Mice depleted for Exchange Proteins Directly Activated by cAMP (Epac) exhibit irregular liver regeneration in response to partial hepatectomy.
The exchange proteins directly activated by cAMP 1 and 2 (Epac1 and Epac2) are expressed in a cell specific manner in the liver, but their biological functions in this tissue are poorly understood. The current study was undertaken to begin to determine the potential roles of Epac1 and Epac2 in liver physiology and disease. Male C57BL/6J mice in which expression of Epac1 and/or Epac2 are deleted, were subjected to partial hepatectomy and the regenerating liver was analyzed with regard to lipid accumulation, cell replication and protein expression. In response to partial hepatectomy, deletion of Epac1 and/or Epac2 led to increased hepatocyte proliferation 36 h post surgery, and the transient steatosis observed in wild type mice was virtually absent in mice lacking both Epac1 and Epac2. The expression of the protein cytochrome P4504a14, which is implicated in hepatic steatosis and fibrosis, was substantially reduced upon deletion of Epac1/2, while a number of factors involved in lipid metabolism were significantly decreased. Moreover, the number of Küpffer cells was affected, and Epac2 expression was increased in the liver of wild type mice in response to partial hepatectomy, further supporting a role for these proteins in liver function. This study establishes hepatic phenotypic abnormalities in mice deleted for Epac1/2 for the first time, and introduces Epac1/2 as regulators of hepatocyte proliferation and lipid accumulation in the regenerative process.


Circulating microRNAs as a fingerprint for endometrial endometrioid adenocarcinoma.
Endometrial cancer is the most common malignancy of the female genital tract worldwide, and endometrial endometrioid adenocarcinoma (EEC) is the major histological type of endometrial cancer. There is a great need for better markers with high sensitivity and specificity to permit early diagnosis and proper management of EEC. The aim of our study is to identify a miRNA classifier within plasma as a noninvasive biomarker for EEC diagnosis. This study was a retrospective case-control analysis which contained two independent cohorts including 93 participants. First, we screened 375 miRNAs in 29 plasma samples. 9 of the miRNAs were selected to be evaluated their expression by quantitative reverse-transcriptase polymerase chain reaction. A stepwise logistic regression model was then used to establish a new classifier in the validation cohort. Area under the receiver operating characteristic curve was used to evaluate the diagnostic accuracy. Co-expression analysis was used to verify the independence of results. miR-15b, -27a, and -223 were found to be differentially expressed in the EEC plasma between the two cohorts and had few connections with other miRNAs. The areas under the curve (AUC) were 0.768, 0.813, and 0.768 for miR-15b, -27a, and 223, respectively. miR-27a and CA125 can be combined as a potential non-invasive biomarker for detecting EEC, with the AUC of 0.894. Our study demonstrated three miRNAs, including miR-15b, -27a, and -233 have a good clinical value in EEC diagnosis. The classifier, including miR-27a and CA125, demonstrated a high accuracy in the diagnosis of EEC and might serve as a novel non-invasive biomarker in the future.


Quadrature phase detector using two-mode waveguides.
We present a novel design for quadrature phase detection utilizing two-mode optical waveguides for optical interferometric systems. A pair of interferometric signals having quadrature optical phase information can be obtained from the near-field and far-field patterns of a two-mode waveguide output. The operational principle is based on a pi/2 differential phase shift between two modal beams occurring during their transition from near-field to far-field radiation patterns.


Anti-inflammatory properties of local anesthetics and their present and potential clinical implications.
Development of new local anesthetic agents has been focused on the potency of their nerve-blocking effects, duration of action and safety and has resulted in a substantial number of agents in clinical use. It is well established and well documented that the nerve blocking effects of local anesthetics are secondary to their interaction with the Na+ channels thereby blocking nerve membrane excitability and the generation of action potentials. Accumulating data suggest however that local anesthetics also possess a wide range of anti-inflammatory actions through their effects on cells of the immune system, as well as on other cells, e.g. microorganisms, thrombocytes and erythrocytes. The potent anti-inflammatory properties of local anesthetics, superior in several aspects to traditional anti-inflammatory agents of the NSAID and steroid groups and with fewer side-effects, has prompted clinicians to introduce them in the treatment of various inflammation-related conditions and diseases. They have proved successful in the treatment of burn injuries, interstitial cystitis, ulcerative proctitis, arthritis and herpes simplex infections. The detailed mechanisms of action are not fully understood but seem to involve a reversible interaction with membrane proteins and lipids thus regulating cell metabolic activity, migration, exocytosis and phagocytosis.


Atmospheric turbulence characterization with the Keck adaptive optics systems. I. Open-loop data.
We present a detailed investigation of different methods of the characterization of atmospheric turbulence with the adaptive optics systems of the W. M. Keck Observatory. The main problems of such a characterization are the separation of instrumental and atmospheric effects and the accurate calibration of the devices involved. Therefore we mostly describe the practical issues of the analysis. We show that two methods, the analysis of differential image motion structure functions and the Zernike decomposition of the wave-front phase, produce values of the atmospheric coherence length r0 that are in excellent agreement with results from long-exposure images. The main error source is the calibration of the wave-front sensor. Values determined for the outer scale L0 are consistent between the methods and with typical L0 values found at other sites, that is, of the order of tens of meters.


Prospective evaluation of criteria for obtaining thoracolumbar radiographs in trauma patients.
This study examined if use of clinical screening criteria for selective radiography of blunt trauma patients can identify all patients with thoracolumbar (TL) spine injuries. The study was a prospective cohort of patients undergoing TL spine radiographs following blunt trauma. Patients were considered at risk for TL spine injury if they had any of the following clinical criteria: 1) complaints of TL spine pain, 2) TL spine tenderness, 3) a decreased level of consciousness, 4) intoxication with ethanol or drugs, 5) a neurologic deficit, or 6) a painful distracting injury. Patients without any of these findings were considered at low risk for TL spine injury. Severity of mechanism of injury was also recorded. Data sheets were completed prior to TL radiography. Injury status was determined by the final faculty radiologist interpretation of all radiographic studies. A total of 2404 patients were enrolled. TL spine injuries were identified in 152 patients. Of these 152 patients with spine injuries, all 152 (100%, 95% confidence interval 98-100%) were considered high risk by having at least one of the high-risk criteria. These criteria have a specificity of 3.9%, a positive predictive value of 6.6%, and a negative predictive value of 100%. All of the high-risk criteria but intoxication with ethanol or drugs were important as sole predictors of TL spine injury. The use of high-risk clinical screening criteria identified virtually all blunt trauma patients with acute TL spine injuries. These criteria, however, have poor specificity and positive predictive value.


SMRT sequencing of the Campylobacter coli BfR-CA-9557 genome sequence reveals unique methylation motifs.
Campylobacter species are the most prevalent bacterial pathogen causing acute enteritis worldwide. In contrast to Campylobacter jejuni, about 5 % of Campylobacter coli strains exhibit susceptibility to restriction endonuclease digestion by DpnI cutting specifically 5'-G(m)ATC-3' motifs. This indicates significant differences in DNA methylation between both microbial species. The goal of the study was to analyze the methylome of a C. coli strain susceptible to DpnI digestion, to identify its methylation motifs and restriction modification systems (RM-systems), and compare them to related organisms like C. jejuni and Helicobacter pylori. Using one SMRT cell and the PacBio RS sequencing technology followed by PacBio Modification and Motif Analysis the complete genome of the DpnI susceptible strain C. coli BfR-CA-9557 was sequenced to 500-fold coverage and assembled into a single contig of 1.7 Mbp. The genome contains a CJIE1-like element prophage and is phylogenetically closer to C. coli clade 1 isolates than clade 3. 45,881 6-methylated adenines (ca. 2.7 % of genome positions) that are predominantly arranged in eight different methylation motifs and 1,788 4-methylated cytosines (ca. 0.1 %) have been detected. Only two of these motifs correspond to known restriction modification motifs. Characteristic for this methylome was the very high fraction of methylation of motifs with mostly above 99 %. Only five dominant methylation motifs have been identified in C. jejuni, which have been associated with known RM-systems. C. coli BFR-CA-9557 shares one (RAATTY) of these, but four ORFs could be assigned to putative Type I RM-systems, seven ORFs to Type II RM-systems and three ORFs to Type IV RM-systems. In accordance with DpnI prescreening RM-system IIP, methylation of GATC motifs was detected in C. coli BfR-CA-9557. A homologous IIP RM-system has been described for H. pylori. The remaining methylation motifs are specific for C. coli BfR-CA-9557 and have been neither detected in C. jejuni nor in H. pylori. The results of this study give us new insights into epigenetics of Campylobacteraceae and provide the groundwork to resolve the function of RM-systems in C. coli.


Synaptic zinc contributes to motor and cognitive deficits in 6-hydroxydopamine mouse models of Parkinson's disease.
Hyperactivity of glutamatergic corticostrial pathways is recognized as a key pathophysiological mechanism contributing to development of PD symptoms and dopaminergic neurotoxicity. Subset of corticostriatal projection neurons uses Zn2+ as a co-transmitter alongside glutamate, but the role of synaptically released Zn2+ in PD remains unexplored. We used genetically modified mice and pharmacological tools in combination with 6-hydroxydopamine (6-OHDA) lesion models of PD to investigate the contribution of synaptic zinc to disease associated behavioral deficits and neurodegeneration. Vesicular zinc transporter-3 (ZnT3) knockout mice lacking releasable Zn2+ were more resistant to locomotor deficit and memory impairment of nigrostriatal dopamine (DA) denervation compared to wildtype littermates. The loss of striatal dopaminergic fibers was comparable between genotypes, indicating that synaptically released Zn2+ contributes to behavioral deficits but not neurotoxic effects of 6-OHDA. To gain further insight into the mechanisms of Zn2+ actions, we used the extracellular Zn2+ chelator CaEDTA and knock-in mice lacking the high affinity Zn2+ inhibition of GluN2A-containing NMDA receptors (GluN2A-NMDARs). Acute chelation of extracellular Zn2+ in the striatum restored locomotor deficit of 6-OHDA lesion, confirming that synaptic Zn2+ suppresses locomotor behavior. Disruption of the Zn2+-GluN2A interaction had, on the other hand, no impact on locomotor deficit or neurotoxic effect of 6-OHDA. Collectively, these findings provide clear evidence for the implication of striatal synaptic Zn2+ in the pathophysiology of PD. They unveil that synaptic Zn2+ plays predominantly a detrimental role by promoting motor and cognitive deficits caused by nigrostriatal DA denervation, pointing towards new therapeutic interventions.


CT scanning-based phenotypes vary with ADRB2 polymorphisms in chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease that is characterized by varying degrees of involvement of airway and lung parenchyma. Although cigarette smoke is the major risk factor for COPD, the principal determining factors of involvement of the airway or lung parenchyma have not been clearly defined. Genetic variability in COPD patients might influence the varying degrees of involvement of airway and parenchyma. We therefore studied whether airway and parenchyma involvement might be associated with the ADRB2 genotype, which has been reported to be associated with COPD susceptibility and the bronchodilator response. One hundred and eleven COPD subjects, whose post-bronchodilator FEV(1)/FVC values were less than 0.7, and who had histories of smoking exceeding 10 pack-years, were prospectively recruited from pulmonology clinics of 11 hospitals in Seoul, Korea. The degrees of involvement of airway and parenchyma were evaluated by volumetric computed tomography (CT) scans. In-house software automatically calculated luminal areas, airway wall areas, percentages of wall areas in segmental bronchi, emphysema indices, and mean lung densities in the whole lung parenchyma. The ADRB2 genotypes at codon 16 were determined for all patients. Gly16 was associated with lumen diameter, luminal area, and percentage of wall area in patients with COPD (p=0.02), whereas neither wall area nor wall thickness differed with ADRB2 genotype. Neither emphysema index nor mean lung density was associated with ADRB2 genotype. Gly16 variant in ADRB2 gene was associated with airway wall phenotypes measured using CT scanning in COPD patients.


Quantification of early adipose-derived stem cell survival: comparison between sodium iodide symporter and enhanced green fluorescence protein imaging.
Strategies to overcome the problem of extensive early stem cell loss following transplantation requires a method to quantitatively assess their efficacy. This study compared the ability of sodium/iodide symporter (NIS) and enhanced green fluorescent protein (EGFP) imaging to monitor the effectiveness of treatments to enhance early stem cell survival. Human adipose-derived stem cells (ADSCs) transduced with an adenoviral vector to express both NIS and EGFP were mixed with culture media (control), matrigel (matrigel group) or pro-survival cocktail (PSC group), and 5×10(6) cells were injected into thigh muscles of C57BL/6 mice. Animals underwent serial optical imaging and (99m)TcO(4)(-) scintigraphy. Image-based EGFP fluorescence and (99m)TcO(4)(-) uptake was measured by region-of-interest analysis, and extracted tissues were measured for (99m)Tc activity. Fluorescent intensity measured from homogenized muscle tissue was used as reference for actual amount of viable ADSCs. ADSCs were efficiently transduced to express EGFP and NIS without affecting proliferative capacity. The absence of significant apoptosis was confirmed by annexin V FACS analysis and Western blots for activated caspase-3. Both fluorescence optical imaging and (99m)TcO(4)(-) scintigraphy visualized implanted cells in living mice for up to 5days. However, optical imaging displayed large variations in fluorescence intensity, and thus failed to detect difference in cell survival between groups or its change over time. In comparison, (99m)TcO(4)(-) scintigraphy provided more reliable assessment of within-in group donor cell content as well as its temporal change. As a result, NIS imaging was able to discern beneficial effects of matrigel and pro-survival cocktail treatment on early ADSC survival, and provided quantitative measurements that correlated to actual donor cell content within implanted tissue. NIS reporter imaging may be useful for noninvasively assessing the efficacies of strategies designed to improve early survival of transplanted stem cells.


Osteology of Carnufex carolinensis (Archosauria: Psuedosuchia) from the Pekin Formation of North Carolina and Its Implications for Early Crocodylomorph Evolution.
Crocodylomorphs originated in the Late Triassic and were the only crocodile-line archosaurs to survive the end-Triassic extinction. Recent phylogenetic analyses suggest that the closest relatives of these generally gracile, small-bodied taxa were a group of robust, large-bodied predators known as rauisuchids implying a problematic morphological gap between early crocodylomorphs and their closest relatives. Here we provide a detailed osteological description of the recently named early diverging crocodylomorph Carnufex carolinensis from the Upper Triassic Pekin Formation of North Carolina and assess its phylogenetic position within the Paracrocodylomorpha. Carnufex displays a mosaic of crocodylomorph, rauisuchid, and dinosaurian characters, as well as highly laminar cranial elements and vertebrae, ornamented dermal skull bones, a large, subtriangular antorbital fenestra, and a reduced forelimb. A phylogenetic analysis utilizing a comprehensive dataset of early paracrocodylomorphs and including seven new characters and numerous modifications to characters culled from the literature recovers Carnufex carolinensis as one of the most basal members of Crocodylomorpha, in a polytomy with two other large bodied taxa (CM 73372 and Redondavenator). The analysis also resulted in increased resolution within Crocodylomorpha and a monophyletic clade containing the holotype and two referred specimens of Hesperosuchus as well as Dromicosuchus. Carnufex occupies a key transition at the origin of Crocodylomorpha, indicating that the morphology typifying early crocodylomorphs appeared before the shift to small body size.


National release of the nursing home quality report cards: implications of statistical methodology for risk adjustment.
To determine how alternative statistical risk-adjustment methods may affect the quality measures (QMs) in nursing home (NH) report cards. Secondary data from the national Minimum Data Set files of 2004 and 2005 that include 605,433 long-term residents in 9,336 facilities. We estimated risk-adjusted QMs of decline in activities of daily living (ADL) functioning using classical, fixed-effects, and random-effects logistic models. Risk-adjusted QMs were compared with each other, and with the published QM (unadjusted) in identifying high- and low-quality facilities by either the rankings or 95 percent confidence intervals of QMs. Risk-adjusted QMs showed better overall agreement (or convergent validity) with each other than did the unadjusted versus each adjusted QM; the disagreement rate between unadjusted and adjusted QM can be as high as 48 percent. The risk-adjusted QM derived from the random-effects shrinkage estimator deviated nonrandomly from other risk-adjusted estimates in identifying the best 10 percent facilities using rankings. The extensively risk-adjusted QMs of ADL decline, even when estimated by alternative statistical methods, show higher convergent validity and provide more robust NH comparisons than the unadjusted QM. Outcome rankings based on ADL decline tend to show lower convergent validity when estimated by the shrinkage estimator rather than other statistical methods.


Hemodynamic forces can be accurately measured in vivo with optical tweezers.
Force sensing and generation at the tissue and cellular scale is central to many biological events. There is a growing interest in modern cell biology for methods enabling force measurements in vivo. Optical trapping allows noninvasive probing of piconewton forces and thus emerged as a promising mean for assessing biomechanics in vivo. Nevertheless, the main obstacles lie in the accurate determination of the trap stiffness in heterogeneous living organisms, at any position where the trap is used. A proper calibration of the trap stiffness is thus required for performing accurate and reliable force measurements in vivo. Here we introduce a method that overcomes these difficulties by accurately measuring hemodynamic profiles in order to calibrate the trap stiffness. Doing so, and using numerical methods to assess the accuracy of the experimental data, we measured flow profiles and drag forces imposed to trapped red blood cells of living zebrafish embryos. Using treatments enabling blood flow tuning, we demonstrated that such a method is powerful in measuring hemodynamic forces in vivo with accuracy and confidence. Altogether this study demonstrates the power of optical tweezing in measuring low range hemodynamic forces in vivo and offers an unprecedented tool in both cell and developmental biology.


In vitro prebiotic effects and quantitative analysis of Bulnesia sarmienti extract.
Prebiotics are used to influence the growth, colonization, survival, and activity of probiotics, and enhance the innate immunity, thus improving the health status of the host. The survival, growth, and activity of probiotics are often interfered with by intrinsic factors and indigenous microbes in the gastrointestinal tract. In this study, Bulnesia sarmienti aqueous extract (BSAE) was evaluated for the growth-promoting activity of different strains of Lactobacillus acidophilus, and a simple, precise, cost-effective high-performance liquid chromatography (HPLC) method was developed and validated for the determination of active prebiotic ingredients in the extract. Different strains of L. acidophilus (probiotic) were incubated in de Man, Rogosa, and Sharpe (MRS) medium with the supplementation of BSAE in a final concentration of 0.0%, 1.0%, and 3.0% (w/v) as the sole carbon source. Growth of the probiotics was determined by measuring the pH changes and colony-forming units (CFU/mL) using the microdilution method for a period of 24 hours. The HPLC method was designed by optimizing mobile-phase composition, flow rate, column temperature, and detection wavelength. The method was validated according to the requirements of a new method, including accuracy, precision, linearity, limit of detection, limit of quantitation, and specificity. The major prebiotic active ingredients in BSAE were determined using the validated HPLC method. The rapid growth rate of different strains of L. acidophilus was observed in growth media with BSAE, whereas the decline of pH values of cultures varied in different strains of probiotics depending on the time of culture. (+)-Catechin and (-)-epicatechin were identified on the basis of their retention time, absorbance spectrum, and mass spectrometry fragmentation pattern. The developed method met the limit of all validation parameters. The prebiotic active components, (+)-catechin and (-)-epicatechin, were quantified as 1.27% and 0.71% (w/w), respectively, in crude extract, and 6.36±0.06 μg/mL and 4.47±0.41 μg/mL (mean±standard deviation), respectively, in a prebiotic capsule of BSAE by HPLC analysis. BSAE contains the active components of prebiotics and enhances the growth of L. acidophilus.


Heritability of Boldness and Hypoxia Avoidance in European Seabass, Dicentrarchus labrax.
To understand the genetic basis of coping style in European seabass, fish from a full factorial mating (10 females x 50 males) were reared in common garden and individually tagged. Individuals coping style was characterized through behavior tests at four different ages, categorizing fish into proactive or reactive: a hypoxia avoidance test (at 255 days post hatching, dph) and 3 risk-taking tests (at 276, 286 and 304 dph). We observed significant heritability of the coping style, higher for the average of risk-taking scores (h2 = 0.45 ± 0.14) than for the hypoxia avoidance test (h2 = 0.19 ± 0.10). The genetic correlations between the three risk-taking scores were very high (rA = 0.96-0.99) showing that although their repeatability was moderately high (rP = 0.64-0.72), successive risk-taking tests evaluated the same genetic variation. A mild genetic correlation between the results of the hypoxia avoidance test and the average of risk-taking scores (0.45 ± 0.27) suggested that hypoxia avoidance and risk-taking tests do not address exactly the same behavioral and physiological responses. Genetic correlations between weight and risk taking traits showed negative values whatever the test used in our population i.e. reactive individual weights were larger. The results of this quantitative genetic analysis suggest a potential for the development of selection programs based on coping styles that could increase seabass welfare without altering growth performances. Overall, it also contributes to a better understanding of the origin and the significance of individual behavioral differences.


Postinfectious glomerulonephritis.
Postinfectious glomerulonephritis (PIGN) is an immunologically mediated glomerular injury triggered by an infection. Poststreptococcal glomerulonephritis (PSGN) is a classic example of PIGN with diffuse proliferative and exudative glomerular histology, dominant C3 staining and subepithelial "humps." Only the nephritogenic streptococcal infections cause PSGN and susceptibility to develop PSGN depends on both host and microbial factors. Over the last decade, two nephritogenic antigens, "nephritis-associated plasmin receptor" and "streptococcal pyrogenic exotoxin B" have been identified. PSGN is a self-limited disease, especially in children, but long-term follow-up studies indicate persistent low-grade renal abnormalities in a significant proportion of patients. PSGN continues to be a serious public health concern in third world countries, but the incidence of streptococcal infections has steadily declined in industrialized nations. PIGN in the western world is now primarily because of nonstreptococcal infections, often affecting older individuals with comorbidities such as diabetes mellitus or alcoholism, and is associated with poor outcomes. Although the acute PIGN has diffuse proliferative, focal segmental proliferative or mesangioproliferative patterns of glomerular injury, chronic or subacute infection-associated glomerulonephritis typically results in membranoproliferative appearance. PIGN has dominant C3 staining with frequent occurrence of subepithelial "humps" as well as subendothelial deposits. The immunoglobulin staining on immunofluorescence is typically weak, but immunoglobulin A-dominant PIGN is a recently defined entity often associated with staphylococcal infections. The wide spectrum of morphologic changes seen in PIGN poses a diagnostic challenge, especially if adequate clinical and serological data are lacking.


Incidence of colorectal cancer in proctocolitis: a retrospective study of 959 cases over 40 years.
The incidence of colorectal cancer was studied by the actuarial method in 959 patients with idiopathic proctocolitis seen from 1942 to 1981. Forty five per cent had rectal, 23% left-sided, and 32% total involvement of the colon. Six cancers were found: one in the rectal, one in the left-sided, and four in the total form of the disease. The risk of cancer per patient year in total colitis was zero per 2151 patient years in the first decade, 1/462 in the second decade, 1/315 in the third decade, and 1/75 in the fourth decade. The cumulative risk of developing cancer was zero at 10 years of duration of the disease, approximately 5% at 20 years, 15% at 30 years, and 20% at 35 years. This increase in risk of cancer is less than reported in some other series. Geographical differences in the incidence of cancer in proctocolitis could influence the risk and therefore also the long-term management of patients with proctocolitis in different geographical areas.


Predicting Consumer Biomass, Size-Structure, Production, Catch Potential, Responses to Fishing and Associated Uncertainties in the World's Marine Ecosystems.
Existing estimates of fish and consumer biomass in the world's oceans are disparate. This creates uncertainty about the roles of fish and other consumers in biogeochemical cycles and ecosystem processes, the extent of human and environmental impacts and fishery potential. We develop and use a size-based macroecological model to assess the effects of parameter uncertainty on predicted consumer biomass, production and distribution. Resulting uncertainty is large (e.g. median global biomass 4.9 billion tonnes for consumers weighing 1 g to 1000 kg; 50% uncertainty intervals of 2 to 10.4 billion tonnes; 90% uncertainty intervals of 0.3 to 26.1 billion tonnes) and driven primarily by uncertainty in trophic transfer efficiency and its relationship with predator-prey body mass ratios. Even the upper uncertainty intervals for global predictions of consumer biomass demonstrate the remarkable scarcity of marine consumers, with less than one part in 30 million by volume of the global oceans comprising tissue of macroscopic animals. Thus the apparently high densities of marine life seen in surface and coastal waters and frequently visited abundance hotspots will likely give many in society a false impression of the abundance of marine animals. Unexploited baseline biomass predictions from the simple macroecological model were used to calibrate a more complex size- and trait-based model to estimate fisheries yield and impacts. Yields are highly dependent on baseline biomass and fisheries selectivity. Predicted global sustainable fisheries yield increases ≈4 fold when smaller individuals (< 20 cm from species of maximum mass < 1 kg) are targeted in all oceans, but the predicted yields would rarely be accessible in practice and this fishing strategy leads to the collapse of larger species if fishing mortality rates on different size classes cannot be decoupled. Our analyses show that models with minimal parameter demands that are based on a few established ecological principles can support equitable analysis and comparison of diverse ecosystems. The analyses provide insights into the effects of parameter uncertainty on global biomass and production estimates, which have yet to be achieved with complex models, and will therefore help to highlight priorities for future research and data collection. However, the focus on simple model structures and global processes means that non-phytoplankton primary production and several groups, structures and processes of ecological and conservation interest are not represented. Consequently, our simple models become increasingly less useful than more complex alternatives when addressing questions about food web structure and function, biodiversity, resilience and human impacts at smaller scales and for areas closer to coasts.


Correlation between CK18 gene and gastric carcinoma micrometastasis.
To explore the biological behavior of gastric carcinoma micrometastasis (MM) with a marker of cytokeratin 18 (CK18) and to evaluate the clinical stage of gastric carcinoma and its prognosis. Reverse transcription-polymerase chain reaction (RT-PCR) was used to examine the expression of CK18 mRNA in 298 lymph nodes from 35 patients with gastric carcinoma and 20 lymph nodes from 10 patients with chronic peptic ulcer and gastric perforation diagnosed by pathological examination and surgery. CK18 mRNA expression of peripheral blood from 54 patients with gastric carcinoma and 10 healthy people were also examined. Expression of CK18 mRNA was not found in 10 patients with benign pathological changes. CK18 mRNA expression in gastric carcinoma tissues was strongly positive. In gastric carcinoma patients, pathological examination revealed that 99 of 298 (33.2%) lymph nodes were positive, while RT-PCR showed that 133 of 298 (44.6%) lymph nodes had expression of CK18 mRNA. The difference was significant (P<0.05). Among the 199 negative lymph nodes identified by pathological examinations, 34 (17.1%) displayed positive expression of CK18 mRNA by RT-PCR. The positive expression of CK18 mRNA was associated with lymph node micrometastasis (LMM) of gastric carcinoma. CK18 mRNA was negatively expressed in all 10 healthy cases and positively expressed in 38.9% of 54 blood specimens from gastric carcinoma patients. The positive rate was not correlated with tumor invasion of gastric carcinoma, but was significantly associated with TNM stage, lymph node metastasis (P=0.0290, P<0.05) and tumor differentiation (P=0.2956, P<0.05). RT-PCR with CK18 mRNA as a molecular marker is highly sensitive and specific in detecting LMM of gastric carcinoma. It can benefit the diagnosis of MM and guide studies on biological behavior, clinical phase, and therapy as well as relapse monitoring.


Ultradian rhythmicity of plasma cortisol is necessary for normal emotional and cognitive responses in man.
Glucocorticoids (GCs) are secreted in an ultradian, pulsatile pattern that emerges from delays in the feedforward-feedback interaction between the anterior pituitary and adrenal glands. Dynamic oscillations of GCs are critical for normal cognitive and metabolic function in the rat and have been shown to modulate the pattern of GC-sensitive gene expression, modify synaptic activity, and maintain stress responsiveness. In man, current cortisol replacement therapy does not reproduce physiological hormone pulses and is associated with psychopathological symptoms, especially apathy and attenuated motivation in engaging with daily activities. In this work, we tested the hypothesis that the pattern of GC dynamics in the brain is of crucial importance for regulating cognitive and behavioral processes. We provide evidence that exactly the same dose of cortisol administered in different patterns alters the neural processing underlying the response to emotional stimulation, the accuracy in recognition and attentional bias toward/away from emotional faces, the quality of sleep, and the working memory performance of healthy male volunteers. These data indicate that the pattern of the GC rhythm differentially impacts human cognition and behavior under physiological, nonstressful conditions and has major implications for the improvement of cortisol replacement therapy.


Health-care climate, perceived self-care competence, and glycemic control among patients with type 2 diabetes in primary care.
This study showed, in line with self-determination theory, that glycemic control among patients with type 2 diabetes (n = 2866) was strongly associated with perceived self-care competence, which in turn was associated with autonomous motivation and autonomy-supportive health-care climate. These associations remained after adjusting for the effect of important life-context factors. Autonomous motivation partially mediated the effect of health-care climate on perceived competence, which fully mediated the effect of autonomous motivation on glycemic control. The results of the study emphasize health-care personnel's important role in supporting patients' autonomous motivation and perceived self-care competence.


Tissue Specificity of Human Disease Module.
Genes carrying mutations associated with genetic diseases are present in all human cells; yet, clinical manifestations of genetic diseases are usually highly tissue-specific. Although some disease genes are expressed only in selected tissues, the expression patterns of disease genes alone cannot explain the observed tissue specificity of human diseases. Here we hypothesize that for a disease to manifest itself in a particular tissue, a whole functional subnetwork of genes (disease module) needs to be expressed in that tissue. Driven by this hypothesis, we conducted a systematic study of the expression patterns of disease genes within the human interactome. We find that genes expressed in a specific tissue tend to be localized in the same neighborhood of the interactome. By contrast, genes expressed in different tissues are segregated in distinct network neighborhoods. Most important, we show that it is the integrity and the completeness of the expression of the disease module that determines disease manifestation in selected tissues. This approach allows us to construct a disease-tissue network that confirms known and predicts unexpected disease-tissue associations.


Total colorectal and terminal ileal duplication presenting as intussusception and intestinal obstruction.
Colonic intussusception and gastrointestinal duplication are diseases that arise in young children. The clinical presentation of adult cases of intussusception and enteric duplication is non-specific and thus poses a diagnostic challenge. A computed tomography (CT) scan is recommended in adult cases as the most sensitive diagnostic tool and the pathognomonic finding of outer intussuscepiens and central intussusceptum is diagnostic. A septum of a duplicated colon in a non-intussuscepted segment has been rarely reported in the literature. With advancements in radiological imaging technology and the increased availability of CT scanners, the capacity for a correct pre-operative diagnosis has been significantly enhanced. Our current case report illustrates the importance of considering an uncommon etiology for enteric intussusception and duplication as a differential diagnosis of acute abdomen in an adult patient. Our analyses of this patient also highlight the successful use of CT scanning to make this diagnosis.


Possible effects of global environmental changes on Antarctic benthos: a synthesis across five major taxa.
Because of the unique conditions that exist around the Antarctic continent, Southern Ocean (SO) ecosystems are very susceptible to the growing impact of global climate change and other anthropogenic influences. Consequently, there is an urgent need to understand how SO marine life will cope with expected future changes in the environment. Studies of Antarctic organisms have shown that individual species and higher taxa display different degrees of sensitivity to environmental shifts, making it difficult to predict overall community or ecosystem responses. This emphasizes the need for an improved understanding of the Antarctic benthic ecosystem response to global climate change using a multitaxon approach with consideration of different levels of biological organization. Here, we provide a synthesis of the ability of five important Antarctic benthic taxa (Foraminifera, Nematoda, Amphipoda, Isopoda, and Echinoidea) to cope with changes in the environment (temperature, pH, ice cover, ice scouring, food quantity, and quality) that are linked to climatic changes. Responses from individual to the taxon-specific community level to these drivers will vary with taxon but will include local species extinctions, invasions of warmer-water species, shifts in diversity, dominance, and trophic group composition, all with likely consequences for ecosystem functioning. Limitations in our current knowledge and understanding of climate change effects on the different levels are discussed.


Respiratory inflammation and infections in high-performance athletes.
Upper respiratory illness is the most common reason for non-injury-related presentation to a sports medicine clinic, accounting for 35-65% of illness presentations. Recurrent or persistent respiratory illness can have a negative impact on health and performance of athletes undertaking high levels of strenuous exercise. The cause of upper respiratory symptoms (URS) in athletes can be uncertain but the majority of cases are related to common respiratory viruses, viral reactivation, allergic responses to aeroallergens and exercise-related trauma to the integrity of respiratory epithelial membranes. Bacterial respiratory infections are uncommon in athletes. Undiagnosed or inappropriately treated asthma and/or allergy are common findings in clinical assessments of elite athletes experiencing recurrent URS. High-performance athletes with recurrent episodes of URS should undergo a thorough clinical assessment to exclude underlying treatable conditions of respiratory inflammation. Identifying athletes at risk of recurrent URS is important in order to prescribe preventative clinical, training and lifestyle strategies. Monitoring secretion rates and falling concentrations of salivary IgA can identify athletes at risk of URS. Therapeutic interventions are limited by the uncertainty of the underlying cause of inflammation. Topical anti-inflammatory sprays can be beneficial for some athletes. Dietary supplementation with bovine colostrum, probiotics and selected antioxidants can reduce the incidence or severity of URS in some athletes. Preliminary studies on athletes prone to URS indicate a genetic predisposition to a pro-inflammatory response and a dysregulated anti-inflammatory cytokine response to intense exercise as a possible mechanism of respiratory inflammation. This review focuses on respiratory infections and inflammation in elite/professional athletes.


The OH stretch vibration of liquid water reveals hydrogen-bond clusters.
Using molecular dynamics simulations, we investigate the fluctuations of the hydrogen-bond network in liquid water and its relation to vibrational spectroscopy. We show that the high-frequency shoulder, which is most evidently found in Raman spectra of the OH stretch vibration of isotope diluted water, is (at least to a certain extent) related to a three-fold hydrogen-bonded ring. This suggests that it is not always sufficient to classify individual water molecules when studying some aspects of hydrogen-bond dynamics, rather, one should consider the topology of the local structure around a given water molecule.


The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease.
Vascular endothelial growth factors (VEGFs) are a family of secreted polypeptides with a highly conserved receptor-binding cystine-knot structure similar to that of the platelet-derived growth factors. VEGF-A, the founding member of the family, is highly conserved between animals as evolutionarily distant as fish and mammals. In vertebrates, VEGFs act through a family of cognate receptor kinases in endothelial cells to stimulate blood-vessel formation. VEGF-A has important roles in mammalian vascular development and in diseases involving abnormal growth of blood vessels; other VEGFs are also involved in the development of lymphatic vessels and disease-related angiogenesis. Invertebrate homologs of VEGFs and VEGF receptors have been identified in fly, nematode and jellyfish, where they function in developmental cell migration and neurogenesis. The existence of VEGF-like molecules and their receptors in simple invertebrates without a vascular system indicates that this family of growth factors emerged at a very early stage in the evolution of multicellular organisms to mediate primordial developmental functions.


First Report of Meloidogyne marylandi Infecting Bermudagrass in Florida.
Root-knot nematodes (Meloidogyne spp.) are common parasites attacking turfgrasses in the United States, but the species of these nematodes is typically unresolved unless targeted surveys are performed (3). Using morphometric analysis and an RFLP method (3), an investigation of a golf course green in Florida with a history of infestation by root-knot nematodes was conducted to identify the species present. This 'Tifdwarf' bermudagrass (Cynodon dactylon × C. transvaalensis) putting green at the University of Florida Research Unit in Citra, FL, exhibited irregular patches of declining turf. Turf roots in these symptomatic areas had galled root tips with adhering egg masses, characteristic of infection from Meloidogyne spp. Mean populations of 5,149 ± 708 Meloidogyne second stage juveniles per 100 cm3 of soil were extracted from the rhizosphere of these symptomatic plants. Morphological measurements from 20 of these juveniles were slightly less than those published previously for M. marylandi, but were still distinct enough to discriminate them from M. graminis, which commonly infects bermudagrass in Florida (3). Body length averaged 396.1 ± 4.9 (376.7 to 420.0) μm with a mean width of 16.3 ± 0.5 (13.3 to 18.3) μm, stylet lengths were 11.2 ± 0.7 (6.7 to 12.3) μm, tail lengths averaged 54.7 ± 1.9 (47.5 to 65.0) μm with the hyaline region of the tails 9.9 ± 0.7 (8.3 to 14.2) μm. Mature females extracted from symptomatic root tissue lacked a posterior cone-like protuberance of the vulva typical of M. graminis. DNA was extracted from 15 single juveniles using a NaOH digestion method (2). The mitochondrial DNA region was amplified with PCR using the primers C2F3/1108 5'-GGTCAATGTTCAGAAATTTGTGG-3' and 5'-TACCTTTGACCAATCACGCT-3' (3). This resulted in a DNA fragment 520 bp in length, which upon digestion with SspI restriction enzyme produced four bands 148, 103, 91, and 67 bp in length, similar to what has been reported for M. marylandi (3). The PCR products were purified with a QIAquick PCR purification kit (QIAGEN, Valencia, CA) and sequenced at the University of Florida, Cancer Research and Genetics Institute. Sequences were compared with those in GenBank by means of BLAST search. The comparison showed a sequence similarity of 98% with M. marylandi (GenBank Accession No. JN241918.1). Although M. marylandi has been reported on bermudagrass in many areas of the United States and other places throughout the world (1,3,4), to our knowledge, this is the first detection of this nematode in Florida. Further studies will be conducted to determine the prevalence, incidence, severity of damage caused by M. marylandi, and determine a possible mode of dispersal on turfgrasses. References: (1) A. M. Golden. J. Nematol. 21:453, 1989. (2) J. Hübschen et al. Euro. J. Plant Pathol. 110:779, 2004. (3) M. A. McClure et al. Plant Dis. 96:635, 2012. (4) Y. Oka et al. Nematol. 5:727, 2003.


Bimolecular reactions of molecular dications: reactivity paradigms and bond-forming processes.
The bimolecular reactivity of molecular dications in the gas phase is reviewed from an experimental point of view. Recent research has demonstrated that in addition to the ubiquitous occurrence of electron transfer in the reactions of gaseous dications with neutral molecules, bond-forming reactions play a much larger role than anticipated before. Thus, quite a number of hydrogen-containing dications show proton transfer to neutral reagents as an abundant or even as the major pathway, and also the nature of the neutral reagent itself is decisive for the amount of proton transfer which takes place. Further, several hydrocarbon dications C(m)H(n)(2+) of medium size (m = 6-14, n = 6-10) undergo bond-forming reactions with unsaturated hydrocarbons such as acetylene or benzene, thereby offering new routes for the formation of larger aromatic compounds under extreme conditions such as interstellar environments. Likewise, recent results on the bimolecular reactivity of multiply charged metal ions have revealed the occurrence of a number of new bond-forming reactions which open promising prospects for further research.


Seeing the Finish Line? Retirement Perceptions and Wellbeing among Social Workers.
Planning for future health and social services (HSS) workforces must be informed by an understanding of how workers view their work within the context of their life and the challenges they will face across the course of life. There is a range of policies and provisions that states and organisations can adopt to create sustainable careers, support wellbeing at work, and extend working lives where appropriate, but the potential impact of these policies on the make-up of the workforce remains under investigation. This paper makes the case that service planners need to appreciate complex interplay between wellbeing and career decisions when planning the future workforce. It makes use of a recent survey of United Kingdom (UK) social workers (n = 1434) to illustrate this interplay in two ways. First, we present the analysis of how social workers' perception of retirement and extended working lives are associated with dimensions of Work-Related Quality of Life (WRQL). We find that social workers who agreed that a flexible working policy would encourage them to delay their retirement scored lower on the Home-Work Interface and Control at Work dimensions of WRQL, while social workers who indicated a perception that their employer would not wish them to work beyond a certain age had lower Job and Career Satisfaction scores. Second, we propose a new typology of retirement outlooks using latent class analysis of these attitudinal measures. An 8-class solution is proposed, and we demonstrate the predictive utility of this scheme. Results are discussed in terms of the challenges for ageing Western populations and the usefulness of analysis such as this in estimating the potential uptake and impact of age-friendly policies and provisions.


Evaluation of a water, sanitation, and hygiene education intervention on diarrhoea in northern Pakistan.
Inadequate water and sanitation services adversely affect the health and socioeconomic development of communities. The Water and Sanitation Extension Programme (WASEP) project, undertaken in selected villages in northern Pakistan between 1997 and 2001, was designed to deliver an integrated package of activities to improve potable water supply at village and household levels, sanitation facilities and their use, and awareness and practices about hygiene behaviour. A case-control study was conducted during July-September 2001 to evaluate whether, after selected confounders were controlled for, children aged <6 years with diarrhoea were more or less likely to reside in villages that participated in the project than in villages that did not participate. Descriptive and logistic regression analyses were performed. Children not living in WASEP villages had a 33% higher adjusted odds ratio for having diarrhoea than children living in WASEP villages (adjusted odds ratio, 1.331; P<0.049). Boys had 25% lower odds of having diarrhoea than girls (adjusted odds ratio, 0.748; P<0.049). A 2.6% decrease was found in the odds of diarrhoea for every yearly increase in the mother's age (adjusted odds ratio, 0.974; P<0.044) and a 1.4% decrease for every monthly increase in the child's age (adjusted odds ratio, 0.986; P<0.001). The findings in this study may help refine the approach to future water, sanitation, and hygiene initiatives in northern Pakistan. The integrated approach taken by WASEP, which incorporates engineering solutions with appropriate education to maximize facility usage and improve hygiene practices, is a useful example of how desired health benefits can be obtained from projects of this type.


Modelling metaldehyde in catchments: a River Thames case-study.
The application of metaldehyde to agricultural catchment areas to control slugs and snails has caused severe problems for drinking water supply in recent years. In the River Thames catchment, metaldehyde has been detected at levels well above the EU and UK drinking water standards of 0.1 μg l-1 at many sites across the catchment between 2008 and 2015. Metaldehyde is applied in autumn and winter, leading to its increased concentrations in surface waters. It is shown that a process-based hydro-biogeochemical transport model (INCA-contaminants) can be used to simulate metaldehyde transport in catchments from areas of application to the aquatic environment. Simulations indicate that high concentrations in the river system are a direct consequence of excessive application rates. A simple application control strategy for metaldehyde in the Thames catchment based on model results is presented.


Reproductive period and epigenetic modifications of the oxidative phosphorylation pathway in the human prefrontal cortex.
Human females have a unique duration of post-reproductive longevity, during which sex-specific mechanisms ma influence later-life mechanisms of neuronal resilience and vulnerability. The maintenance of energy metabolism, through the oxidative phosphorylation (OXPHOS) apparatus, is essential for brain health. Given the known association between reproductive period (years from menarche to menopause) and cognitive aging, we examined the hypothesis that cumulative estrogen exposure across the lifetime may be associated with differential methylation of genes in the OXPHOS pathway. Using DNA methylation patterns in the post-mortem dorsolateral prefrontal cortex (DLPFC) of 426 women prospectively followed until death in the Religious Orders Study and Rush Memory and Aging Project, we examined the relationship between reproductive period (subtracting age at menarche from age at menopause) and DNA methylation of a published set of autosomal OXPHOS genes previously implicated in stroke susceptibility. We then performed an unsupervised analysis of methylation levels across the Hallmark pathways from the Molecular Signatures Database. We observed a strong association between reproductive period and DNA methylation status across OXPHOS CpGs. We replicated this association between reproductive period and DNA methylation in a much larger set of OXPHOS genes in our unsupervised analysis. Here, reproductive period also showed associations with methylation in genes related to E2F, MYC and MTORC1 signaling, fatty acid metabolism and DNA repair. This study provides evidence from both a supervised and unsupervised analyses, that lifetime cumulative endogenous steroid exposures may play a role in maintenance of post-menopausal cellular balance, including in brain tissue.


Men's involvement in the South African family: engendering change in the AIDS era.
The literature on the South African family and its response to the HIV/AIDS epidemic is rife with accounts of men that reflect a deficit model of male involvement. Few acknowledge the historical, economic and social complexities of male involvement in family life. As the South African family undergoes demographic, social and economic transformation there is a need to describe the range of roles played by all household members, including men. This paper examines data collected over two and a half years from a small sample of households affected by HIV/AIDS in rural KwaZulu Natal, South Africa. Non-participant observations were made during outreach visits by research staff to twenty households caring for at least one adult with disease symptoms indicative of TB or AIDS. We find that men are positively involved with their families and households in a wide range of ways. They care for patients and children, financially support immediate and extended family members and are present at home, thereby enabling women to work or support other households. As the qualitative data demonstrate, however, such activities are often not acknowledged. The dominant perception of both female respondents and research assistants continues to be that men are not caring for their families because they are irresponsible and profligate. We consider reasons why this disjuncture exists and how more men might be encouraged to fulfil such roles and activities as their families and households suffer the social and economic impacts of HIV/AIDS.


Creating an occupational therapy Level II fieldwork experience in a county jail setting.
Although occupational therapy services have been rendered in prisons historically, only one occupational therapy program currently exists in a county jail: the Allegheny County Jail Project (ACJ Project). The offenders who populate county jails experience occupational deprivation. The participants of the ACJ Project have benefited from occupational therapy intervention that was initiated during incarceration and continued following their release from jail in order to help them resume productive life roles and to reduce the reoccurrence of engagement in criminal behaviors (recidivism rate). As of June 2003, the ACJ Project has successfully affected the lifestyle patterns of its participants and overall public safety by helping 63% of participants secure gainful employment and by helping 91.8% of participants maintain their freedom after prison. The purpose of this report is to describe the process and benefits of implementing fieldwork opportunities for Level II occupational therapy students in a best practice occupational therapy program in a nontraditional environment: a county jail.


Tooth Loss and Metabolic Syndrome in South Korea: The 2012 Korean National Health and Nutrition Examination Survey.
To evaluate the relationship between tooth loss and metabolic syndrome (MS) in South Korean adults. A total of 3589 adults (1511 men and 2078 women aged over 40 years) from the 2012 Korean National Health and Nutrition Examination Survey were included and divided into 3 groups according to the number of remaining teeth (0-19, 20-27, and 28). We recorded the number of remaining teeth and measured MS components such as waist circumference, systolic and diastolic blood pressure, fasting blood glucose, serum high-density lipoprotein-cholesterol, and triglyceride concentration. We also calculated the number of subjects who met the inclusion criteria of MS in each group. Multiple logistic regression analysis was performed to estimate the prevalence of MS components according to the number of remaining teeth after adjusting for covariates. Women without MS had significantly more teeth than those with MS (24.5 ± 0.2 vs 21.0 ± 0.3). In men, the prevalence of high blood pressure and high fasting blood glucose levels were significantly different among the 3 groups (P = 0.003 and P < 0.001, respectively); however, the prevalence of MS and all MS components were significantly different in women (P < 0.001 for all comparisons). Men with 0 to 19 remaining teeth were most likely to have high blood pressure and high fasting blood glucose, while women with 0 to 19 remaining teeth had the highest prevalence of MS and each MS component. Multiple logistic regression analysis revealed that women with fewer remaining teeth had a higher prevalence of MS and MS components after adjusting for covariates. Having only a few remaining teeth was associated with MS in women in South Korea.


B lymphocytes and B-cell activating factor promote collagen and profibrotic markers expression by dermal fibroblasts in systemic sclerosis.
B lymphocytes might play a pathogenic role in dermal fibrosis in systemic sclerosis (SSc). B-cell activating factor (BAFF), a key cytokine for B-cell activation, is increased in the serum and the skin of patients with SSc. However, the ability of B cells directly to stimulate dermal fibroblasts and the role of BAFF are not fully understood. We therefore investigated the involvement of B cells and BAFF in the expression of collagen and profibrotic markers by dermal fibroblasts. Cocultures of blood B cells from healthy blood donors and normal or SSc dermal fibroblasts stimulated with anti-IgM and BAFF were performed. Alpha-SMA, TIMP1, MMP9, COL1A1, COL1A2, and COL3A1 mRNA expression were determined by quantitative RT-PCR. Soluble collagen, BAFF, IL-6, IL-1β, TGF-β1, and CCL2 protein secretion were assessed. Coculture of blood B cells and dermal fibroblasts isolated from SSc patients induced IL-6, TGF-β1, CCL2, and collagen secretion, as well as Alpha-SMA, TIMP1, and MMP9 expression in dermal fibroblasts. Transwell assays demonstrated that this induction was dependent on cell-cell contact. Addition of anti-IgM and BAFF to the coculture increased IL-6, CCL2, TGF-β1, and collagen secretion. B cell- and BAFF-induced collagen secretion was highly reduced by anti-TGF-β1 antibodies. Our results showed for the first time a direct role of B cells on the production of collagen by dermal fibroblasts, which is further enhanced by BAFF. Thus, these results demonstrate a new pathogenic role of B cells and BAFF in fibrosis and systemic sclerosis.


A qualitative study on the term CAM: is there a need to reinvent the wheel?
As complementary and alternative medicine (CAM) has developed extensively, uncertainty about the appropriateness of the terms CAM and other CAM-related terms has grown both in the research and practice communities. Various terms and definitions have been proposed over the last three decades, highlighting how little agreement exits in the field. Contextual use of current terms and their respective definitions needs to be discussed and addressed. Relying upon the results of a large international Delphi survey on the adequacy of the term CAM, a focus group of 13 international experts in the field of CAM was held. A forum was also set up for 28 international experts to discuss and refine proposed definitions of both CAM and integrative healthcare (IHC) terms. Audio recordings of the meeting and forum discussion threads were analyzed using interpretive description. Multiple terms to describe the therapies, products, and disciplines often referred to as CAM, were considered. Even though participants generally agreed there is a lack of optimal definitions for popular CAM-related umbrella terms and that all terms that have so far been introduced are to some extent problematic, CAM and IHC remained the most popular and accepted terms by far. The names of the specific disciplines were also deemed adequate in certain contexts. Focus group participants clarified the context in which those three terms are appropriate. Existing and emergent definitions of both CAM and integrative healthcare terms were discussed. CAM and other related terms could be used more effectively, provided they are used in the proper context. It appears difficult for the time being to reach a consensus on the definition of the term CAM due to the uncertainty of the positioning of CAM in the contemporary healthcare systems. While umbrella terms such as CAM and IHC are useful in the context of research, policy making and education, relevant stakeholders should limit the use of those terms.


Bumble bee nest abundance, foraging distance, and host-plant reproduction: implications for management and conservation.
Recent reports of global declines in pollinator species imply an urgent need to assess the abundance of native pollinators and density-dependent benefits for linked plants. In this study, we investigated (1) pollinator nest distributions and estimated colony abundances, (2) the relationship between abundances of foraging workers and the number of nests they represent, (3) pollinator foraging ranges, and (4) the relationship between pollinator abundance and plant reproduction. We examined these questions in an alpine ecosystem in the Colorado Rocky Mountains, focusing on four alpine bumble bee species (Bombus balteatus, B. flavifrons, B. bifarius, and B. sylvicola), and two host plants that differ in their degrees of pollinator specialization (Trifolium dasyphyllum and T. parryi). Using microsatellites, we found that estimated colony abundances among Bombus species ranged from ~18 to 78 colonies/0.01 km2. The long-tongued species B. balteatus was most common, especially high above treeline, but the subalpine species B. bifarius was unexpectedly abundant for this elevation range. Nests detected among sampled foragers of each species were correlated with the number of foragers caught. Foraging ranges were smaller than expected for all Bombus species, ranging from 25 to 110 m. Fruit set for the specialized plant, Trifolium parryi, was positively related to the abundance of its Bombus pollinator. In contrast, fruit set for the generalized plant, T. dasyphyllum, was related to abundance of all Bombus species. Because forager abundance was related to nest abundance of each Bombus species and was an equally effective predictor of plant fecundity, forager inventories are probably suitable for assessing the health of outcrossing plant populations. However, nest abundance, rather than forager abundance, better reflects demographic and genetic health in populations of eusocial pollinators such as bumble bees. Development of models incorporating the parameters we have measured here (nest abundance, forager abundance, and foraging distance) could increase the usefulness of foraging worker inventories in nionitoring, managing, and conserving pollinator populations.


Value of systolic time intervals in assessing severity of congenital aortic stenosis in children.
Simultaneous recordings have been made of electrocardiogram, phonocardiogram, carotid pulse tracing, left ventricular pressure, and aortic pressure in 27 children with aortic valve stenosis and 3 children with membranous subaortic stenosis. Peak systolic pressure difference ranged from 10 to 110 mmHg (1.3 to 14.6 kPa). None of the patients had congestive heart failure and cardiac output was in the normal range in all. Total electromechanical systole, left ventricular ejection time, and pre-ejection time were corrected for heart rate, age, and sex. Mild stenosis (peak systolic pressure difference less than or equal to 50 mmHg (6.7 kPa)) was present in 18, severe stenosis (peak systolic pressure difference greater than 50 mmHg) in 12 patients. The externally measured pre-ejection time and ejection time proved to be nearly equal to the corresponding intervals measured internally; from these data it is concluded that pre-ejection time and ejection time in children with aortic stenosis can be measured reliably by non-invasive methods. Mean values for corrected total electromechanical systole and ejection time were prolonged, but the corrected pre-ejection time did not differ from the normal value. When corrected time intervals were plotted against severity of the aortic stenosis as expressed by the peak systolic pressure difference or the aortic valve orifice index, a wide scatter was found. It is concluded that a normal ejection time is strong evidence against a peak systolic pressure difference of more than 50 mmHg (6.7 kPa) or an aortic valve orifice index less than 0.70 cm2 per m2 BSA. A prolonged ejection time, however, may occur in mild as well as in severe stenosis. Total electromechanical systole and pre-ejection time have no value in predicting the severity of aortic stenosis in children.


Nurses' compliance with central line associated blood stream infection prevention guidelines.
To assess nurses' compliance with central line associated bloodstream infection (CLABSI) prevention guidelines related to maintenance of the central line and the predictors of compliance. Method: This was an observational study that used a descriptive cross-sectional design. A sample of 171 intensive care unit (ICU) nurses were observed and their compliance was recorded on a structured observational sheet. The study was conducted in the ICUs of 15 hospitals located in 5 cities in Jordan. Data were collected over a 5-month period from March to July 2017. Central lines were all inserted by physicians inside the ICUs. One hundred and twenty participants (70%) showed sufficient compliance. The mean compliance scores were 14.2±4.7 (min=8, max=20); however, the rate of CLABSI was variable across the participating ICUs. Logistic regression with 4 independent variables (years of experience, previous education with CLABSI, nurse-patient ratio and the ICU's bed capacity) was conducted to investigate predictors of sufficient compliance. The model was significant (χ2(4)=133.773, p=0.00). The nurse-patient ratio was the only significant predictor. Nurses with a 1:1 nurse:patient ratio demonstrated superior compliance over their counterparts with a 1:2 ratio. Further improvement in compliance and patients' outcomes could be achieved by lowering the nurse-patient ratio.


Public health research implementation and translation: evidence from practice-based research networks.
Research on how best to deliver efficacious public health strategies in heterogeneous community and organizational contexts remains limited. Such studies require the active engagement of public health practice settings in the design, implementation, and translation of research. Practice-based research networks (PBRNs) provide mechanisms for research engagement, but until now they have not been tested in public health settings. This study uses data from participants in 14 public health PBRNs and a national comparison group of public health agencies to study processes influencing the engagement of public health settings in research implementation and translation activities. A cross-sectional network analysis survey was fielded with participants in public health PBRNs approximately 1 year after network formation (n=357) and with a nationally representative comparison group of U.S. local health departments not participating in PBRNs (n=625). Hierarchic regression models were used to estimate how organizational attributes and PBRN network structures influence engagement in research implementation and translation activities. Data were collected in 2010-2012 and analyzed in 2012. Among PBRN participants, both researchers and practice agencies reported high levels of engagement in research activities. Local public health agencies participating in PBRNs were two to three times more likely than nonparticipating agencies to engage in research implementation and translation activities (p<0.05). Participants in less densely connected PBRN networks and in more peripheral locations within these networks reported higher levels of research engagement, greater perceived benefits from engagement, and greater likelihood of continued participation. PBRN networks can serve as effective mechanisms for facilitating research implementation and translation among public health practice settings.


Targeting hunter distribution based on host resource selection and kill sites to manage disease risk.
Endemic and emerging diseases are rarely uniform in their spatial distribution or prevalence among cohorts of wildlife. Spatial models that quantify risk-driven differences in resource selection and hunter mortality of animals at fine spatial scales can assist disease management by identifying high-risk areas and individuals. We used resource selection functions (RSFs) and selection ratios (SRs) to quantify sex- and age-specific resource selection patterns of collared (n = 67) and hunter-killed (n = 796) nonmigratory elk (Cervus canadensis manitobensis) during the hunting season between 2002 and 2012, in southwestern Manitoba, Canada. Distance to protected area was the most important covariate influencing resource selection and hunter-kill sites of elk (AICw = 1.00). Collared adult males (which are most likely to be infected with bovine tuberculosis (Mycobacterium bovis) and chronic wasting disease) rarely selected for sites outside of parks during the hunting season in contrast to adult females and juvenile males. The RSFs showed selection by adult females and juvenile males to be negatively associated with landscape-level forest cover, high road density, and water cover, whereas hunter-kill sites of these cohorts were positively associated with landscape-level forest cover and increasing distance to streams and negatively associated with high road density. Local-level forest was positively associated with collared animal locations and hunter-kill sites; however, selection was stronger for collared juvenile males and hunter-killed adult females. In instances where disease infects a metapopulation and eradication is infeasible, a principle goal of management is to limit the spread of disease among infected animals. We map high-risk areas that are regularly used by potentially infectious hosts but currently underrepresented in the distribution of kill sites. We present a novel application of widely available data to target hunter distribution based on host resource selection and kill sites as a promising tool for applying selective hunting to the management of transmissible diseases in a game species.


Routes of entry of Piscirickettsia salmonis in rainbow trout Oncorhynchus mykiss.
Since 1989, Piscirickettsia salmonis, the causal agent of piscirickettsiosis, has killed millions of farmed salmonids each year in southern Chile. The portal of entry for the pathogen was investigated by use of selected experimental infections in juvenile rainbow trout (12 g). The methods used were intraperitoneal injection, subcutaneous injection, patch contact on skin, patch contact on gills, intestinal intubation and gastric intubation. Cumulative mortalities at Day 33 post-inoculation were 98, 100, 52, 24, 24, and 2%, respectively. It was shown that intact skin and gills could be penetrated by P. salmonis. The high mortality obtained in subcutaneously injected fish indicated that skin injuries could facilitate the invasion of this pathogen. Results suggested that the main entry sites are through the skin and gills and that the oral route may not be the normal method by which P. salmonis initiates infection of salmonids.


Energy-efficient spatial-domain-based hybrid multidimensional coded-modulations enabling multi-Tb/s optical transport.
In addition to capacity, the future high-speed optical transport networks will also be constrained by energy consumption. In order to solve the capacity and energy constraints simultaneously, in this paper we propose the use of energy-efficient hybrid D-dimensional signaling (D>4) by employing all available degrees of freedom for conveyance of the information over a single carrier including amplitude, phase, polarization and orbital angular momentum (OAM). Given the fact that the OAM eigenstates, associated with the azimuthal phase dependence of the complex electric field, are orthogonal, they can be used as basis functions for multidimensional signaling. Since the information capacity is a linear function of number of dimensions, through D-dimensional signal constellations we can significantly improve the overall optical channel capacity. The energy-efficiency problem is solved, in this paper, by properly designing the D-dimensional signal constellation such that the mutual information is maximized, while taking the energy constraint into account. We demonstrate high-potential of proposed energy-efficient hybrid D-dimensional coded-modulation scheme by Monte Carlo simulations.


Causal models of leukaemia and lymphoma.
In this chapter, we apply the molecular epidemiological paradigm of biomarkers of exposure, early effect and susceptibility to causal models of leukaemia and lymphoma. The aim is to enhance the development of biomarkers for use in studying the causes of these haematopoeitic cancers in the general population. Two causal models of acute myeloid leukaemia are discussed in detail: chemotherapy-induced and benzene-induced acute myeloid leukaemia. Specific chromosomal changes found in acute myeloid leukaemia may serve as useful biomarkers of early effect in these models, and genetic variants in glutathione S-transferases, NQO1 and DNA-repair enzymes may serve as useful biomarkers of susceptibility. Several causal models of lymphoma exist in which biomarkers could be developed and validated. These include human immunodeficiency virus (HIV) immunosuppression, families with inherited disorders and workers exposed to petroleum products, pesticides or organochlorines. Biomarkers of early effect could include markers of DNA double-strand breaks and aberrant V(D)J recombination, and susceptibility may be related to polymorphisms in genes controlling DNA repair and immunological status. We predict that biomarkers of susceptibility will continue to be studied in the case-control format, perhaps in large pooled studies, but that for biomarkers of early effect, there will be a move away from the study of diseased populations to the study of individuals 'at risk' in the causal models described above.


A study on drug utilization and prescription habits of physicians in a government homeopathic hospital in West Bengal, India.
Improper prescribing habits and inappropriate drug use lead to serious health and economic consequences. This study was undertaken to evaluate drug utilization services and prescription patterns of homeopathic doctors in a government homeopathic teaching hospital in India. No standardized homeopathic drug use indicators are available. The researchers used indicators for health care setting (drug availability)-modified prescribing indicators and patient care indicators, based on World Health Organization's core drug use indicators. A cross-sectional, prospective, institutional, observational study of 2-month duration with record analysis was conducted on 600 patients visiting seven different outpatient departments (OPDs) for the first time at Mahesh Bhattacharyya Homeopathic Medical College and Hospital, Howrah, West Bengal, India, using the developed indicators. Overall availability of prescribed drugs was quite satisfactory (92.28%). Centesimal potencies accounted for the majority of prescriptions (74.76%). There was a poor record of diagnosis (39.17%) except in the OPDs of Gynecology and Obstetrics (68.48%, P < 0.01) and Dermatology (64.58%, P < 0.01). Records of investigational findings and ongoing therapies, if any, were also poor except OPDs of Gynecology and Obstetrics, and Pediatrics. Structure of prescriptions was maintained satisfactorily in all the OPDs. Though tendency of using 'individualized homeopathy' predominated, there also existed the use of 'polypharmacy'. Mean consultation time was 5.9 min. Labeling was extremely poor and is an area needing improvement. The prescriptions were highly legible. This was a preliminary study, conducted for the first time in homeopathy using newly developed indicators that yield meaningful results. Further studies are necessary in order to evaluate the different factors involved and to plan future interventions to improve the quality of care in healthcare settings.


Locus-specific mutation databases for neurodegenerative brain diseases.
The Alzheimer disease and frontotemporal dementia (AD&FTLD) and Parkinson disease (PD) Mutation Databases make available curated information of sequence variations in genes causing Mendelian forms of the most common neurodegenerative brain disease AD, frontotemporal lobar degeneration (FTLD), and PD. They are established resources for clinical geneticists, neurologists, and researchers in need of comprehensive, referenced genetic, epidemiologic, clinical, neuropathological, and/or cell biological information of specific gene mutations in these diseases. In addition, the aggregate analysis of all information available in the databases provides unique opportunities to extract mutation characteristics and genotype-phenotype correlations, which would be otherwise unnoticed and unexplored. Such analyses revealed that 61.4% of mutations are private to one single family, while only 5.7% of mutations occur in 10 or more families. The five mutations with most frequent independent observations occur in 21% of AD, 43% of FTLD, and 48% of PD families recorded in the Mutation Databases, respectively. Although these figures are inevitably biased by a publishing policy favoring novel mutations, they probably also reflect the occurrence of multiple rare and few relatively common mutations in the inherited forms of these diseases. Finally, with the exception of the PD genes PARK2 and PINK1, all other genes are associated with more than one clinical diagnosis or characteristics thereof.


Protein dynamics and mechanisms controlling the rotational behaviour of the bacterial flagellar motor.
The proteins that make up the bacterial flagellar rotary motor have recently been shown to be more dynamic than previously thought, with some key proteins exchanging with pools of proteins in the membrane/cytoplasm. It has also become clear that in addition to simply switching in response to chemosensory signals, the rotation of the bacterial flagellar motor can be slowed or stopped, using a clutch or a brake, by signals from metabolism and growth state.


Coherent electrical control of a single high-spin nucleus in silicon.
Nuclear spins are highly coherent quantum objects. In large ensembles, their control and detection via magnetic resonance is widely exploited, for example, in chemistry, medicine, materials science and mining. Nuclear spins also featured in early proposals for solid-state quantum computers1 and demonstrations of quantum search2 and factoring3 algorithms. Scaling up such concepts requires controlling individual nuclei, which can be detected when coupled to an electron4-6. However, the need to address the nuclei via oscillating magnetic fields complicates their integration in multi-spin nanoscale devices, because the field cannot be localized or screened. Control via electric fields would resolve this problem, but previous methods7-9 relied on transducing electric signals into magnetic fields via the electron-nuclear hyperfine interaction, which severely affects nuclear coherence. Here we demonstrate the coherent quantum control of a single 123Sb (spin-7/2) nucleus using localized electric fields produced within a silicon nanoelectronic device. The method exploits an idea proposed in 196110 but not previously realized experimentally with a single nucleus. Our results are quantitatively supported by a microscopic theoretical model that reveals how the purely electrical modulation of the nuclear electric quadrupole interaction results in coherent nuclear spin transitions that are uniquely addressable owing to lattice strain. The spin dephasing time, 0.1 seconds, is orders of magnitude longer than those obtained by methods that require a coupled electron spin to achieve electrical driving. These results show that high-spin quadrupolar nuclei could be deployed as chaotic models, strain sensors and hybrid spin-mechanical quantum systems using all-electrical controls. Integrating electrically controllable nuclei with quantum dots11,12 could pave the way to scalable, nuclear- and electron-spin-based quantum computers in silicon that operate without the need for oscillating magnetic fields.


Healthier fundraising in U. S. elementary schools: associations between policies at the state, district, and school levels.
We examined whether state laws and district policies pertaining to nutritional restrictions on school fundraisers were associated with school policies as reported by administrators in a nationally-representative sample of United States public elementary schools. We gathered data on school-level fundraising policies via a mail-back survey during the 2009-10 and 2010-11 school years. Surveys were received from 1,278 public elementary schools (response rate = 60.9%). Data were also gathered on corresponding school district policies and state laws. After removing cases with missing data, the sample size for analysis was 1,215 schools. After controlling for school characteristics, school policies were consistently associated with state laws and district policies, both those pertaining to fundraising generally, as well as specific restrictions on the sale of candy and soda in fundraisers (all Odds Ratios >2.0 and Ps<.05). However, even where district policies and state laws required fundraising restrictions, school policies were not uniformly present; school policies were also in place at only 55.8% of these schools, but were more common at schools in the West (77.1%) and at majority-Latino schools (71.4%), indicating uneven school-level implementation of district policy and state law. District policies and state laws were associated with a higher prevalence of elementary school-level fundraising policies, but many schools that were subject to district policies and state laws did not have school-level restrictions in place, suggesting the need for further attention to factors hindering policy implementation in schools.


50 Years of Cetacean Strandings Reveal a Concerning Rise in Chilean Patagonia.
Cetacean strandings (CS) have been reported in increasing numbers in coastal areas worldwide. Although the causes of these strandings are unknown, a number of anthropogenic and environmental factors have been suggested. This paper aims to characterize CS patterns and describe their fine-scale spatiotemporal dynamics. We analysed spatial and spatiotemporal CS patterns in Chile from January 1968 to January 2020. We identified a total of 389 CS events affecting eight cetacean families, 21 genera, and 35 species, which represent more than 85% of the reported species richness for the country. Most CS events (94.1%) were single (i.e., ≤two individuals). There were also 18 mass stranding (three to 24 individuals, 4.1%) and nine unusually large mass stranding events (>25 individuals, 2%). Purely spatial tests showed CS events appearing in random occurrence along the Chilean coast. Local tests for spatio-temporal clusters, however, identified a greater number of hotspots reported in the southernmost part of the country, namely, Chilean Patagonia. Specifically, significant spatio-temporal clusters were identified and defined as containing three or more individuals within a two-month period as a focal coastal event (<1 km radius). It is a cause of concern that CS events in Chile have been increasing consistently over the last decades, and although we were not able to identify their causes, we are able to highlight the importance of changes in climate conditions and of an increase in monitoring activities as primary drivers for such patterns, particularly important in Chilean Patagonia.


[Does abbreviation of preoperative fasting to two hours with carbohydrates increase the anesthetic risk?].
The objective of the present study was to evaluate the incidence of possible anesthetic complications related with the abbreviation of preoperative fasting to two hours with a solution of 12.5% dextrinomaltose within the ACERTO (from the Portuguese for Acceleration of Total Postoperative Recovery) project. All patients undergoing different types of digestive tract and abdominal wall surgeries within a new protocol of perioperative conducts, established by the ACERTO project, between August 2005 and December 2007 were evaluated. All patients received oral nutritional supplementation (12.5% dextrinomaltose) six and two hours before the procedure. Data were collected prospectively without the knowledge of the professionals in the department. The length of preoperative fasting and anesthetic complications related with the short fasting time (pulmonary aspiration) were recorded. Three hundred and seventy five patients, 174 male (46.4%) and 201 female (53.6%), ages 18 to 90 years, were evaluated. The mean preoperative fasting time was four hours, ranging from two to 20 hours. Pulmonary aspiration was not observed during the procedures. The length of fasting was longer (p < 0.01) when combined anesthesia (blockade + general) was used. Adopting the multidisciplinary preoperative measures of the ACERTO project was not associated with any preoperative fasting-associated complications. Dextrinomaltose is a useful and safe nutritional supplement for the patient.


GLI2-mediated melanoma invasion and metastasis.
The transforming growth factor-beta (TGF-beta) pathway, which has both tumor suppressor and pro-oncogenic activities, is often constitutively active in melanoma and is a marker of poor prognosis. Recently, we identified GLI2, a mediator of the hedgehog pathway, as a transcriptional target of TGF-beta signaling. We used real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blotting to determine GLI2 expression in human melanoma cell lines and subsequently classified them as GLI2high or as GLI2low according to their relative GLI2 mRNA and protein expression levels. GLI2 expression was reduced in a GLI2high cell line with lentiviral expression of short hairpin RNA targeting GLI2. We assessed the role of GLI2 in melanoma cell invasiveness in Matrigel assays. We measured secretion of matrix metalloproteinase (MMP)-2 and MMP-9 by gelatin zymography and expression of E-cadherin by western blotting and RT-PCR. The role of GLI2 in development of bone metastases was determined following intracardiac injection of melanoma cells in immunocompromised mice (n = 5-13). Human melanoma samples (n = 79) at various stages of disease progression were analyzed for GLI2 and E-cadherin expression by immunohistochemistry, in situ hybridization, or RT-PCR. All statistical tests were two-sided. Among melanoma cell lines, increased GLI2 expression was associated with loss of E-cadherin expression and with increased capacity to invade Matrigel and to form bone metastases in mice (mean osteolytic tumor area: GLI2high vs GLI2low, 2.81 vs 0.93 mm(2), difference = 1.88 mm(2), 95% confidence interval [CI] = 1.16 to 2.60, P < .001). Reduction of GLI2 expression in melanoma cells that had expressed high levels of GLI2 substantially inhibited both basal and TGF-beta-induced cell migration, invasion (mean number of Matrigel invading cells: shGLI2 vs shCtrl (control), 52.6 vs 100, difference = 47.4, 95% CI = 37.0 to 57.8, P = .024; for shGLI2 + TGF-beta vs shCtrl + TGF-beta, 31.0 vs 161.9, difference = -130.9, 95% CI = -96.2 to -165.5, P = .002), and MMP secretion in vitro and the development of experimental bone metastases in mice. Within human melanoma lesions, GLI2 expression was heterogeneous, associated with tumor regions in which E-cadherin was lost and increased in the most aggressive tumors. GLI2 was directly involved in driving melanoma invasion and metastasis in this preclinical study.


Visceral hyperalgesia and intestinal dysmotility in a mouse model of postinfective gut dysfunction.
We established the concept that transient enteric infection may lead to persistent gut dysfunction, evident in vitro, in nematode-infected mice. The present study determined whether gut dysfunction in this model involves motor and sensory changes reminiscent of changes found in patients with postinfective irritable bowel syndrome (PI-IBS) and investigated underlying mechanisms. Mice infected up to 70 days previously with Trichinella spiralis (Tsp) underwent videofluoroscopy with image analysis to assess upper gastrointestinal motility. Pseudoaffective responses to colorectal distention (CRD) were assessed using a barostat and validated by single fiber recordings from spinal nerves during CRD. Tissues were examined at different time points for histology, immunohistochemistry, and cytokine analysis. Some mice received dexamethasone intraperitoneally on days 23-25 PI or Tsp antigen orally on days 29, 43, and 57 PI. From day 28 PI, no discernible inflammation was present in the gut. Frequency and propagation velocity of intestinal contractions decreased, and retroperistalsis increased at days 28 to 42 PI. CRD induced an allodynic and hyperalgesic response in PI mice, which was accompanied by increased single unit discharge. Gavage of Tsp antigen induced T-cell responses and sustained gut dysfunction for 70 days PI. Administration of dexamethasone postinfection normalized dysmotility and visceral hyperalgesia. Long-lasting gut dysmotility and hyperalgesia develop in mice after transient intestinal inflammation. These changes are maintained by luminal exposure to antigen and reversed by corticosteroid treatment. The findings prompt consideration of this as a model of PI-IBS.


Plasticity in binding confers selectivity in ligand-induced protein degradation.
Heterobifunctional small-molecule degraders that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. However, we currently lack a detailed understanding of the molecular basis for target recruitment and selectivity, which is critically required to enable rational design of degraders. Here we utilize a comprehensive characterization of the ligand-dependent CRBN-BRD4 interaction to demonstrate that binding between proteins that have not evolved to interact is plastic. Multiple X-ray crystal structures show that plasticity results in several distinct low-energy binding conformations that are selectively bound by ligands. We demonstrate that computational protein-protein docking can reveal the underlying interprotein contacts and inform the design of a BRD4 selective degrader that can discriminate between highly homologous BET bromodomains. Our findings that plastic interprotein contacts confer selectivity for ligand-induced protein dimerization provide a conceptual framework for the development of heterobifunctional ligands.


Campylobacter, a zoonotic pathogen of global importance: Prevalence and risk factors in the fast-evolving chicken meat system of Nairobi, Kenya.
Campylobacteriosis is a leading foodborne zoonosis worldwide, and is frequently associated with handling and consumption of poultry meat. Various studies indicate that Campylobacter causes a substantial human disease burden in low to middle-income countries, but data regarding the organism's epidemiology in countries like Kenya are scarce. In sub-Saharan Africa, 3.8 million deaths of children under-5 years of age are reported annually. Of those, 25% are caused by diarrheal diseases, and Campylobacter is one of the most frequently isolated bacteria from diarrheic children. With the growth of urban conglomerates, such as Kenya's capital, Nairobi, changes in diets, food production systems, and retailing dynamics, it is likely that exposure and susceptibility to this pathogen will change. Therefore, the importance of Campylobacter disease burden in Kenya may increase further. The objectives of this study were: 1) to determine the prevalence of Campylobacter spp. in Nairobi's small-scale chicken farms and meat retailers, and 2) to identify potential risk factors associated with its presence in those sites. The prevalence data provides the first detailed baseline for this pathogen in the urban Kenyan context. The risk factors provide context-specific insights for disease managers. A cross-sectional study of broiler, indigenous chicken farms, and chicken meat retailers, was conducted in a peri-urban, low to middle-income area (Dagoretti), and a very-low income informal settlement (Kibera) of Nairobi. Chicken faeces were collected using one pair of boot socks per farm, and 3 raw chicken meat samples were purchased per retailer. Samples were cultured for viable Campylobacter spp. using mCCDA, followed by blood agar plates in aerobic/microaerobic conditions for prevalence calculations. A questionnaire-based survey on sanitary, sourcing and selling practices was conducted at each site for risk factor identification using logistic regression analyses. A total of 171 farm premises and 53 retailers were sampled and interviewed. The prevalence results for Campylobacter spp. were between 33 to 44% for broiler and indigenous chicken farms, 60% and 64% for retailers, in Dagoretti and Kibera, respectively. Univariable logistic regression showed an association between Campylobacter spp. presence and the easiness of cleaning the display material used by the retailer. Restricting access to the flock was also associated with the pathogen's presence. Multivariable logistic regression identified the selling of defrosted meat as a retailer risk factor (OR: 4.69; 95% CI: 1.31-19.97), calling for more investigation of the reported repetitive freezing-thawing processes and cold chain improvement options. At the farm-level, having a pen floor of material not easy to clean was found to increase the risk (OR: 2.31; 95%CI: 1.06-5.37). The relatively high prevalence of Campylobacter spp. across different areas and value chain nodes indicates a clear human exposure risk. The open nature of both small-scale broiler and indigenous chicken production practices with low biosecurity, hygiene and informal transactions, likely plays a role in this. While gradual improvement of farm biosecurity is recommended, risk factors identified suggest that consumer education and enforcement of basic food safety principles at the retailer end of the food continuum represent key targets for risk reduction in informal settings.


Phosphatase complex Pph3/Psy2 is involved in regulation of efficient non-homologous end-joining pathway in the yeast Saccharomyces cerevisiae.
One of the main mechanisms for double stranded DNA break (DSB) repair is through the non-homologous end-joining (NHEJ) pathway. Using plasmid and chromosomal repair assays, we showed that deletion mutant strains for interacting proteins Pph3p and Psy2p had reduced efficiencies in NHEJ. We further observed that this activity of Pph3p and Psy2p appeared linked to cell cycle Rad53p and Chk1p checkpoint proteins. Pph3/Psy2 is a phosphatase complex, which regulates recovery from the Rad53p DNA damage checkpoint. Overexpression of Chk1p checkpoint protein in a parallel pathway to Rad53p compensated for the deletion of PPH3 or PSY2 in a chromosomal repair assay. Double mutant strains Δpph3/Δchk1 and Δpsy2/Δchk1 showed additional reductions in the efficiency of plasmid repair, compared to both single deletions which is in agreement with the activity of Pph3p and Psy2p in a parallel pathway to Chk1p. Genetic interaction analyses also supported a role for Pph3p and Psy2p in DNA damage repair, the NHEJ pathway, as well as cell cycle progression. Collectively, we report that the activity of Pph3p and Psy2p further connects NHEJ repair to cell cycle progression.


Mechanisms underlying vascular effect of chronic resveratrol in streptozotocin-diabetic rats.
In this study, some underlying mechanisms responsible for the beneficial effect of chronic oral administration of resveratrol on aortic reactivity of streptozotocin (STZ)-diabetic rats were investigated. Male diabetic rats received resveratrol (10 mg/kg/day) for 8 weeks, 1 week after diabetes induction. Treatment of diabetic rats with resveratrol produced a hypoglycaemic effect and there were appropriate changes regarding serum lipids. Resveratrol also attenuated the increased malondialdehyde (MDA) content and reduced activity of superoxide dismutase (SOD) in liver and aortic tissues. Maximum contractile response of endothelium-intact aortic rings to KCl and phenylephrine (PE) was significantly lower in resveratrol-treated diabetic rats relative to untreated diabetics. Endothelium removal abolished the significant difference between resveratrol-treated and untreated diabetic groups regarding contractile response to KCl and PE. Meanwhile, endothelium-dependent relaxation to acetylcholine (ACh) was significantly higher in resveratrol-treated diabetic rats as compared to diabetic group and pretreatment with N(omega)-L-arginine methyl ester (L-NAME) and indomethacin (INDO) significantly attenuated these responses. Chronic treatment with resveratrol may prevent diabetes-related changes in vascular reactivity observed in diabetic rats directly and/or indirectly due to its hypoglycaemic and hypolipidaemic effects and attenuation of lipid peroxidation and through endothelial-derived factors.