Laser transport through thin scattering layers.
Many modern applications of lasers involve understanding the transport of radiation through thin layers. The interactions of continuous wave and pulsed lasers with skin in dermatological use related to surgery and cosmetic procedures are examples of such. These highly scattering thin layers in skin are best modeled by the Monte Carlo method. However, most traditional Monte Carlo models may inaccurately account for the presence of thin layers. As an example, the very thin epidermis, with its highly absorbing melanin, is known to influence the laser penetration significantly. If the Monte Carlo model is implemented without special features, then the results of the simulation will show incorrect effects of thin layers because the path length of most photons would be significantly larger than the layer thickness. As a result, the computed photon travel path length would simply not feel the presence of the layer. In this paper, we present numerical and algorithmic features for computation of radiation transport through thin layers. It is noted that, while Monte Carlo without special features smears the radiative effect of the layers, the refined technique indicates that layers have a great impact on the absorption of energy, especially if the layer properties are distinctly different from those of the adjacent layers. The results have significant implications in the study of diagnostic and therapeutic applications of lasers in biomedicine and surgery.


Comparison of the GlideScope Cobalt® and Storz DCI® Video Laryngoscopes in Children Younger Than 2 Years of Age During Manual In-Line Stabilization: A Randomized Trainee Evaluation Study.
Video laryngoscopy facilitates tracheal intubation during manual in-line stabilization in adults, but it is not clear whether these findings translate to children. We compared trainee intubation times obtained using the GlideScope Cobalt® and Storz DCI® video laryngoscopes versus direct laryngoscopy in young children with immobilized cervical spines. Ninety-three children younger than 2 years underwent laryngoscopy with manual in-line stabilization using direct laryngoscopy, GlideScope Cobalt® video laryngoscopy, or Storz DCI® video laryngoscopy. Laryngoscopists were anesthesiology trainees in postgraduate training year of 3 or more. Total time to successful intubation (TTSI), best glottic view, and maximum degrees of neck deviation were recorded. An intubation time difference longer than 10 seconds was defined as clinically significant. Data are reported as median; 95% confidence interval. The TTSI was similar among groups although Storz times were longer (median, 33.3 seconds; 95% confidence interval, 26.2-43.3 seconds) when compared to direct laryngoscopy (median, 23.3 seconds; 95% confidence interval, 20.7-26.5 seconds; P = 0.02). Obtaining a grade 1 Cormack-Lehane glottic view was less likely with direct laryngoscopy (P = 0.002). Maximum degrees of neck deviation were: Storz (median, 2.0; 95% confidence interval, 1.2-2.8), GlideScope (median, 2.0; 95% confidence interval, 1.4-2.6), and direct laryngoscopy (median, 1.9; 95% confidence interval, 1.2-2.1; P = 0.48). Trainees were able to safely perform tracheal intubation in children younger than 2 years using any of the studied laryngoscopes, although Storz use resulted in a longer TTSI when compared to direct laryngoscopy. Video laryngoscopy may enhance best Cormack-Lehane glottic view during manual in-line cervical spine immobilization, but additional technical skills are needed to successfully complete tracheal intubation.


Vascular angiotensin II receptors in SHR.
We investigated the density (Bmax) of angiotensin II (ANG II) receptors in the mesenteric vascular bed of spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) control rats. In 12-week-old SHR, the Bmax and the dissociation constant (Kd) of ANG II binding sites were not different from those of WKY rats in the sodium replete state or after sodium depletion. In prehypertensive (4- and 6-week-old) SHR, the Bmax of the vascular ANG II receptors was significantly higher (p less than 0.05) than in age-matched WKY rats. This result could not be attributed entirely to differences in the circulating renin-angiotensin-aldosterone system in 4-week-old-rats. In 6-week-old WKY rats, the plasma renin activity was significantly higher (p less than 0.05), which may account in part for the higher density of ANG II binding sites in SHR. There was an age-related decrease in the number of ANG II receptors in SHR. The increased density of vascular ANG II receptors in young SHR may play a role in the development of high blood pressure in this model of spontaneous hypertension. The higher number of ANG II binding sites in young SHR is not selective for ANG II receptors, since an increased density of alpha 1-adrenergic receptors was also found in the mesenteric arteries of 4-week-old SHR.


Bioerosion of Inorganic Hard Substrates in the Ordovician of Estonia (Baltica).
The earliest bioeroded inorganic hard substrates in the Ordovician of Estonia appear in the Dapingian. Hardgrounds are also known from the Sandbian and Katian. Most of the bioerosion of inorganic hard substrates occurs as the boring Trypanites Mägdefrau, 1932 along with some possible Gastrochaenolites borings. North American hardground borings are more diverse than those in Baltica. In contrast to a worldwide trend of increasing boring intensity, the Estonian record seems to show no increase in boring intensities during the Middle and Late Ordovician. Hardgrounds seem to be more common during the temperate climate interval of the Ordovician calcite sea in Estonia (seven hardgrounds during 15 my) than in the part with a tropical climate (four hardgrounds during 12 my). Bioerosion is mostly associated with carbonate hardgrounds, but cobbles and pebbles broken from the hardgrounds are also often penetrated by Trypanites borings. The general diversity of boring ichnotaxa in Baltica increased from one ichnospecies in the Cambrian to seven by the end of Ordovician, showing the effect of the GOBE on bioeroding ichnotaxa. The diversity of inorganic hard substrate borers increased by only two times. This difference can be explained by the wider environmental distribution of organic as compared to inorganic substrates in the Ordovician seas of Baltica, and their more continuous temporal availability, which may have caused increased specialization of several borers. The inorganic substrates may have been bioreroded only by the generalists among boring organisms.


The effect of neonatal exposure to DES and o,p'-DDT on pituitary responsiveness to GnRH in adult castrated rats.
While exposure of vertebrates to estrogens during early development has been shown to alter adult reproductive behavior, neuroanatomy, and neurophysiology, effects on gonadotropin secretion have not been studied. We conducted the present studies to assess the effects of neonatal exposure to xenobiotic estrogens on luteinizing hormone secretion in castrated adult rats. Rat pups were injected with either corn oil, 1 micrograms diethylstilbestrol (DES), or 0.5 mg o,p'-DDT on postnatal days 1 to 10, and castration was performed on day 21. On day 42 of life, GnRH (50 ng/kg) was administered via right heart catheters, and blood was sampled for LH at 0, 5, 10, 15, and 30 min. Neonatal exposure to DES in both males and females significantly decreased basal and GnRH-induced LH secretion throughout the sampling period in castrated adults. o,p'-DDT significantly suppressed initial LH levels and blunted GnRH-induced release in males at the 5 min interval, while in females it had no effect. These data show that early exposure to environmental estrogens alters adult pituitary response to GnRH. Our results suggest that sexually distinct effects of environmental estrogens occur and can be readily demonstrated in this experimental model.


A light-induced shortcut in the planktonic microbial loop.
Mixotrophs combine photosynthesis with phagotrophy to cover their demands in energy and essential nutrients. This gives them a competitive advantage under oligotropihc conditions, where nutrients and bacteria concentrations are low. As the advantage for the mixotroph depends on light, the competition between mixo- and heterotrophic bacterivores should be regulated by light. To test this hypothesis, we incubated natural plankton from the ultra-oligotrophic Eastern Mediterranean in a set of mesocosms maintained at 4 light levels spanning a 10-fold light gradient. Picoplankton (heterotrophic bacteria (HB), pico-sized cyanobacteria, and small-sized flagellates) showed the fastest and most marked response to light, with pronounced predator-prey cycles, in the high-light treatments. Albeit cell specific activity of heterotrophic bacteria was constant across the light gradient, bacterial abundances exhibited an inverse relationship with light. This pattern was explained by light-induced top-down control of HB by bacterivorous phototrophic eukaryotes (PE), which was evidenced by a significant inverse relationship between HB net growth rate and PE abundances. Our results show that light mediates the impact of mixotrophic bacterivores. As mixo- and heterotrophs differ in the way they remineralize nutrients, these results have far-reaching implications for how nutrient cycling is affected by light.


Methyl tert-butyl ether occurrence and related factors in public and private wells in southeast New Hampshire.
The occurrence of methyl tert-butyl ether (MTBE) in water from public wells in New Hampshire has increased steadily over the past several years. Using a laboratory reporting level of 0.2 microg/L, 40% of samples from public wells and 21% from private wells in southeast New Hampshire have measurable concentrations of MTBE. The rate of occurrence of MTBE varied significantly for public wells by establishmenttype; for example, 63% of public wells serving residential properties have MTBE concentrations above 0.2 microg/L, whereas lower rates were found for schools (21%). MTBE concentrations correlate strongly with urban factors, such as population density. Surprisingly, MTBE was correlated positively with well depth for public supply wells. Well depth is inversely related to yield in New Hampshire bedrock wells, which may mean that there is less opportunity for dilution of MTBE captured by deep wells. Another possibility is that the source(s) of water to low-yield wells may be dominated by leakage from potentially contaminated shallow groundwater through near-surface fractures or along the well casing. These wells may also have relatively large contributing areas (due to low recharge at the bedrock surface) and therefore have a greater chance of intersecting MTBE sources. This finding is significant because deep bedrock wells are often considered to be less vulnerable to contamination than shallow wells, and in southeast New Hampshire, wells are being drilled deeper in search of increased supply.


High-temperature adult-plant (HTAP) stripe rust resistance gene Yr36 from Triticum turgidum ssp. dicoccoides is closely linked to the grain protein content locus Gpc-B1.
Several new races of the stripe rust pathogen have become frequent throughout the wheat growing regions of the United States since 2000. These new races are virulent to most of the wheat seedling resistance genes limiting the resistance sources that can be used to combat this pathogen. High-temperature adult-plant (HTAP) stripe rust resistance has proven to be more durable than seedling resistance due to its non-race-specific nature, but its use is limited by the lack of mapping information. We report here the identification of a new HTAP resistance gene from Triticum turgidum ssp. dicoccoides (DIC) designated as Yr36. Lines carrying this gene were susceptible to almost all the stripe rust pathogen races tested at the seedling stage but showed adult-plant resistance to the prevalent races in California when tested at high diurnal temperatures. Isogenic lines for this gene were developed by six backcross generations. Field tests in two locations showed increased levels of field resistance to stripe rust and increased yields in isogenic lines carrying the Yr36 gene compared to those without the gene. Recombinant substitution lines of chromosome 6B from DIC in the isogenic background of durum cv. Langdon were used to map the Yr36 gene on the short arm of chromosome 6B completely linked to Xbarc101, and within a 2-cM interval defined by PCR-based markers Xucw71 and Xbarc136. Flanking locus Xucw71 is also closely linked to the grain protein content locus Gpc-B1 (0.3-cM). Marker-assisted selection strategies are presented to improve stripe rust resistance and simultaneously select for high or low Gpc-B1 alleles.


A qualitative study of adult AAC users' experiences communicating with medical providers.
To study the experiences of adults who use augmentative and alternative communication (AAC) systems and methods when interacting with medical providers, specifically primary care providers. Individual face-to-face interviews were conducted with 12 participants, four of whom also participated in an online focus group. Diagnoses of the participants included cerebral palsy, undifferentiated developmental disability, head and neck cancer, amyotrophic lateral sclerosis and primary lateral sclerosis. Transcripts from the interviews and the focus group were analyzed to create a list of codes. From these codes themes that captured particular concepts discussed were identified. Participants described multiple frustrations in communicating with medical care providers. Themes that arose included: planning and preparing for the appointment, time barriers, inappropriate assumptions, relationship building and establishing rapport, medical decision making and implementing the plan. All but one participant reported bringing a caregiver with them to their appointments and this person, whether a family member, friend or paid aide, had a substantial role throughout the appointment. The participants' stories highlight important barriers they experience when communicating with medical providers. These barriers bring attention to the need for education for physicians, caregivers and patients with communication disabilities, along with increased research to improve patient-provider communication. Patients with communication disabilities face multiple barriers to communicating with medical care providers. Patients, caregivers, and medical care providers all play a role in effective and ineffective communication during appointments. Education for medical care providers, caregivers, and patients with communication disabilities, along with increased research is needed to improve patient-provider communication.


Facilitated process improvement: an approach to the seamless linkage between evidence and practice in CKD.
Two common strategies for guideline implementation are preformed practice improvement tools, such as flowcharts, and process reengineering by total quality management (TQM) teams. Prespecified tools fail to accommodate local circumstances, TQM requires an unrealistic level of local commitment, and neither has a proven track record for success. We describe an alternative approach termed facilitated process improvement (FPI), a systematic exploration of potential modifications to systems of care, and its application to the implementation of an evidence-based chronic kidney disease (CKD) guideline, focusing on individuals not yet requiring renal replacement therapy. The FPI steps followed by the implementation work group to develop a set of implementation tools for the Renal Physicians Association Advanced CKD Guideline included: (1) developing functional specifications of processes, including actions and prerequisites required; (2) investigating processes of care in a variety of site types to understand processes and reasons for failures; (3) developing practical tools corresponding to root causes of failures of processes and subprocesses; and (4) developing a meta-tool to tailor local selection of tools. Formal needs assessment identified processes of care related to 3 major tasks: identify patients, develop and communicate patient-specific management plan, and implement plan. Subtasks were identified to address root causes of failures, and, for each, tools were modified from existing or developed de novo by the work group, which further developed an organized management approach that uses 4 categories of tools: (1) assessment tools identify opportunities for improvements; (2) tailoring tools, a unique feature of this approach, determine which tools are applicable; (3) implementation tools identify patients and communicate and implement management plan; and (4) evaluation tools assess the impact of implementation. The work group, in collaboration with community clinicians, patients, and CKD and tool experts, developed and used FPI to provide a range of tools in a fashion that supports and simplifies local assessment, tailoring, implementation, and evaluation. With the formative work completed, practitioners whose practice improvement experience level and other resources may be limited will find it more feasible and practical to provide optimal advanced CKD management without the demands of conventional TQM or continuous quality improvement.


Role of videocapsule endoscopy for gastrointestinal bleeding.
Obscure gastrointestinal bleeding (OGIB) is defined as bleeding of an unknown origin that persists or recurs after negative initial upper and lower endoscopies. Several techniques, such as endoscopy, arteriography, scintigraphy and barium radiology are helpful for recognizing the bleeding source; nevertheless, in about 5%-10% of cases the bleeding lesion cannot be determined. The development of videocapsule endoscopy (VCE) has permitted a direct visualization of the small intestine mucosa. We will analyze those techniques in more detail. The diagnostic yield of CE for OGIB varies from 38% to 93%, being in the higher range in those cases with obscure-overt bleeding.


Fetal pulmonary and cerebral artery Doppler velocumetry in normal and high risk pregnancy.
Studies on fetal lung/brain circulation by means of power Doppler technique have suggested a marked reduction in lung perfusion in high-risk pregnancies as a sign of circulation redistribution. The ratio between lung/brain perfusion might therefore give a new method to predict fetal circulation centralization. The aim of the present study was to obtain fetal lung and cerebral artery ratio in normal and high-risk pregnancies. Doppler samples from proximal right pulmonary artery blood velocities and middle cerebral artery (MCA) were recorded cross-sectionally in 228 normal singleton pregnancies at gestational age 22 to 40 weeks. MCA/right pulmonary artery pulsatility index (PI) ratio was calculated. Doppler samples from proximal right pulmonary artery and MCA were also recorded in 89 high-risk singleton pregnancies and the results related to perinatal outcome. In the normal controls, right pulmonary artery PI remained stable until 30 weeks of gestation with slight increase thereafter until term. The MCA to right pulmonary artery PI ratio increased between 22 and 28 weeks of gestation with the rapid fall towards term. In the high-risk pregnancies group, right pulmonary artery PI showed no significant correlation to perinatal outcome, but signs of brain-sparing in the MCA were correlated to all adverse outcome parameters. Velocimetry of the middle cerebral artery is better than velocimetry of right pulmonary artery in predicting adverse outcome of pregnancy The brain/lung PI ratio does not improve the prediction of adverse outcome of pregnancy.


Constructing hierarchical porous nanospheres for versatile microwave response approaches: the effect of architectural design.
Owing to their immense potential in functionalized applications, tremendous interest has been devoted to the design and synthesis of nanostructures. The introduction of sufficient amount of microwaves into the absorbers on the premise that the dissipation capacity is strong enough remains a key challenge. Pursuing a general methodology to overcome the incompatibility is of great importance. There is widespread interest in designing the materials with specific architectures. Herein, the common absorber candidates were chosen to feature the hierarchical porous Fe3O4@C@Fe3O4 nanospheres. Due to the reduced skin effect (induced by low-conductivity Fe3O4 outer layer), multiple interfacial polarizations and scattering (due to the ternary hierarchical structures and nanoporous inner core) as well as the improved magnetic dissipation ability (because of multiple magnetic components), the material design enabled a promising microwave absorption performance. This study not only illustrates the primary mechanisms for the improved microwave absorption performance but also underscores the potential in designing the particular architectures as a strategy for achieving the compatibility characteristics.


Double minute chromosomes carrying the human multidrug resistance 1 and 2 genes are generated from the dimerization of submicroscopic circular DNAs in colchicine-selected KB carcinoma cells.
This study characterizes amplified structures carrying the human multidrug resistance (MDR) genes in colchicine-selected multidrug resistant KB cell lines and strongly supports a model of gene amplification in which small circular extrachromosomal DNA elements generated from contiguous chromosomal DNA regions multimerize to form cytologically detectable double minute chromosomes (DMs). The human MDR1 gene encodes the 170-kDa P-glycoprotein, which is a plasma membrane pump for many structurally unrelated chemotherapeutic drugs. MDR1 and its homolog, MDR2, undergo amplification when KB cells are subjected to stepwise selection in increasing concentrations of colchicine. The structure of the amplification unit at each step of drug selection was characterized using both high-voltage gel electrophoresis and pulsed-field gel electrophoresis (PFGE) techniques. An 890-kb submicroscopic extrachromosomal circular DNA element carrying the MDR1 and MDR2 genes was detected in cell line KB-ChR-8-5-11, the earliest step in drug selection in which conventional Southern/hybridization analyses detected MDR gene amplification. When KB-ChR-8-5-11 was subjected to stepwise increases in colchicine, this circular DNA element dimerized as detected by PFGE with and without digestion with Not 1, which linearizes the 890-kb amplicon. This dimerization process, which also occurred at the next step of colchicine selection, resulted in the formation of cytologically detectable DMs revealed by analysis of Giemsa-stained metaphase spreads.


The Effect of Retrieval Focus and Emotional Valence on the Inferior Frontal Cortex Activity during Autobiographical Recollection.
Although available evidence points to a role of the inferior frontal cortex (IFC) in both emotion processing and autobiographical memory (AM) recollection, it is unclear what the role of this region is in emotional AM recollection. The present study investigated whether IFC activity can be influenced by manipulations of the retrieval focus (emotional vs. non-emotional) and whether this influence is similar for AMs with positive and negative emotional valence. Participants were asked to focus either on emotional (Emotion condition) or on non-emotional contextual (Context condition) details during the elaboration of positive and negative AMs, while fMRI data were collected. The study yielded two main findings: (1) Focusing on Emotion compared to Context during AM recollection was associated with increased activity in bilateral IFC, for positive AMs, whereas negative AMs produced similarly high IFC activity during Emotion and Context conditions; (2) There was a hemispheric dissociation in the IFC linked to the experiencing of emotion and the focus of AM recollection, such that the left IFC activity correlated positively with the subjective re-experience of emotion during the Emotion condition, whereas the right IFC activity correlated negatively with the subjective re-experience of emotion during the Context condition, for both positive and negative AMs. Overall, the present findings suggest that IFC's involvement during the recollection of emotional AMs is susceptible to manipulations of the retrieval focus only in the case of positive AMs, and that this region plays a role in both the enhancement and inhibition of emotional experience during AM recollection.


First Molecular Detection and Phylogenetic Analysis of Anaplasma phagocytophilum from a Clinical Case of Canine Granulocytic Anaplasmosis in Japan.
Anaplasma phagocytophilum DNA was detected from a dog with canine granulocytic anaplasmosis (CGA) in Japan. Phylogenetic analysis of the DNA using 16S rRNA, gltA, and groEL sequences revealed that the strain was nearly identical to A. phagocytophilum detected from Apodemus agrarius (black-striped field mouse) in China and Korea. To our knowledge, this is the first report of molecular detection and phylogenetic analysis of A. phagocytophilum from a clinical case of CGA in Japan.


Salicylic acid and NIM1/NPR1-independent gene induction by incompatible Peronospora parasitica in arabidopsis.
To identify pathogen-induced genes distinct from those involved in systemic acquired resistance, we used cDNA-amplified fragment length polymorphism to examine RNA levels in Arabidopsis thaliana wild type, nim1-1, and salicylate hydroxylase-expressing plants after inoculation with an incompatible isolate of the downy mildew pathogen Peronospora parasitica. Fifteen genes are described, which define three response profiles on the basis of whether their induction requires salicylic acid (SA) accumulation and NIM1/NPR1 activity, SA alone, or neither. Sequence analysis shows that the genes include a calcium binding protein related to TCH3, a protein containing ankyrin repeats and potential transmembrane domains, three glutathione S-transferase gene family members, and a number of small, putatively secreted proteins. We further characterized this set of genes by assessing their expression patterns in each of the three plant lines after inoculation with a compatible P. parasitica isolate and after treatment with the SA analog 2,6-dichloroisonicotinic acid. Some of the genes within subclasses showed different requirements for SA accumulation and NIM1/NPR1 activity, depending upon which elicitor was used, indicating that those genes were not coordinately regulated and that the regulatory pathways are more complex than simple linear models would indicate.


Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome.
Aneurysms-osteoarthritis syndrome (AOS) is a new autosomal dominant syndromic form of thoracic aortic aneurysms and dissections characterised by the presence of arterial aneurysms and tortuosity, mild craniofacial, skeletal and cutaneous anomalies, and early-onset osteoarthritis. AOS is caused by mutations in the SMAD3 gene. A cohort of 393 patients with aneurysms without mutation in FBN1, TGFBR1 and TGFBR2 was screened for mutations in SMAD3. The patients originated from The Netherlands, Belgium, Switzerland and USA. The clinical phenotype in a total of 45 patients from eight different AOS families with eight different SMAD3 mutations is described. In all patients with a SMAD3 mutation, clinical records were reviewed and extensive genetic, cardiovascular and orthopaedic examinations were performed. Five novel SMAD3 mutations (one nonsense, two missense and two frame-shift mutations) were identified in five new AOS families. A follow-up description of the three families with a SMAD3 mutation previously described by the authors was included. In the majority of patients, early-onset joint abnormalities, including osteoarthritis and osteochondritis dissecans, were the initial symptom for which medical advice was sought. Cardiovascular abnormalities were present in almost 90% of patients, and involved mainly aortic aneurysms and dissections. Aneurysms and tortuosity were found in the aorta and other arteries throughout the body, including intracranial arteries. Of the patients who first presented with joint abnormalities, 20% died suddenly from aortic dissection. The presence of mild craniofacial abnormalities including hypertelorism and abnormal uvula may aid the recognition of this syndrome. The authors provide further insight into the phenotype of AOS with SMAD3 mutations, and present recommendations for a clinical work-up.


Bayesian Joint Spike-and-Slab Graphical Lasso.
In this article, we propose a new class of priors for Bayesian inference with multiple Gaussian graphical models. We introduce Bayesian treatments of two popular procedures, the group graphical lasso and the fused graphical lasso, and extend them to a continuous spike-and-slab framework to allow self-adaptive shrinkage and model selection simultaneously. We develop an EM algorithm that performs fast and dynamic explorations of posterior modes. Our approach selects sparse models efficiently and automatically with substantially smaller bias than would be induced by alternative regularization procedures. The performance of the proposed methods are demonstrated through simulation and two real data examples.


Pharmacology of the human gamma-aminobutyric acidA receptor alpha 4 subunit expressed in Xenopus laevis oocytes.
The human gamma-aminobutyric acidA (GABAA) receptor alpha 4 subunit was recently cloned and characterized pharmacologically using radioligand binding techniques. These studies suggested that alpha 4 subunits confer a novel diazepam-insensitive binding site. To further investigate the pharmacology of the alpha 4 subunit, we expressed human alpha 4 beta 2 gamma 2L subunit combinations in oocytes and compared the expression and pharmacology of these receptors with alpha 1 beta 2 gamma 2L, beta 2 gamma 2L, and other possible binary subunit combinations. Apparent GABA affinity was 2-3-fold higher for alpha 4 beta 2 gamma 2L than for alpha 1 beta 2 gamma 2L receptors. Functional modulation of receptors by benzodiazepine-site ligands and other classes of allosteric modulator were assayed over a broad concentration range (0.01-100 microM) on currents that were 10% of the maximum GABA response. Diazepam (0.01-1 microM) did not modulate GABA responses at alpha 4 beta 2 gamma 2L receptors, whereas it increased alpha 1 beta 2 gamma 2L responses by approximately 110%. Bretazenil (0.01-1 microM), a benzodiazepine partial agonist, induced higher efficacy modulation of alpha 4 beta 2 gamma 2L receptors (approximately 83%) than of alpha 1 beta 2 gamma 2L (approximately 25%). The benzodiazepine antagonist flumazenil (0.1-10 microM) unexpectedly potentiated alpha 4 beta 2 gamma 2L responses up to approximately 41%, and the benzodiazepine partial inverse agonist Ro15-4513 (1 microM) potentiated alpha 4 beta 2 gamma 2L responses by approximately 63%. Two other benzodiazepine-site ligands, CGS-9895 and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate, had qualitatively similar effects at alpha 1 beta 2 gamma 2L and alpha 4 beta 2 gamma 2L. Modulators such as pentobarbital, 3 alpha-hydroxy-5 alpha-pregnan-20-one, mefenamic acid, and loreclezole also induced similar potentiation at both subtypes of receptor. The pharmacology conferred by the alpha 4 subunit was similar to that conferred by the alpha 6 subunit, to which it shows highest levels of homology, but the two subunits differ in sensitivity to the beta-carboline methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate. Properties of the alpha 4-containing receptors are consistent with diazepam-insensitive binding sites found in cerebral cortex and other forebrain structures. Characterization of these receptors should further our understanding of mechanisms underlying the behavioral effects of GABA modulators and help in the design of drugs with improved, or novel, therapeutic profiles.


Performance-Based Outcomes After Anterior Cruciate Ligament Reconstruction in Professional Athletes Differ Between Sports.
Excellent outcomes have been reported for anterior cruciate ligament (ACL) reconstruction (ACLR) in professional athletes in a number of different sports. However, no study has directly compared these outcomes between sports. To determine if differences in performance-based outcomes exist after ACLR between professional athletes of each sport. Cohort study; Level of evidence, 3. National Football League (NFL), National Basketball Association (NBA), National Hockey League (NHL), and Major League Baseball (MLB) athletes undergoing primary ACLR for an acute rupture were identified through an established protocol of injury reports and public archives. Sport-specific performance statistics were collected before and after surgery for each athlete. Return to play (RTP) was defined as a successful return to the active roster for at least 1 regular-season game after ACLR. Of 344 professional athletes who met the inclusion criteria, a total of 298 (86.6%) returned to play. NHL players had a significantly higher rate of RTP (95.8% vs 83.4%, respectively; P = .04) and a shorter recovery time (258 ± 110 days vs 367 ± 268 days, respectively; P < .001) than athletes in all the other sports. NFL athletes experienced significantly shorter careers postoperatively than players in all the other sports (2.1 vs 3.2 years, respectively; P < .001). All athletes played fewer games ( P ≤ .02) 1 season postoperatively, while those in the NFL had the lowest rate of active players 2 and 3 seasons postoperatively (60%; P = .002). NBA and NFL players showed decreased performance at season 1 after ACLR ( P ≤ .001). NFL players continued to have lower performance at seasons 2 and 3 ( P = .002), while NBA players recovered to baseline performance. The data indicate that NFL athletes fare the worst after ACLR with the lowest survival rate, shortest postoperative career length, and sustained decreases in performance. NHL athletes fare the best with the highest rates of RTP, highest survival rates, longest postoperative career lengths, and no significant changes in performance. The unique physical demand that each sport requires is likely one of the explanations for these differences in outcomes.


Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy.
The role of the giant protein titin in patients with heart failure is not well established. We investigated titin expression in patients with end-stage heart failure resulting from nonischemic dilated cardiomyopathy, in particular as it relates to left ventricular (LV) myocardial stiffness and LV function. SDS-agarose gels revealed small N2B (stiff) and large N2BA (compliant) cardiac titin isoforms with a mean N2BA:N2B expression ratio that was significantly (P<0.003) increased in 20 heart failure patients versus 6 controls. However, total titin was unchanged. The coexpression ratio was highest in a subsample of patients with an impaired LV relaxation pattern (n=7), intermediate in those with pseudonormal filling (n=6), and lowest in the group with restrictive filling (n=7). Mechanical measurements on LV muscle strips dissected from these hearts (n=8) revealed that passive muscle stiffness was significantly reduced in patients with a high N2BA:N2B expression ratio. Clinical correlations support the relevance of these changes for LV function (assessed by invasive hemodynamics and Doppler echocardiography). A positive correlation between the N2BA:N2B titin isoform ratio and deceleration time of mitral E velocity, A wave transit time, and end diastolic volume/pressure ratio was found. These changes affect exercise tolerance, as indicated by the positive correlation between the N2BA:N2B isoform ratio and peak O2 consumption (n=10). Upregulated N2BA expression was accompanied by increased expression levels of titin-binding proteins (cardiac ankyrin repeat protein, ankrd2, and diabetes ankyrin repeat protein) that bind to the N2A element of N2BA titin (studied in 13 patients). Total titin content was unchanged in end-stage failing hearts and the more compliant N2BA isoform comprised a greater percentage of titin in these hearts. Changes in titin isoform expression in heart failure patients with dilated cardiomyopathy significantly impact diastolic filling by lowering myocardial stiffness. Upregulation of titin-binding proteins indicates that the importance of altered titin expression might extend to cell signaling and regulation of gene expression.


Genome-wide identification and analysis of the ALTERNATIVE OXIDASE gene family in diploid and hexaploid wheat.
A comprehensive understanding of wheat responses to environmental stress will contribute to the long-term goal of feeding the planet. ALERNATIVE OXIDASE (AOX) genes encode proteins involved in a bypass of the electron transport chain and are also known to be involved in stress tolerance in multiple species. Here, we report the identification and characterization of the AOX gene family in diploid and hexaploid wheat. Four genes each were found in the diploid ancestors Triticum urartu, and Aegilops tauschii, and three in Aegilops speltoides. In hexaploid wheat (Triticum aestivum), 20 genes were identified, some with multiple splice variants, corresponding to a total of 24 proteins for those with observed transcription and translation. These proteins were classified as AOX1a, AOX1c, AOX1e or AOX1d via phylogenetic analysis. Proteins lacking most or all signature AOX motifs were assigned to putative regulatory roles. Analysis of protein-targeting sequences suggests mixed localization to the mitochondria and other organelles. In comparison to the most studied AOX from Trypanosoma brucei, there were amino acid substitutions at critical functional domains indicating possible role divergence in wheat or grasses in general. In hexaploid wheat, AOX genes were expressed at specific developmental stages as well as in response to both biotic and abiotic stresses such as fungal pathogens, heat and drought. These AOX expression patterns suggest a highly regulated and diverse transcription and expression system. The insights gained provide a framework for the continued and expanded study of AOX genes in wheat for stress tolerance through breeding new varieties, as well as resistance to AOX-targeted herbicides, all of which can ultimately be used synergistically to improve crop yield.


Health-related quality-of-life results from multinational clinical trials of insulin lispro. Assessing benefits of a new diabetes therapy.
To compare health-related quality of life (HRQOL) in patients with diabetes receiving insulin lispro with patients receiving regular human insulin (Humulin R). We performed two randomized comparative studies over a 6-month period (3 months per treatment). Primary analyses used crossover baseline to 3-month changes in HRQOL scores. Ninety-three principal investigators in Canada, France, Germany, and the U.S. participated in these studies. One HRQOL crossover study included 468 patients with type I diabetes; the other HRQOL crossover study included 474 patients with type II diabetes. In both studies, patients were taking insulin at least 2 months before enrollment. Primary outcomes included two generic HRQOL domains, energy/fatigue and health distress, and two diabetes-specific domains, treatment satisfaction and treatment flexibility. Thirty secondary outcomes included both generic and diabetes-specific measures. Secondary outcome domains were controlled for multiplicity in the analyses. Primary analyses showed that treatment satisfaction scores (P < 0.001) and treatment flexibility scores (P = 0.001) were higher for insulin lispro in type I diabetic patients. No other significant treatment differences were detected using the data from these 6-month crossover studies. Treatment satisfaction and treatment flexibility were significantly improved in patients with type I diabetes using insulin lispro. Other HRQOL findings were comparable for insulin lispro and regular human insulin. Insulin lispro appears to have a measurable impact on lifestyle benefits in patients with type I diabetes, as demonstrated by increased treatment satisfaction and treatment flexibility.


hCG-Leydig cell functional binding kinetics: threshold and nonlinearity in response.
Functional kinetic methods, developed to measure the interaction of human chorionic gonadotropin (hCG) with rat Leydig-cell receptors, appear to be useful tools for correlating response with receptor occupancy. In the functional procedures, hCG was allowed to bind to the cells (period I), the free hormone was removed by washing and/or antiserum treatment (period II), and the response of the cells was measured at 37 degrees C (period III). Once initiated, the response to hCG was stable throughout period III. Assuming a one-to-one relationship between occupancy and response during period III, we estimated the rate of association to be 10(8) M-1/min at 37 degrees C with an activation energy of 14-17 kcal/mol. Removal of sialic acid from hCG increased this rate; removal of other carbohydrate residues decreased it. Similar values for the kinetics of binding were observed when either steroidogenesis or cyclic AMP accumulation was measured, suggesting that the same receptor may mediate both processes. Use of either functional or direct (i.e., 125I-labeled hCG) methods to estimate response as a function of occupancy gave equal results, suggesting that most binding sites were coupled to a response. Response was nonlinearly coupled to occupany. Threshold amounts of hormone-receptor complex (0.1% total receptors testosterone synthesis; 2.7% total receptors cyclic AMP accumulation) were required to induce any response. Increased stimulation required progressively larger increments of receptor occupancy. The threshold was inversely proportional to the efficacy of the hCG derivative used and was reduced by the presence of isobutylmethylxanthine.


Trans-resveratrol: a magical elixir of eternal youth?
Trans-resveratrol or (E)-resveratrol [3,4',5 trihydroxy-trans-stilbene, t-RESV or (E)-RESV] is a natural component of Vitis vinifera L. (Vitaceae), abundant in the skin of grapes (but not in the flesh) and in the leaf epidermis and present in wines (especially red wines). In in vitro, ex vivo and in vivo experiments, t-RESV exhibits a number of biological activities, including anti inflammatory, antioxidant, platelet antiaggregatory and anticarcinogenic properties, and modulation of lipoprotein metabolism. Some of these activities have been implicated in the cardiovascular protective effects attributed to t-RESV and to red wine. Prior to 2002 there had been no previous studies describing the potential effects of t-RESV on the lifespan extension. However, in the last 5 years, several researchers have reported that t-RESV is a potent activator of sirtuin enzymatic activity, mimics the beneficial effects of caloric restriction (CR), retards the aging process and increases longevity in a number of organisms from different phyla such as yeasts, worms, flies and short-lived fish. In addition, t-RESV seems to be effective in delaying the onset of a variety of age-related diseases in mammals (e.g.: rodents). Therefore, this review will basically focus on the possible role of t-RESV to extend life duration and on some of the mechanisms by which t-RESV may act as an anti-aging agent.


A Comparative Study of Hummingbirds and Chickens Provides Mechanistic Insight on the Histidine Containing Dipeptide Role in Skeletal Muscle Metabolism.
Histidine containing dipeptides (HCDs) have numerous ergogenic and therapeutic properties, but their primary role in skeletal muscle remains unclear. Potential functions include pH regulation, protection against reactive oxygen/nitrogen species, or Ca2+ regulation. In recognition of the challenge of isolating physiological processes in-vivo, we employed a comparative physiology approach to investigate the primary mechanism of HCD action in skeletal muscle. We selected two avian species (i.e., hummingbirds and chickens), who represented the extremes of the physiological processes in which HCDs are likely to function. Our findings indicate that HCDs are non-essential to the development of highly oxidative and contractile muscle, given their very low content in hummingbird skeletal tissue. In contrast, their abundance in the glycolytic chicken muscle, indicate that they are important in anaerobic bioenergetics as pH regulators. This evidence provides new insights on the HCD role in skeletal muscle, which could inform widespread interventions, from health to elite performance.


Review of Offshore Wind Farm Impact Monitoring and Mitigation with Regard to Marine Mammals.
Monitoring and mitigation reports from 19 UK and 9 other European Union (EU) offshore wind farm (OWF) developments were reviewed, providing a synthesis of the evidence associated with the observed environmental impact on marine mammals. UK licensing conditions were largely concerned with mitigation measures reducing the risk of physical and auditory injury from pile driving. At the other EU sites, impact monitoring was conducted along with mitigation measures. Noise-mitigation measures were developed and tested in UK and German waters in German government-financed projects. We highlight some of the review's findings and lessons learned with regard to noise impact on marine mammals.


Close to me: the effect of asymmetrical environments on spatial attention.
Attention can be captured by distractors and can affect performance. To examine whether asymmetrical distractors, such as a wall, affect spatial attention, Experiment 1 required participants (n = 20) to determine the relative length of pre-bisected lines when a temporary barrier was placed close to the left or right sides of the display. Post-hoc tests showed that attention was drawn towards left, but not right, walls. Experiment 2 (n = 18) sought to increase this effect using a solid brick wall rather than a temporary barrier. Instead of strengthening the result, no effect of barrier was observed. A non-effect was also observed in Experiment 3 (n = 18) when participants moved a cursor to the line's middle. Finally, Experiment 4 (n = 26) showed that asymmetrical barriers had no effect on visual search. While the data showed some evidence that attention is distracted by walls placed to the left, this effect is weak and task-specific. The ability to monitor critical information on displays can be affected by asymmetrical distractors. In many workplaces, a display may be placed alongside a wall. This study explored whether a wall placed to the left/right affects spatial attention. A weak, task-specific, attraction effect was observed for walls on the left.


Polyamines as mediators of APC-dependent intestinal carcinogenesis and cancer chemoprevention.
Combination chemoprevention for cancer was proposed a quarter of a century ago, but has not been implemented in standard medical practice owing to limited efficacy and toxicity. Recent trials have targeted inflammation and polyamine biosynthesis, both of which are increased in carcinogenesis. Preclinical studies have demonstrated that DFMO (difluoromethylornithine), an irreversible inhibitor of ODC (ornithine decarboxylase) which is the first enzyme in polyamine biosynthesis, combined with NSAIDs (non-steroidal anti-inflammatory drugs) suppresses colorectal carcinogenesis in murine models. The preclinical rationale for combination chemoprevention with DFMO and the NSAID sulindac, was strengthened by the observation that a SNP (single nucleotide polymorphism) in the ODC promoter was prognostic for adenoma recurrence in patients with prior sporadic colon polyps and predicted reduced risk of adenoma in those patients taking aspirin. Recent results from a phase III clinical trial showed a dramatic reduction in metachronous adenoma number, size and grade. Combination chemoprevention with DFMO and sulindac was not associated with any serious toxicity. A non-significant trend in subclinical ototoxicity was detected by quantitative audiology in a subset of patients identified by a genetic marker. These preclinical, translational and clinical data provide compelling evidence for the efficacy of combination chemoprevention. DFMO and sulindac is a rational strategy for the prevention of metachronous adenomas, especially in patients with significant risk for colorectal cancer. Toxicities from this combination may be limited to subsets of patients identified by either past medical history or clinical tests.


Protective efficacy of Bluetongue virus-like and subvirus-like particles in sheep: presence of the serotype-specific VP2, independent of its geographic lineage, is essential for protection.
There have been multiple separate outbreaks of Bluetongue (BT) disease of ruminants in Europe since 1998, often entering via the Mediterranean countries of Italy, Spain and Greece. BT is caused by an orbivirus, Bluetongue virus (BTV), a member of the family Reoviridae. BTV is a non-enveloped double-capsid virus, which encodes 7 structural proteins (VP1-VP7) and several non-structural proteins (NS1, NS2, NS3/3a and NS4) from ten double-stranded RNA segments of the genome. In this report, we have prepared BTV virus-like particles (VLPs, composed of VP2, VP3, VP5 and VP7) and sub-viral, inner core-like particles (CLPs, VP3 and VP7) using a recombinant baculovirus expression system. We compared the protective efficacy of VLPs and CLPs in sheep and investigated the importance of geographical lineages of BTV in the development of vaccines. The Greek crossbred Karagouniko sheep, which display mild to sub-clinical BT, were vaccinated with VLPs or CLPs of BTV-1, derived from western lineage and were challenged with virulent BTV-1 from an eastern lineage. All VLP-vaccinated animals developed a neutralising antibody response to BTV-1 from both lineages prior to challenge. Moreover, post-challenged animals had no clinical manifestation or viraemia and the challenged virus replication was completely inhibited. In contrast, CLP-vaccinated animals did not induce any neutralising antibody response but developed the group specific VP7 antibodies. CLPs also failed to prevent the clinical manifestation and virus replication, but in comparison to controls, the severity of disease manifestation and viraemia was mitigated. The data demonstrated that the outer capsid was essential for complete protection, while the geographical origin of the BTV was not critical for development of a serotype specific vaccine.


Variable thyrotropin response to thyrotropin-releasing hormone after small decreases in plasma free thyroid hormone concentrations in patients with nonthyroidal diseases.
Although a normal serum thyrotropin (TSH) concentration is generally considered to be the most important finding to support the clinical impression of euthyroidism in patients with nonthyroidal diseases and decreased serum triiodothyronine (T(3)), the regulation of TSH secretion in sick patients has not been studied previously. Accordingly, we studied the regulation of TSH secretion in 23 patients with nonthyroidal diseases; 15 of the patients had decreased serum T(3). TSH regulation was studied by measuring the TSH response to injected thyrotropin-releasing hormone (TRH) before and after effecting a small decrease in serum thyroxine (T(4)) and/or T(3) concentrations by iodide treatment, 262 mg daily for 10 d. Iodide treatment significantly decreased (> 10%) the free T(4) index (FT(4)-I) and/or free T(3) index (FT(3)-I) in all patients. FT(4)-I values were correlated (0.611, P < 0.001), with free T(4) concentration determined by equilibrium dialysis. Despite decreased FT(4)-I and/or FT(3)-I after iodide treatment in all patients, the TSH response to TRH after iodide treatment was augmented in only 8 of 15 patients who had decreased serum T(3) (group 1) and in only 5 of 8 patients who had a normal serum T(3). Mean base-line TSH concentration was increased significantly (P < 0.05) from 0.9+/-0.1 to 1.5+/-0.3 muU/ml in group 1 only. Comparison of the mean TSH response to TRH showed that there was no significant difference between groups 1 and 2. Moreover, no significant difference in thyroidal parameters was observed between patients who had augmented TSH response to TRH after iodides and those who had either similar or decreased TSH response irrespective of the initial serum T(3). These studies show that an augmented TSH response to TRH in response to a small reduction in serum T(4) and T(3) concentration occurred in only 57% of the entire group of patients with nonthyroidal diseases and that the presence or absence of a normal TSH response to this stimulus did not seem to be related to the base-line serum T(3) concentration. Because an increase in serum TSH in response to decreased serum T(4) and T(3) did not occur in about one-half of patients with nonthyroidal diseases, normal serum TSH may not be a reliable index of the euthyroid state in these patients.


Stress among medical students: factor structure of the University Stress Scale among Italian students.
The main purpose of the current study was to investigate the psychometric properties of the Italian version of the University Stress Scale (USS) among Italian medical students. A cross-sectional observational study based on data from an online cross-sectional survey from 11 to 23 December 2018. A total of 1858 Italian medical students participated in the study. We measured perceived stress among medical students using the USS, the Effort-Reward Imbalance Student Questionnaire (ERI-SQ) and the Kessler-10 (K10). Results showed that a bifactor-Exploratory Structural Equation Modeling solution provided excellent levels of fit to the data. Our results suggest that the modified version of 19 items of the Italian version of the USS does not have a simple unidimensional structure. Overall, an inspection of ancillary indices (omega indices, ECV and percentage of uncontaminated correlations) revealed that these were too low to suggest the use of the USS as a composite measure of university stress. We tested an alternative unidimensional short form (eight items; USS-S) that assessed all the five sources of stress. This version provided a good fit to the data. Evidence of convergent validity of the USS-S was observed by analysing the correlations between the USS and ERI-SQ (ranging from -0.34 to 0.37, all p<0.01). Finally, based on the clinical cut-off recommended on the K10, results from receiver operating characteristic showed that considering the clinical cut-off of the USS is 7.5 and that 59.70% of medical students reported stress levels in the clinical range. Finally, our results showed a lack of support for using the USS to measure a general university stress factor, as the general USS factor accounted for little variance in our sample. In this sense, stress scores among Italian students can be better assessed by the use of the USS-S.


Predictors of food variety and dietary diversity among older persons in Botswana.
We investigated whether food variety and diversity are associated with physical and cognitive functioning in older adults in Botswana and designed a simple set of screening questions that predict food variety in this population. Data were collected (1998) as a national household survey of 1085 subjects 60 y and older. A food variety score, based on a food frequency checklist, was calculated by summing the frequency of weekly intakes of 16 food items (0 to 66). A dietary diversity score was calculated as the number of food groups consumed weekly (0 to 5). A representative subsample (n = 393) was randomly selected for the clinical component of the survey, and measurements on dependency and cognitive function were conducted. Low food variety was found: 35.2%, 59.3%, and 22.4% of subjects consumed no dairy products, fruits, and vegetables, respectively. A higher food variety score was associated with urban residence, ownership of cattle, higher education, and more frequent meals, and these indicators were used to construct a nutritional risk indicator. Higher food variety score was associated with better self-reported health and better cognitive function. Similarly, a higher score on the nutritional risk indicator screening tool was associated with desirable health outcomes. A limited number of foods is consumed, leading to an overall pattern of poor food variety. Higher food variety was associated with improved physical and cognitive functions. A screening tool that predicts food variety in this population has been developed and is recommended to be incorporated at a primary care level to identify older adults most at risk of a poor quality diet.


The long-term use of garlic in ischemic heart disease--an appraisal.
The hypocholesterolemic and fibrinolysis-enhancing properties of garlic were assessed in patients with ischemic heart disease (IHD) and in healthy control subjects. The peak of blood fibrinolytic activity (BFA) achieved at the 4th week of garlic therapy was not sustained despite its continuous use and returned to about the pre-garlic values at the 12th week. Garlic withdrawal did not cause any further change in BFA. Under the same conditions serum total cholesterol (STC) values did not show any significant change. Both of the foregoing features were observed in the IHD as well as in the control group. Garlic therapy for 12 weeks did not cause any appreciable changes in serum triglyceride, beta-lipoprotein, plasma fibrinogen levels or coagulation time in either IHD or control subjects. The evidence cited above does not appear to substantiate the prevalent popular belief in the efficacy of garlic in the management of IHD either as a hypocholesterolemic or as a fibrinolytic agent.


Caulobacter Lon protease has a critical role in cell-cycle control of DNA methylation.
CcrM, an adenine DNA methyltransferase, is essential for viability in Caulobacter crescentus. The CcrM protein is present only in the predivisional stage of the cell cycle, resulting in cell-cycle-dependent variation of the DNA methylation state of the chromosome. The availability of CcrM is controlled in two ways: (1) the ccrM gene is transcribed only in the predivisional. cell, and (2) the CcrM protein is rapidly degraded prior to cell division. We demonstrate here that CcrM is an important target of the Lon protease pathway in C. crescentus. In a lon null mutant, ccrM transcription is still temporally regulated, but the CcrM protein is present throughout the cell cycle because of a dramatic increase in its stability that results in a fully methylated chromosome throughout the cell cycle. Because the Lon protease is present throughout the cell cycle, it is likely that the level of CcrM in the cell is controlled by a dynamic balance between temporally varied transcription and constitutive degradation. We have shown previously that restriction of CcrM to the C. crescentus predivisional cell is essential for normal morphogenesis and progression through the cell cycle. Comparison of the lon null mutant strain with a strain whose DNA remains fully methylated as a result of constitutive expression of ccrM suggests that the effect of Lon on DNA methylation contributes to several developmental defects observed in the lon mutant. These defects include a frequent failure to complete cell division and loss of precise cell-cycle control of initiation of DNA replication. Other developmental abnormalities exhibited by the lon null mutant, such as the formation of abnormally long stalks, appear to be unrelated to altered chromosome methylation state. The Lon protease thus exhibits pleiotropic effects in C. crescentus growth and development.


Zinc and glycemic control: a meta-analysis of randomised placebo controlled supplementation trials in humans.
Impaired zinc metabolism is prominent in chronic disorders including cardiovascular disease and diabetes. Zinc has the potential to affect glucose homeostasis in animals and humans and hence impact the risk of type 2 diabetes mellitus. A systematic review and meta-analysis of randomised placebo controlled trials was conducted to determine the effect of zinc supplementation on fasting blood glucose, HbA1c, serum insulin and serum zinc concentrations. Relevant studies for inclusion were identified from a literature search of electronic databases up to July 2011. Fourteen reports (n=3978 subjects) were included in the meta-analysis. In the overall analysis, a small but statistically significant reduction in fasting glucose concentrations was observed (-0.19±0.08mmol/L, P=0.013) after zinc supplementation. HbA1c tended to decrease in zinc-supplemented individuals (-0.64±0.36%, P=0.072). No significant effect was observed for serum insulin concentrations. Plasma zinc concentrations increased significantly following supplementation (+4.03±0.81μmol/L, P=0.001). In secondary analyses of participants with chronic metabolic disease (types 1 and 2 diabetes mellitus, metabolic syndrome and obesity), zinc supplementation produced a greater reduction in glucose concentrations (-0.49±0.11mmol/L, P=0.001) compared to the effect that was observed in healthy participants. The significant albeit modest reduction in glucose concentrations and tendency for a decrease in HbA1c following zinc supplementation suggest that zinc may contribute to the management of hyperglycemia in individuals with chronic metabolic disease.


Enhanced acute apoptotic response to azoxymethane-induced DNA damage in the rodent colonic epithelium by Tyrian purple precursors: a potential colorectal cancer chemopreventative.
Colorectal cancer (CRC) is the second most prevalent and deadly cancer worldwide. Due to the mortality and morbidity associated with chemotherapeutic regimes, research is turning to natural product enhancement of the acute apoptotic response to genotoxic carcinogens (AARGC). Although Tyrian purple dye pigments and precursors from muricid molluscs are known for their anti-proliferative and proapoptotic activity, the chemoprotective properties of these edible molluscs has not been assessed. Enhancement of AARGC by oral administration of muricid extract (ME), containing a mixture of the cytotoxins tyrindoleninone and 6-bromoisatin, was assessed in an azoxymethane (AOM) rodent model. A dose-dependent increase in apoptotic index was observed in the distal colon, with a significant increase detected at an ME dose of 1.0 mg/g (p < 0.01). Proliferation (PCNA) index failed to vary significantly at this ME concentration, which confirms the ME-induced increase in apoptotic response to DNA alkylation. ME also appears to confer no major toxic side effects, as all mice consistently gained weight during the trial and colonic crypt height was maintained (p > 0.05) independent of ME dose. Although, this is the first example of AARGC enhancement by indole-based compounds, bioactive precursor degradation in simulated gastric fluid may prevent introduction of muricids as a chemopreventative food. Nevertheless, the protective effect of ME against CRC in vivo clearly substantiates further research into the chemopreventative efficacy of Muricidae natural products.


Determining the neural substrates of goal-directed learning in the human brain.
Instrumental conditioning is considered to involve at least two distinct learning systems: a goal-directed system that learns associations between responses and the incentive value of outcomes, and a habit system that learns associations between stimuli and responses without any link to the outcome that that response engendered. Lesion studies in rodents suggest that these two distinct components of instrumental conditioning may be mediated by anatomically distinct neural systems. The aim of the present study was to determine the neural substrates of the goal-directed component of instrumental learning in humans. Nineteen human subjects were scanned with functional magnetic resonance imaging while they learned to choose instrumental actions that were associated with the subsequent delivery of different food rewards (tomato juice, chocolate milk, and orange juice). After training, one of these foods was devalued by feeding the subject to satiety on that food. The subjects were then scanned again, while being re-exposed to the instrumental choice procedure (in extinction). We hypothesized that regions of the brain involved in goal-directed learning would show changes in their activity as a function of outcome devaluation. Our results indicate that neural activity in one brain region in particular, the orbitofrontal cortex, showed a strong modulation in its activity during selection of a devalued compared with a nondevalued action. These results suggest an important contribution of orbitofrontal cortex in guiding goal-directed instrumental choices in humans.


Excitatory and inhibitory actions of isoprostanes in human and canine airway smooth muscle.
Isoprostanes are generated nonenzymatically during free radical-mediated lipid peroxidation, and are used clinically and experimentally as markers of oxidative stress. However, their biological effects are poorly understood. We examined the effects of seven different 8-isoprostanes in human and canine airway smooth muscles. In large order airways (carina) of the human, several isoprostanes evoked powerful contractions, with 8-iso-prostaglandin (PG) E(2), 8-iso-PGF(1 alpha), and 8-iso-PGF(2 alpha) being the most efficacious (and with logEC(50) values of 7.0, 5.9, and 6.2 microM, respectively). These contractions were sensitive to the prostanoid TP receptor antagonist ICI 192,605 (0.1-1 microM), but not the EP prostanoid receptor antagonist AH-6809 (50 microM), or the leukotriene receptor antagonists monteleukast or ICI 198,615 (both 1 microM). Qualitatively similar results were obtained in small order human airways (<2 mm o.d.), except that the isoprostanes were generally slightly less potent. None of the isoprostanes had any marked excitatory effect in canine airways. In carbachol-preconstricted tissues (pretreated with ICI 192,605 to block any potential contraction), several isoprostanes completely relaxed canine airways: 8-iso-PGE(1), 8-iso-PGE(2), and 8-iso-PGF(3 alpha) were the most potent, with logIC(50) values of 6.9, 6.9, and 5.7, respectively. Only 8-iso-PGF(3 alpha) relaxed human airways (logIC(50) = 4.9). Our results show that several 8-isoprostanes are highly biologically active in human and canine airways, evoking both excitatory and/or inhibitory effects, and that these effects are compound, species, and tissue dependent.


Novel method for isolating untouched rat natural killer cells with higher purity compared with positive selection and fluorescence-activated cell sorting.
Natural killer (NK) cells are important effectors of both innate and adaptive immune responses. Although human and mouse NK cells are extensively characterized, much less is known about the rat cells, partly because of the current lack of reliable isolation techniques. We aimed to develop a method for isolating highly pure 'untouched' rat NK cells by negative selection from splenocytes. Thereafter, we characterized them phenotypically and functionally in comparison with those isolated by positive selection targeting the NKR-P1 receptor. Our novel method isolated highly pure untouched NK cells reproducibly with 97 ± 0.7% (n = 7), 96.6 ± 0.8% (n = 3) and 88.3 ± 1.5% (n = 9) in LEWIS, Fischer and athymic nude rats, respectively. The positively selected NK cells were less homogeneous and exhibited undesired method-related activation profiles. Resting negatively selected NK cells were less proliferative and less robust compared with positively selected NK cells. Although resting positively selected NK cells were more cytotoxic, interleukin-2 (IL-2) activation increased the cytotoxicity of negatively selected cells three-fold. The negatively selected NK cells responded to cross-linking of the NKR-P1 receptor by calcium mobilization from intracellular stores. However, combined IL-2 and IL-12 activation resulted in significantly more interferon-γ release from positively selected NK cells. This new NK-cell isolation method will allow a deeper insight into rat NK-cell phenotypes and the roles of their receptors in the biology of these cells.


Psychosocial difficulties in patients with Parkinson's disease.
The aim of this study was to report the most frequent psychosocial difficulties (PSDs) in patients with Parkinson disease (PD), to explore the relationship between PSDs, disability and quality of life (QoL), and to address the predictors of PSDs. Patients with PD were interviewed using a protocol composed of a questionnaire investigating PSDs (PARADISE 24), QoL, disability, comorbidity, and social support questionnaires, scales on resilience, personality traits, and empathy in physician. Most frequent PSDs were reported. Spearman's correlation was used to address the relationship between PARADISE 24 and QoL and disability measures. Multiple linear regression was performed to investigate predictors of PARADISE 24. Eighty patients were enrolled: 40% women, mean age 61.2 years. The most frequent PSDs were related to cognitive and motor slowness, tiredness, sleeping, facing all things to do, depressive mood, and anxiety. PARADISE 24 were correlated with disability (ρ=0.831) and QoL (ρ=-0.685). Lower QoL, higher disability, early age at onset, and shorter disease duration were significant predictors of PSDs (adjusted R=0.762). PARADISE 24 is an easy to use questionnaire that could contribute toward describing the impact of PD on patients' life more extensively, thus helping to define more tailored interventions.


The gliding speed of migrating birds: slow and safe or fast and risky?
Aerodynamic theory postulates that gliding airspeed, a major flight performance component for soaring avian migrants, scales with bird size and wing morphology. We tested this prediction, and the role of gliding altitude and soaring conditions, using atmospheric simulations and radar tracks of 1346 birds from 12 species. Gliding airspeed did not scale with bird size and wing morphology, and unexpectedly converged to a narrow range. To explain this discrepancy, we propose that soaring-gliding birds adjust their gliding airspeed according to the risk of grounding or switching to costly flapping flight. Introducing the Risk Aversion Flight Index (RAFI, the ratio of actual to theoretical risk-averse gliding airspeed), we found that inter- and intraspecific variation in RAFI positively correlated with wing loading, and negatively correlated with convective thermal conditions and gliding altitude, respectively. We propose that risk-sensitive behaviour modulates the evolution (morphology) and ecology (response to environmental conditions) of bird soaring flight.


Gene expression profiling in persons with multiple chemical sensitivity before and after a controlled n-butanol exposure session.
To investigate the pathophysiological pathways leading to symptoms elicitation in multiple chemical sensitivity (MCS) by comparing gene expression in MCS participants and healthy controls before and after a chemical exposure optimised to cause symptoms among MCS participants.The first hypothesis was that unexposed and symptom-free MCS participants have similar gene expression patterns to controls and a second hypothesis that MCS participants can be separated from controls based on differential gene expression upon a controlled n-butanol exposure. Participants were exposed to 3.7 ppm n-butanol while seated in a windowed exposure chamber for 60 min. A total of 26 genes involved in biochemical pathways found in the literature have been proposed to play a role in the pathogenesis of MCS and other functional somatic syndromes were selected. Expression levels were compared between MCS and controls before, within 15 min after being exposed to and 4 hours after the exposure. Participants suffering from MCS and healthy controls were recruited through advertisement at public places and in a local newspaper. 36 participants who considered themselves sensitive were prescreened for eligibility. 18 sensitive persons fulfilling the criteria for MCS were enrolled together with 18 healthy controls. 17 genes showed sufficient transcriptional level for analysis. Group comparisons were conducted for each gene at the 3 times points and for the computed area under the curve (AUC) expression levels. MCS participants and controls displayed similar gene expression levels both at baseline and after the exposure and the computed AUC values were likewise comparable between the 2 groups. The intragroup variation in expression levels among MCS participants was noticeably greater than the controls. MCS participants and controls have similar gene expression levels at baseline and it was not possible to separate MCS participants from controls based on gene expression measured after the exposure.


Herbal therapy use in a pediatric emergency department population: expect the unexpected.
In recent years investigators have reported widespread use of alternative medicine. Some herbal therapies have potentially harmful side effects as well as adverse interactions with medications. Data are lacking on the use in children and caregiver understanding of these products. To determine the reported use of herbal products among a pediatric emergency department population and to evaluate the caregivers' understanding and source of information concerning these products. A convenience sampling of pediatric emergency department patients and their caregivers occurred during a 3-month period in 2001. The interview consisted of 18 questions regarding the types of non-Food and Drug Administration-regulated herbal products and home remedies used, general product knowledge and sources of information used by the child's caregiver (including discussions with their child's primary physician). One hundred forty-two (93%) of 153 families approached participated in the study. The mean patient age was 5.3 years (range: 3 weeks-18 years). Forty-five percent of caregivers reported giving their child an herbal product, and 88% of these caregivers had at least 1 year of college education. Of the children receiving these therapies, 53% had been given 1 type and 27% were given 3 or more in the past year. The most common therapies reportedly used were aloe plant/juice (44%), echinacea (33%), and sweet oil (25%). The most dangerous potential herbal and prescription medication combination reported was ephedra and albuterol in an adolescent with asthma. The most unusual products reportedly used included turpentine, pine needles, and cowchips. Of all people interviewed, 77% did not believe or were uncertain if herbal products had any side effects and only 27% could name a potential side effect. Sixty-six percent were unsure or thought that herbal products did not interact with other medications and only 2 people correctly named a drug interaction. Of the people who used these therapies, 80% reported either friends or relatives as their primary source of information. Only 45% of those giving their children herbal products report discussing the use with their child's primary health care provider. Herbal and home therapies are commonly used in this pediatric population. An unexpectedly wide variety of products were reportedly given to this patient population. Caregivers reported limited knowledge regarding potential adverse medication interactions and side effects. Limited discussions with the child's primary health care provider were reported. It is therefore important for health care providers to have knowledge about herbal medications, to inquire about their use and to educate families about the risk/benefit as well as potential interactions these products may have with over-the-counter and prescription medications.


Hypothesized mechanisms through which acute exercise influences episodic memory.
Emerging research demonstrates that exercise is favorably associated with several cognitive outcomes, including episodic memory function. The majority of the mechanistic work describing the underlying mechanisms of this effect has focused on chronic exercise engagement. Such mechanisms include, e.g., chronic exercise-induced neurogenesis, gliogenesis, angiogenesis, cerebral circulation, and growth factor production. Less research has examined the mechanisms through which acute (vs. chronic) exercise subserves episodic memory function. The purpose of this review is to discuss these potential underlying mechanisms, which include, e.g., acute exercise-induced (via several pathways, such as vagus nerve and muscle spindle stimulation) alterations in neurotransmitters, synaptic tagging/capturing, associativity, and psychological attention.


Synergy between LRH-1 and beta-catenin induces G1 cyclin-mediated cell proliferation.
LRH-1 is an orphan nuclear receptor predominantly expressed in tissues of endodermal origin, where it controls development and cholesterol homeostasis. We show here that LRH-1 induces cell proliferation through the concomitant induction of cyclin D1 and E1, an effect that is potentiated by its interaction with beta-catenin. Whereas beta-catenin coactivates LRH-1 on the cyclin E1 promoter, LRH-1 acts as a potent tissue-restricted coactivator of beta-catenin on the cyclin D1 promoter. The implication of LRH-1 in cell proliferation highlights an unanticipated crosstalk between LRH-1 and the beta-catenin/Tcf4 signaling pathway, which is relevant for the renewal of intestinal crypt cells.


Selective differentiation during the colonization and establishment of a newly invasive species.
The potential for rapid evolution in invasive species makes them useful for studying adaptive responses of populations to novel environments. However, phenotypic divergence during invasion is not necessarily due to selection, but may be a product of neutral processes resulting from population bottlenecks during colonization and range expansion. We investigated phenotypic adaptation during the establishment and range expansion of the invasive bunchgrass, slender false brome (Brachypodium sylvaticum; Poaceae). Utilizing a novel approach, we made robust comparisons of functional traits using genetic similarity based on unique alleles to determine the genetic probability of contribution from native source regions and integrated these probabilities into our QST -FST comparisons for 12 physiological and anatomical traits associated with drought stress in the introduced range. Our results indicate phenotypic divergence greater than neutral expectations in five traits between native and invasive populations, indicating selective divergence occurred during invasive species establishment. The results indicate that the majority of divergence in B. sylvaticum occurred after introduction to the novel environment, but prior to invasive range expansion. This study provides evidence for adaptive genetic differentiation during the establishment of an invasive species, while also describing a robust method for the detection of selective processes after species introduction to a novel environment.


Keystone predators govern the pathway and pace of climate impacts in a subarctic marine ecosystem.
Predator loss and climate change are hallmarks of the Anthropocene yet their interactive effects are largely unknown. Here, we show that massive calcareous reefs, built slowly by the alga Clathromorphum nereostratum over centuries to millennia, are now declining because of the emerging interplay between these two processes. Such reefs, the structural base of Aleutian kelp forests, are rapidly eroding because of overgrazing by herbivores. Historical reconstructions and experiments reveal that overgrazing was initiated by the loss of sea otters, Enhydra lutris (which gave rise to herbivores capable of causing bioerosion), and then accelerated with ocean warming and acidification (which increased per capita lethal grazing by 34 to 60% compared with preindustrial times). Thus, keystone predators can mediate the ways in which climate effects emerge in nature and the pace with which they alter ecosystems.


Recursive partitioning for the prediction of cytochromes P450 2D6 and 1A2 inhibition: importance of the quality of the dataset.
The purpose of this study was to explore the use of detailed biological data in combination with a statistical learning method for predicting the CYP1A2 and CYP2D6 inhibition. Data were extracted from the Aureus-Pharma highly structured databases which contain precise measures and detailed experimental protocol concerning the inhibition of the two cytochromes. The methodology used was Recursive Partitioning, an easy and quick method to implement. The building of models was preceded by the evaluation of the chemical space covered by the datasets. The descriptors used are available in the MOE software suite. The models reached at least 80% of Accuracy and often exceeded this percentage for the Sensitivity (Recall), Specificity, and Precision parameters. CYP2D6 datasets provided 11 models with Accuracy over 80%, while CYP1A2 datasets counted 5 high-accuracy models. Our models can be useful to predict the ADME properties during the drug discovery process and are indicated for high-throughput screening.


Microarray-based analysis of the Staphylococcus aureus sigmaB regulon.
Microarray-based analysis of the transcriptional profiles of the genetically distinct Staphylococcus aureus strains COL, GP268, and Newman indicate that a total of 251 open reading frames (ORFs) are influenced by sigmaB activity. While sigmaB was found to positively control 198 genes by a factor of > or =2 in at least two of the three genetic lineages analyzed, 53 ORFs were repressed in the presence of sigmaB. Gene products that were found to be influenced by sigmaB are putatively involved in all manner of cellular processes, including cell envelope biosynthesis and turnover, intermediary metabolism, and signaling pathways. Most of the genes and/or operons identified as upregulated by sigmaB were preceded by a nucleotide sequence that resembled the sigmaB consensus promoter sequence of Bacillus subtilis. A conspicuous number of virulence-associated genes were identified as regulated by sigmaB activity, with many adhesins upregulated and prominently represented in this group, while transcription of various exoproteins and toxins were repressed. The data presented here suggest that the sigmaB of S. aureus controls a large regulon and is an important modulator of virulence gene expression that is likely to act conversely to RNAIII, the effector molecule of the agr locus. We propose that this alternative transcription factor may be of importance for the invading pathogen to fine-tune its virulence factor production in response to changing host environments.


Long-term prevalence and predictors of urinary incontinence among women in the Diabetes Prevention Program Outcomes Study.
To examine the long-term prevalence and predictors of weekly urinary incontinence in the Diabetes Prevention Program Outcomes Study, a follow-up study of the Diabetes Prevention Program randomized clinical trial of overweight adults with impaired glucose tolerance. This analysis included 1778 female participants of the Diabetes Prevention Program Outcomes Study who had been randomly assigned during the Diabetes Prevention Program to intensive lifestyle intervention (n = 582), metformin (n = 589) or placebo (n = 607). The study participants completed semi-annual assessments after the final Diabetes Prevention Program visit and for 6 years until October 2008. At the study entry, the prevalence of weekly urinary incontinence was lower in the intensive lifestyle intervention group compared with the metformin and placebo groups (44.2% vs 51.8%, 48.0% urinary incontinence/week, P = 0.04); during the 6-year follow-up period, these lower rates in intensive lifestyle intervention were maintained (46.7%, 53.1%, 49.9% urinary incontinence/week; P = 0.03). Statistically adjusting for urinary incontinence prevalence at the end of the Diabetes Prevention Program, the treatment arm no longer had a significant impact on urinary incontinence during the Diabetes Prevention Program Outcomes Study. Independent predictors of lower urinary incontinence during the Diabetes Prevention Program Outcomes Study included lower body mass index (odds ratio 0.988, 95% confidence interval 0.982-0.994) and greater physical activity (odds ratio 0.999, 95% confidence interval 0.998-1.000) at the Diabetes Prevention Program Outcomes Study entry, and greater reductions in body mass index (odds ratio 0.75, 95% confidence interval 0.60-0.94) and waist circumference (odds ratio 0.998, 95% confidence interval 0.996-1.0) during the Diabetes Prevention Program Outcomes Study. Diabetes was not significantly related to urinary incontinence. Intensive lifestyle intervention has a modest positive and enduring impact on urinary incontinence, and should be considered for the long-term prevention and treatment of urinary incontinence in overweight/obese women with glucose intolerance.


Feasibility of Underwater Endoscopic Mucosal Resection for Colorectal Lesions: A Single Center Study in Japan.
Underwater endoscopic mucosal resection (U-EMR) has emerged as an alternative technique for the resection of colorectal lesions. This study aimed to evaluate our initial experience using U-EMR. This is a single-center, retrospective case series study. We analyzed the clinical outcomes of consecutive patients who underwent U-EMR in our endoscopy center, from December 2015 to February 2017. Our analysis included 64 lesions, contributed by 38 patients, with a mean age of 68.6 years (range, 25 to 90 years). The study sample included 33 right-sided and 25 left-sided colon lesions, and seven rectal lesions, with an average size of 16.2 mm (6 - 40 mm). Of these, 46 lesions were polypoid and 18 ones non-polypoid. Histologically, 31 lesions were low-grade adenomas, eight ones were high-grade adenomas, 11 were mucosal cancers, four were submucosal cancers, and 10 were classified as "others". En bloc resection was achieved in 52 (81%) lesions, with an en bloc resection rate of 95% for lesions < 20 mm and 55% for lesions ≥ 20 mm. Complete resection of neoplastic epithelial lesions, defined by a negative pathological margin, was achieved in 32 of 59 neoplastic epithelial lesions (54%). We identified three cases (5%) of post-procedural bleeding and one case of perforation (2%). U-EMR can be feasibly used for resection of colonic lesions, including lesions ≥ 20 mm, although the en bloc resection rate for these lesions was lower than for lesions < 20 mm.


Persistence with stroke prevention medications 3 months after hospitalization.
To measure longitudinal use of stroke prevention medications following stroke hospital discharge. We hypothesized that a combination of patient-, provider-, and system-level factors influence medication-taking behavior. Observational cohort design. One hundred six US hospitals participating in the American Heart Association Get With The Guidelines-Stroke program. Two thousand eight hundred eighty-eight patients 18 years or older admitted with ischemic stroke or transient ischemic attack. Regimen persistence, including use of antiplatelet therapies, warfarin, antihypertensive therapies, lipid-lowering therapies, or diabetes medications, from discharge to 3 months. Reasons for nonpersistence were also ascertained. Two thousand five hundred ninety-eight patients (90.0%) were eligible for analysis. At 3 months, 75.5% of subjects continued taking all secondary prevention medications prescribed at discharge. Persistence at 3 months was associated with decreasing number of medication classes prescribed, increasing age, medical history, less severe stroke disability, having insurance, working status, understanding why medications are prescribed and how to refill them, increased quality of life, financial hardship, geographic region, and hospital size. One-quarter of stroke patients reported discontinuing 1 or more of their prescribed regimen of secondary prevention medications within 3 months of hospitalization for an acute stroke. Several modifiable factors associated with regimen persistence were identified and could be targets for improving long-term secondary stroke prevention.


Optimization and Reproducibility of Aortic Valve 18F-Fluoride Positron Emission Tomography in Patients With Aortic Stenosis.
18F-Fluoride positron emission tomography (PET) and computed tomography (CT) can measure disease activity and progression in aortic stenosis. Our objectives were to optimize the methodology, analysis, and scan-rescan reproducibility of aortic valve 18F-fluoride PET-CT imaging. Fifteen patients with aortic stenosis underwent repeated 18F-fluoride PET-CT. We compared nongated PET and noncontrast CT, with a modified approach that incorporated contrast CT and ECG-gated PET. We explored a range of image analysis techniques, including estimation of blood-pool activity at differing vascular sites and a most diseased segment approach. Contrast-enhanced ECG-gated PET-CT permitted localization of 18F-fluoride uptake to individual valve leaflets. Uptake was most commonly observed at sites of maximal mechanical stress: the leaflet tips and the commissures. Scan-rescan reproducibility was markedly improved using enhanced analysis techniques leading to a reduction in percentage error from ±63% to ±10% (tissue to background ratio MDS mean of 1.55, bias -0.05, limits of agreement -0·20 to +0·11). Optimized 18F-fluoride PET-CT allows reproducible localization of calcification activity to different regions of the aortic valve leaflet and commonly to areas of increased mechanical stress. This technique holds major promise in improving our understanding of the pathophysiology of aortic stenosis and as a biomarker end point in clinical trials of novel therapies. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02132026.


Genomic analysis of Acidianus hospitalis W1 a host for studying crenarchaeal virus and plasmid life cycles.
The Acidianus hospitalis W1 genome consists of a minimally sized chromosome of about 2.13 Mb and a conjugative plasmid pAH1 and it is a host for the model filamentous lipothrixvirus AFV1. The chromosome carries three putative replication origins in conserved genomic regions and two large regions where non-essential genes are clustered. Within these variable regions, a few orphan orfB and other elements of the IS200/607/605 family are concentrated with a novel class of MITE-like repeat elements. There are also 26 highly diverse vapBC antitoxin-toxin gene pairs proposed to facilitate maintenance of local chromosomal regions and to minimise the impact of environmental stress. Complex and partially defective CRISPR/Cas/Cmr immune systems are present and interspersed with five vapBC gene pairs. Remnants of integrated viral genomes and plasmids are located at five intron-less tRNA genes and several non-coding RNA genes are predicted that are conserved in other Sulfolobus genomes. The putative metabolic pathways for sulphur metabolism show some significant differences from those proposed for other Acidianus and Sulfolobus species. The small and relatively stable genome of A. hospitalis W1 renders it a promising candidate for developing the first Acidianus genetic systems.


Emissive CdTe/ZnO/GO quasi-core-shell-shell hybrid quantum dots for white light emitting diodes.
Colloidal quantum dots (QDs) have been extensively studied for optoelectronic and biological applications due to their unique physical and optical properties. In particular, among the optoelectronics applications, the white light emitting diode (WLED) has great potential in flat panel displays and solid-state lighting. Herein, we demonstrate a novel, facile, and efficient technique for the synthesis of CdTe/ZnO/GO quasi-core-shell-shell hybrid quantum dots containing the CdTe core with multi shells of ZnO and graphene oxide (GO) and fabrication of WQDLEDs. The CdTe/ZnO/GO quasi-core-shell-shell QDs have a unique strong photoluminescence (PL) peak at 624 nm related to the CdTe core and new weak peaks at 382, 404, 422, and 440 nm due to conjugation with ZnO and GO. Also, in the electroluminescence (EL), multiple emission peaks are observed, which can be correlated to the recombination process inside the CdTe core and also recombination of electrons in the lowest unoccupied molecular orbital (LUMO) and LUMO+2 of GO and holes in the valence band (VB) of ZnO. The QDLEDs show clear white color emission with a maximum luminance value of about 480 cd m-2 with Commission Internationale de l'Eclairage (CIE) color coordinates of (0.35, 0.28).


Performance of young children on ''traveling salesperson'' navigation tasks presented on a touch screen.
The traveling salesperson problem (TSP) refers to a task in which one finds the shortest path when traveling through multiple spatially distributed points. Little is known about the developmental course of the strategies used to solve TSPs. The present study examined young children's performance and route selection strategies in one-way TSPs using a city-block metric. A touch screen-based navigation task was applied. Children (39-70 months) and adults (21-35 years) made serial responses on a touch screen to move a picture of a dog (the target) to two or three identical pictures of a bone (the goals). For all the versions of the tasks, significant improvement in measures of performance was observed from younger to older participants. In TSPs in which a specific route selection strategy such as the nearest-neighbor strategy minimized the total traveling distance, older participants used that strategy more frequently than younger ones. By contrast, in TSPs in which multiple strategies equally led to the minimal traveling distance, children tended to use strategies different from those used by adults, such as traveling straight to the farthest goal first. The results primarily suggest development of efficient route selection strategies that can optimize total numbers of movements and/or solution time. Unlike adults, children sometimes prioritized other strategies such as traveling straight ahead until being forced to change directions. This may reflect the fact that children were either less attentive to the task or less efficient at perceiving the overall shape of the problem and/or the relative distance from the starting location to each goal.


The maintenance of genetic polymorphism in small island populations: large mammals in the Hebrides.
Conventionally, small populations living on islands are expected to lose genetic variation by drift. Fluctuations in population size, combined with polygynous mating systems, are expected to contribute to the process by increasing sampling effects on genetic variation. However, in individually monitored populations of Red deer on Rum and Soay sheep on St. Kilda, which experience fluctuations in population size, two processes have been identified which mitigate loss of genetic variation. First, in a number of examples, population reductions are associated with selection. Selection may be in favour of heterozygotes, or, as we have documented in several cases, it may fluctuate in direction temporally. Second, in Soay sheep, in which mortality over population crashes is male-biased, ostensibly leading to low effective numbers of males, molecular studies show that there are systematic changes in the reproductive success of young males, and in variance in male success, that broaden genetic representation compared with expectation.


Healing process after rigid plate fixation of humeral shaft fractures revisited.
The purpose of this study was to describe the radiological healing process after open reduction and internal fixation (ORIF) of humeral shaft fractures with plate. We reviewed the data of 53 consecutive patients who had undergone rigid plate fixation of OTA 12 A or B humeral shaft fracture. The mean age of the patients at the time of surgery was 39.4 (range 16-82). Quality of reduction and healing process was analysed on radiographs. Clinical symptom and disabilities of the arm, shoulder and hand (DASH) scores were recorded at follow-up visits. There were 28 compression and 25 neutralization platings. The mean gap size on the postoperative radiograph was 1.4 (range 0.1-6.1). 50 cases (94.3 %) healed, while three cases ended up with non-union. 28 (52.8 %) cases showed primary healing and 22 cases (41.5 %) showed secondary healing with callus bridging. Among the cases with secondary healing, callus formation with resorption was identified in 13 cases. The type of fracture, mode of compression and size of gap on radiographs after rigid plate fixation were found to be statistically significant factors for healing type (p = 0.026, 0.002, and <0.001, respectively). Three cases with non-union showed no improvement in DASH scores. Both primary and secondary healing processes were observed after rigid plate fixation of OTA 12 A or B humeral shaft fractures. Our study revealed that size of gap, mode of compression, type of fracture could affect the type of healing, and that periosteal callus formation can occur after rigid plate fixation.


Fish swimming: patterns in muscle function.
Undulatory swimming in fish is powered by the segmental body musculature of the myotomes. Power generated by this muscle and the interactions between the fish and the water generate a backward-travelling wave of lateral displacement of the body and caudal fin. The body and tail push against the water, generating forward thrust. The muscle activation and strain patterns that underlie body bending and thrust generation have been described for a number of species and show considerable variation. This suggests that muscle function may also vary among species. This variation must be due in large part to the complex interactions between muscle mechanical properties, fish body form, swimming mode, swimming speed and phylogenetic relationships. Recent work in several laboratories has been directed at studying patterns of muscle power output in vitro under simulated swimming conditions. This work suggests that the way that fish generate muscle power and convert it into thrust through the body and caudal fin does indeed vary. However, despite the differences, several features appear to be common to virtually all species studied and suggest where future effort should be directed if muscle function in swimming fish is to be better understood.