Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan.
Rapamycin, an inhibitor of the mechanistic target of rapamycin (mTOR), robustly extends the lifespan of model organisms including mice. We recently found that chronic treatment with rapamycin not only inhibits mTOR complex 1 (mTORC1), the canonical target of rapamycin, but also inhibits mTOR complex 2 (mTORC2) in vivo. While genetic evidence strongly suggests that inhibition of mTORC1 is sufficient to promote longevity, the impact of mTORC2 inhibition on mammalian longevity has not been assessed. RICTOR is a protein component of mTORC2 that is essential for its activity. We examined three different mouse models of Rictor loss: mice heterozygous for Rictor, mice lacking hepatic Rictor, and mice in which Rictor was inducibly deleted throughout the body in adult animals. Surprisingly, we find that depletion of RICTOR significantly decreases male, but not female, lifespan. While the mechanism by which RICTOR loss impairs male survival remains obscure, we find that the effect of RICTOR depletion on lifespan is independent of the role of hepatic mTORC2 in promoting glucose tolerance. Our results suggest that inhibition of mTORC2 signaling is detrimental to males, which may explain in part why interventions that decrease mTOR signaling show greater efficacy in females.


A Bioinformatics Approach to Prioritize Single Nucleotide Polymorphisms in TLRs Signaling Pathway Genes.
It has been suggested that single nucleotide polymorphisms (SNPs) in genes involved in Toll-like receptors (TLRs) pathway may exhibit broad effects on function of this network and might contribute to a range of human diseases. However, the extent to which these variations affect TLR signaling is not well understood. In this study, we adopted a bioinformatics approach to predict the consequences of SNPs in TLRs network. The consequences of non-synonymous coding SNPs (nsSNPs) were predicted by SIFT, PolyPhen, PANTHER, SNPs&GO, I-Mutant, ConSurf and NetSurf tools. Structural visualization of wild type and mutant protein was performed using the project HOPE and Swiss PDB viewer. The influence of 5'-UTR and 3'- UTR SNPs were analyzed by appropriate computational approaches. Nineteen nsSNPs in TLRs pathway genes were found to have deleterious consequences as predicted by the combination of different algorithms. Moreover, our results suggested that SNPs located at UTRs of TLRs pathway genes may potentially influence binding of transcription factors or microRNAs. By applying a pathway-based bioinformatics analysis of genetic variations, we provided a prioritized list of potentially deleterious variants. These findings may facilitate the selection of proper variants for future functional and/or association studies.


2019 EULAR points to consider for non-physician health professionals to prevent and manage fragility fractures in adults 50 years or older.
To establish European League Against Rheumatism (EULAR) points to consider for non-physician health professionals to prevent and manage fragility fractures in adults 50 years or older. Points to consider were developed in accordance with EULAR standard operating procedures for EULAR-endorsed recommendations, led by an international multidisciplinary task force, including patient research partners and different health professionals from 10 European countries. Level of evidence and strength of recommendation were determined for each point to consider, and the mean level of agreement among the task force members was calculated. Two overarching principles and seven points to consider were formulated based on scientific evidence and the expert opinion of the task force. The two overarching principles focus on shared decisions between patients and non-physician health professionals and involvement of different non-physician health professionals in prevention and management of fragility fractures. Four points to consider relate to prevention: identification of patients at risk of fracture, fall risk evaluation, multicomponent interventions to prevent primary fracture and discouragement of smoking and overuse of alcohol. The remaining three focus on management of fragility fractures: exercise and nutritional interventions, the organisation and coordination of multidisciplinary services for post-fracture models of care and adherence to anti-osteoporosis medicines. The mean level of agreement among the task force for the overarching principles and the points to consider ranged between 8.4 and 9.6. These first EULAR points to consider for non-physician health professionals to prevent and manage fragility fractures in adults 50 years or older serve to guide healthcare practice and education.


Dothistroma septosporum Identified in Greece on Pinus brutia and Pinus nigra Plantations.
Dothistroma needle blight (DNB) is caused by two ascomycete fungi, Dothistroma septosporum with a worldwide distribution and D. pini found in the United States, Russia, Ukraine, Hungary, and France (1). DNB has been known in Greece since the early 1980s (3) and the species responsible for the disease was reported as D. pini. In December 2011, needles were collected from three trees in Lagada, Thessaloniki regional unit of Central Macedonia (northern Greece), where the disease was first recorded. DNB infection seems to be limited to a valley in this area in Pinus nigra and P. brutia plantations established more than 50 years ago in an originally deciduous oak forest. Infections were observed over an area of 50 to 60 ha of pine plantations. Although the majority of pine trees were infected by the pathogen, the severity of the disease was relatively low and mortality of infected trees was not observed. Infections were limited to the lower branches in the 50-year-old trees, while on a limited number of younger trees of P. brutia (10 to 15 years old), infection was more severe, extending to the entire crowns of the trees. DNB does not appear to be very common in Greece. Infected needles had reddish-brown bands, usually with necrotic tips or entirely necrotic needles. Black sub-epidermal fruiting bodies (acervuli) were observed with the needle epidermis split and raised. Isolations were made from fruiting structures on needles of P. nigra and P. brutia (50-year-old trees) and P. brutia (10-year-old trees) after surface disinfection with 70% ethanol. Conidia from single fruiting bodies were transferred onto 3% malt extract agar (MEA) in petri dishes and incubated at 20°C. Colonies on MEA had a radial growth rate of 1.3 to 1.6 mm per week, were crustose, brown to grey-brown, and partly covered with slimy masses of conidia. The agar surrounding the colonies had a reddish color. Conidia from acervuli on the needles and the cultures were similar in shape and size, filiform, hyaline, 2 to 4 septate, and 1.8 to 2.5 (3.3) × 22 to 47 μm long. DNA was extracted from three cultures: one from P. nigra (CMW 37966) and two from P. brutia (CMW 37965, CMW 37967) using a standard phenol/chloroform method. The internal transcribed spacer (ITS) region was amplified and sequenced (1). Sequences were 100% identical to D. septosporum isolates in GenBank (e.g., AY808291). In addition, up to 12 randomly selected acervuli were excised directly from the needles of each of the three trees and DNA was extracted using PrepMan solution (Applied Biosystems). The mating types of these samples were determined using species-specific mating type primers for D. pini and D. septosporum (2). All acervuli were confirmed to be those of D. septosporum. Both mating types were found on needles from P. brutia and P. nigra. However, the teleomorph of D. septosporum was not detected on infected needles. References: (1) I. Barnes et al. For. Pathol. 41:361, 2011. (2) M. Groenewald et al. Phytopathology 97:825, 2007. (3) D. S. Kailidis and S. Markalas. Dasika Chronika 24:257, 1981 (in Greek).


Factors associated with the magnitude of limitations during recovery from a fracture of the proximal humerus: predictors of limitations after proximal humerus fracture.
The purpose of this study was to identify factors associated with limitations in function, measured by patient-reported outcome measures (PROMs), six to nine months after a proximal humeral fracture, from a range of demographic, injury, psychological, and social variables measured within a week and two to four weeks after injury. We enrolled 177 adult patients who sustained an isolated proximal humeral fracture into the study and invited them to complete PROMs at their initial outpatient visit within one week of injury, between two and four weeks, and between six to nine months after injury. There were 128 women and 49 men; the mean age was 66 years (sd 16; 18 to 95). In all, 173 patients completed the final assessment. Bivariate analysis was performed followed by multivariable regression analysis accounting for multicollinearity using partial R2, correlation matrices, and variable inflation factor. Many variables within a week of injury and between two and four weeks after injury correlated with six- to nine-month PROMs in bivariate analysis. Kinesiophobia measured within a week of injury (Tampa Scale for Kinesiophobia-11: partial R2 = 0.14; p = 0.000) and self-efficacy measured between two and four weeks (Pain Self-efficacy Questionnaire-2: partial R2 = 0.266; p < 0.001) were the strongest predictors of limitations (measured by Patient Reported Outcome Measurement Information System Upper Extremity Physical Function Computer Adaptive Test (PROMIS UE)) at six to nine months in multivariable analysis. Similar findings were observed with other types of PROM. Regression models accounted for a substantial amount of variance in all PROMs at both timepoints (e.g. 66% of the overall variance within one week, and 70% within two to four weeks for PROMIS UE at six to nine months). Recovery from a proximal humeral fracture appears to be enhanced by overcoming fears of movement or reinjury within a week after injury and greater self-efficacy (developing resilience and more effective coping strategies) within a month. Such factors are modifiable using enhanced communication skills and cognitive behavioural treatments. These findings could be a catalyst for the routine assessment and treatment of psychological and social factors in the management of patients with fractures. Cite this article: Bone Joint J 2019;101-B:715-723.


Atrial septal defect treatment options.
Atrial septal defects have traditionally been repaired by surgical closure. Recently, transcatheter device closure has increasingly been used with excellent results. Although there is limited comparative research evaluating long-term outcomes of the transcatheter technique, preliminary data reveal significantly fewer complications and shorter hospital stays than those reported for surgical repair. This article reviews relevant literature comparing efficacy, cost, and complications of the transcatheter device procedures with the surgical closure of ASDs.


Effects of different spinal morphine doses in rats.
Spinal morphine promotes adequate pain relief, but is not free from side effects. This study aimed at investigating the effects of different spinal morphine doses. Five groups of seven rats were studied, 24 h after spinal catheter insertion via cisterna magna under anesthesia with muscular ketamine and xylazine. G1 received 10 microl saline solution; groups G2, G3, G4 and G5 received respectively 0.1; 0.3; 0.5 and 1 microg morphine in 10 microl saline solution. Animals were submitted to tail immersion test in hot water at M0 (prior to injection), and M15, M30, M60, M120 and M180 minutes after the injection. Analgesic effects were observed in groups receiving morphine, in different times, as compared to control and to time before morphine injection. In G1 there was paws weakness in 4 animals. Agitation was observed at M15 in G2 and at M15 and M30 in G3. Mandible tremors were observed at moments M5, M15, M30 and M60 in G2; at M5 and M15 in G3, in M5 in G4, and in M5 in G5. Pruritus was observed at M5, M15, M30 and M60 in G2; at M5, M15, M30, M60 and M120 in G3; at M5, M15, M30, M60, and M120 in G4; and at M5, M15, M30, M60 and M120 in G5. Absence of diuresis was observed at M60 in G2; at M15, M30, M60 and M120 in G3; at M30 and M120 in G4, and at M30, and M60 in G5. Sedation was observed at M15, M30 and M60 in groups 2, 3 and 4; and at M15, M30, M60 and M120 in G5. Respiratory changes were observed at M15, M30 and M60 in G2; at M15, M30 and M60 in G3; at M15 and M30 in groups 4 and 5. In this study all morphine doses below 1 microg have promoted short duration analgesia; all spinal morphine doses have produced side effects.


Early Numerosity Encoding in Visual Cortex Is Not Sufficient for the Representation of Numerical Magnitude.
Recent studies have demonstrated that the numerosity of visually presented dot arrays is represented in low-level visual cortex extremely early in latency. However, whether or not such an early neural signature reflects the perceptual representation of numerosity remains unknown. Alternatively, such a signature may indicate the raw sensory representation of the dot-array stimulus before becoming the perceived representation of numerosity. Here, we addressed this question by using the connectedness illusion, whereby arrays with pairwise connected dots are perceived to be less numerous compared with arrays containing isolated dots. Using EEG and fMRI in two independent experiments, we measured neural responses to dot-array stimuli comprising 16 or 32 dots, either isolated or pairwise connected. The effect of connectedness, which reflects the segmentation of the visual stimulus into perceptual units, was observed in the neural activity after 150 msec post stimulus onset in the EEG experiment and in area V3 in the fMRI experiment using a multivariate pattern analysis. In contrast, earlier neural activity before 100 msec and in area V2 was strictly modulated by numerosity regardless of connectedness, suggesting that this early activity reflects the sensory representation of a dot array before perceptual segmentation. Our findings thus demonstrate that the neural representation for numerosity in early visual cortex is not sufficient for visual number perception and suggest that the perceptual encoding of numerosity occurs at or after the segmentation process that takes place later in area V3.


Five-year experience of cementless Oxford unicompartmental knee replacement.
Cementless unicompartmental knee replacement (UKR) was introduced to address some of the problems that can occur following cemented UKR. The aim of this study was to report the 5-year experience of the first 512 medial cementless Oxford UKR implanted by two surgeons for the recommended indications. The first consecutive 512 cementless Phase 3 Oxford UKRs implanted by two surgeons for the recommended indications between June 2004 and October 2013 were prospectively identified and followed up independently. All the procedures were carried out through a minimally invasive approach without eversion or dislocation of the patella. Patients were assessed clinically pre-operatively and at 1, 2, 5, 7 and 10 years after surgery with functional outcome scores and radiographs. There were eight reoperations of which six were revisions giving a 5-year survival of 98 % (95 % CI 94-100 %). At a mean follow-up of 3.4 years (1.0-10.2), the mean OKS was 43 (SD 7), AKSS (objective) was 81 (SD 13), and AKSS (functional) was 86 (SD 17). The first 120 cases had a minimum follow-up of 5 years (mean 5.9; range 5-10.2). In these patients, the mean OKS was 41 (SD 8), AKSS (objective) was 81 (SD 14), and AKSS (functional) was 82 (SD 18). There were no femoral radiolucencies and no complete tibial radiolucencies. 11 % of tibial components had partial radiolucent lines; the remaining 89 % had no radiolucencies. The clinical results are as good as or better than those previously reported for cemented fixation. The radiographic results are better with secure bony attachment to the implants in every case. IV.


Oxidative DNA damage in human cells induced by paraquat.
Oxidative DNA damage was studied after exposing two human transformed cell lines (HeLa and Hep G2) and freshly isolated human peripheral lymphocytes to the herbicide, paraquat. We used the alkaline comet assay, modified by incubating nucleoid DNA with endonuclease III to detect oxidised pyrimidines, and with formamidopyrimidine glycosylase to detect 8-oxo-guanine and ring-opened purines. Paraquat induces both strand breaks and oxidised bases, the amounts of each being dependent on the concentration of paraquat and the cell type exposed. Exposure to lower concentrations of paraquat for 1 hour induced dose-dependent DNA damage in Hep G2 cells and in human peripheral lymphocytes. DNA damage was reduced at higher concentrations. Our results support the finding that paraquat induces oxidative stress but, over a certain concentration range, also stimulates antioxidant protection. Reduction of DNA damage was not found in HeLa cells after exposure for 1 hour or 24 hours. Short-term exposure to paraquat induced a moderate amount of oxidative DNA damage (mainly oxidized pyrimidines) in HeLa cells. Exposure for 24 hours induced a high proportion of oxidised bases and strand breaks. Hep G2 cells showed the greatest number of DNA strand breaks, with no sign of base oxidation.


Association between traumatic brain injury and the subsequent risk of brain cancer.
This population-based study in Taiwan aimed to investigate the risk of having a diagnosis of malignant brain tumors within 3 years after a traumatic brain injury (TBI). This study used data from the Traumatic Brain Injury Registry and the National Health Insurance Research Database. The study cohort comprised 5007 patients who had visited ambulatory care centers or had been hospitalized with a diagnosis of TBI between 2001 and 2002. The comparison cohort was 25,035 randomly selected enrollees. Each patient's brain cancer status was individually tracked for a 3-year period following their index date. Stratified Cox proportional hazards regressions were performed for analyses. During the 3 years of follow-up, nine patients in each cohort, both the TBI and the non-TBI cohort, were diagnosed with brain cancer. As compared to those patients without TBI, patients with TBI were more likely to receive a diagnosis of malignant brain tumors within the 3-year period following their index date: the incidence rate of malignant brain tumors was 6.28 (95% CI: 3.06-11.53) per 10,000 person-years in patients with TBI and 1.25 (95% CI: 0.61-2.29) per 10,000 person-years in patients without TBI. After adjusting for sociodemographic characteristics, the hazard of being diagnosed with malignant brain tumors during the 3-year follow-up period was 4.67 (95% CI: 1.84-11.83) times greater for those who sustained a TBI than for patients in the comparison cohort. In addition, we found an association between TBI severity and malignant brain tumor among patients with TBI (p=0.033). Our findings suggest a positive correlation between TBI and the relatively short-term development of malignant neoplasms of the brain.


Human ATAC Is a GCN5/PCAF-containing acetylase complex with a novel NC2-like histone fold module that interacts with the TATA-binding protein.
Eukaryotic GCN5 acetyltransferases influence diverse biological processes by acetylating histones and non-histone proteins and regulating chromatin and gene-specific transcription as part of multiprotein complexes. In lower eukaryotes and invertebrates, these complexes include the yeast ADA complex that is still incompletely understood; the SAGA (Spt-Ada-Gcn5 acetylase) complexes from yeast to Drosophila that are mostly coactivators; and the ATAC (Ada Two-A containing) complex, only known in Drosophila and still poorly characterized. In contrast, vertebrate organisms, express two paralogous GCN5-like acetyltransferases (GCN5 and PCAF), which have been found so far only in SAGA-type complexes referred to hereafter as the STAGA (SPT3-TAF9-GCN5/PCAF acetylase) complexes. We now report the purification and characterization of vertebrate (human) ATAC-type complexes and identify novel components of STAGA. We show that human ATAC complexes incorporate in addition to GCN5 or PCAF (GCN5/PCAF), other epigenetic coregulators (ADA2-A, ADA3, STAF36, and WDR5), cofactors of chromatin assembly/remodeling and DNA replication machineries (POLE3/CHRAC17 and POLE4), the stress- and TGFbeta-activated protein kinase (TAK1/MAP3K7) and MAP3-kinase regulator (MBIP), additional cofactors of unknown function, and a novel YEATS2-NC2beta histone fold module that interacts with the TATA-binding protein (TBP) and negatively regulates transcription when recruited to a promoter. We further identify the p38 kinase-interacting protein (p38IP/FAM48A) as a novel component of STAGA with distant similarity to yeast Spt20. These results suggest that vertebrate ATAC-type and STAGA-type complexes link specific extracellular signals to modification of chromatin structure and regulation of the basal transcription machinery.


Contrasting Computational Models of Mate Preference Integration Across 45 Countries.
Humans express a wide array of ideal mate preferences. Around the world, people desire romantic partners who are intelligent, healthy, kind, physically attractive, wealthy, and more. In order for these ideal preferences to guide the choice of actual romantic partners, human mating psychology must possess a means to integrate information across these many preference dimensions into summaries of the overall mate value of their potential mates. Here we explore the computational design of this mate preference integration process using a large sample of n = 14,487 people from 45 countries around the world. We combine this large cross-cultural sample with agent-based models to compare eight hypothesized models of human mating markets. Across cultures, people higher in mate value appear to experience greater power of choice on the mating market in that they set higher ideal standards, better fulfill their preferences in choice, and pair with higher mate value partners. Furthermore, we find that this cross-culturally universal pattern of mate choice is most consistent with a Euclidean model of mate preference integration.


Vitexin confers HSF-1 mediated autophagic cell death by activating JNK and ApoL1 in colorectal carcinoma cells.
Heat shock transcription factor-1 (HSF-1) guards the cancerous cells proteome against the alterations in protein homeostasis generated by their hostile tumor microenvironment. Contrasting with the classical induction of heat shock proteins, the pro-oncogenic activities of HSF-1 remains to be explored. Therefore, cancer's fragile proteostatic pathway governed by HSF-1 could be a potential therapeutic target and novel biomarker by natural compounds. Vitexin, a natural flavonoid has been documented as a potent anti-tumor agent on various cell lines. However, in the present study, when human colorectal carcinoma HCT-116 cells were exposed to vitexin, the induction of HSF-1 downstream target proteins, such as heat shock proteins were suppressed. We identified HSF-1 as a potential molecular target of vitexin that interact with DNA-binding domain of HSF-1, which inhibited HSF-1 oligomerization and activation (in silico). Consequently, HSF-1 hyperphosphorylation mediated by JNK operation causes transcriptional inactivation of HSF-1, and supported ROS-mediated autophagy induction. Interestingly, in HSF-1 immunoprecipitated and silenced HCT-116 cells, co-expression of apolipoprotein 1 (ApoL1) and JNK was observed which promoted the caspase independent autophagic cell death accompanied by p62 downregulation and increased LC3-I to LC3-II conversion. Finally, in vivo findings confirmed that vitexin suppressed tumor growth through activation of autophagic cascade in HCT-116 xenograft model. Taken together, our study insights a probable novel association between HSF-1 and ApoL-1 was established in this study, which supports HSF-1 as a potential target of vitexin to improve treatment outcome in colorectal cancer.


Diversity and carbon storage across the tropical forest biome.
Tropical forests are global centres of biodiversity and carbon storage. Many tropical countries aspire to protect forest to fulfil biodiversity and climate mitigation policy targets, but the conservation strategies needed to achieve these two functions depend critically on the tropical forest tree diversity-carbon storage relationship. Assessing this relationship is challenging due to the scarcity of inventories where carbon stocks in aboveground biomass and species identifications have been simultaneously and robustly quantified. Here, we compile a unique pan-tropical dataset of 360 plots located in structurally intact old-growth closed-canopy forest, surveyed using standardised methods, allowing a multi-scale evaluation of diversity-carbon relationships in tropical forests. Diversity-carbon relationships among all plots at 1 ha scale across the tropics are absent, and within continents are either weak (Asia) or absent (Amazonia, Africa). A weak positive relationship is detectable within 1 ha plots, indicating that diversity effects in tropical forests may be scale dependent. The absence of clear diversity-carbon relationships at scales relevant to conservation planning means that carbon-centred conservation strategies will inevitably miss many high diversity ecosystems. As tropical forests can have any combination of tree diversity and carbon stocks both require explicit consideration when optimising policies to manage tropical carbon and biodiversity.


The E-cadherin gene is silenced by CpG methylation in human oral squamous cell carcinomas.
Reduction of E-cadherin strongly relates to invasiveness and metastasis in vitro. To clarify CpG methylation around the promoter region of the E-cadherin gene in oral squamous cell carcinoma (SCC), we examined the DNA samples of various human SCC cell lines and primary oral SCC tissues by methylation-specific polymerase chain reaction (MSP). CpG methylation of the E-cadherin gene markedly correlated to the reduction of E-cadherin expression in human oral SCC cell lines. In primary oral SCC tissues, only 1 of 5 preserved E-cadherin-expressing tissues was methylated, whereas methylation was found in 17 (94.4%) of 18 E-cadherin-reduced tissues. Our results suggest that reduction of E-cadherin expression is associated with CpG methylation of the E-cadherin gene promoter. We recently established two cell lines with high and low metastatic potential, UM1 and UM2, from SCC primary tongue tissue of a patient. E-cadherin expression of high-metastatic UM1 was clearly lower than that of low-metastatic UM2, and MSP results showed CpG methylation in the UM1 but not the UM2 cell line. To investigate whether demethylation of CpG methylation of the E-cadherin gene could restore expression and function of E-cadherin, we treated UM1 with the demethylating agent 5-azacytidine (5-aza) and found that E-cadherin expression was indeed restored by demethylation. Moreover, in the demethylated UM1, invasion of the collagen gel was clearly suppressed compared with the untreated UM1. These results suggested that inactivation of E-cadherin expression resulted from CpG methylation of the gene promoter; a correlation between CpG methylation of the E-cadherin gene promoter and invasive potential was also suggested.


ASAP, a systematic annotation package for community analysis of genomes.
ASAP (a systematic annotation package for community analysis of genomes) is a relational database and web interface developed to store, update and distribute genome sequence data and functional characterization (https://asap.ahabs.wisc.edu/annotation/php/ASAP1.htm). ASAP facilitates ongoing community annotation of genomes and tracking of information as genome projects move from preliminary data collection through post-sequencing functional analysis. The ASAP database includes multiple genome sequences at various stages of analysis, corresponding experimental data and access to collections of related genome resources. ASAP supports three levels of users: public viewers, annotators and curators. Public viewers can currently browse updated annotation information for Escherichia coli K-12 strain MG1655, genome-wide transcript profiles from more than 50 microarray experiments and an extensive collection of mutant strains and associated phenotypic data. Annotators worldwide are currently using ASAP to participate in a community annotation project for the Erwinia chrysanthemi strain 3937 genome. Curation of the E. chrysanthemi genome annotation as well as those of additional published enterobacterial genomes is underway and will be publicly accessible in the near future.


Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis.
Interactions between C-C chemokine receptor types 2 (CCR2) and 5 (CCR5) and their ligands, including CCL2 and CCL5, mediate fibrogenesis by promoting monocyte/macrophage recruitment and tissue infiltration, as well as hepatic stellate cell activation. Cenicriviroc (CVC) is an oral, dual CCR2/CCR5 antagonist with nanomolar potency against both receptors. CVC's anti-inflammatory and antifibrotic effects were evaluated in a range of preclinical models of inflammation and fibrosis. Monocyte/macrophage recruitment was assessed in vivo in a mouse model of thioglycollate-induced peritonitis. CCL2-induced chemotaxis was evaluated ex vivo on mouse monocytes. CVC's antifibrotic effects were evaluated in a thioacetamide-induced rat model of liver fibrosis and mouse models of diet-induced non-alcoholic steatohepatitis (NASH) and renal fibrosis. Study assessments included body and liver/kidney weight, liver function test, liver/kidney morphology and collagen deposition, fibrogenic gene and protein expression, and pharmacokinetic analyses. CVC significantly reduced monocyte/macrophage recruitment in vivo at doses ≥20 mg/kg/day (p < 0.05). At these doses, CVC showed antifibrotic effects, with significant reductions in collagen deposition (p < 0.05), and collagen type 1 protein and mRNA expression across the three animal models of fibrosis. In the NASH model, CVC significantly reduced the non-alcoholic fatty liver disease activity score (p < 0.05 vs. controls). CVC treatment had no notable effect on body or liver/kidney weight. CVC displayed potent anti-inflammatory and antifibrotic activity in a range of animal fibrosis models, supporting human testing for fibrotic diseases. Further experimental studies are needed to clarify the underlying mechanisms of CVC's antifibrotic effects. A Phase 2b study in adults with NASH and liver fibrosis is fully enrolled (CENTAUR Study 652-2-203; NCT02217475).


[Benign cystic mesothelioma, a rare tumor of the peritoneum].
We report the case of a 28-year-old woman, who presented with acute abdominal and pelvic pain, the appearance of appendicitis. Because of her symptoms urgent operation was performed. Appendicetomy was performed, during the operation multiple cystic lesions were discovered on the right ovary and the peritoneal surface of the mesentery. Laparatomy was performed with removal of the visible cystic lesions, which contained mucous fluid. Final histology revealed benign cystic mesothelioma, which is a rare lesion of the peritoneum, occurring mainly in women in reproductive age. The etiology of cystic mesothelioma is still unclear. The short-term prognosis is favourable, but high recurrence rate. Some authors reported effective intraperitoneal chemotherapy, but no clinical study is available about long term outcome. We hope that surgical eradication was effective to prevent recurrence. One year after the operation the patient is complaint and symptom free.


Attitude of Dental Students towards the Rubber Dam Use in Operative Dentistry.
Operative dentistry and endodontics are the two major areas where rubber dam is used extensively with special emphasis to train students on its application during dental curriculum. The purpose of the present study was to evaluate the attitude of dental students toward the use of rubber dam in operative dentistry clinics along with emphasis on evaluation of its prospective application after graduation. A structured questionnaire-based analysis was performed among internship students of a dentistry program, Batterjee Medical College, Jeddah, Saudi Arabia. The questions were based on training, latex allergy, and selection of jaws for application of rubber dam and prospective use of rubber dam during practice. A completed questionnaire by all participants (n = 110) was analyzed and subjected to statistical analysis. Around 80.9% of the students agreed that adequate and satisfactory training for rubber dam placement was imparted while 59.1% agreed that they enquire about latex allergy before placement of rubber dam. Further, 85.5% of the students planned to use rubber dam for all procedures after graduation. A promising response was exhibited by this group of future dentists toward the application of rubber dam during restorative procedures.


First Report of Blight on Ipomoea purpurea Caused by Phytophthora ipomoeae.
Several wild species of Ipomoea grow in the central highlands of Mexico. During the summer of 1999, in Metepec, Mexico, blighted leaves and petioles of Ipomoea purpurea were collected from diseased plants and placed in a moist chamber to induce sporulation. Sporangia that formed on the lesions were transferred with a piece of agar to selective rye agar medium (2). Phytophthora ipomoeae was consistently isolated. Species identification was based on sporangial and gametangial characteristics of five cultures grown on rye agar. Sporangia were mainly ellipsoid but occasionally ovoid, semipapillated, and deciduous with a short pedicel. All isolates were homothallic with smooth-walled and aplerotic oospores. Genotypic analysis for the allozymes Peptidase (Pep) and Glucose-6-phosphate isomerase (Gpi) indicated that all five isolates belonged to one genotype with alleles 78/78 (Pep) and 108/108 (Gpi). Morphological characteristics and the allozyme genotype correspond to the new, recently described species P. ipomoeae Flier & Grünwald (1) isolated from I. orizabensis (Pelletan) Ledeb. ex Steud. (I. tyrianthina) Lindl. and I. longepedunculata (Mart. & Gal.) Hemsl. Pathogenicity tests were carried out with leaves from greenhouse-grown I. purpurea plants. Detached leaves were inoculated with a suspension of 103 sporangia per ml and kept in a moist chamber at room temperature (17 ± 3°C). Lesions were observed between 7 and 15 days after inoculation and were characteristic of those observed in the field. The pathogen was reisolated from inoculated symptomatic tissue. To our knowledge, this is the first report of blight on I. purpurea caused by P. ipomoeae. References: (1) W. Flier et al. Mycol. Res. 106:848, 2002. (2) N. J. Grünwald et al. Phytopathology 91:882, 2001.


DNA polymerase III of Escherichia coli is required for UV and ethyl methanesulfonate mutagenesis.
Strains of Escherichia coli possessing the pcbA1 mutation, a functional DNA polymerase I, and a temperature-sensitive mutation in DNA polymerase III can survive at the restrictive temperature (43 degrees C) for DNA polymerase III. The mutation rate of the bacterial genome of such strains after exposure to either UV light or ethyl methanesulfonate was measured by its rifampicin resistance or amino acid requirements. In addition, Weigle mutagenesis of preirradiated lambda phage was also measured. In all cases, no increase in mutagenesis was noted at the restrictive temperature for DNA polymerase III. Introduction of a cloned DNA polymerase III gene returned the mutation rate of the bacterial genome as well as the Weigle mutagenesis to normal at 43 degrees C. Using a recA-lacZ fusion, the SOS response after UV irradiation was measured and found to be normal at the restrictive and permissive temperature for DNA polymerase III, as was induction of lambda prophage. Recombination was also normal at either temperature. Our studies demonstrate that a functional DNA polymerase III is strictly required for mutagenesis at a step other than SOS induction.


Immune responses in Atlantic salmon (Salmo salar) following protective vaccination against infectious salmon anemia (ISA) and subsequent ISA virus infection.
Infectious salmon anemia (ISA) is an orthomyxoviral disease that has had devastating effects on farmed Atlantic salmon. ISA is still a disease resulting in continued loss of revenues and therefore development of effective vaccines is of great importance. Commercial vaccines against ISA are available, but the efficacy is poorly described. There is little information about vaccine-induced immune factors preventing ISA virus (ISAV) infection today. In this study we assessed the protective effects and immunogenicity of vaccines containing three different quantities of the inactivated ISAV antigen. Our findings indicated that immunization induced effective protection in Atlantic salmon with a relative percent survival (RPS) as high as 86. The level of protection was correlated to the amount of ISAV antigen in the vaccine, and fish immunized with high antigen amounts produced detectable ISAV-specific and neutralizing antibodies. While ISAV infection was detectable in non-vaccinated control fish challenged by cohabitation, no infection was detected in fish immunized with high antigen amounts. After challenge, transcriptional analysis of selected immune-related genes demonstrated activation of innate immune responses in ISAV-infected control fish, but not in vaccine protected fish. This study furthers the knowledge about vaccine efficacy and vaccine-induced immunity to ISAV challenge in Atlantic salmon.


Progress in understanding and engineering primary plant metabolism.
The maximum yield of crop plants depends on the efficiency of conversion of sunlight into biomass. This review summarises recent models that estimate energy conversion efficiency for successive steps in photosynthesis and metabolism. Photorespiration was identified as a major reason for energy loss during photosynthesis and strategies to modify or suppress photorespiration are presented. Energy loss during the conversion of photosynthate to biomass is also large but cannot be modelled as precisely due to incomplete knowledge about pathways and turnover and maintenance costs. Recent research on pathways involved in metabolite transport and interconversion in different organs, and recent insights into energy requirements linked to the production, maintenance and turnover of the apparatus for cellular growth and repair processes are discussed.


Rapid eye movement sleep behavior disorder and rapid eye movement sleep without atonia in narcolepsy.
Narcolepsy is a rare disabling hypersomnia disorder that may include cataplexy, sleep paralysis, hypnagogic hallucinations, and sleep-onset rapid eye movement (REM) periods, but also disrupted nighttime sleep by nocturnal awakenings, and REM sleep behavior disorder (RBD). RBD is characterized by dream-enacting behavior and impaired motor inhibition during REM sleep (REM sleep without atonia, RSWA). RBD is commonly associated with neurodegenerative disorders including Parkinsonisms, but is also reported in narcolepsy in up to 60% of patients. RBD in patients with narcolepsy is, however, a distinct phenotype with respect to other RBD patients and characterized also by absence of gender predominance, elementary rather than complex movements, less violent behavior and earlier age at onset of motor events, and strong association to narcolepsy with cataplexy/hypocretin deficiency. Patients with narcolepsy often present dissociated sleep features including RSWA, increased density of phasic chin EMG and frequent shift from REM to NREM sleep, with or without associated clinical RBD. Most patients with narcolepsy with cataplexy lack the hypocretin neurons in the lateral hypothalamus. Tonic and phasic motor activities in REM sleep and dream-enacting behavior are mostly reported in presence of cataplexy. Narcolepsy without cataplexy is a condition rarely associated with hypocretin deficiency. We proposed that hypocretin neurons are centrally involved in motor control during wakefulness and sleep in humans, and that hypocretin deficiency causes a functional defect in the motor control involved in the development of cataplexy during wakefulness and RBD/RSWA/phasic motor activity during REM sleep.


Prioritizing wetland restoration for sediment yield reduction: a conceptual model.
In a climate of limited resources, it is often necessary to prioritize restoration efforts geographically. The synoptic approach is an ecologically based tool for geographic prioritization of wetland protection and restoration efforts. The approach was specifically designed to incorporate best professional judgment in cases where information and resources are otherwise limited. Synoptic assessments calculate indices for functional criteria in subunits (watersheds, counties, etc.) of a region and then rank the subunits. Ranks can be visualized in region-scale maps which enable managers to identify areas where efforts optimize functional performance on a regional scale. In this paper, we develop a conceptual model for prioritizing watersheds whose wetlands can be restored to reduce total sediment yield at the watershed outlet. The conceptual model is designed to rank watersheds but not individual wetlands within a watershed. The synoptic approach is valid for applying the sediment yield reduction model because there is high demand for prioritizing disturbed wetlands for restoration, but there is limited, quantitative, accurate information available with which to make decisions. Furthermore, the cost of creating a comprehensive database is prohibitively high. Finally, because the model will be used for planning purposes, and, specifically, for prioritizing based on multiple decisions rather than optimizing a single decision, the consequence of prioritization errors is low. Model results cannot be treated as scientific findings. The conclusions of an assessment are based on judgement, but this judgement is guided by scientific principles and a general understanding of relevant ecological processes. The conceptual model was developed as the first step towards prioritizing of wetland restoration for sediment yield reduction in US EPA Region 4.


Epigenetic modifications of distinct sequences of the p1 regulatory gene specify tissue-specific expression patterns in maize.
Tandemly repeated endogenous genes are common in plants, but their transcriptional regulation is not well characterized. In maize, the P1-wr allele of pericarp color1 is composed of multiple copies arranged in a head-to-tail fashion. P1-wr confers a white kernel pericarp and red cob glume pigment phenotype that is stably inherited over generations. To understand the molecular mechanisms that regulate tissue-specific expression of P1-wr, we have characterized P1-wr*, a spontaneous loss-of-function epimutation that shows a white kernel pericarp and white cob glume phenotype. As compared to its progenitor P1-wr, the P1-wr* is hypermethylated in exon 1 and intron 2 regions. In the presence of the epigenetic modifier Ufo1 (Unstable factor for orange1), P1-wr* plants exhibit a range of cob glume pigmentation whereas pericarps remain colorless. In these plants, the level of cob pigmentation directly correlates with the degree of DNA demethylation in the intron 2 region of p1. Further, genomic bisulfite sequencing indicates that a 168-bp region of intron 2 is significantly hypomethylated in both CG and CNG context in P1-wr* Ufo1 plants. Interestingly, P1-wr* Ufo1 plants did not show any methylation change in a distal enhancer region that has previously been implicated in Ufo1-induced gain of pericarp pigmentation of the P1-wr allele. These results suggest that distinct regulatory sequences in the P1-wr promoter and intron 2 regions can undergo independent epigenetic modifications to generate tissue-specific expression patterns.


A critique of the literature on women's request for cesarean section.
The influence of women's birth preferences on the rising cesarean section rates is uncertain and possibly changing. This review of publications relating to women's request for cesarean delivery explores assumptions related to the social, cultural, and political-economic contexts of maternity care and decision making. A search of major databases was undertaken using the following terms: "c(a)esarean section" with "maternal request,""decision-making,""patient participation,""decision-making-patient,""patient satisfaction,""patient preference,""maternal choice,""on demand," and "consumer demand." Seventeen papers examining women's preferred type of birth were retrieved. No studies systematically examined information provided to women by health professionals to inform their decision. Some studies did not adequately acknowledge the influence of obstetric and psychological factors in relation to women's request for a cesarean section. Other potential influences were poorly addressed, including whether or not the doctor advised a vaginal birth, women's access to midwifery care in pregnancy, information provision, quality of care, and cultural issues. The psychosocial context of obstetric care reveals a power imbalance in favor of physicians. Research into decision making about cesarean section that does not account for the way care is offered, observe interactions between women and practitioners, and analyze the context of care should be interpreted with caution.


Probing the pore of the auditory hair cell mechanotransducer channel in turtle.
Hair cell mechano-electric transducer (MET) channels play a pivotal role in auditory and vestibular signal detection, yet few data exist regarding their molecular nature. Present work characterizes the MET channel pore, a region whose properties are thought to be intrinsically determined. Two approaches were used. First, the channel was probed with antagonists of candidate channel subtypes including: cyclic nucleotide-gated channels, transient receptor potential channels and gap-junctional channels. Eight new antagonists were identified. Most of the effective antagonists had a partially charged amine group predicted to penetrate the channel pore, antagonizing current flow, while the remainder of the molecule prevented further permeation of the compound through the pore. This blocking mechanism was tested using curare to demonstrate the open channel nature of the block and by identifying methylene blue as a permeant channel blocker. The second approach estimated dimensions of the channel pore with simple amine compounds. The narrowest diameter of the pore was calculated as 12.5 +/- 0.8 A and the location of a binding site approximately 45% of the way through the membrane electric field was calculated. Channel length was estimated as approximately 31 A and the width of the pore mouth at < 17 A. Each effective antagonist had a minimal diameter, measured about the penetrating amine, of less than the pore diameter, with a direct correlation between IC(50) and minimal diameter. The IC(50) was also directly related to the length of the amine side chains, further validating the proposed pore blocking mechanism. Data provided by these two approaches support a hypothesis regarding channel permeation and block that incorporates molecular dimensions and ion interactions within the pore.


Directed Repeats Co-occur with Few Short-Dispersed Repeats in Plastid Genome of a Spikemoss, Selaginella vardei (Selaginellaceae, Lycopodiopsida).
It is hypothesized that the highly conserved inverted repeats (IR) structure of land plant plastid genomes (plastomes) is beneficial for stabilizing plastome organization, whereas the mechanism of the occurrence and stability maintenance of the recently reported direct repeats (DR) structure is yet awaiting further exploration. Here we describe the DR structure of the Selaginella vardei (Selaginellaceae) plastome, to elucidate the mechanism of DR occurrence and stability maintenance. The plastome of S. vardei is 121,254 bp in length and encodes 76 genes, of which 62 encode proteins, 10 encode tRNAs, and four encode rRNAs. Unexpectedly, the two identical rRNA gene regions (13,893 bp) are arranged in a direct orientation (DR), rather than inverted. Comparing to the IR organization in Isoetes flaccida (Isoetaceae, Lycopodiopsida) plastome, a ca. 50-kb trnN-trnF inversion that spans one DR copy was found in the plastome of S. vardei, which might cause the orientation change. In addition, we find extremely rare short dispersed repeats (SDRs) in the plastomes of S. vardei and its closely related species S. indica. We suggest that the ca. 50-kb inversion resulted in the DR structure, and the reduction in SDRs plays a key role in maintaining the stability of plastomes with DR structure by avoiding potential secondary recombination. We further confirmed the presence of homologous recombination between DR regions, which are able to generate subgenomes and form diverse multimers. Our study deepens the understanding of Selaginella plastomes and provides new insights into the diverse plastome structures in land plants.


CRISPR-Mediated Activation of Endogenous Gene Expression in the Postnatal Heart.
Genome editing by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 is evolving rapidly. Recently, second-generation CRISPR/Cas9 activation systems based on nuclease inactive dead (d)Cas9 fused to transcriptional transactivation domains were developed for directing specific guide (g)RNAs to regulatory regions of any gene of interest, to enhance transcription. The application of dCas9 to activate cardiomyocyte transcription in targeted genomic loci in vivo has not been demonstrated so far. We aimed to develop a mouse model for cardiomyocyte-specific, CRISPR-mediated transcriptional modulation, and to demonstrate its versatility by targeting Mef2d and Klf15 loci (2 well-characterized genes implicated in cardiac hypertrophy and homeostasis) for enhanced transcription. A mouse model expressing dCas9 with the VPR transcriptional transactivation domains under the control of the Myh (myosin heavy chain) 6 promoter was generated. These mice innocuously expressed dCas9 exclusively in cardiomyocytes. For initial proof-of-concept, we selected Mef2d, which when overexpressed, led to hypertrophy and heart failure, and Klf15, which is lowly expressed in the neonatal heart. The most effective gRNAs were first identified in fibroblast (C3H/10T1/2) and myoblast (C2C12) cell lines. Using an improved triple gRNA expression system (TRISPR [triple gRNA expression construct]), up to 3 different gRNAs were transduced simultaneously to identify optimal conditions for transcriptional activation. For in vivo delivery of the validated gRNA combinations, we employed systemic administration via adeno-associated virus serotype 9. On gRNA delivery targeting Mef2d expression, we recapitulated the anticipated cardiac hypertrophy phenotype. Using gRNA targeting Klf15, we could enhance its transcription significantly, although Klf15 is physiologically silenced at that time point. We further confirmed specific and robust dCas9VPR on-target effects. The developed mouse model permits enhancement of gene expression by using endogenous regulatory genomic elements. Proof-of-concept in 2 independent genomic loci suggests versatile applications in controlling transcription in cardiomyocytes of the postnatal heart.


Peritoneal mesothelioma metastasis to the tongue - Comparison with 8 pleural mesothelioma reports with tongue metastases.
Malignant mesothelioma (MM) rarely arises from the peritoneum. We describe the 1st such case which metastasised to the head and neck region (tongue). We briefly surveyed the American Surveillance Epidemiology and End Results (SEER) database, and the British Cancer Research UK database for the latest trends in MM incidence. We did a systematic Pubmed search for other MM reports with tongue metastases. American and British data show that MM incidence in men has stabilised in the last 10 years, earlier than previously predicted. The tongue is an unusual site for MM spread, with ours being only the 9th such case described. Our summary of published cases of MM metastasising to the tongue brings out our patient to be the least in age(35 years), and the only one to have peritoneal MM as the primary. Seven of the 9 cases were male. Only 2 had a recorded history of exposure to asbestos. All 9 patients had the epithelioid subtype of MM. Surgery was done as the exclusive reported intervention in 4 out of the 9 patients. Only 2 cases received radiotherapy, amongst whom, only our patient responded. Metastasis of MM to the tongue is rare and usually in the uncommon context of MM with multiple sites of extra-thoracic or extra-abdominal spread. We have described a unique clinical manifestation of a rare subtype of mesothelioma. Moreover, we have tabulated and summarised details (including responses to surgery or/and radiotherapy) regarding all reported cases of mesotheliomas with tongue metastasis.


Gap junctions and epileptic seizures--two sides of the same coin?
Electrical synapses (gap junctions) play a pivotal role in the synchronization of neuronal ensembles which also makes them likely agonists of pathological brain activity. Although large body of experimental data and theoretical considerations indicate that coupling neurons by electrical synapses promotes synchronous activity (and thus is potentially epileptogenic), some recent evidence questions the hypothesis of gap junctions being among purely epileptogenic factors. In particular, an expression of inter-neuronal gap junctions is often found to be higher after the experimentally induced seizures than before. Here we used a computational modeling approach to address the role of neuronal gap junctions in shaping the stability of a network to perturbations that are often associated with the onset of epileptic seizures. We show that under some circumstances, the addition of gap junctions can increase the dynamical stability of a network and thus suppress the collective electrical activity associated with seizures. This implies that the experimentally observed post-seizure additions of gap junctions could serve to prevent further escalations, suggesting furthermore that they are a consequence of an adaptive response of the neuronal network to the pathological activity. However, if the seizures are strong and persistent, our model predicts the existence of a critical tipping point after which additional gap junctions no longer suppress but strongly facilitate the escalation of epileptic seizures. Our results thus reveal a complex role of electrical coupling in relation to epileptiform events. Which dynamic scenario (seizure suppression or seizure escalation) is ultimately adopted by the network depends critically on the strength and duration of seizures, in turn emphasizing the importance of temporal and causal aspects when linking gap junctions with epilepsy.


Atomic layer oxidation on graphene sheets for tuning their oxidation levels, electrical conductivities, and band gaps.
Graphene sheets that can exhibit electrical conducting and semiconducting properties are highly desirable and have potential applications in fiber communications, photodetectors, solar cells, semiconductors, and broadband modulators. However, there is currently no efficient method that is able to tune the band gap of graphene sheets. This work adopts an efficient atomic layer oxidation (ALO) technique to cyclically increase the oxidation level of graphene sheets, thus, tuning their electrical conductance, band-gap structure, and photoluminescence (PL) response. The O/C atomic ratio as an increasing function of the ALO cycle number reflects two linear regions: 0.23% per cm2 per cycle (0-15 cycles) and 0.054% per cm2 per cycle (15-100 cycles). The excellent correlation coefficients reveal that the ALO process follows a self-limiting route to step-by-step oxidize graphene layers. The interlayer distance of ALO-graphene sheets shows an obvious increase after the ALO treatment, proved by X-ray diffraction. As analyzed by X-ray photon spectroscopy, the hydroxyl or epoxy group acts as a major contributor to the interlayer spacing distance and oxidation extent in the initial ALO stage, as compared to carbonyl and carboxyl groups. The ALO mechanism, based on Langmuir-Hinshelwood and Eley-Rideal models, is proposed to clarify the formation of oxygen functionalities and structural transformation from pristine graphene sheets to oxidized ones during the ALO cycle. With a tunable oxidation level, the electrical resistivity, semiconductor character, and PL response of ALO-graphene samples can be systematically controlled for desired applications. The ALO approach is capable of offering a straightforward route to tune the oxidation level of graphene sheets or other carbons.


Cloning and expression of the gene for a novel protein from Mycobacterium smegmatis with functional similarity to eukaryotic calmodulin.
A calmodulin-like protein (CAMLP) from Mycobacterium smegmatis was purified to homogeneity and partially sequenced; these data were used to produce a full-length clone, whose DNA sequence contained a 55-amino-acid open reading frame. M. smegmatis CAMLP, expressed in Escherichia coli, exhibited properties characteristic of eukaryotic calmodulin: calcium-dependent stimulation of eukaryotic phosphodiesterase, which was inhibited by the calmodulin antagonist trifluoperazine, and reaction with anti-bovine brain calmodulin antibodies. Consistent with the presence of nine acidic amino acids (16%) in M. smegmatis CAMLP, there is one putative calcium-binding domain in this CAMLP, compared to four such domains for eukaryotic calmodulin, reflecting the smaller molecular size (approximately 6 kDa) of M. smegmatis CAMLP. Ultracentrifugation and mass spectral studies excluded the possibility that calcium promotes oligomerization of purified M. smegmatis CAMLP.


A Stenotrophomonas maltophilia Strain Evades a Major Caenorhabditis elegans Defense Pathway.
Stenotrophomonas maltophilia is a ubiquitous bacterium and an emerging nosocomial pathogen. This bacterium is resistant to many antibiotics, associated with a number of infections, and a significant health risk, especially for immunocompromised patients. Given that Caenorhabditis elegans shares many conserved genetic pathways and pathway components with higher organisms, the study of its interaction with bacterial pathogens has biomedical implications. S. maltophilia has been isolated in association with nematodes from grassland soils, and it is likely that C. elegans encounters this bacterium in nature. We found that a local S. maltophilia isolate, JCMS, is more virulent than the other S. maltophilia isolates (R551-3 and K279a) tested. JCMS virulence correlates with intestinal distension and bacterial accumulation and requires the bacteria to be alive. Many of the conserved innate immune pathways that serve to protect C. elegans from various pathogenic bacteria also play a role in combating S. maltophilia JCMS. However, S. maltophilia JCMS is virulent to normally pathogen-resistant DAF-2/16 insulin-like signaling pathway mutants. Furthermore, several insulin-like signaling effector genes were not significantly differentially expressed between S. maltophilia JCMS and avirulent bacteria (Escherichia coli OP50). Taken together, these findings suggest that S. maltophilia JCMS evades the pathogen resistance conferred by the loss of DAF-2/16 pathway components. In summary, we have discovered a novel host-pathogen interaction between C. elegans and S. maltophilia and established a new animal model with which to study the mode of action of this emerging nosocomial pathogen.


Intimate partner aggression-related shame and posttraumatic stress disorder symptoms: The moderating role of substance use problems.
A dearth of literature has examined the consequences of women's use of aggression in intimate relationships. Women's use of aggression against their intimate partners, regardless of their motivation (e.g., self-defense, retaliation), may elicit shame. Shame, in turn, may contribute to the maintenance and/or exacerbation of posttraumatic stress disorder (PTSD) symptoms, which are commonly experienced in this population. Further, emerging research suggests that emotionally avoidant coping strategies, such as substance use, may strengthen the relation between shame and PTSD symptoms. The goal of the present study was to examine whether women's shame concerning their use of intimate partner aggression is associated with their PTSD symptoms, and whether drug and alcohol use problems moderate this association. Participants were 369 community women who had used and been victimized by physical aggression in an intimate relationship with a male partner in the past six months. The intimate partner aggression-related shame × drug (but not alcohol) use problems interaction on PTSD symptom severity was significant. Analysis of simple slopes revealed that women's intimate partner aggression-related shame was positively associated with their PTSD symptoms when drug use problems were high, but not when drug use problems were low. Findings have implications for the potential utility of PTSD treatments targeting a reduction in shame and maladaptive shame regulation strategies (i.e., drug use) in this population. Aggr. Behav. 42:427-440, 2016. © 2015 Wiley Periodicals, Inc.


Eugenol prevents amyloid formation of proteins and inhibits amyloid-induced hemolysis.
Eugenol has attracted considerable attention because of its potential for many pharmaceutical applications including anti-inflammatory, anti-tumorigenic and anti-oxidant properties. Here, we have investigated the effect of eugenol on amyloid formation of selected globular proteins. We find that both spontaneous and seed-induced aggregation processes of insulin and serum albumin (BSA) are significantly suppressed in the presence of eugenol. Isothermal titration calorimetric data predict a single binding site for eugenol-insulin complex confirming the affinity of eugenol for native soluble insulin species. We also find that eugenol suppresses amyloid-induced hemolysis. Our findings reveal the inherent ability of eugenol to stabilize native proteins and to delay the conversion of protein species of native conformation into β-sheet assembled mature fibrils, which seems to be crucial for its inhibitory effect.


Inducible operation of the erythropoietin 3' enhancer in multiple cell lines: evidence for a widespread oxygen-sensing mechanism.
Adaptive responses to hypoxia occur in many biological systems. A well-characterized example is the hypoxic induction of the synthesis of erythropoietin, a hormone which regulates erythropoiesis and hence blood oxygen content. The restricted expression of the erythropoietin gene in subsets of cells within kidney and liver has suggested that this specific oxygen-sensing mechanism is restricted to specialized cells in those organs. Using transient transfection of reporter genes coupled to a transcriptional enhancer lying 3' to the erythropoietin gene, we show that an oxygen-sensing system similar, or identical, to that controlling erythropoietin expression is wide-spread in mammalian cells. The extensive distribution of this sensing mechanism contrasts with the restricted expression of erythropoietin, suggesting that it mediates other adaptive responses to hypoxia.


Factors associated with receipt of preventive dental treatment procedures among adult patients at a dental training school in Wisconsin, 2001-2002.
Gender differences in oral health-related quality of life and the fear of dental pain in seeking and receiving preventive dental care have been recognized and documented. Preventive dental treatment procedures (PDTPs) are commonly accepted as the primary approach to prevent dental disease. We examined whether the likelihood of receiving PDTPs differed by gender in adult patients receiving dental care at a dental training institution in Milwaukee, Wisconsin. Data from the Marquette University School of Dentistry electronic patient management database for 2001 through 2002 were analyzed. Descriptive, bivariate, and multivariable analyses were performed. The preventive procedures used in the study were those coded in accordance with the American Dental Association's classification system: D1110 (adult prophylaxis: professional cleaning and polishing of the teeth), D1204 (adult topical application of fluoride), D1205 (adult topical application of fluoride plus prophylaxis), and D1330 (oral hygiene instruction). Of the 1563 consecutive patient records (888 women, 675 men) reviewed for the years 2001-2002, 794 individuals (51%), aged 18 to 60 years, were identified as having received PDTPs. At the bivariate level, a significant gender difference in the receipt of PDTPs was identified (423 women [48%] vs 371 men [55%]; P = 0.004). In the multivariable analyses, age, race/ethnicity, marital status, poverty level, and health insurance type (public, private, none) were significantly associated with the receipt of PDTPs (all, P < 0.05), but gender was not. Gender differences in receiving PDTPs were not found in this dental school patient population. Receipt of PDTPs was associated with other demographic factors such as age, race/ethnicity, marital status, income level, and health insurance.


Detection of PCR products using self-probing amplicons and fluorescence.
Molecular diagnostics is progressing from low-throughput, heterogeneous, mostly manual technologies to higher throughput, closed-tube, and automated methods. Fluorescence is the favored signaling technology for such assays, and a number of techniques rely on energy transfer between a fluorophore and a proximal quencher molecule. In these methods, dual-labeled probes hybridize to an amplicon and changes in the quenching of the fluorophore are detected. We describe a new technology that is simple to use, gives highly specific information, and avoids the major difficulties of the alternative methods. It uses a primer with an integral tail that is used to probe an extension product of the primer. The probing of a target sequence is thereby converted into a unimolecular event, which has substantial benefits in terms of kinetics, thermodynamics, assay design, and probe reliability.


Longitudinal trajectories of neurocognitive test performance among individuals with perinatal HIV-infection and -exposure: adolescence through young adulthood.
There are an estimated 2.1 million youth less than 15 years of age living with HIV globally (the majority perinatally HIV-infected [PHIV]) and millions more perinatally HIV-exposed uninfected (PHEU) youth who are expected to survive through adolescence and into adulthood. Transitioning from adolescence to young adulthood requires adaptation to more demanding social interactions, academic pressures, and individual responsibilities which place distinct demands on neurocognitive functions. This study examined longitudinal trajectories of neurocognitive test performance in the domains of processing speed (PS), working memory (WM), and executive functioning (EF) among PHIV and demographically similar PHEU from adolescence through young adulthood. Data for this paper come from four time points, spanning approximately 10 years, within the Child and Adolescent Self-Awareness and Health Study (CASAH). Youth age ranged from 15 to 29 years. Longitudinal linear mixed effect models were computed for each test. Few differences in performance were found on tests of EF and WM between PHIV and PHEU youth as they aged, though PHEU youth showed significantly better PS as they aged than PHIV youth. Future research is needed to understand these vulnerable youth's neurocognitive trajectories as a function of HIV infection and -exposure, biological functions and psychosocial stressors.


Polymorphisms in genes implicated in dopamine, serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis.
Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major monoamine metabolites in the central nervous system (CNS). Their cerebrospinal fluid (CSF) concentrations, reflecting the monoamine turnover rates in CNS, are partially under genetic influence and have been associated with schizophrenia. We have hypothesized that CSF monoamine metabolite concentrations represent intermediate steps between single nucleotide polymorphisms (SNPs) in genes implicated in monoaminergic pathways and psychosis. We have searched for association between 119 SNPs in genes implicated in monoaminergic pathways [tryptophan hydroxylase 1 (TPH1), TPH2, tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), dopamine beta-hydroxylase (DBH), catechol-O-methyltransferase (COMT), monoamine oxidase A (MAOA) and MAOB] and monoamine metabolite concentrations in CSF in 74 patients with psychotic disorder. There were 42 nominally significant associations between SNPs and CSF monoamine metabolite concentrations, which exceeded the expected number (20) of nominal associations given the total number of tests performed. The strongest association (p = 0.0004) was found between MAOB rs5905512, a SNP previously reported to be associated with schizophrenia in men, and MHPG concentrations in men with psychotic disorder. Further analyses in 111 healthy individuals revealed that 41 of the 42 nominal associations were restricted to patients with psychosis and were absent in healthy controls. The present study suggests that altered monoamine turnover rates in CNS reflect intermediate steps in the associations between SNPs and psychosis.


Nonalcoholic fatty liver disease and the ongoing role of liver biopsy evaluation.
Nonalcoholic fatty liver disease (NAFLD) is one of the most common underlying causes of chronically elevated liver tests and liver disease in adults and children worldwide and may be strongly suspected if not diagnosed by ever evolving and available serologic and imaging-based noninvasive tests. However, the definitive diagnosis of the most progressive form of NAFLD, nonalcoholic steatohepatitis, and the identification of fibrosis stage still require liver biopsy evaluation as noninvasive testing has not replaced some of the specifics or the totality of information obtainable from liver biopsy. In this review, both the role and value of a liver biopsy evaluation in NAFLD/ nonalcoholic steatohepatitis are examined from publications related to a selected variety of settings. Details of the most commonly used semiquantitative methods of analysis are discussed, and some useful potential pitfalls for differential diagnostic consideration in liver biopsy interpretation are given. (Hepatology Communications 2017;1:370-378).


Road runoff management using over-the-shoulder infiltration: real-scale experimentation.
A new management policy regarding road runoff was proposed in 2002 by the Swiss Federal Office for the Environment (FOEN). This new concept is based on the diffuse infiltration of road runoff into embankment slopes, where soils will filter particles and contaminants. The shoulder lying between road surface and infiltration slopes must be impervious in order to maximise the amount of water reaching the slope and avoid losses in the road structure. The implementation of this new concept should lower the impact of roads on the environment, improve aquifer recharge and reduce construction costs. The Swiss Federal Road Office (FedRO) decided to carry out real-scale investigations regarding this new policy and thus commissioned the GEOLEP to design, build, and test 5 different shoulder structures. This paper presents the results of a 2-years survey of infiltration processes in these shoulders to establish the best performing structure. The first three shoulders were overlaid with 5 cm of gravel mixed with humus, gravel mixed with clay, and seeded with lawn, respectively. The latter two had impervious layers located 26 cm deep: the road bituminous basement (road base) was prolonged and coated with bitumen in the first case, and a sodic-bentonite geotextile was used in the second. Both were covered with gravel. All shoulders were equipped with basal collecting devices that measured hydraulic fluxes seeping through the shoulders. In total, 112 natural precipitations and 3 artificial events were monitored. Artificial events mimicked known transitory regimes (thunderstorms) or were performed with constant regime. The goal was to effectively assess infiltration processes in shoulders. Results showed that shoulders made of gravel and humus or lawn were highly ineffective (only 30 to 40% of runoff is conducted to the infiltration slope). Gravel and clay was more efficient with a proportion of approximately 60%. The shoulder with prolonged road base showed similar results since the bituminous coating was in fact rather permeable. The best results were exhibited by the shoulder waterproofed with bentonitic geotextile, which allowed no water to penetrate. This material already proved to be very powerful in groundwater catchments. The authors thus proposed a combination of sodic-bentonite geotextile covered by a gravel and clay mixture. This would be the most efficient shoulder: it will convey all the runoff to infiltration slopes, thereby optimising its filtration, which in turn will enhance environmental conditions in the vicinity of roads.


The effect of life history on retroviral genome invasions.
Endogenous retroviruses (ERV), or the remnants of past retroviral infections that are no longer active, are found in the genomes of most vertebrates, typically constituting approximately 10% of the genome. In some vertebrates, particularly in shorter-lived species like rodents, it is not unusual to find active endogenous retroviruses. In longer-lived species, including humans where substantial effort has been invested in searching for active ERVs, it is unusual to find them; to date none have been found in humans. Presumably the chance of detecting an active ERV infection is a function of the length of an ERV epidemic. Intuitively, given that ERVs or signatures of past ERV infections are passed from parents to offspring, we might expect to detect more active ERVs in species with longer generation times, as it should take more years for an infection to run its course in longer than in shorter lived species. This means the observation of more active ERV infections in shorter compared to longer-lived species is paradoxical. We explore this paradox using a modeling approach to investigate factors that influence ERV epidemic length. Our simple epidemiological model may explain why we find evidence of active ERV infections in shorter rather than longer-lived species.


20-year trends in the prevalence of asthma and chronic airflow obstruction in an HMO.
Although asthma is on the rise in the United States and elsewhere, data on age-sex-specific patterns of change in various types of health care utilization are scarce. We report on 20-yr trends in the treated prevalence of asthma among members of a large health maintenance organization. Data are presented separately for each of six age-sex categories, and include both the treated prevalence of asthma as well as the treated prevalence of the broader category of chronic airflow obstruction (CAO), defined as asthma, chronic bronchitis, or emphysema. During the period 1967-1987 the treated prevalence of asthma and CAO increased significantly in all age-sex categories except males aged 65 and older. These patterns are in contrast to previous studies of this population that showed that increases in asthma hospitalizations and hospital-based episodes of care were limited primarily to young boys. Not only do these findings support other evidence of a real increase in asthma prevalence, but they also highlight the risks associated with drawing inferences about changing disease epidemiology based on a single type of health care utilization.


Glutathione S-transferase mu genotype, diet, and smoking as determinants of sister chromatid exchange frequency in lymphocytes.
Polymorphisms in inherited metabolic traits and intake of dietary antioxidants have been reported to be associated with risk for the development of lung cancer in smokers. This increased risk of lung cancer is presumably attributable to the accumulation of DNA damage. We conducted a study to investigate whether genetic metabolic variants and antioxidant consumption affected the sister chromatid exchange (SCE) level in lymphocytes. Study subjects were 78 friends and spouses of cases from a case-control study of lung cancer designed to investigate the association of metabolic polymorphisms with lung cancer. The metabolic traits studied included glutathione S-transferase class mu and variants of P-450 isoenzymes CYP1A1 and CYP2D6. Intake of antioxidants including vitamins A, C, and E and selenium was determined through the administration of a validated, semiquantitative food frequency questionnaire. Detailed information on smoking, family history of cancer, medical history, and environmental and occupational exposures was also obtained in an interviewer-administered questionnaire. Smoking status was found to be significantly associated with SCE frequency. In addition SCE frequency decreased with the period of time since quitting smoking. The presence of one or more glutathione S-transferase class mu alleles was associated with significantly lower SCE. Higher intake of vitamin A and selenium was also inversely associated with SCE level. Thus, the results suggest that glutathione S-transferase class mu and the intake of vitamin A and selenium may modulate the accumulation of chromosomal damage in lymphocytes.


Species delimitation using genome-wide SNP data.
The multispecies coalescent has provided important progress for evolutionary inferences, including increasing the statistical rigor and objectivity of comparisons among competing species delimitation models. However, Bayesian species delimitation methods typically require brute force integration over gene trees via Markov chain Monte Carlo (MCMC), which introduces a large computation burden and precludes their application to genomic-scale data. Here we combine a recently introduced dynamic programming algorithm for estimating species trees that bypasses MCMC integration over gene trees with sophisticated methods for estimating marginal likelihoods, needed for Bayesian model selection, to provide a rigorous and computationally tractable technique for genome-wide species delimitation. We provide a critical yet simple correction that brings the likelihoods of different species trees, and more importantly their corresponding marginal likelihoods, to the same common denominator, which enables direct and accurate comparisons of competing species delimitation models using Bayes factors. We test this approach, which we call Bayes factor delimitation (*with genomic data; BFD*), using common species delimitation scenarios with computer simulations. Varying the numbers of loci and the number of samples suggest that the approach can distinguish the true model even with few loci and limited samples per species. Misspecification of the prior for population size θ has little impact on support for the true model. We apply the approach to West African forest geckos (Hemidactylus fasciatus complex) using genome-wide SNP data. This new Bayesian method for species delimitation builds on a growing trend for objective species delimitation methods with explicit model assumptions that are easily tested. [Bayes factor; model testing; phylogeography; RADseq; simulation; speciation.].


Removal of total organic carbon from sewage wastewater using poly(ethylenimine)-functionalized magnetic nanoparticles.
The increased levels of organic carbon in sewage wastewater during recent years impose a great challenge to the existing wastewater treatment process (WWTP). Technological innovations are therefore sought that can reduce the release of organic carbon into lakes and seas. In the present study, magnetic nanoparticles (NPs) were synthesized, functionalized with poly(ethylenimine) (PEI), and characterized using TEM (transmission electron microscopy), X-ray diffraction (XRD), FTIR (Fourier transform infrared spectroscopy), CCS (confocal correlation spectroscopy), SICS (scattering interference correlation spectroscopy), magnetism studies, and thermogravimetric analysis (TGA). The removal of total organic carbon (TOC) and other contaminants using PEI-coated magnetic nanoparticles (PEI-NPs) was tested in wastewater obtained from the Hammarby Sjöstadsverk sewage plant, Sweden. The synthesized NPs were about 12 nm in diameter and showed a homogeneous particle size distribution in dispersion by TEM and CCS analyses, respectively. The magnetization curve reveals superparamagnetic behavior, and the NPs do not reach saturation because of surface anisotropy effects. A 50% reduction in TOC was obtained in 60 min when using 20 mg/L PEI-NPs in 0.5 L of wastewater. Along with TOC, other contaminants such as turbidity (89%), color (86%), total nitrogen (24%), and microbial content (90%) were also removed without significant changes in the mineral ion composition of wastewater. We conclude that the application of PEI-NPs has the potential to reduce the processing time, complexity, sludge production, and use of additional chemicals in the WWTP.


Role of the EGF receptor pathway in growth and patterning of the Drosophila wing through the regulation of vestigial.
Growth and patterning of the Drosophila wing disc depends on the coordinated expression of the key regulatory gene vestigial both in the Dorsal-Ventral (D/V) boundary cells and in the wing pouch. We propose that a short-range signal originating from the core of the D/V boundary cells is responsible for activating EGFR in a zone of organizing cells on the edges of the D/V boundary. Using loss-of-function mutations and ectopic expression studies, we show that EGFR signaling is essential for vestigial transcription in these cells and for making them competent to undergo subsequent vestigial-mediated proliferation within the wing pouch.


Scattering by two-component random distributions of spheres.
Theory and prototype (at wavelength lambda = 5 mm) partial coherence scattering data for optical applications in diagnostic measurements on two component suspensions or gases are presented. Results are given for equal volume mixtures of two sizes of moving randomly distributed large spheres for all realizable values of the fractional volume w (the fraction of the slab region container filled by scattering material). The relative index of refraction of the spheres was about 1.017, and their diameters were 6.52lambda and 3.33lambda (so that we used about eight times as many small spheres as large ones for each value of w). The spheres were of lightweight Styrofoam, and their motion arose from turbulent air streams (flowing through grids that form the top and bottom of a Styrofoam container), and the data were obtained in real time by processing the instantaneous phase quadrature components of the scattered field with an electronic analog computer. We give results for the forward scattered coherent phase, for the coherent, incoherent, and total intensities, and for the covariant magnitude and phase which (together with the incoherent intensity) provide the variances and covariance of the instantaneous phase quadrature components. We also consider certain reduced data records (from which the major effects of scatterer size and material have been eliminated) to indicate the dependence of the scattering on the fractional volume and to facilitate comparison with earlier data for distributions of identical spheres.


Tobacco-Related Health Disparities Across the Cancer Care Continuum.
Use of tobacco is the leading preventable cause of death in the United States. Racial/ethnic minorities and individuals of low socioeconomic status disproportionately experience tobacco-related disease and illness. Unique challenges and circumstances exist at each point in the cancer care continuum that may contribute to the greater cancer burden experienced by these groups. We reviewed tobacco-related disparities from cancer prevention to cancer survivorship. We also describe research that seeks to reduce tobacco-related disparities. Racial/ethnic minorities and low-income individuals experience unique social and environmental contextual challenges such as greater environmental cues to smoke and greater levels of perceived stress and social discrimination. Clinical practice guidelines support the effectiveness of pharmacotherapy and behavioral counseling for racial and ethnic minorities, yet smoking cessation rates are lower in this group when compared with non-Hispanic whites. Superior efficacy for culturally adapted interventions has not yet been established. To reduce health disparities in this population, a comprehensive strategy is needed with efforts directed at each point along the cancer care continuum. Strategies are needed to reduce the impact of contextual factors such as targeted tobacco marketing and social discrimination on smoking initiation and maintenance. Future efforts should focus on increasing the use of evidence-based cessation treatment methods and studying its effectiveness in these populations. Attention must also be focused on improving treatment outcomes by reducing smoking in diverse racial and ethnic patient populations.


Bioactivity and osteointegration of hydroxyapatite-coated stainless steel and titanium wires used for intramedullary osteosynthesis.
A lot of research was conducted on the use of various biomaterials in orthopedic surgery. Our study investigated the effects of nanostructured calcium-phosphate coating on metallic implants introduced into the bone marrow canal. Stainless steel or titanium 2-mm wires (groups 1 and 2, respectively), and hydroxyapatite-coated stainless steel or titanium wires of the same diameter (groups 3 and 4, respectively) were introduced into the tibial bone marrow canal of 20 dogs (each group = 5 dogs). Hydroxyapatite coating was deposited on the wires with the method of microarc oxidation. Light microscopy to study histological diaphyseal transverse sections, scanning electron microscopy to study the bone marrow area around the implant and an X-ray electron probe analyzer to study the content of calcium and phosphorus were used to investigate bioactivity and osteointegration after a four weeks period. Osteointegration was also assessed by measuring wires' pull-off strength with a sensor dynamometer. Bone formation was observed round the wires in the bone marrow canal in all the groups. Its intensity depended upon the features of wire surfaces and implant materials. Maximum percentage volume of trabecular bone was present in the bone marrow canals of group 4 dogs that corresponded to a mean of 27.1 ± 0.14%, while it was only 6.7% in group 1. The coating in groups 3 and 4 provided better bioactivity and osteointegration. Hydroxyapatite-coated titanium wires showed the highest degree of bone formation around them and greater pull-off strength. Nanostructured hydroxyapatite coating of metallic wires induces an expressed bone formation and provides osteointegration. Hydroxyapatite-coated wires could be used along with external fixation for bone repair enhancement in diaphyseal fractures, management of osteogenesis imperfecta and correction of bone deformities in phosphate diabetes.


Self assembly of a model amphiphilic phenylalanine peptide/polyethylene glycol block copolymer in aqueous solution.
There has been great interest recently in peptide amphiphiles and block copolymers containing biomimetic peptide sequences due to applications in bionanotechnology. We investigate the self-assembly of the peptide-PEG amphiphile FFFF-PEG5000 containing the hydrophobic sequence of four phenylalanine residues conjugated to PEG of molar mass 5000. This serves as a simple model peptide amphiphile. At very low concentration, association of hydrophobic aromatic phenylalanine residues occurs, as revealed by circular dichroism and UV/vis fluorescence experiments. A critical aggregation concentration associated with the formation of hydrophobic domains is determined through pyrene fluorescence assays. At higher concentration, defined beta-sheets develop as revealed by FTIR spectroscopy and X-ray diffraction. Transmission electron microscopy reveals self-assembled straight fibril structures. These are much shorter than those observed for amyloid peptides, the finite length may be set by the end cap energy due to the hydrophobicity of phenylalanine. The combination of these techniques points to different aggregation processes depending on concentration. Hydrophobic association into irregular aggregates occurs at low concentration, well-developed beta-sheets only developing at higher concentration. Drying of FFFF-PEG5000 solutions leads to crystallization of PEG, as confirmed by polarized optical microscopy (POM), FTIR and X-ray diffraction (XRD). PEG crystallization does not disrupt local beta-sheet structure (as indicated by FTIR and XRD). However on longer lengthscales the beta-sheet fibrillar structure is perturbed because spherulites from PEG crystallization are observed by POM.


Manipulating Carbohydrate Availability Between Twice-Daily Sessions of High-Intensity Interval Training Over 2 Weeks Improves Time-Trial Performance.
Commencing some training sessions with reduced carbohydrate (CHO) availability has been shown to enhance skeletal muscle adaptations, but the effect on exercise performance is less clear. We examined whether restricting CHO intake between twice daily sessions of high-intensity interval training (HIIT) augments improvements in exercise performance and mitochondrial content. Eighteen active but not highly trained subjects (peak oxygen uptake [VO2peak] = 44 ± 9 ml/kg/min), matched for age, sex, and fitness, were randomly allocated to two groups. On each of 6 days over 2 weeks, subjects completed two training sessions, each consisting of 5 × 4-min cycling intervals (60% of peak power), interspersed by 2 min of recovery. Subjects ingested either 195 g of CHO (HI-HI group: ~2.3 g/kg) or 17 g of CHO (HI-LO group: ~0.3 g/kg) during the 3-hr period between sessions. The training-induced improvement in 250-kJ time trial performance was greater (p = .02) in the HI-LO group (211 ± 66 W to 244 ± 75 W) compared with the HI-HI group (203 ± 53 W to 219 ± 60 W); however, the increases in mitochondrial content was similar between groups, as reflected by similar increases in citrate synthase maximal activity, citrate synthase protein content and cytochrome c oxidase subunit IV protein content (p > .05 for interaction terms). This is the first study to show that a short-term "train low, compete high" intervention can improve whole-body exercise capacity. Further research is needed to determine whether this type of manipulation can also enhance performance in highly-trained subjects.


Lesion detection performance: comparative analysis of low-dose CT data of the chest on two hybrid imaging systems.
Incidental findings on low-dose CT images obtained during hybrid imaging are an increasing phenomenon as CT technology advances. Understanding the diagnostic value of incidental findings along with the technical limitations is important when reporting image results and recommending follow-up, which may result in an additional radiation dose from further diagnostic imaging and an increase in patient anxiety. This study assessed lesions incidentally detected on CT images acquired for attenuation correction on two SPECT/CT systems. An anthropomorphic chest phantom containing simulated lesions of varying size and density was imaged on an Infinia Hawkeye 4 and a Symbia T6 using the low-dose CT settings applied for attenuation correction acquisitions in myocardial perfusion imaging. Twenty-two interpreters assessed 46 images from each SPECT/CT system (15 normal images and 31 abnormal images; 41 lesions). Data were evaluated using a jackknife alternative free-response receiver-operating-characteristic analysis (JAFROC). JAFROC analysis showed a significant difference (P < 0.0001) in lesion detection, with the figures of merit being 0.599 (95% confidence interval, 0.568, 0.631) and 0.810 (95% confidence interval, 0.781, 0.839) for the Infinia Hawkeye 4 and Symbia T6, respectively. Lesion detection on the Infinia Hawkeye 4 was generally limited to larger, higher-density lesions. The Symbia T6 allowed improved detection rates for midsized lesions and some lower-density lesions. However, interpreters struggled to detect small (5 mm) lesions on both image sets, irrespective of density. Lesion detection is more reliable on low-dose CT images from the Symbia T6 than from the Infinia Hawkeye 4. This phantom-based study gives an indication of potential lesion detection in the clinical context as shown by two commonly used SPECT/CT systems, which may assist the clinician in determining whether further diagnostic imaging is justified.


X-ray microfocussing combined with microfluidics for on-chip X-ray scattering measurements.
This work describes the fabrication of thin microfluidic devices in Kapton (polyimide). These chips are well-suited to perform X-ray scattering experiments using intense microfocussed beams, as Kapton is both relatively resistant to the high intensities generated by a synchrotron, and almost transparent to X-rays. We show networks of microchannels obtained using laser ablation of Kapton films, and we also present a simple way to perform fusion bonding between two Kapton films. The possibilities offered using such devices are illustrated with X-ray scattering experiments. These experiments demonstrate that structural measurements in the 1 A-20 nm range can be obtained with spatial resolutions of a few microns in a microchannel.


The TIGRFAMs database of protein families.
TIGRFAMs is a collection of manually curated protein families consisting of hidden Markov models (HMMs), multiple sequence alignments, commentary, Gene Ontology (GO) assignments, literature references and pointers to related TIGRFAMs, Pfam and InterPro models. These models are designed to support both automated and manually curated annotation of genomes. TIGRFAMs contains models of full-length proteins and shorter regions at the levels of superfamilies, subfamilies and equivalogs, where equivalogs are sets of homologous proteins conserved with respect to function since their last common ancestor. The scope of each model is set by raising or lowering cutoff scores and choosing members of the seed alignment to group proteins sharing specific function (equivalog) or more general properties. The overall goal is to provide information with maximum utility for the annotation process. TIGRFAMs is thus complementary to Pfam, whose models typically achieve broad coverage across distant homologs but end at the boundaries of conserved structural domains. The database currently contains over 1600 protein families. TIGRFAMs is available for searching or downloading at www.tigr.org/TIGRFAMs.


Hippocampal Offline Reactivation Consolidates Recently Formed Cell Assembly Patterns during Sharp Wave-Ripples.
The ability to reinstate neuronal assemblies representing mnemonic information is thought to require their consolidation through offline reactivation during sleep/rest. To test this, we detected cell assembly patterns formed by repeated neuronal co-activations in the mouse hippocampus during exploration of spatial environments. We found that the reinstatement of assembly patterns representing a novel, but not a familiar, environment correlated with their offline reactivation and was impaired by closed-loop optogenetic disruption of sharp wave-ripple oscillations. Moreover, we discovered that reactivation was only required for the reinstatement of assembly patterns whose expression was gradually strengthened during encoding of a novel place. The context-dependent reinstatement of assembly patterns whose expression did not gain in strength beyond the first few minutes of spatial encoding was not dependent on reactivation. This demonstrates that the hippocampus can hold concurrent representations of space that markedly differ in their encoding dynamics and their dependence on offline reactivation for consolidation. VIDEO ABSTRACT.


Concurrent Validity of the International Family Quality of Life Survey.
The measurement of the social construct of Family Quality of Life (FQOL) is a parsimonious alternative to the current approach of measuring familial outcomes using a battery of tools related to individual-level outcomes. The purpose of this study was to examine the internal consistency and concurrent validity of the International FQOL Survey (FQOLS-2006), using cross-sectional data collected from 65 family caregivers of children with developmental disabilities. It shows a moderate correlation between the total FQOL scores of the FQOLS-2006 and the Beach Center's FQOL scale. The validity of five FQOLS-2006 domains was supported by the correlations between conceptually related domains.


Mortality after hip fracture with vertebral compression fracture is poor.
Due to the increasing elderly population, the prevalence of osteoporotic hip fractures in Japanese patients continues to rise. It is well established that patients with either hip fracture or both symptomatic and asymptomatic morphometric vertebral compression fracture (VCF) have a poor health prognosis compared with the general population. The purpose of this study was to retrospectively investigate vertebral fracture rates among patients with hip fracture and their influence on mortality. We examined 182 cases of osteoporotic hip fracture in patients admitted to our institution between January 2009 and May 2011. The average age at the time of fracture was 85 years. Radiographs of the lumbar spine were obtained from all of the participants and the lateral spinal radiographs were examined for evidence of VCF. The patients were classified into two groups, those with VCF and those without. A VCF was identified in approximately 78 % of the patients. The mortality rate 1 year after the hip fracture was approximately 22 % and it was significantly higher in patients with VCF. Through multivariate statistics we found that VCF, post-operative complication, loss of ambulation after operation and medication for osteoporosis were statistically significant. In other words, VCF, post-operative complication and loss of ambulation were considered to be poor prognostic factors and medication for osteoporosis was likely to improve the prognosis. We concluded that the risk of mortality after hip fracture is significantly greater in patients who also have VCF compared to patients without VCF, and that medication for osteoporosis is likely to improve prognosis.