increased levels when prescribed grassland fire activity was highest. This detailed characterization of prescribed fire activity in the Flint Hills and associated air quality impacts will benefit future efforts to understand changes in atmospheric composition due to changing land management practices.


Metabolism in cancer metastasis: bioenergetics, biosynthesis, and beyond.
Metabolic changes accompany tumor progression and metastatic dissemination of cancer cells. Yet, until recently, metabolism has received little attention in the study of cancer metastasis. Cancer cells undergo significant metabolic rewiring as they acquire metastatic traits and adapt to survive in multiple environments with varying nutrient availability, oxygen concentrations, and extracellular signals. Therefore, to effectively treat metastatic cancer, it is important to understand the metabolic strategies adopted by cancer cells during the metastatic process. Here, we focus on the metabolic pathways known to play a role in cancer metastasis, including glycolysis, the pentose phosphate pathway, tricarboxylic acid cycle, oxidative phosphorylation, amino acid metabolism, and fatty acid metabolism. Recent studies have uncovered roles for these pathways in cellular events that promote metastasis, including reactive oxygen species-mediated signaling, epigenetic regulation, and interaction with the extracellular matrix. We also discuss the metabolic interplay between immune cells and cancer cells supporting metastasis. Finally, we highlight the current limitations of our knowledge on this topic, and present future directions for the field. WIREs Syst Biol Med 2018, 10:e1406. doi: 10.1002/wsbm.1406 This article is categorized under: Biological Mechanisms > Metabolism.


Characterization of a topoisomerase II gene rearrangement in a human small-cell lung cancer cell line.
Small-cell lung cancer (SCLC) is a highly chemosensitive tumor, but the recurrent disease that is common after initial response is often unresponsive to further chemotherapy. Although the mechanisms of drug resistance in SCLC have not been established, studies suggest that alterations of the nuclear enzyme DNA topoisomerase II may reduce the sensitivity of the cell to drug action. This enzyme is recognized as a primary target for cytotoxic activity of important antitumor agents. In this study, we attempted to determine if altered forms of DNA topoisomerase II are responsible for reduced drug sensitivity. We characterized a rearrangement of the topoisomerase II p170 gene (also known as TOP2) in a relatively chemoresistant SCLC cell line, NCI-H69, and compared topoisomerase II expression and activity in this line with those in the chemosensitive NCI-H187 cell line. Fragments of complementary DNA from the topoisomerase II gene were generated by polymerase chain reaction. Immunodetection was accomplished by using the monoclonal antibody 7E6 against the human topoisomerase II p170 isoform. Using DNA probes corresponding to different complementary DNA regions, we showed that the rearrangement was localized at the 3' terminus of one allele of the topoisomerase II gene. In addition to the normal 6.2-kilobase (kb) topoisomerase II messenger RNA (mRNA), the NCI-H69 line expressed a 7.4-kb topoisomerase II transcript, presumably encoded by the rearranged allele. Moreover, this transcript, although longer than the normal mRNA, lacked a substantial portion of the 3'-terminal p170 gene coding sequence. Topoisomerase II activity in nuclear extracts, as determined by the P4 phage DNA-unknotting assay, was more easily detected and measured at lower NaCl concentrations in NCI-H69 than in NCI-H187 cells. These results are consistent with the hypothesis that the chemoresistant NCI-H69 cell line may express, in addition to the normal enzyme, an altered topoisomerase II enzyme possibly encoded by the 7.4-kb mRNA, which in turn may be transcribed from the rearranged gene allele. These observations emphasize the role of topoisomerase II in determining drug sensitivity and suggest that such gene rearrangements may contribute to resistance of SCLC cells to topoisomerase II inhibitors.


Gasohol: Does It or Doesn't It Produce Positive Net Energy?
A detailed analysis of energy inputs and outputs is performed on grain-based gasohol (10 percent grain-based ethanol, 90 percent gasoline). Existing differences of opinion on the energy balance derive mainly from variations in interpretation which are several examples of inherent methodological problems in energy analysis. The result is strongly dependent on assumptions about use of crop residues for fuel and the miles-per-gallon rating of gasohol. In terms of total nonrenewable energy, gasohol is close to the energy break-even point. On the other hand, in terms of petroleum or petroleum-substitutable energy, gasohol is an unambiguous energy producer, since most energy inputs to the process can be supplied by nonpetroleum sources such as coal.


Wasabi Compound 6-(Methylsulfinyl) Hexyl Isothiocyanate Induces Cell Death with Coexisting Mitotic Arrest and Autophagy in Human Chronic Myelogenous Leukemia K562 Cells.
A natural compound from Wasabia japonica, 6-(methylsulfinyl) hexyl isothiocyanate (6-MITC) was investigated for its anti-leukemia activity and mechanism of action. It was found that 6-MITC inhibited the viability of human chronic myelogenous leukemia K562 cells along with extensive mitotic arrest, spindle multipolarity, and cytoplasmic vacuole accumulation. The evidence of autophagy included the validation of autophagosomes with double-layered membranes under transmission electron microscopy, LC3I/II conversion, and the induction of G2/M phase arrest observed with acridine orange staining of treated cells, as well as the elevation of phosphorylated-histone H3 expression at the M phase. With regard to the expression of proteins related to mitosis, the downregulation of p-CHK1, p-CHK2, p-cdc25c, and p-cdc2, as well as the upregulation of cyclin B1, p-cdc20, cdc23, BubR1, Mad2, and p-plk-1 was observed. The knockdown of cdc20 was unable to block the effect of 6-MITC. The differentiation of k562 cells into monocytes, granulocytes, and megakaryocytes was not affected by 6-MITC. The 6-MITC-induced unique mode of cell death through the concurrent induction of mitosis and autophagy may have therapeutic potential. Further studies are required to elucidate the pathways associated with the counteracting occurrence of mitosis and autophagy.


Case mix reimbursement for nursing homes.
Nursing home care is growing in importance as the population ages and as Medicare's prospective payment system encourages earlier discharges from acute care settings to nursing homes. Nursing home reimbursement policy is primarily a Medicaid issue, since Medicaid pays for about half the nation's nursing home care. The research reviewed in this article suggests a strong association between case mix and cost, and a weaker but still positive association between quality and cost. The research also implies that traditional nursing home reimbursement methodologies may impede access and may lower quality for Medicaid (and Medicare) recipients. To offset these problems, several states have recently begun to incorporate case mix directly into the reimbursement process. These systems deserve careful policy consideration.


Qualitative Analysis of Palliative Care for Pediatric Patients With Cancer at Bugando Medical Center: An Evaluation of Barriers to Providing End-of-Life Care in a Resource-Limited Setting.
Purpose Palliative care remains an urgent, neglected need in the developing world. Global disparities in end-of-life care for children, such as those with advanced cancers, result from barriers that are complex and largely unstudied. This study describes these barriers at Bugando Medical Center, one of three consultant hospitals in Tanzania, to identify areas for palliative care development suitable to this context. Methods In-depth interviews were conducted with 20 caregivers of pediatric patients with cancer and 14 hospital staff involved in pediatric end-of-life care. This was combined with 1 month of participant observation through direct clinical care of terminally ill pediatric patients. Results Data from interviews as well as participant observation revealed several barriers to palliative care: financial, infrastructure, knowledge and cultural (including perceptions of pediatric pain), and communication challenges. Although this study focused on barriers, what also emerged were the unique advantages of end-of-life care in this setting, including community cohesiveness and strong faith background. Conclusion This study provides a unique but focused description of barriers to palliative care common in a low-resource setting, extending beyond resource needs. This multidisciplinary qualitative approach combined interviews with participant observation, providing a deeper understanding of the logistical and cultural challenges in this setting. This new understanding will inform the design of more effective-and more appropriate-palliative care policies for young patients with cancer in the developing world.


A qualitative study of how self-harm starts and continues among Chinese adolescents.
It is essential to investigate the experiences behind why adolescents start and continue to self-harm in order to develop targeted treatment and prevent future self-harming behaviours. The aims of this study are to understand the motivations for initiating and repeating nonfatal self-harm, the different methods used between first-time and repeated self-harm and the reasons that adolescents do not seek help from health services. Adolescents with repeated nonfatal self-harm experiences were recruited to participate in individual, semi-structured qualitative interviews. The interviews were analysed with interpretative phenomenological analysis. We found that nonfatal self-harm among adolescents occurred comparatively early and was often triggered by specific reasons. However, the subsequent nonfatal self-harm could be causeless, with repeated self-harm becoming a maladaptive coping strategy to handle daily pressure and negative emotions. The choice of tools used was related to the ease of accessibility, the life-threatening risk and the size of the scars. Adolescents often concealed their scars on purpose, which made early identification insufficient. Peer influence, such as online chat groups encouraging self-harm by discussing and sharing self-harm pictures, could also lead to increased self-harm. The results also included participants' opinions on how to stop nonfatal self-harm and their dissatisfaction with the current healthcare services. The current study provides important implications both for early identification and interventions for adolescents who engage in repeated nonfatal self-harm, and for individualising treatment planning that benefits them. It is also worthwhile to further investigate how peer influence and social media may affect self-harm in adolescents.


Assessing the dosimetric impact of real-time prostate motion during volumetric modulated arc therapy.
To develop a method for dose reconstruction by incorporating the interplay effect between aperture modulation and target motion, and to assess the dosimetric impact of real-time prostate motion during volumetric modulated arc therapy (VMAT). Clinical VMAT plans were delivered with the TrueBeam linac for 8 patients with prostate cancer. The real-time target motion during dose delivery was determined based on the 2-dimensional fiducial localization using an onboard electronic portal imaging device. The target shift in each image was correlated with the control point with the same gantry angle in the VMAT plan. An in-house-developed Monte Carlo simulation tool was used to calculate the 3-dimensional dose distribution for each control point individually, taking into account the corresponding real-time target motion (assuming a nondeformable target with no rotation). The delivered target dose was then estimated by accumulating the dose from all control points in the plan. On the basis of this information, dose-volume histograms and 3-dimensional dose distributions were calculated to assess their degradation from the planned dose caused by target motion. Thirty-two prostate motion trajectories were analyzed. The minimum dose to 0.03 cm(3) of the gross tumor volume (D0.03cc) was only slightly degraded after taking motion into account, with a minimum value of 94.1% of the planned dose among all patients and fractions. However, the gross tumor volume receiving prescription dose (V100%) could be largely affected by motion, dropping below 60% in 1 trajectory. We did not observe a correlation between motion magnitude and dose degradation. Prostate motion degrades the delivered dose to the target in an unpredictable way, although its effect is reduced over multiple fractions, and for most patients the degradation is small. Patients with greater prostate motion or those treated with stereotactic body radiation therapy would benefit from real-time prostate tracking to reduce the margin.


Direct molecular detection and genotyping of Borrelia burgdorferi from whole blood of patients with early Lyme disease.
Direct molecular tests in blood for early Lyme disease can be insensitive due to low amount of circulating Borrelia burgdorferi DNA. To address this challenge, we have developed a sensitive strategy to both detect and genotype B. burgdorferi directly from whole blood collected during the initial patient visit. This strategy improved sensitivity by employing 1.25 mL of whole blood, a novel pre-enrichment of the entire specimen extract for Borrelia DNA prior to a multi-locus PCR and electrospray ionization mass spectrometry detection assay. We evaluated the assay on blood collected at the initial presentation from 21 endemic area patients who had both physician-diagnosed erythema migrans (EM) and positive two-tiered serology either at the initial visit or at a follow-up visit after three weeks of antibiotic therapy. Results of this DNA analysis showed detection of B. burgdorferi in 13 of 21 patients (62%). In most cases the new assay also provided the B. burgdorferi genotype. The combined results of our direct detection assay with initial physician visit serology resulted in the detection of early Lyme disease in 19 of 21 (90%) of patients at the initial visit. In 5 of 21 cases we demonstrate the ability to detect B. burgdorferi in early Lyme disease directly from whole blood specimens prior to seroconversion.


Human dissemination of genes and microorganisms in Earth's Critical Zone.
Earth's Critical Zone sustains terrestrial life and consists of the thin planetary surface layer between unaltered rock and the atmospheric boundary. Within this zone, flows of energy and materials are mediated by physical processes and by the actions of diverse organisms. Human activities significantly influence these physical and biological processes, affecting the atmosphere, shallow lithosphere, hydrosphere, and biosphere. The role of organisms includes an additional class of biogeochemical cycling, this being the flow and transformation of genetic information. This is particularly the case for the microorganisms that govern carbon and nitrogen cycling. These biological processes are mediated by the expression of functional genes and their translation into enzymes that catalyze geochemical reactions. Understanding human effects on microbial activity, fitness and distribution is an important component of Critical Zone science, but is highly challenging to investigate across the enormous physical scales of impact ranging from individual organisms to the planet. One arena where this might be tractable is by studying the dynamics and dissemination of genes for antibiotic resistance and the organisms that carry such genes. Here we explore the transport and transformation of microbial genes and cells through Earth's Critical Zone. We do so by examining the origins and rise of antibiotic resistance genes, their subsequent dissemination, and the ongoing colonization of diverse ecosystems by resistant organisms.


Osmotic regulation of cyclic 1,2-beta-glucan synthesis.
In contrast to what happens in AGROBACTERIUM: tumefaciens and RHIZOBIUM: meliloti, synthesis of periplasmic cyclic 1,2-beta-glucan in BRUCELLA: spp. was not inhibited when bacteria were grown in media of high osmolarity. Studies performed with crude membrane preparations showed that cyclic 1,2-beta-glucan synthetase of BRUCELLA: spp. was not inhibited by 0.5 M KCl or potassium glutamate; concentrations that completely inhibit the osmosensitive enzymes of A. tumefaciens A348 or R. meliloti 102F34, respectively encoded by the chvB or ndvB genes. The BRUCELLA: abortus cyclic 1, 2-beta-glucan synthetase gene (cgs) was introduced into A. tumefaciens A1011 chvB and R. meliloti GRT21s ndvB mutants. Synthesis of cyclic 1,2-beta-glucan by the recombinant strains was not inhibited when grown in media of high osmolarity (0.25 M NaCl or 0.5 M mannitol). On the other hand, when the A. tumefaciens cyclic 1, 2-beta-glucan synthetase gene was introduced into the R. meliloti GRT21s ndvB mutant, the recombinant strain displayed marked inhibition of cyclic 1,2-beta-glucan synthesis when grown in high-osmolarity media. However, the same gene introduced into a B. abortus cgs mutant background resulted in no inhibition of glucan synthesis at high osmolarity. In vitro studies with crude membranes isolated from recombinant strains revealed that BRUCELLA: cyclic 1, 2-beta-glucan synthetase was not inhibited by high concentrations of KCl or potassium glutamate even when expressed in AGROBACTERIUM: or RHIZOBIUM: backgrounds. It was concluded that the lack of effect of high osmolarity on 1,2-beta-glucan synthesis in BRUCELLA: is due to two convergent mechanisms: a) the presence of a cyclic 1, 2-beta-glucan synthetase that is not affected by concentrations of solutes such as KCl or potassium glutamate and b) either the possible accumulation of compatible solutes that might protect the enzyme from the inhibition by potassium glutamate or the accumulation of other osmolytes that do not affect the 1, 2-beta-glucan synthetase.


Impact of bottle size on in-home consumption of sugar-sweetened beverages: protocol for a feasibility and acceptability study.
Intake of free sugars in the population exceeds recommendations, with the largest source in the diet being sugar-sweetened beverages (SSBs). SSB consumption is linked to adverse health consequences and contributes to health inequalities, given greater consumption amongst the most deprived. One possible intervention is to reduce the available sizes of SSB packaging but there is an absence of evidence that this would reduce consumption. Based on evidence from studies targeting food consumption that people consume less when exposed to smaller package sizes, we hypothesise that presenting SSBs in smaller containers reduces consumption. We are planning a crossover randomised controlled trial to assess the impact of presenting a fixed volume of SSB in different bottle sizes on consumption at home. To reduce the uncertainties related to this trial, we propose a preliminary study to assess the feasibility and acceptability of the recruitment, allocation, measurement, retention and intervention procedures. Households which purchase at least 2 l of regular cola drinks per week and live in Cambridgeshire, UK will have a set amount of a cola SSB (based on their typical weekly purchasing of cola) delivered to their homes each week by the research team. This total amount of cola will be packaged into bottles of one of four sizes: (i) 1500 ml, (ii) 1000 ml, (iii) 500 ml or (iv) 250 ml. A crossover design will be used in which households will each receive all four of the week-long interventions (the four different bottle sizes) over time, randomised in their order of presentation. Approximately 100 eligible households will be approached to assess the proportion interested in actively participating in the study. Of those interested, 16 will be invited to continue participation. The findings will inform the procedures for a crossover randomised controlled trial assessing the impact of presenting a fixed volume of SSB in different bottle sizes on consumption at home. The findings from such a trial are expected to provide the best estimate to date of the effect of container size on beverage consumption and inform ongoing scientific and policy discussions about the effectiveness of this intervention at reducing population intake of free sugars in beverages. ISRCTN14964130.


Systematic Exploration of Protein Conformational Space Using a Distance Geometry Approach.
The optimization approaches classically used during the determination of protein structure encounter various difficulties, especially when the size of the conformational space is large. Indeed, in such a case, algorithmic convergence criteria are more difficult to set up. Moreover, the size of the search space makes it difficult to achieve a complete exploration. The interval branch-and-prune (iBP) approach, based on the reformulation of the distance geometry problem (DGP) provides a theoretical frame for the generation of protein conformations, by systematically sampling the conformational space. When an appropriate subset of interatomic distances is known exactly, this worst-case exponential-time algorithm is provably complete and fixed-parameter tractable. These guarantees, however, immediately disappear as distance measurement errors are introduced. Here we propose an improvement of this approach: threading-augmented interval branch-and-prune (TAiBP), where the combinatorial explosion of the original iBP approach arising from its exponential complexity is alleviated by partitioning the input instances into consecutive peptide fragments and by using self-organizing maps (SOMs) to obtain clusters of similar solutions. A validation of the TAiBP approach is presented here on a set of proteins of various sizes and structures. The calculation inputs are a uniform covalent geometry extracted from force field covalent terms, the backbone dihedral angles with error intervals, and a few long-range distances. For most of the proteins smaller than 50 residues and interval widths of 20°, the TAiBP approach yielded solutions with RMSD values smaller than 3 Å with respect to the initial protein conformation. The efficiency of the TAiBP approach for proteins larger than 50 residues will require the use of nonuniform covalent geometry and may have benefits from the recent development of residue-specific force-fields.


Broadening the impact of plant science through innovative, integrative, and inclusive outreach.
Population growth and climate change will impact food security and potentially exacerbate the environmental toll that agriculture has taken on our planet. These existential concerns demand that a passionate, interdisciplinary, and diverse community of plant science professionals is trained during the 21st century. Furthermore, societal trends that question the importance of science and expert knowledge highlight the need to better communicate the value of rigorous fundamental scientific exploration. Engaging students and the general public in the wonder of plants, and science in general, requires renewed efforts that take advantage of advances in technology and new models of funding and knowledge dissemination. In November 2018, funded by the National Science Foundation through the Arabidopsis Research and Training for the 21st century (ART 21) research coordination network, a symposium and workshop were held that included a diverse panel of students, scientists, educators, and administrators from across the US. The purpose of the workshop was to re-envision how outreach programs are funded, evaluated, acknowledged, and shared within the plant science community. One key objective was to generate a roadmap for future efforts. We hope that this document will serve as such, by providing a comprehensive resource for students and young faculty interested in developing effective outreach programs. We also anticipate that this document will guide the formation of community partnerships to scale up currently successful outreach programs, and lead to the design of future programs that effectively engage with a more diverse student body and citizenry.


Genotype directed therapy in murine mismatch repair deficient tumors.
The PI3K/AKT/mTOR pathway has frequently been found activated in human tumors. We show that in addition to Wnt signaling dysfunction, the PI3K/AKT/mTOR pathway is often upregulated in mouse Msh2(-/-) initiated intestinal tumors. NVP-BEZ235 is a dual PI3K/mTOR inhibitor toxic to many cancer cell lines and currently involved in clinical trials. We have treated two mouse models involving Msh2 that develop small intestinal and/or colonic tumors with NVP-BEZ235, and a subset of animals with NVP-BEZ235 and MEK inhibitor ADZ4266. The disease phenotype has been followed with pathology, (18)F FDG PET imaging, and endoscopy. Intestinal adenocarcinomas are significantly decreased in multiplicity by both drug regimens. The majority of tumors treated with combined therapy regress significantly, while a small number of highly progressed tumors persist. We have examined PTEN, AKT, MEK 1&2, MAPK, S6K, mTOR, PDPK1, and Cyclin D1 and find variable alterations that include downregulation of PTEN, upregulation of AKT and changes in its phosphorylated forms, upregulation of pMEK 1&2, p42p44MAPK, pS6K, and Cyclin D1. Apoptosis has been found intact in some tumors and not in others. Our data indicate that NVP-BEZ235 alone and in combination with ADZ4266 are effective in treating a proportion of colorectal cancers, but that highly progressed resistant tumors grow in the presence of the drugs. Pathways upregulated in some resistant tumors also include PDPK1, suggesting that metabolic inhibitors may also be useful in treating these tumors.


Child Housing Assessment for a Safe Environment (CHASE): a new tool for injury prevention inside the home.
To develop a tool to assess the safety of the home environment that could produce valid measures of a child's risk of suffering an injury. Tool development: A four-step process was used to develop the CHASE (Child Housing Assessment for a Safe Environment) tool, including (1) a literature scan, (2) reviewing of existing housing inspection tools, (3) key informants interviews, and (4) reviewing the National Electronic Injury Surveillance System to determine the leading housing elements associated with paediatric injury. Retrospective case-control study to validate the CHASE tool: Recruitment included case (injured) and control (sick but not injured) children and their families from a large, urban paediatric emergency department in Baltimore, Maryland in 2012. Trained inspectors applied both the well-known Home Quality Standard (HQS) and the CHASE tool to each enrollee's home, and we compared scores on individual and summary items between cases and controls. Twenty-five items organised around 12 subdomains were included on the CHASE tool. 71 matched pairs were enrolled and included in the analytic sample. Comparisons between cases and controls revealed statistically significant differences in scores on individual items of the CHASE tool as well as on the overall score, with the cases systematically having worse scores. No differences were found between groups on the HQS measures. Programmes conducting housing inspections in the homes of children should consider including the CHASE tool as part of their inspection measures. Future study of the CHASE inspection tool in a prospective trial would help assess its efficacy in preventing injuries and reducing medical costs.


Expert range maps of global mammal distributions harmonised to three taxonomic authorities.
Comprehensive, global information on species' occurrences is an essential biodiversity variable and central to a range of applications in ecology, evolution, biogeography and conservation. Expert range maps often represent a species' only available distributional information and play an increasing role in conservation assessments and macroecology. We provide global range maps for the native ranges of all extant mammal species harmonised to the taxonomy of the Mammal Diversity Database (MDD) mobilised from two sources, the Handbook of the Mammals of the World (HMW) and the Illustrated Checklist of the Mammals of the World (CMW). Global. All extant mammal species. Range maps were digitally interpreted, georeferenced, error-checked and subsequently taxonomically aligned between the HMW (6253 species), the CMW (6431 species) and the MDD taxonomies (6362 species). Range maps can be evaluated and visualised in an online map browser at Map of Life (mol.org) and accessed for individual or batch download for non-commercial use. Expert maps of species' global distributions are limited in their spatial detail and temporal specificity, but form a useful basis for broad-scale characterizations and model-based integration with other data. We provide georeferenced range maps for the native ranges of all extant mammal species as shapefiles, with species-level metadata and source information packaged together in geodatabase format. Across the three taxonomic sources our maps entail, there are 1784 taxonomic name differences compared to the maps currently available on the IUCN Red List website. The expert maps provided here are harmonised to the MDD taxonomic authority and linked to a community of online tools that will enable transparent future updates and version control.


Optimization and phase matching of fiber-laser-driven high-order harmonic generation at high repetition rate.
High-repetition-rate sources are very attractive for high-order harmonic generation (HHG). However, due to their pulse characteristics (low energy, long duration), those systems require a tight focusing geometry to achieve the necessary intensity to generate harmonics. In this Letter, we investigate theoretically and experimentally the optimization of HHG in this geometry, to maximize the extreme UV (XUV) photon flux and improve the conversion efficiency. We analyze the influence of atomic gas media (Ar, Kr, or Xe), gas pressure, and interaction geometries (a gas jet and a finite and a semi-infinite gas cell). Numerical simulations allow us to define optimal conditions for HHG in this tight focusing regime and to observe the signature of on-axis phase matching. These conditions are implemented experimentally using a high-repetition-rate Yb-doped fiber laser system. We achieve optimization of emission with a recorded XUV photon flux of 4.5×10(12) photons/s generated in Xe at 100 kHz repetition rate.


Maternal age effects on myometrial expression of contractile proteins, uterine gene expression, and contractile activity during labor in the rat.
Advanced maternal age of first time pregnant mothers is associated with prolonged and dysfunctional labor and significant risk of emergency cesarean section. We investigated the influence of maternal age on myometrial contractility, expression of contractile associated proteins (CAPs), and global gene expression in the parturient uterus. Female Wistar rats either 8 (YOUNG n = 10) or 24 (OLDER n = 10) weeks old were fed laboratory chow, mated, and killed during parturition. Myometrial strips were dissected to determine contractile activity, cholesterol (CHOL) and triglycerides (TAG) content, protein expression of connexin-43 (GJA1), prostaglandin-endoperoxide synthase 2 (PTGS2), and caveolin 1 (CAV-1). Maternal plasma concentrations of prostaglandins PGE2, PGF2α, and progesterone were determined by RIA. Global gene expression in uterine samples was compared using Affymetrix Genechip Gene 2.0 ST arrays and Ingenuity Pathway analysis (IPA). Spontaneous contractility in myometrium exhibited by YOUNG rats was threefold greater than OLDER animals (P < 0.027) but maternal age had no significant effect on myometrial CAP expression, lipid profiles, or pregnancy-related hormones. OLDER myometrium increased contractile activity in response to PGF2α, phenylephrine, and carbachol, a response absent in YOUNG rats (all P < 0.002). Microarray analysis identified that maternal age affected expression of genes related to immune and inflammatory responses, lipid transport and metabolism, steroid metabolism, tissue remodeling, and smooth muscle contraction. In conclusion YOUNG laboring rat myometrium seems primed to contract maximally, whereas activity is blunted in OLDER animals and requires stimulation to meet contractile potential. Further work investigating maternal age effects on myometrial function is required with focus on lipid metabolism and inflammatory pathways.


Acceptability of male condom: an Indian scenario.
The National Family Planning Programme of India had introduced condom as one of the family planning methods in the late 1960s. Condom was promoted as a family planning method through social marketing since its inception. With the increasing prevalence and incidence of sexually transmitted infections (STIs) including HIV/AIDS, condom was also promoted as a dual method for protection against both unintended pregnancies as well as sexually transmitted infections. Despite efforts at various levels, the overall use of condom among couples in India is low. Here we present literature review of studies to understand the condom acceptability among couples in India. Specifically, the paper assesses research and programmes that have been carried out to increase the use of condom among couples; determinants of condom use; reason for not using condom; and perception versus experience of condom failure. The reported problems related to condom use included non acceptance by partner, perceived ineffectiveness, less comfort, lack of sexual satisfaction, husband's alcohol use, depression, and anxiety, and not available at that instant. The role of media in the promotion of condom use was indicated as an important way to increase awareness and use. Multiple strategies would help in acceptance of male condom.


Measuring vincristine-induced peripheral neuropathy in children with cancer: validation of the Dutch pediatric-modified Total Neuropathy Score.
The aims were to evaluate the construct validity and reliability of the Dutch version of the pediatric-modified Total Neuropathy Score (ped-mTNS) for assessing vincristine-induced peripheral neuropathy (VIPN) in Dutch pediatric oncology patients aged 5-18 years. Construct validity (primary aim) of the ped-mTNS was determined by testing hypotheses about expected correlation between scores of the ped-mTNS (range: 0-32) and the Common Terminology Criteria for Adverse Events (CTCAE) (range: 0-18) for patients and healthy controls and by comparing patients and controls regarding their total ped-mTNS scores and the proportion of children identified with VIPN. Inter-rater and intra-rater reliability and measurement error (secondary aims) were assessed in a subgroup of study participants. Among the 112 children (56 patients and 56 age- and gender-matched healthy controls) evaluated, correlation between CTCAE and ped-mTNS scores was as expected (moderate (r = 0.60)). Moreover, as expected, patients had significantly higher ped-mTNS scores and more frequent symptoms of VIPN compared with controls (both p < .001). Reliability as measured within the intra-rater group (n = 10) (intra-class correlation coefficient (ICCagreement) = 0.64, standard error of measurement (SEMagreement) = 2.92, and smallest detectable change (SDCagreement) = 8.1) and within the inter-rater subgroup (n = 10) (ICCagreement = 0.63, SEMagreement = 3.7, and SDCagreement = 10.26) indicates insufficient reliability. The Dutch version of the ped-mTNS appears to have good construct validity for assessing VIPN in a Dutch pediatric oncology population, whereas reliability appears to be insufficient and measurement error high. To improve standardization of VIPN assessment in children, future research aimed at evaluating and further optimizing the psychometric characteristics of the ped-mTNS is needed.