Contemporary psychology and women: A gender analysis of the scientific production.
Despite important advances made in recent decades, women are still underrepresented in science (less than 30% of authorships). This study presents a bibliometric analysis of all the Psychology articles published in 2009 included in the Web of Science database (Thomson Reuters) in order to examine the contribution of women in contemporary Psychology, their pattern of research collaboration, the scientific content and the scientific impact from a gender perspective. From a total of 90,067 authorships, gender could be identified in 74,413 (82.6%) of them, being 40,782 (54.8%) male authorships and 33,631 (45.2%) female authorships. These data corresponded to 24,477 (49.9%) individual men and 24,553 (50.1%) women, respectively. Therefore, Psychology presents gender parity in the number of authors, and a gender asymmetry in the number of authorships that it is much lower than in science in general and other specific scientific fields. In relative terms, women tend to be concentrated in the first position of the authorship by-line and much less in the last (senior) position. This double pattern suggests that age probably plays a role in (partly) explaining the slight gender disparity of authorships.


12-year Temporal Trend in Referral Pattern and Test Results of Stress Echocardiography in a Tertiary Care Referral Center with Moderate Volume Activities and Cath-lab Facility.
Data on stress echocardiography (SE) time-related changes in referral patterns and diagnostic yield for detection of inducible ischemia could enhance Echo Lab quality benchmarks and performance measures. This study aims to evaluate temporal trends in SE test results among ambulatory patients with suspected or known coronary artery disease (CAD) in a tertiary care referral center with moderate (>100/year) volume SE activities and Cath-Lab facility. From January 2004 to December 2015, 1954 patients (mean age 62 ± 12 years, 42% women, 27% with known CAD) underwent SE (1673 exercise SE, 86%, 246 pharmacological SE, 12%, 35 pacing SE, 2%). Time was grouped into three 4 year periods, where clinical data and test results were evaluated. Our series comprised low-to-intermediate pretest probability of CAD throughout the observation period (overall pretest probability of CAD 19% ± 15%). A progressive decline over time in the rate of pharmacological SE instead of a dramatic increment of exercise SE (79%-96%, P < 0.0001) was noted. The use of beta-blockers increased (from 43% to 66%, P < 0.0001), while the use of nitrates decreased (from 11% to 4%, P < 0.0001) over time. We noted a very uncommon occurrence of abnormal test results with a further decrease in the last period (from 11% to 3%, P < 0.0001). We observed, over a 12-year period, a progressive decrease in the frequency of inducible myocardial ischemia among patients with known or suspected CADe referred to our Echo Lab for SE with Cath-Lab facility, and this trend was parallel to changes in SE referral practice. These findings are particularly relevant if we consider the practical implications on diagnostic SE accuracy and risk assessment.


Headache associated with sexual activity: prognosis and treatment options.
The aim of this study was to provide data on the prognosis and treatment options of headache associated with sexual activity (HSA). Sixty patients diagnosed with HSA between 1996 and 2004 were followed up between 2003 and 2006 at least 12 months after the first interview. The further course of the disease and their contentedness with therapy were requested. On average, the second interview was performed 35.9 months after the first examination. Of the 45 patients who had suffered from single attacks or bouts prior to baseline examination, 37 had no further attacks. Seven patients suffered from at least one further bout with an average duration of 2.1 months. One patient developed a chronic course of the disease after an episodic start. Of the 15 patients with chronic disease at the first examination, seven were in remission and five had ongoing attacks at follow-up. Ten patients received indomethacin for preemptive therapy, with good results in nine patients. Eighteen patients received beta-blockers for prophylaxis, with good results in 15 patients. Episodic HSA occurs in approximately three-quarters and chronic HSA in approximately one-quarter of patients. Even in chronic HAS, the prognosis is favourable, with remission rates of 69% during an observation period of 3 years. For patients with longer-lasting bouts or with chronic HSA, prophylactic treatment with beta-blockers or preemptive therapy with indomethacin are often successful.


Comprehensive Analysis of Aspergillus nidulans PKA Phosphorylome Identifies a Novel Mode of CreA Regulation.
In filamentous fungi, an important kinase responsible for adaptation to changes in available nutrients is cyclic AMP (cAMP)-dependent protein kinase (protein kinase A [PKA]). This kinase has been well characterized at a molecular level, but its systemic action and direct/indirect targets are generally not well understood in filamentous fungi. In this work, we used a pkaA deletion strain (ΔpkaA) to identify Aspergillus nidulans proteins for which phosphorylation is dependent (either directly or indirectly) on PKA. A combination of phosphoproteomic and transcriptomic analyses revealed both direct and indirect targets of PKA and provided a global perspective on its function. One of these targets was the transcription factor CreA, the main repressor responsible for carbon catabolite repression (CCR). In the ΔpkaA strain, we identified a previously unreported phosphosite in CreA, S319, which (based on motif analysis) appears to be a direct target of Stk22 kinase (AN5728). Upon replacement of CreA S319 with an alanine (i.e., phosphonull mutant), the dynamics of CreA import to the nucleus are affected. Collectively, this work provides a global overview of PKA function while also providing novel insight regarding significance of a specific PKA-mediated phosphorylation event.IMPORTANCE The cyclic AMP (cAMP)-dependent protein kinase A (PKA) signaling pathway is well conserved across eukaryotes, and previous work has shown that it plays an important role in regulating development, growth, and virulence in a number of fungi. PKA is activated in response to extracellular nutrients and acts to regulate metabolism and growth. While a number of components in the PKA pathway have been defined in filamentous fungi, current understanding does not provide a global perspective on PKA function. Thus, this work is significant in that it comprehensively identifies proteins and functional pathways regulated by PKA in a model filamentous fungus. This information enhances our understanding of PKA action and may provide information on how to manipulate it for specific purposes.


Chaotic Ising-like dynamics in traffic signals.
The green and red lights of a traffic signal can be viewed as the up and down states of an Ising spin. Moreover, traffic signals in a city interact with each other, if they are controlled in a decentralised way. In this paper, a simple model of such interacting signals on a finite-size two-dimensional lattice is shown to have Ising-like dynamics that undergoes a ferromagnetic phase transition. Probabilistic behaviour of the model is realised by chaotic billiard dynamics that arises from coupled non-chaotic elements. This purely deterministic model is expected to serve as a starting point for considering statistical mechanics of traffic signals.


Early identification of individuals with prostate cancer in negative biopsies.
The use of prostate specific antigen (PSA) to screen individuals for prostate cancer has changed the management of the disease, permitting early detection in men. Repeat biopsies for persistently increased PSA are not uncommon with prostate cancer never being detected in many of the men. The novel prostate cancer marker, EPCA, is expressed throughout the prostate of individuals with prostate cancer but not in those without the disease. The expression of ECPA was studied to identify those men with initially negative biopsies who were ultimately found to have prostate cancer. Negative biopsies, subsequent biopsies and prostatectomy specimens were evaluated by quantitative immunohistochemistry. The EPCA staining intensity in the samples analyzed from the patient cohort with prostate carcinoma were significantly different compared to controls (p <0.001) with almost no overlap in staining results. Sensitivity of the EPCA immunohistochemistry is 84% and specificity is 85%. An immunohistochemical test for EPCA could serve as an adjunct to the current diagnostic approach to a patient who undergoes prostate needle biopsy, and could identify individuals with prostate cancer as much as 5 or more years earlier than the current diagnostic approach and algorithms. In addition, this test might also help limit the numbers of biopsies performed as part of subsequent routine evaluation for increased PSA.


Use of secret simulated patient followed by workshop based education to assess and improve inhaler counseling in community pharmacy in Jordan.
To assess inhaler technique demonstration skills of community pharmacists located in Amman, Jordan via incorporating the trained secret simulated patient (SSP) approach. Secondly, to evaluate the effectiveness of a 2-hour educational workshop focused on SSP feedback. This cross-sectional study involved community pharmacies located in Amman, Jordan. Initially, a trained SSP was involved to enact baseline visits requesting advice on how to use Ventolin® (a pressurized metered-dose inhaler; pMDI) and Pulmicort® (a Turbohaler inhaler, TH). Immediately after each visit, the SSP completed an inhaler technique evaluation form with inhaler checklists based on previously published checklists (consisting of 9 and 10 items for pMDI and TH respectively). The SSP invited all participating pharmacists to a 2-hour workshop that included feedback on their demonstration skills, and the second evaluation of their inhaler technique. The workshop included a summary of the initial visits' results highlighting pharmacists' performance. Sixty pharmacies were visited and 120 inhaler assessments were completed. During baseline assessment, pharmacists scored an average of 4.5 out of 9 for pMDI and 4.9 out of 10 for TH. Only 11 pharmacists (18.3%) attended the workshop. During the workshop, inhaler technique demonstration skills significantly improved, as scores improved from 5.4 (SD 1.6) to 7.8 (SD 0.9) (p=0.008) and from 4.6 (SD 2.5) to 9.9 (SD 0.6) (p=0.003) for pMDI and TH respectively. The SSP approach revealed a lack of ability to demonstrate correct inhaler technique for pMDI and TH inhalers by community pharmacists in Amman, Jordan. A focused educational workshop based on SSP feedback improved inhaler technique significantly.


Neutrophil extracellular trap production contributes to pathogenesis in SIV-infected nonhuman primates.
Neutrophil extracellular traps (NETs) are involved in the pathogenesis of many infectious diseases, yet their dynamics and impact on HIV/SIV infection have not yet been assessed. We hypothesized that SIV infection and the related microbial translocation trigger NET activation and release (NETosis), and we investigated the interactions between NETs and immune cell populations and platelets. We compared and contrasted the levels of NETs between SIV-uninfected, SIV-infected, and SIV-infected antiretroviral-treated nonhuman primates. We also cocultured neutrophils from these animals with either peripheral blood mononuclear cells or platelets. Increased NET production was observed throughout SIV infection. In chronically infected animals, NETs were found in the gut, lung, and liver, and in the blood vessels of kidney and heart. Antiretroviral therapy (ART) decreased NETosis, albeit above preinfection levels. NETs captured CD4+ and CD8+ T cells, B cells, and monocytes, irrespective of their infection status, potentially contributing to the indiscriminate generalized immune cell loss characteristic to HIV/SIV infection, and limiting the CD4+ T cell recovery under ART. By capturing and facilitating aggregation of platelets, and through expression of increased tissue factor levels, NETs may also enhance HIV/SIV-related coagulopathy and promote cardiovascular comorbidities.


Chronic kidney disease and the outcomes of fibrinolysis for ST-segment elevation myocardial infarction: A real-world study.
In low-resource regions, fibrinolytic therapy is often the only option for ST-elevation myocardial infarction (STEMI) patients as primary percutaneous coronary intervention (PCI) is often not available and patients are hardly transferred to a medical center with PCI capacity within the first 120 minutes. Chronic kidney disease (CKD) is one of the most frequently encountered complications of STEMI. However, the evidence for the efficacy of fibrinolytic therapy in STEMI patients with CKD is still limited. The aim of this study is to test whether CKD modifies the association between fibrinolytic therapy and short-term major adverse cardiovascular events (MACEs) among patients with STEMI. This is a real-world study analyzing the data from 9508 STEMI patients (mean age: 64.0±12.4 years; male: 70.1%) in the third phase of Clinical Pathways in Acute Coronary Syndromes program (CPACS-3), which is a large study of the management of acute coronary syndromes (ACS) in 101 county hospitals without PCI capacity in China. CKD was defined as an estimated glomerular filtration rate of less than 60 mL/min per 1·73 m2 at the admission. The primary outcome is short-term MACEs, including all-cause death, recurrent myocardial infarction, or nonfatal stroke. Patients were recruited consecutively between October 2011 and November 2014. Out of them, 1282 patients (13.5%) were classified as having CKD. Compared with non-CKD patients, CKD patients were less likely to receive fibrinolytic therapy than non-CKD patients (26.4% vs. 38.9%, P<0.001), more likely to experience a failed fibrinolytic therapy (32.8% vs. 16.9%), and had a higher risk of short-term MACEs (19.7% vs. 5.6%). After full adjustment, use of fibrinolytic therapy was associated with a significantly lower risk of short-term MACEs in non-CKD patients (relative risk [RR] = 0.87, 95% confidence interval [CI]: 0.76-0.99), but not in CKD patients (P for interaction = 0.026). Further analysis stratified by the success of fibrinolysis showed that compared with patients who did not receive fibrinolytic therapy, patients with successful fibrinolysis had a lower risk of short-term MACEs that was similar between patients with (RR = 0.71, 95% CI: 0.55-0.82) and without CKD (RR = 0.67, 95% CI: 0.55-0.92), while patients with unsuccessful fibrinolysis had a similarly higher risk in CKD patients (RR = 1.25, 95% CI: 1.09-1.43) and non-CKD patients (RR = 1.30, 95% CI: 1.13-1.50). CKD reduced the likelihood of successful fibrinolysis and increased the risk of short-term MACEs in patients with STEMI. Attention should be paid to how to improve the success rate of fibrinolytic therapy for STEMI patients with CKD. The CPACS-3 study was registered on www.clinicaltrials.gov (NCT01398228).


Reconstructing disease outbreaks from genetic data: a graph approach.
Epidemiology and public health planning will increasingly rely on the analysis of genetic sequence data. In particular, genetic data coupled with dates and locations of sampled isolates can be used to reconstruct the spatiotemporal dynamics of pathogens during outbreaks. Thus far, phylogenetic methods have been used to tackle this issue. Although these approaches have proved useful for informing on the spread of pathogens, they do not aim at directly reconstructing the underlying transmission tree. Instead, phylogenetic models infer most recent common ancestors between pairs of isolates, which can be inadequate for densely sampled recent outbreaks, where the sample includes ancestral and descendent isolates. In this paper, we introduce a novel method based on a graph approach to reconstruct transmission trees directly from genetic data. Using simulated data, we show that our approach can efficiently reconstruct genealogies of isolates in situations where classical phylogenetic approaches fail to do so. We then illustrate our method by analyzing data from the early stages of the swine-origin A/H1N1 influenza pandemic. Using 433 isolates sequenced at both the hemagglutinin and neuraminidase genes, we reconstruct the likely history of the worldwide spread of this new influenza strain. The presented methodology opens new perspectives for the analysis of genetic data in the context of disease outbreaks.


Resistance Patterns of Typhoid Fever in Children: A Longitudinal Community-Based Study.
Salmonella typhi and S. paratyphi are important causes of bacteremia in children, especially those from the developing world. There is a lack of standardized treatment protocols for such patients in the literature, and there are also reports of therapeutic failure related to resistance to commonly used antibiotics. We analyzed the epidemiological, clinical, and antimicrobiological sensitivity patterns of disease in patients diagnosed with blood culture-positive typhoid fever over a 6-month period in a tertiary-care pediatric hospital in western India. Data were retrospectively analyzed for all patients with Salmonella isolates on blood culture between January 1 and June 30, 2011 at the Synergy Neonatal and Pediatric Hospital. Susceptibility of isolates to antimicrobials and minimum inhibitory concentrations were determined. Demographic data, symptoms and signs, basic laboratory results, treatment courses, and clinical outcomes were collected from clinical charts. All of the 61 isolates of S. typhi were sensitive to cefepime (fourth-generation cephalosporin), 96% to third-generation cephalosporins, and 95% to quinolones. There was intermediate sensitivity to ampicillin (92%) and chloramphenicol (80%). Notably, azithromycin resistance was observed in 63% of isolates. All patients ultimately made full recoveries. There is an urgent need for large scale, community-based clinical trials to evaluate the effectiveness of different antibiotics in enteric fever. Our antimicrobial susceptibility data suggest that quinolones and third-generation cephalosporins should be used as first-line antimicrobials in enteric fever. Although fourth-generation cephalosporins are useful, we feel their use should be restricted to complicated or resistant cases.


Obesity-related hormones and endometrial cancer among postmenopausal women: a nested case-control study within the B~FIT cohort.
Endometrial cancer risk is strongly influenced by obesity, but the mechanisms of action remain unclear. Leptin and adiponectin, secreted from adipose tissue, reportedly play a role in such carcinogenic processes as cell proliferation, angiogenesis, and insulin regulation. In this case-control study, nested within the Breast and Bone Follow-up of the Fracture Intervention Trial (n=15,595), we assessed pre-diagnostic serum leptin, total adiponectin, and high-molecular-weight (HMW) adiponectin in relation to endometrial cancer among postmenopausal women. During the 10-year follow-up, 62 incident endometrial cases were identified and matched to 124 controls on age, geographical site, time of fasting blood draw at baseline (1992-1993), and trial participation status. Adipokines and C-peptide were measured by ELISA. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated via conditional logistic regression, with exposures categorized in tertiles (T). Multivariable models considered C-peptide, BMI (kg/m(2)), and estradiol (E2) as potential confounders. Endometrial cancer risk was significantly associated with higher leptin levels, adjusted for E2 and C-peptide (OR(T3 vs T1)=2.96; 95% CI, 1.21-7.25; P trend <0.01). After further adjustment for BMI, the estimates were attenuated and the positive trend was no longer statistically significant (OR(T3 vs T1)=2.11; 95% CI, 0.69-6.44; P trend=0.18). No significant associations were observed with adiponectin or HMW adiponectin and endometrial cancer. Our findings with leptin suggest that the leptin-BMI axis might increase endometrial cancer risk through mechanisms other than estrogen-driven proliferation. Continued exploration of these pathways in larger prospective studies may help elucidate mechanisms underlying observed obesity-endometrial cancer associations.


Accounting for the Material Stock of Nations.
National material stock (MS) accounts have been a neglected field of analysis in industrial ecology, possibly because of the difficulty in establishing such accounts. In this research, we propose a novel method to model national MS based on historical material flow data. This enables us to avoid the laborious data work involved with bottom-up accounts for stocks and to arrive at plausible levels of stock accumulation for nations. We apply the method for the United States and Japan to establish a proof of concept for two very different cases of industrial development. Looking at a period of 75 years (1930-2005), we find that per capita MS has been much higher in the United States for the entire period, but that Japan has experienced much higher growth rates throughout, in line with Japan's late industrial development. By 2005, however, both Japan and the United States arrive at a very similar level of national MS of 310 to 375 tonnes per capita, respectively. This research provides new insight into the relationship between MS and flows in national economies and enables us to extend the debate about material efficiency from a narrow perspective of throughput to a broader perspective of stocks.


Severe functional limitation in patients with hypertrophic cardiomyopathy and only mild localized left ventricular hypertrophy.
Ten patients with nonobstructive hypertrophic cardiomyopathy and only mild localized left ventricular hypertrophy who had severe symptoms of cardiac failure are described. During a mean follow-up period of 7 years, 6 of these 10 patients showed a substantial increase in left ventricular internal dimension (6 to 15 mm, mean 10) as assessed with M-mode echocardiography, although absolute left ventricular cavity size remained within normal limits in 5 of the 6. Four patients demonstrated substantial septal thinning (5 to 14 mm, mean 8). Left ventricular diastolic function, assessed by radionuclide angiography in nine patients, was impaired in eight who showed decreased peak filling rate (less than 2.5 end-diastolic volumes/s) and prolonged time to peak rate of filling (greater than or equal to 180 ms). Furthermore, left ventricular systolic function, usually supernormal in patients with hypertrophic cardiomyopathy, was depressed (ejection fraction less than or equal to 45%) in six patients. Hence, a subset of patients was identified with nonobstructive hypertrophic cardiomyopathy and only mild localized left ventricular hypertrophy who experienced severe cardiac symptoms. The majority of these patients showed both systolic and diastolic left ventricular dysfunction in the presence of a progressive increase in left ventricular internal dimension (but without absolute left ventricular dilation) or ventricular septal thinning or both. Such patients may represent an important component of the natural history of hypertrophic cardiomyopathy which has not been previously fully appreciated.


Genome-wide linkage scan to identify loci associated with type 2 diabetes and blood lipid phenotypes in the Sikh Diabetes Study.
In this investigation, we have carried out an autosomal genome-wide linkage analysis to map genes associated with type 2 diabetes (T2D) and five quantitative traits of blood lipids including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, and triglycerides in a unique family-based cohort from the Sikh Diabetes Study (SDS). A total of 870 individuals (526 male/344 female) from 321 families were successfully genotyped using 398 polymorphic microsatellite markers with an average spacing of 9.26 cM on the autosomes. Results of non-parametric multipoint linkage analysis using S(all) statistics (implemented in Merlin) did not reveal any chromosomal region to be significantly associated with T2D in this Sikh cohort. However, linkage analysis for lipid traits using QTL-ALL analysis revealed promising linkage signals with p≤0.005 for total cholesterol, LDL cholesterol, and HDL cholesterol at chromosomes 5p15, 9q21, 10p11, 10q21, and 22q13. The most significant signal (p = 0.0011) occurred at 10q21.2 for HDL cholesterol. We also observed linkage signals for total cholesterol at 22q13.32 (p = 0.0016) and 5p15.33 (p = 0.0031) and for LDL cholesterol at 10p11.23 (p = 0.0045). Interestingly, some of linkage regions identified in this Sikh population coincide with plausible candidate genes reported in recent genome-wide association and meta-analysis studies for lipid traits. Our study provides the first evidence of linkage for loci associated with quantitative lipid traits at four chromosomal regions in this Asian Indian population from Punjab. More detailed examination of these regions with more informative genotyping, sequencing, and functional studies should lead to rapid detection of novel targets of therapeutic importance.


The first Oligocene sea turtle (Pan-Cheloniidae) record of South America.
The evolution and occurrence of fossil sea turtles at the Pacific margin of South America is poorly known and restricted to Neogene (Miocene/Pliocene) findings from the Pisco Formation, Peru. Here we report and describe the first record of Oligocene (late Oligocene, ∼24 Ma) Pan-Cheloniidae sea turtle remains of South America. The fossil material corresponds to a single, isolated and well-preserved costal bone found at the Montañita/Olón locality, Santa Elena Province, Ecuador. Comparisons with other Oligocene and extant representatives allow us to confirm that belongs to a sea turtle characterized by: lack of lateral ossification, allowing the dorsal exposure of the distal end of ribs; dorsal surface of bone sculptured, changing from dense vermiculation at the vertebral scute region to anastomosing pattern of grooves at the most lateral portion of the costal. This fossil finding shows the high potential that the Ecuadorian Oligocene outcrops have in order to explore the evolution and paleobiogeography distribution of sea turtles by the time that the Pacific and the Atlantic oceans were connected via the Panama basin.


Metabolomic profiles delineate mycolactone signature in Buruli ulcer disease.
Infection of human skin with Mycobacterium ulcerans, the causative agent of Buruli ulcer, is associated with the systemic diffusion of a bacterial macrolide named mycolactone. Patients with progressive disease show alterations in their serum proteome, likely reflecting the inhibition of secreted protein production by mycolactone at the cellular level. Here, we used semi-quantitative metabolomics to characterize metabolic perturbations in serum samples of infected individuals, and human cells exposed to mycolactone. Among the 430 metabolites profiled across 20 patients and 20 healthy endemic controls, there were significant differences in the serum levels of hexoses, steroid hormones, acylcarnitines, purine, heme, bile acids, riboflavin and lysolipids. In parallel, analysis of 292 metabolites in human T cells treated or not with mycolactone showed alterations in hexoses, lysolipids and purine catabolites. Together, these data demonstrate that M. ulcerans infection causes systemic perturbations in the serum metabolome that can be ascribed to mycolactone. Of particular importance to Buruli ulcer pathogenesis is that changes in blood sugar homeostasis in infected patients are mirrored by alterations in hexose metabolism in mycolactone-exposed cells.


Sentinel lymph node mapping using SPECT/CT and gamma probe in endometrial cancer: an analysis of parameters affecting detection rate.
SPECT/CT after pericervical injection of technetium-99 m-nanocolloid was shown to be suitable for sentinel lymph node (SLN) mapping in endometrial cancer (EC). The aim of this study was to analyze factors affecting successful SLN detection by means of SPECT/CT such as imaging findings, patient characteristics and tumor biology in a large cohort of patients. One hundred and forty-five consecutive patients suffering from EC who received pre-surgical SLN mapping at our institution between 2011 and 2016 were included in this analysis. SPECT/CT data of abdomen and pelvis (mean 4:20 ± 1:20 h p.i.) were acquired after pericervical injection of technetium-99 m-nanocolloid (mean 230 ± 45 MBq) in all patients. Surgical staging was performed on the day after. Acquisition parameters, patient characteristics, SPECT/CT findings as well as histopathological results were collected. A total of 282 SLNs were identified by means of SPECT/CT. Overall, preoperative and intraoperative SLN detection rates were 86%, 76% and 74% respectively. The most important factor associated with failure to detect SLNs was the presence of high bone marrow on SPECT/CT (p = 0.005). Peritoneal/abdominal radioactivity was also associated with missed SLN detection in SPECT/CT (p = 0.02). However, the presence of liver/spleen uptake on its own was not predictive for detection failure. Low numbers of detected SLNs in SPECT/CT were slightly related with older age and lower injected activity. No significant influence was found for the parameters of tumor histology and stage, lymph node involvement and the time gap between injection and imaging. Venous drainage as indicated by bone marrow uptake is the most important factor associated with scintigraphic SLN detection failure. Moreover, high peritoneal and abdominal activity was also associated with detection failure. Thus, meticulous application of the radiotracer is crucial in EC.


Drug-related problems identified in post-discharge medication reviews for patients taking warfarin.
To characterise the nature of the drug-related problems with warfarin therapy identified in pharmacist-conducted medication reviews during a collaborative post-discharge warfarin management service, with a focus on potentially serious drug interactions. Australian community pharmacy practice. Medication review reports submitted by pharmacists to patients' general practitioners as part of the service were reviewed and the type and clinical significance of the warfarin-associated drug-related problems, and the pharmacists' recommendations were classified. The prevalence of prescribing of 'potentially hazardous' warfarin drug interactions was investigated and compared with the frequency of documentation of these interactions in the medication review reports. The number and nature of warfarin-associated drug-related problems identified and the rate of documentation of 'potentially hazardous' warfarin drug interactions in the reports from pharmacist-conducted medication reviews. A total of 157 warfarin-associated drug-related problems were documented in 109 medication review reports (mean 1.4 per patient, 95% CI 1.3-1.6, range 0-5). Drug selection and Education or information were the most commonly identified warfarin-associated drug-related problems; most drug-related problems were of moderate clinical significance. Eight of 23 potentially serious warfarin drug interactions (34.8%) were identified in the medication review reports. Pharmacists addressing drug selection and warfarin education drug-related problems during medication reviews may have contributed to the positive outcomes of the post-discharge service. Warfarin drug interactions were frequently identified; however, well-recognised potentially hazardous interactions were under-reported. Improved communication along the continuum of care would permit improved targeting of drug-related problem reporting, especially in relation to preventable drug interactions.


Do topological models provide good information about electricity infrastructure vulnerability?
In order to identify the extent to which results from topological graph models are useful for modeling vulnerability in electricity infrastructure, we measure the susceptibility of power networks to random failures and directed attacks using three measures of vulnerability: characteristic path lengths, connectivity loss, and blackout sizes. The first two are purely topological metrics. The blackout size calculation results from a model of cascading failure in power networks. Testing the response of 40 areas within the Eastern U.S. power grid and a standard IEEE test case to a variety of attack/failure vectors indicates that directed attacks result in larger failures using all three vulnerability measures, but the attack-vectors that appear to cause the most damage depend on the measure chosen. While the topological metrics and the power grid model show some similar trends, the vulnerability metrics for individual simulations show only a mild correlation. We conclude that evaluating vulnerability in power networks using purely topological metrics can be misleading.


An Early Cretaceous pterosaur with an unusual mandibular crest from China and a potential novel feeding strategy.
The Aptian Jiufotang Formation of northeast China is a Konservat Lagerstätte particularly rich in pterosaurs, notably azhdarchoids. Here we describe a new genus and species of toothed pteranodontoid pterosaur, Ikrandraco avatar gen. et sp. nov., based on two laterally flattened specimens. Ikrandraco avatar is diagnosed by a suite of features, including a very low and elongate skull, strongly inclined quadrate, and a deep, blade-like bony mandibular crest with a hook-like process on its posterior edge, an unusual structure so far unique to this taxon. The particular skull shape hints at a distinct feeding habit for pterosaurs that potentially includes temporary skimming and an extensible skin acting as a throat pouch that was more developed than in any other pterosaur known so far. The presence of two other taxa of purported piscivorous pterosaurs in the Jiufotang Formation suggests distinct resource exploitation in this part of China during the Early Cretaceous.


Retinal oximetry images must be standardized: a methodological analysis.
Retinal vessel oximetry is a new technology and needs detailed methodological scrutiny. We determine (1) the repeatability of retinal vessel oxygen saturation measurements, (2) whether measured saturation is different between retinal quadrants, and (3) whether the angle of gaze changes measurements of the same vessels. Fundus oximetry images were obtained from 26 healthy individuals, 18 to 30 years old, using the Oxymap retinal oximeter. Oxygen saturation in the same vessel segments was compared between two similar images of each individual to determine repeatability. Vessel oxygen saturation was also compared between different quadrants of the retina in the same oximetry image. Finally, oxygen saturation measurements were made on the same vessel segments at different angles of gaze. Mean and standard deviation of saturation measurements was 93.1% ± 2.3% in arterioles and 64.9% ± 3.3% in venules. Standard deviation of repeated saturation measurements on the same vessel segment was 1.0% in arterioles and 1.4% in venules. Significant differences were seen between retinal quadrants. When angle of gaze was altered, measured saturation was lower in the same vessels when they were located in the inferior portion compared with other parts of the image (-1.3% ± 1.7%, P = 0.0004 in arterioles and -1.9 ± 2.4%, P = 0.0007 in venules). Retinal vessel oxygen saturation measurements are repeatable with a small standard deviation. When oximetry results are compared between time points or eyes, the imaging must be standardized and similar parts of the images analyzed.


Interactions of Water and Alkanes: Modifying Additive Force Fields to Account for Polarization Effects.
Atomistic biomolecular simulations predominantly utilize additive force fields (FF), where the electrostatic potential is modeled by fixed point charges. Among other consequences, the lack of polarizability in these models undermines the balance of hydrophilic/hydrophobic nonbonded interactions. Simulations of water/alkane systems using the TIP3P water model and CHARMM36 parameters reveal a 1 kcal/mol overestimate of the experimental transfer free energy of water to hexadecane; more recent optimized water models (SPC/E, TIP4P/2005, TIP4P-Ew, TIP3P-FB, TIP4P-FB, OPC, TIP4P-D) overestimate this transfer free energy by approximately 2 kcal/mol. In contrast, the polarizable SWM4-NDP and SWM6 water models reproduce experimental values to within statistical error. As an alternative to explicitly modeling polarizability, this paper develops an efficient automated workflow to optimize pair-specific Lennard-Jones parameters within an additive FF. Water/hexadecane is used as a prototype and the free energy of water transfer to hexadecane as a target. The optimized model yields quantitative agreement with the experimental transfer free energy and improves the water/hexadecane interfacial tension by 6%. Simulations of five different lipid bilayers show a strong increase of water permeabilities compared to the unmodified CHARMM36 lipid FF which consistently improves match with experiment: the order-of-magnitude underestimate for monounsaturated bilayers is rectified and the factor of 2.8-4 underestimate for saturated bilayers is turned into a factor of 1.5-3 overestimate. While agreement with experiment is decreased for the diffusion constant of water in hexadecane, alkane transfer free energies, and the bilayers' area per lipid, the method provides a permeant-specific route to achieve a wide range of heterogeneous observables via rapidly optimized pairwise parameters.


Blastocyst transfer in mice alters the placental transcriptome and growth.
Assisted reproduction technologies (ARTs) are becoming increasingly common. Therefore, how these procedures influence gene regulation and foeto-placental development are important to explore. Here, we assess the effects of blastocyst transfer on mouse placental growth and transcriptome. C57Bl/6 blastocysts were transferred into uteri of B6D2F1 pseudopregnant females and dissected at embryonic day 10.5 for analysis. Compared to non-transferred controls, placentas from transferred conceptuses weighed less even though the embryos were larger on average. This suggested a compensatory increase in placental efficiency. RNA sequencing of whole male placentas revealed 543 differentially expressed genes (DEGs) after blastocyst transfer: 188 and 355 genes were downregulated and upregulated, respectively. DEGs were independently validated in male and female placentas. Bioinformatic analyses revealed that DEGs represented expression in all major placental cell types and included genes that are critical for placenta development and/or function. Furthermore, the direction of transcriptional change in response to blastocyst transfer implied an adaptive response to improve placental function to maintain foetal growth. Our analysis revealed that CpG methylation at regulatory regions of two DEGs was unchanged in female transferred placentas and that DEGs had fewer gene-associated CpG islands (within ~20 kb region) compared to the larger genome. These data suggested that altered methylation at proximal promoter regions might not lead to transcriptional disruption in transferred placentas. Genomic clustering of some DEGs warrants further investigation of long-range, cis-acting epigenetic mechanisms including histone modifications together with DNA methylation. We conclude that embryo transfer, a protocol required for ART, significantly impacts the placental transcriptome and growth.


The continuous changes in the aetiology and epidemiology of invasive candidiasis: from familiar Candida albicans to multiresistant Candida auris.
Recent changes in the aetiology and epidemiology of invasive candidiasis have serious implications for current and future diagnosis, treatment and prognosis. The aim of the current review was to discuss the epidemiology of invasive candidiasis, the distribution of Candida species in different regions of the world, the medical concerns of the changing aetiology and the emergence of antifungal resistance. Overall burden of invasive candidiasis remains high, especially in vulnerable persons, such as the elderly, immunosuppressed or debilitated patients. Moreover, there is a progressive shift in the aetiology of invasive candidiasis from Candida albicans to other species of Candida, probably related to the increased use of azole drugs with a clear trend towards increased antifungal resistance. Finally, the emergence and rise of multiresistant species, such as Candida auris or Candida glabrata, is a major threat making necessary invasive candidiasis worldwide surveillances. These changes have serious implications for the diagnosis, treatment and prognosis of invasive candidiasis. Updated knowledge of the current local epidemiology of invasive candidiasis is critical for the clinical management.


A shot at AIDS.
In the almost 35 years since the discovery of HIV, there has been great progress in developing effective treatments. More recently, there have also been advances in developing novel prevention strategies. Yet a vaccine that could prevent HIV infection remains elusive. Most licensed vaccines provide protection by inducing antibodies. For HIV, vaccine-induced antibodies must be capable of protecting against the multiple variants of HIV in circulation around the globe, so-called broadly neutralizing antibodies. Recent progress in the identification and characterization of such antibodies, as well as advances in designing candidates that stimulate cellular immunity and results from recent clinical trials are fueling efforts to develop an HIV vaccine that could vanquish the virus once and for all.


DNA polymerase activity of hepatitis B virus particles: differential inhibition by L-enantiomers of nucleotide analogs.
DNA polymerase activity was assayed in hepatitis B virus (HBV) and core particles isolated from chronic producer lines. The particle-associated DNA polymerase activity, which was found to be limited to incorporation of only a few nucleotides, was inhibited by the 5'-triphosphates of nucleoside analogs. The 1-beta-L (1S,4R) and 1-beta-D (1R,4S) enantiomers of antiviral nucleoside analogs were compared for the ability to inhibit incorporation of natural nucleoside triphosphates into the viral DNA. Previously, both enantiomers of several analogs were found to be substrates for human immunodeficiency virus type 1 reverse transcriptase (HIV RT); the 1-beta-D enantiomers of some pairs were preferred as substrates. In contrast, the 1-beta-L enantiomers of all pairs tested were the more potent inhibitors of labeled substrate incorporation into hepatitis B virus DNA; the concentration required to inhibit the incorporation of the natural substrate by 50% was 6-fold to several hundred-fold lower than the concentration of the 1-beta-D enantiomer required for the same inhibitory effect. This preference for the 1-beta-L enantiomers was observed for both RNA-directed synthesis in core particles and DNA-directed synthesis in viral particles. The observed antiviral effect of the nucleoside analogs in cell culture seemed to be limited chiefly by their phosphorylation in cells.


Functional properties of rare missense variants of human CDH13 found in adult attention deficit/hyperactivity disorder (ADHD) patients.
The CDH13 gene codes for T-cadherin, a GPI-anchored protein with cell adhesion properties that is highly expressed in the brain and cardiovascular system. Previous studies have suggested that CDH13 may be a promising candidate gene for Attention Deficit/Hyperactivity Disorder (ADHD). The aims of this study were to identify, functionally characterize, and estimate the frequency of coding CDH13 variants in adult ADHD patients and controls. We performed sequencing of the CDH13 gene in 169 Norwegian adult ADHD patients and 63 controls and genotyping of the identified variants in 641 patients and 668 controls. Native and green fluorescent protein tagged wild type and variant CDH13 proteins were expressed and studied in CHO and HEK293 cells, respectively. Sequencing identified seven rare missense CDH13 variants, one of which was novel. By genotyping, we found a cumulative frequency of these rare variants of 2.9% in controls and 3.2% in ADHD patients, implying that much larger samples are needed to obtain adequate power to study the genetic association between ADHD and rare CDH13 variants. Protein expression and localization studies in CHO cells and HEK293 cells showed that the wild type and mutant proteins were processed according to the canonical processing of GPI-anchored proteins. Although some of the mutations were predicted to severely affect protein secondary structure and stability, no significant differences were observed between the expression levels and distribution of the wild type and mutant proteins in either HEK293 or CHO cells. This is the first study where the frequency of coding CDH13 variants in patients and controls is reported and also where the functional properties of these variants are examined. Further investigations are needed to conclude whether CDH13 is involved in the pathogenesis of ADHD or other conditions.


3-Iodothyronamine Induces Tail Vasodilation Through Central Action in Male Mice.
3-Iodothyronamine (3-T1AM) is an endogenous thyroid hormone (TH)-derived metabolite that induces severe hypothermia in mice after systemic administration; however, the underlying mechanisms have remained enigmatic. We show here that the rapid 3-T1AM-induced loss in body temperature is a consequence of peripheral vasodilation and subsequent heat loss (e.g., over the tail surface). The condition is subsequently intensified by hypomotility and a lack of brown adipose tissue activation. Although the possible 3-T1AM targets trace amine-associated receptor 1 or α2a-adrenergic receptor were detected in tail artery and aorta respectively, myograph studies did not show any direct effect of 3-T1AM on vasodilation, suggesting that its actions are likely indirect. Intracerebroventricular application of 3-T1AM, however, replicated the phenotype of tail vasodilation and body temperature decline and led to neuronal activation in the hypothalamus, suggesting that the metabolite causes tail vasodilation through a hypothalamic signaling pathway. Consequently, the 3-T1AM response constitutes anapyrexia rather than hypothermia and closely resembles the heat-stress response mediated by hypothalamic temperature-sensitive neurons. Our results thus underline the well-known role of the hypothalamus as the body's thermostat and suggest an additional molecular link between TH signaling and the central control of body temperature.


Crossing paths in Human Renal Cell Carcinoma (hRCC).
Historically, cell-signaling pathways have been studied as the compilation of isolated elements into a unique cascade that transmits extracellular stimuli to the tumor cell nucleus. Today, growing evidence supports the fact that intracellular drivers of tumor progression do not flow in a single linear pathway, but disseminate into multiple intracellular pathways. An improved understanding of the complexity of cancer depends on the elucidation of the underlying regulatory networks at the cellular and intercellular levels and in their temporal dimension. The high complexity of the intracellular cascades causes the complete inhibition of the growth of one tumor cell to be very unlikely, except in cases in which the so-called "oncogene addiction" is known to be a clear trigger for tumor catastrophe, such as in the case of gastrointestinal stromal tumors or chronic myeloid leukemia. In other words, the separation and isolation of the driver from the passengers is required to improve accuracy in cancer treatment. This review will summarize the signaling pathway crossroads that govern renal cell carcinoma proliferation and the emerging understanding of how these pathways facilitate tumor escape. We outline the available evidence supporting the putative links between different signaling pathways and how they may influence tumor proliferation, differentiation, apoptosis, angiogenesis, metabolism and invasiveness. The conclusion is that tumor cells may generate their own crossroads/crosstalk among signaling pathways, thereby reducing their dependence on stimulation of their physiologic pathways.


In vitro performance of different methods in detecting occlusal caries lesions.
Early caries detection is essential for the implementation of preventive, therapeutic and intervention strategies within general dental practice. The aim of this study was to compare the in vitro performance of the International Caries Detection and Assessment System (ICDAS), digital photographs scored with ICDAS (ICDAS photographs), fibre-optic transillumination (FOTI), optical coherence tomography (OCT), SoproLife(®) camera and two implementations of quantitative light-induced fluorescence a commercial (QLF-Inspektor Research systems) and a custom (QLF-Custom) system, to detect early and intermediate occlusal lesions. One hundred and twelve permanent extracted teeth were selected and assessed with each detection method. Histological validation was used as a gold standard. The detection methods were compared by means of sensitivity, specificity, areas under receiver operating characteristic (AUROC) curves for enamel and dentine levels and with the Spearman's rank correlation coefficient against histology. For any enamel or dentine caries detection, the AUROC curves ranged from 0.86 (OCT) to 0.98 (ICDAS and ICDAS photographs, SoproLife(®) camera) and at the dentine level from 0.83 (OCT) to 0.96 for FOTI. The correlations with histology ranged between 0.65 (OCT) and 0.88 (ICDAS and FOTI). Under in vitro conditions, the assessed detection methods showed excellent intra-examiner reproducibility. All the methods were strongly correlated with histology (p<0.01) except OCT which showed a moderate correlation (0.65). Even though all methods present similar performance in detecting occlusal caries lesions, visual inspection seems to be sufficient to be used in clinical practice for detection and assessment of lesion depth. Other methods may be useful in monitoring caries lesion behaviour.


Multiple photopigments from the Mexican blind cavefish, Astyanax fasciatus: a microspectrophotometric study.
The cave-dwelling (hypogean) form of the teleost Astyanax fasciatus is blind, having only subdermal eye rudiments, but nevertheless maintains intact opsin genes. Second generation offspring of a cross between these and the normally sighted surface (epigean) form inherit opsin genes from both ancestries. A study of the expressed hypogean opsins of the hybrids, in comparison to the epigean forms, was undertaken by microspectrophotometry. The hybrid population showed considerable variation in the visual pigments of double cones, with evidence for two groups of cells with lambda(max) intermediate to those of the epigean pigments. Possible explanations for these intermediate pigments are discussed, including the hypothesis that they may represent hybrid genes similar to the genes for anomalous cone pigments in humans. Evidence was also found for ultraviolet-sensitive single cones and for an additional MWS pigment.


Surgical experiences of functioning neuroendocrine neoplasm of the pancreas.
We present our surgical experiences with functioning neuroendocrine neoplasms of the pancreas to define its natural history, and to suggest its proper management. From June 1990 to June 2005, patients with diagnosis of functioning neuroendocrine (islet cell) neoplasms of the pancreas were retrospectively reviewed. Fourteen patients (5 men and 9 women) with a median age of 49 years (range, 12 - 68 years) were identified. Twelve patients (86%) had insulinoma, two (14%) had gastrinoma. One (7%) with pancreatic insulinoma was multiple endocrine neoplasia type 1. Intraoperative ultrasound scan (sensitivity, 83%) was the most powerful modality for tumor localization. Fifteen neoplasms with median tumor size 1 cm (range 0-3 cm) were resected. Four insulinomas (26.7%) were located in the head of the pancreas and 5 (36%), in the tail. Another 5 (36%) insulinomas and 1 (7%) gastrinoma were located around the neck area near the SMV or PV. Eleven patients (79%) underwent enucleation, and 2 patients (14%), distal pancreatectomy with splenectomy. 100% of patients with functioning neuroendocrine neoplasms of the pancreas have survived. The overall disease free 10-year survival was found to be about 81%. Exact localization of tumor by intraoperative ultrasound and surgical removal are promising for good prognosis.


A genome-wide association study on copy-number variation identifies a 11q11 loss as a candidate susceptibility variant for colorectal cancer.
Colorectal cancer (CRC) is a complex disease, and therefore its development is determined by the combination of both environmental factors and genetic variants. Although genome-wide association studies (GWAS) of SNP variation have conveniently identified 20 genetic variants so far, a significant proportion of the observed heritability is yet to be explained. Common copy-number variants (CNVs) are one of the most important genomic sources of variability, and hence a potential source to explain part of this missing genetic fraction. Therefore, we have performed a GWAS on CNVs to explore the relationship between common structural variation and CRC development. Phase 1 of the GWAS consisted of 881 cases and 667 controls from a Spanish cohort. Copy-number status was validated by quantitative PCR for each of those common CNVs potentially associated with CRC in phase I. Subsequently, SNPs were chosen as proxies for the validated CNVs for phase II replication (1,342 Spanish cases and 1,874 Spanish controls). Four common CNVs were found to be associated with CRC and were further replicated in Phase II. Finally, we found that SNP rs1944682, tagging a 11q11 CNV, was nominally associated with CRC susceptibility (p value = 0.039; OR = 1.122). This locus has been previously related to extreme obesity phenotypes, which could suggest a relationship between body weight and CRC susceptibility.


High Prevalence of Low Bone Mineral Density and Substantial Bone Loss over 4 Years Among HIV-Infected Persons in the Era of Modern Antiretroviral Therapy.
HIV-infected persons are living longer on combination antiretroviral therapy (cART) but experiencing more comorbidities including low bone mineral density (BMD). Using data from the Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN Study), we determined the prevalence of low BMD (T-score below one standard deviation of the reference mean) and compared it with matched controls from the National Health and Nutrition Examination Survey (NHANES). We also assessed 4-year longitudinal BMD changes among participants virologically suppressed on cART. Of 653 participants included in this analysis (77% male, 29% black, median age 41 years, median CD4(+) cell count 464 cells/mm(3), 89% with HIV RNA <400 copies/ml), 51% and 10% had baseline osteopenia and osteoporosis, respectively. Low BMD at the femoral neck was significantly more prevalent than for the NHANES controls (47% versus 29%, p<0.001). Lower body mass index, nonwhite race, longer tenofovir exposure, older age, being unemployed or retired, and lower apolipoprotein E were independently associated with baseline osteoporosis. Among 170 participants virologically suppressed on cART and with longitudinal BMD data, 31% experienced substantial bone loss (≥5% BMD decline from baseline) over 4 years. Female sex, current smoking, and longer stavudine use were more common among participants who had substantial bone loss, although these variables failed to reach statistical significance. Low BMD was highly prevalent among HIV-infected persons. One-third of participants experienced substantial bone loss despite cART, suggesting the need for monitoring and potential clinical interventions.


On the effectiveness of compact biomedical transformers.
Language models pre-trained on biomedical corpora, such as BioBERT, have recently shown promising results on downstream biomedical tasks. Many existing pre-trained models, on the other hand, are resource-intensive and computationally heavy owing to factors such as embedding size, hidden dimension and number of layers. The natural language processing community has developed numerous strategies to compress these models utilizing techniques such as pruning, quantization and knowledge distillation, resulting in models that are considerably faster, smaller and subsequently easier to use in practice. By the same token, in this article, we introduce six lightweight models, namely, BioDistilBERT, BioTinyBERT, BioMobileBERT, DistilBioBERT, TinyBioBERT and CompactBioBERT which are obtained either by knowledge distillation from a biomedical teacher or continual learning on the Pubmed dataset. We evaluate all of our models on three biomedical tasks and compare them with BioBERT-v1.1 to create the best efficient lightweight models that perform on par with their larger counterparts. We trained six different models in total, with the largest model having 65 million in parameters and the smallest having 15 million; a far lower range of parameters compared with BioBERT's 110M. Based on our experiments on three different biomedical tasks, we found that models distilled from a biomedical teacher and models that have been additionally pre-trained on the PubMed dataset can retain up to 98.8% and 98.6% of the performance of the BioBERT-v1.1, respectively. Overall, our best model below 30 M parameters is BioMobileBERT, while our best models over 30 M parameters are DistilBioBERT and CompactBioBERT, which can keep up to 98.2% and 98.8% of the performance of the BioBERT-v1.1, respectively. Codes are available at: https://github.com/nlpie-research/Compact-Biomedical-Transformers. Trained models can be accessed at: https://huggingface.co/nlpie.


MRM-DIFF: data processing strategy for differential analysis in large scale MRM-based lipidomics studies.
Based on theoretically calculated comprehensive lipid libraries, in lipidomics as many as 1000 multiple reaction monitoring (MRM) transitions can be monitored for each single run. On the other hand, lipid analysis from each MRM chromatogram requires tremendous manual efforts to identify and quantify lipid species. Isotopic peaks differing by up to a few atomic masses further complicate analysis. To accelerate the identification and quantification process we developed novel software, MRM-DIFF, for the differential analysis of large-scale MRM assays. It supports a correlation optimized warping (COW) algorithm to align MRM chromatograms and utilizes quality control (QC) sample datasets to automatically adjust the alignment parameters. Moreover, user-defined reference libraries that include the molecular formula, retention time, and MRM transition can be used to identify target lipids and to correct peak abundances by considering isotopic peaks. Here, we demonstrate the software pipeline and introduce key points for MRM-based lipidomics research to reduce the mis-identification and overestimation of lipid profiles. The MRM-DIFF program, example data set and the tutorials are downloadable at the "Standalone software" section of the PRIMe (Platform for RIKEN Metabolomics, http://prime.psc.riken.jp/) database website.


Comparative FAIRE-seq analysis reveals distinguishing features of the chromatin structure of ground state- and primed-pluripotent cells.
Both pluripotent embryonic stem cells (ESCs), established from preimplantation murine blastocysts, and epiblast stem cells (EpiSCs), established from postimplantation embryos, can self-renew in culture or differentiate into each of the primary germ layers. While the core transcription factors (TFs) OCT4, SOX2, and NANOG are expressed in both cell types, the gene expression profiles and other features suggest that ESCs and EpiSCs reflect distinct developmental maturation stages of the epiblast in vivo. Accordingly, "naïve" or "ground state" ESCs resemble cells of the inner cell mass, whereas "primed" EpiSCs resemble cells of the postimplantation egg cylinder. To gain insight into the relationship between naïve and primed pluripotent cells, and of each of these pluripotent states to that of nonpluripotent cells, we have used FAIRE-seq to generate a comparative atlas of the accessible chromatin regions within ESCs, EpiSCs, multipotent neural stem cells, and mouse embryonic fibroblasts. We find a distinction between the accessible chromatin patterns of pluripotent and somatic cells that is consistent with the highly related phenotype of ESCs and EpiSCs. However, by defining cell-specific and shared regions of open chromatin, and integrating these data with published gene expression and ChIP analyses, we also illustrate unique features of the chromatin of naïve and primed cells. Functional studies suggest that multiple stage-specific enhancers regulate ESC- or EpiSC-specific gene expression, and implicate auxiliary TFs as important modulators for stage-specific activation by the core TFs. Together these observations provide insights into the chromatin structure dynamics accompanying transitions between these pluripotent states.


A monoclonal antibody discriminating between subsets of T and B cells.
A description is given of a rat anti-mouse hybridoma antibody, JIId, which reacts with erythrocytes, neutrophils, greater than 90% of thymus cells, and most B cells. JIId does not have detectable activity for mature T cells, pluripotential stem cells, platelets, or cells of the monocyte-macrophage lineage. Although the JIId antigen is present on 90 to 95% of typical small B lymphocytes, pretreatment of spleen cells with JIId plus complement has no effect on secondary IgG antibody responses; by contrast, primary IgM responses and proliferative responses to lipopolysaccharide are substantially reduced. Unlike the precursors of IgG antibody-producing cells (AFC), IgG AFC per se are strongly JIId-positive. Rapid acquisition of the JIId antigen also applied to the early progeny of pluripotential stem cells.


Computational identification of tissue-specific alternative splicing elements in mouse genes from RNA-Seq.
Tissue-specific alternative splicing is a key mechanism for generating tissue-specific proteomic diversity in eukaryotes. Splicing regulatory elements (SREs) in pre-mature messenger RNA play a very important role in regulating alternative splicing. In this article, we use mouse RNA-Seq data to determine a positive data set where SREs are over-represented and a reliable negative data set where the same SREs are most likely under-represented for a specific tissue and then employ a powerful discriminative approach to identify SREs. We identified 456 putative splicing enhancers or silencers, of which 221 were predicted to be tissue-specific. Most of our tissue-specific SREs are likely different from constitutive SREs, since only 18% of our exonic splicing enhancers (ESEs) are contained in constitutive RESCUE-ESEs. A relatively small portion (20%) of our SREs is included in tissue-specific SREs in human identified in two recent studies. In the analysis of position distribution of SREs, we found that a dozen of SREs were biased to a specific region. We also identified two very interesting SREs that can function as an enhancer in one tissue but a silencer in another tissue from the same intronic region. These findings provide insight into the mechanism of tissue-specific alternative splicing and give a set of valuable putative SREs for further experimental investigations.


Spatial farming systems diversity and micronutrient intakes of rural children in Ethiopia.
Own production contributes much of the food supply in smallholder production systems in low- and middle-income countries like Ethiopia. Understanding the potential as well as constraints of these production systems in terms of nutrient supplies is thus a critical step to design interventions to improve nutrient intakes. The objectives of this study were (1) to assess the usual total intakes of vitamin A, iron and zinc among rural children and (2) to investigate whether the intakes these nutrients are associated with differences in the dominant farming systems between spatial clusters. Using nationally representative intake data of 4,902 children 6-35 months of age, usual intake and the proportion of inadequate intakes of vitamin A, iron and zinc were calculated. A multi-level model was used to examine the association between individual-level and cluster-level variables with the usual total dietary intakes of these nutrients. The diet was dominated by starchy foods. Consumption of animal source foods, vitamin A-rich fruits and vegetables was low. We found a high prevalence of inadequate intake of vitamin A and zinc (85.4% and 49.5%, respectively). Relatively, low prevalence of inadequate intake of iron (8.4%) was reported. The spatial farming systems diversity across the rural clusters explained 48.2%, 57.2% and 26.7% of the observed variation in the usual total dietary intakes of vitamin A, iron and zinc, respectively. Our findings indicated the importance of farming system diversity at the landscape level as one of the determinant factors for individual usual total dietary intakes of vitamin A, iron and zinc.


Neurotoxic alkaloids: saxitoxin and its analogs.
Saxitoxin (STX) and its 57 analogs are a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). PSTs are the causative agents of paralytic shellfish poisoning (PSP) and are mostly associated with marine dinoflagellates (eukaryotes) and freshwater cyanobacteria (prokaryotes), which form extensive blooms around the world. PST producing dinoflagellates belong to the genera Alexandrium, Gymnodinium and Pyrodinium whilst production has been identified in several cyanobacterial genera including Anabaena, Cylindrospermopsis, Aphanizomenon Planktothrix and Lyngbya. STX and its analogs can be structurally classified into several classes such as non-sulfated, mono-sulfated, di-sulfated, decarbamoylated and the recently discovered hydrophobic analogs--each with varying levels of toxicity. Biotransformation of the PSTs into other PST analogs has been identified within marine invertebrates, humans and bacteria. An improved understanding of PST transformation into less toxic analogs and degradation, both chemically or enzymatically, will be important for the development of methods for the detoxification of contaminated water supplies and of shellfish destined for consumption. Some PSTs also have demonstrated pharmaceutical potential as a long-term anesthetic in the treatment of anal fissures and for chronic tension-type headache. The recent elucidation of the saxitoxin biosynthetic gene cluster in cyanobacteria and the identification of new PST analogs will present opportunities to further explore the pharmaceutical potential of these intriguing alkaloids.


The Dynamic Epigenetic Landscape of the Retina During Development, Reprogramming, and Tumorigenesis.
In the developing retina, multipotent neural progenitors undergo unidirectional differentiation in a precise spatiotemporal order. Here we profile the epigenetic and transcriptional changes that occur during retinogenesis in mice and humans. Although some progenitor genes and cell cycle genes were epigenetically silenced during retinogenesis, the most dramatic change was derepression of cell-type-specific differentiation programs. We identified developmental-stage-specific super-enhancers and showed that most epigenetic changes are conserved in humans and mice. To determine how the epigenome changes during tumorigenesis and reprogramming, we performed integrated epigenetic analysis of murine and human retinoblastomas and induced pluripotent stem cells (iPSCs) derived from murine rod photoreceptors. The retinoblastoma epigenome mapped to the developmental stage when retinal progenitors switch from neurogenic to terminal patterns of cell division. The epigenome of retinoblastomas was more similar to that of the normal retina than that of retina-derived iPSCs, and we identified retina-specific epigenetic memory.


First Confirmed Report of Powdery Scab Caused by Spongospora subterranea f. sp. subterranea on Potato in Sri Lanka.
White, wart-like outgrowths on roots and stolons - root galls - and blisters and pustules on tubers (lesions) are characteristic symptoms of the potato powdery scab disease caused by Spongospora subterranea (Wallr.) f. sp. subterranea. In Sri Lanka, potato is a major cash crop primarily in two agroecological zones of higher altitude, Nuwara Eliya and Badulla. Approximately 50% of the seed is produced nationally and the other half is imported from the Netherlands, France, Germany, and recently the United States (mainly high quality seed). During the 2002-2003 cultivation season, galls and lesions were observed on certified seed lots of potato cvs. Dura, Desiree, Roko, Cykoda, and Delawae imported from the Netherlands and planted in fields at the Seed Certification Service, Site Eliya near Nuwara Eliya, SriLanka after first inspection. Since then, similar symptoms were also observed on tubers and roots of cv. Granola at seed potato production sites in 2006 at Diagama, in 2007 at Bopathalawa, and in 2007 through 2010 at Pedru. In 2009 and 2010, blister-like lesions on tubers and root galls were again observed on seed of cvs. Calwhite, Keuka Gold, Red la Soda, and Chieftain imported from the United States and planted at the Agricultural Research Station, Site Eliya. In February 2004, a bioassay was carried out using healthy tubers of cvs. Roko, Cykoda, Delawae, and Isna to evaluate the potential contamination of field soils. Clay pots filled with soil samples collected from the suspected contaminated fields were planted with seed of the above cultivars. The pots were arranged in a complete random design with three replicates per cultivar in a place isolated from any potato-production location. Seventy-five days after planting, all varieties were recorded with white root galls but no lesions on the tubers. With light microscopy, suspected root and tuber tissue was examined to confirm the presence of the characteristic sporosori of the soilborne pathogen S. subterranea (Wallr.) f. sp. subterranea with their unique sponge-like structure (1). Additionally, two root galls and three tuber lesions were prepared for diagnostics by ELISA using antiserum produced against S. subterranea (Wallr.) f. sp. subterranea (3) and reactions were positive. Furthermore, in a lab-based bioassay (2), sporosori obtained from a single root gall and a single tuber lesion were used to inoculate tomato bait plants, cv. Marmande. Eight days postinoculation, zoosporangia were observed microscopically in roots at frequencies of 10 of 12 and 11 of 12 plants for the root gall and the tuber lesion, respectively. To our knowledge, the results presented here are the first confirmed report of the presence of S. subterranea (Wallr.) f. sp. subterranea, the causal agent of potato powdery scab in Sri Lanka. Powdery scab currently occurs at several places in Sri Lanka. Therefore, more attention should be paid to this disease in the seed certification process and seed import regulations concerning powdery scab should be strictly enforced. References: (1) C. H. Lawrence and A. R. McKenzie. Powdery scab. Page 35 in: Compendium of Potato Diseases. The American Phytopathological Society, St, Paul, MN, 1981. (2) U. Merz et al. Eur. J. Plant Pathol. 110:71, 2004. (3) U. Merz et al. Eur. J. Plant Pathol. 111:171, 2005.


Blunt popliteal artery trauma: a challenging injury.
Blunt popliteal artery trauma is a challenging injury, particularly when associated with major soft tissue damage. We reviewed our experience with this injury to determine 1) the incidence of vascular injury associated with fractures and/or dislocations about the knee, 2) the incidence of limb loss, and 3) factors associated with amputation. We treated 37 patients with 38 blunt popliteal artery injuries and either fractures about the knee or posterior knee dislocations. Patients who underwent primary amputations were excluded. The incidence of popliteal artery injuries with fractures about the knee was 3 per cent, whereas 16 per cent of patients with posterior knee dislocations had vascular injuries (P < 0.05). Amputations were required in 14 of the 38 injured limbs (36%). None of these patients had a pulse or Doppler signal on admission, and 13 had major soft tissue injury. No patient with a pulse or Doppler signal lost a limb (P < 0.05). Limb loss was primarily related to limited venous outflow and/or severe infection in damaged tissue. Failure of the arterial repair rarely led to amputation, particularly in recent years. Two patients with angiographically proven arterial injuries were treated nonoperatively without complications. The incidence of vascular injuries associated with fractures about the knee is low, but somewhat higher with posterior knee dislocations. The overall 9 per cent rate of positive angiograms suggests that a selective approach may be indicated. The amputation rate remains high, but it has improved with an integrated, multidisciplinary team approach. In patients without a pulse or Doppler signal and with severe soft tissue injuries, primary amputation may be appropriate.


Reproductive endocrine effects of acute exposure to toluene in men and women.
Despite observation of adverse reproductive effects of toluene, including alterations of serum gonadotropins (luteinising hormone (LH) and follicle stimulating hormone (FSH)) in humans, little is known of the mechanism of toxicity. The hypothesis was tested that toluene acutely suppresses pulsatile gonadotropin secretion by measuring LH and FSH at frequent intervals during controlled exposure to toluene. Women in the follicular and luteal phases of the menstrual cycle and men were randomised to inhale filtered air with or without 50 ppm toluene through a mouthpiece for 3 hours (19% of the OSHA permissible exposure limit). Blood was sampled by intravenous catheter at 20 minute intervals for 3 hours before, 3 hours during, and 3 hours after exposure. Plasma LH, FSH, and testosterone were measured. Pulse amplitude, pulse frequency, and mean concentrations of LH and FSH for each of the 3 hour periods before, during and after exposure to toluene versus sham exposure were calculated with the ULTRA pulse detection program and compared by analysis of variance (ANOVA) with repeated measures. In men mean concentrations of LH showed a significant interaction (p < 0.05) between exposure and sampling period, with a greater LH decline during exposure to toluene than sham exposure. However, there was no concomitant effect on testosterone concentrations. The LH pulse frequency of women in the luteal phase showed a trend towards a significant interaction between exposure and sampling period (p = 0.06), with a greater decline in pulse frequency during exposure to toluene than sham exposure. There were no other significant effects of exposure to toluene. Three hour exposure to 50 ppm toluene did not result in abnormal episodic LH or FSH secretion profiles, however, subtle effects on LH secretion in men and women in the luteal phase were found. The clinical relevance of these effects is unclear, indicating the need for further study of reproductive function in exposed workers.


Perpetual superhydrophobicity.
A liquid droplet placed on a geometrically textured surface may take on a "suspended" state, in which the liquid wets only the top of the surface structure, while the remaining geometrical features are occupied by vapor. This superhydrophobic Cassie-Baxter state is characterized by its composite interface which is intrinsically fragile and, if subjected to certain external perturbations, may collapse into the fully wet, so-called Wenzel state. Restoring the superhydrophobic Cassie-Baxter state requires a supply of free energy to the system in order to again nucleate the vapor. Here, we use microscopic classical density functional theory in order to study the Cassie-Baxter to Wenzel and the reverse transition in widely spaced, parallel arrays of rectangular nanogrooves patterned on a hydrophobic flat surface. We demonstrate that if the width of the grooves falls below a threshold value of ca. 7 nm, which depends on the surface chemistry, the Wenzel state becomes thermodynamically unstable even at very large positive pressures, thus realizing a "perpetual" superhydrophobic Cassie-Baxter state by passive means. Building upon this finding, we demonstrate that hierarchical structures can achieve perpetual superhydrophobicity even for micron-sized geometrical textures.


Physiological Role of Vascular Endothelial Growth Factors as Homeostatic Regulators.
The vascular endothelial growth factor (VEGF) family of proteins are key regulators of physiological systems. Originally linked with endothelial function, they have since become understood to be principal regulators of multiple tissues, both through their actions on vascular cells, but also through direct actions on other tissue types, including epithelial cells, neurons, and the immune system. The complexity of the five members of the gene family in terms of their different splice isoforms, differential translation, and specific localizations have enabled tissues to use these potent signaling molecules to control how they function to maintain their environment. This homeostatic function of VEGFs has been less intensely studied than their involvement in disease processes, development, and reproduction, but they still play a substantial and significant role in healthy control of blood volume and pressure, interstitial volume and drainage, renal and lung function, immunity, and signal processing in the peripheral and central nervous system. The widespread expression of VEGFs in healthy adult tissues, and the disturbances seen when VEGF signaling is inhibited support this view of the proteins as endogenous regulators of normal physiological function. This review summarizes the evidence and recent breakthroughs in understanding of the physiology that is regulated by VEGF, with emphasis on the role they play in maintaining homeostasis. © 2017 American Physiological Society. Compr Physiol 8:955-979, 2018.


Knowledge and utilization of sexual and reproductive healthcare services among Thai immigrant women in Sweden.
Migration from Thailand to Sweden has increased threefold over the last 10 years. Today Thailand is one of the most common countries of origin among immigrants in Sweden. Since the year 2000, new HIV cases are also more prevalent among Thai immigrants compared to other immigrant nationalities in Sweden. The purpose of this study was to investigate the association between knowledge and utilization of sexual and reproductive healthcare services, contraceptive knowledge and socio-demographic characteristics and social capital among Thai immigrant women in Sweden. This is a cross-sectional study using a postal questionnaire to all Thai women (18-64) in two Swedish regions, who immigrated to the country between 2006 and 2011. The questionnaire was answered by 804 women (response rate 62.3 %). Bivariate and multivariate logistic regression analyses were used. The majority (52.1 %) of Thai women had poor knowledge of where they should turn when they need sexual and reproductive healthcare services. After controlling for potential confounders, living without a partner (OR = 2.02, CI: 1.16-3.54), having low trust in others (OR = 1.61, CI: 1.10-2.35), having predominantly bonding social capital (OR = 1.50, CI: 1.02-2.23) and belonging to the oldest age group (OR = 2.65, CI: 1.32-5.29) were identified as risk factors for having poor knowledge. The majority (56.7 %) had never been in contact with healthcare services to get advice on contraception, and about 75 % had never been HIV/STI tested in Sweden. Low utilization of healthcare was associated with poor knowledge about healthcare services (OR = 6.07, CI: 3.94-9.34) and living without a partner (OR = 2.53, CI: 1.30-4.90). Most Thai women had knowledge of how to prevent an unwanted pregnancy (91.6 %) and infection with HIV/STI (91.1 %). The findings indicate that social capital factors such as high trust in others and predominantly bridging social capital promote access to knowledge about healthcare services. However, only one-fourth of the women had been HIV/STI tested, and due to the HIV prevalence among Thai immigrants in Sweden, policy makers and health professionals need to include Thai immigrants in planning health promotion efforts and healthcare interventions.


Comparison of tear lipid profile among basal, reflex, and flush tear samples.
To determine whether tear collection by flushing the ocular surface with saline (flush tears) or collection by stimulation (reflex tears) can be used as an alternative to basal tear collection for the identification and quantification of lipids in the tear film. Tear samples were collected from 10 participants with no history of ocular surface disease or contact lens wear. Up to 10 μl of basal, reflex, and flush tear samples were collected from each eye using a microcapillary tube on three occasions with the order of methods randomized and allowing at least 24 hours between each collection method. Lipids were quantified from each tear sample using nano-electrospray ionization tandem mass spectrometry. Total lipids significantly differed in their concentration (pmol/μl) and mole % with each collection technique. Cholesterol esters [mean % (SE)] formed the major component of the total lipidome in basal [54.8% (3.1)], reflex [35.7% (6.4)], and flush [33.0% (3.1)] tear samples. However, the mole % of each lipid class substantially varied with each tear collection method. Nonpolar lipids, including cholesterol, wax esters, and triacylglycerols, dominated the tear lipidome in basal [92.8% (1.9)], reflex [71.8% (7.9)], and flush [83.6% (3.8)] tear samples. However, the mole % of phospholipids in reflex [27.5% (8.1)] and flush [15.8% (3.8)] tear samples was higher (p = 0.005) than that in basal tears [5.4% (2.0)]. Flush or reflex tears did not have similar lipid profiles in either concentration or in mole % to basal tears. It is recommended that basal tears are used for tear lipid analysis as the reflex or flush tears contain very low levels of most lipid components.


Different usage of the same oncology information system in two hospitals in Sydney--lessons go beyond the initial introduction.
The experience of clinicians at two public hospitals in Sydney, Australia, with the introduction and use of an oncology information system (OIS) was examined to extract lessons to guide the introduction of clinical information systems in public hospitals. Semi-structured interviews were conducted with 12 of 15 radiation oncologists employed at the two hospitals. The personnel involved in the decision making process for the introduction of the system were contacted and their decision making process revisited. The transcribed data were analyzed using NVIVO software. Themes emerged included implementation strategies and practices, the radiation oncologists' current use and satisfaction with the OIS, project management and the impact of the OIS on clinical practice. The hospitals had contrasting experiences in their introduction and use of the OIS. Hospital A used the OIS in all aspects of clinical documentation. Its implementation was associated with strong advocacy by the Head of Department, input by a designated project manager, and use and development of the system by all staff, with timely training and support. With no vision of developing a paperless information system, Hospital B used the OIS only for booking and patient tracking. A departmental policy that data entry for the OIS was centrally undertaken by administrative staff distanced clinicians from the system. All the clinicians considered that the OIS should continuously evolve to meet changing clinical needs and departmental quality improvement initiatives. This case study indicates that critical factors for the successful introduction of clinical information systems into hospital environment were an initial clear vision to be paperless, strong clinical leadership and management at the departmental level, committed project management, and involvement of all staff, with appropriate training. Clinician engagement is essential for post-adoption evolution of clinical information systems.


Psychosocial factors, alcohol use, and hangover signs among social drinkers: a reappraisal.
To reappraise a prior study of hangover signs and psychosocial factors among a sample of current drinkers, we excluded a subgroup termed Sobers, who report "never" being "tipsy, high or drunk." The non-sober current drinkers then formed the sample for this report (N = 1104). About 23% of this group reported no hangover signs regardless of their intake level or gender, and the rest showed no sex differences for any of 8 hangover signs reported. Using multiple regression, including ethanol, age and weight, it was found that psychosocial variables contributed independently in predicting to hangover for both men and women in this order: (1) guilt about drinking; (2) neuroticism; (3) angry or (4) depressed when high/drunk and (5) negative life events. For men only, ethanol intake was also significant; for women only, being younger and reporting first being high/drunk at a relatively earlier age were also predictors of the Hangover Sign Index (HSI). These multiple predictors accounted for 5-10 times more of the hangover variance than alcohol use alone: for men, R = 0.43, R2 = 19%; and for women, R = 0.46, R2 = 21%. The findings suggest that hangover signs are a function of age, sex, ethanol level and psychosocial factors.


Safety and efficacy of topical cantharidin for the treatment of pediatric molluscum contagiosum: a prospective, randomized, double-blind, placebo-controlled pilot trial.
Topical cantharidin is a commonly used treatment for molluscum contagiosum (MC). However, studies validating its safety and efficacy are limited. We conducted a 6-week, randomized, double-blind, placebo-controlled trial with subsequent open-label extension to assess the safety and effectiveness of cantharidin in treating pediatric MC. Ninety-four participants with MC were randomized to receive cantharidin or placebo, with or without occlusion. The primary outcome was complete lesion clearance. Secondary outcomes included post-treatment lesion count, adverse events, and side effects. No significant differences between the study arms, including baseline lesion count, were observed. The overall mean (SD) baseline lesion count was 22.2 (12.9). The number of participants achieving total clearance is as follows: 7/23 (30.4%) in the cantharidin only arm, 10/24 (41.7%) in the cantharidin with occlusion arm, 2/25 (8.0%) in the placebo with occlusion arm, and 3/22 (13.6%) in the placebo only arm. Post hoc analysis demonstrated that 17/47 (36.2%) participants in the combined cantharidin arms achieved clearance compared to 5/47 (10.6%) in the placebo arms (P = 0.0065). The mean (SD) lesion count change from baseline was -5.1 (12.2) in the placebo only arm; the mean change (SD) was -17.4 (12.8) in the cantharidin only arm (P = 0.0033) and -15.9 (11.6) in the cantharidin with occlusion arm (P = 0.0101). No serious adverse events or side effects were observed. Topical cantharidin was well-tolerated and associated with the resolution of MC.


Effect of dynamic weight bearing on neuromuscular activation after spinal cord injury.
To determine whether individuals who have a spinal cord injury have neuromuscular and physiologic responses to a personalized exercise program during dynamic weight bearing (DWB). Four subjects with spinal cord injuries (T6, T5-6, C2-5, and C5) completed a 12-wk exercise program that included DWB. Surface electromyography (EMG) was recorded from the right gastrocnemius, biceps femoris, rectus femoris, rectus abdominus, and external oblique. Heart rate (HR) and blood pressure (BP) were recorded throughout training. Descriptive statistics were used to analyze the data. The results of this study indicate that the subjects actively responded to exercise during DWB, as measured by EMG, HR, and BP. The results suggest that exercise during DWB can induce physiologic and neuromuscular responses in individuals who have a spinal cord injury, and that exercise during DWB may serve as a preparatory program for more advanced rehabilitation.


TELP, a sensitive and versatile library construction method for next-generation sequencing.
Next-generation sequencing has been widely used for the genome-wide profiling of histone modifications, transcription factor binding and gene expression through chromatin immunoprecipitated DNA sequencing (ChIP-seq) and cDNA sequencing (RNA-seq). Here, we describe a versatile library construction method that can be applied to both ChIP-seq and RNA-seq on the widely used Illumina platforms. Standard methods for ChIP-seq library construction require nanograms of starting DNA, substantially limiting its application to rare cell types or limited clinical samples. By minimizing the DNA purification steps that cause major sample loss, our method achieved a high sensitivity in ChIP-seq library preparation. Using this method, we achieved the following: (i) generated high-quality epigenomic and transcription factor-binding maps using ChIP-seq for murine adipocytes; (ii) successfully prepared a ChIP-seq library from as little as 25 pg of starting DNA; (iii) achieved paired-end sequencing of the ChIP-seq libraries; (iv) systematically profiled gene expression dynamics during murine adipogenesis using RNA-seq and (v) preserved the strand specificity of the transcripts in RNA-seq. Given its sensitivity and versatility in both double-stranded and single-stranded DNA library construction, this method has wide applications in genomic, epigenomic, transcriptomic and interactomic studies.


Two patients with complete defects in interferon gamma receptor-dependent signaling.
Unusual susceptibility to mycobacterial infections can be caused by deleterious mutations in genes that encode the interferon-gamma receptor 1 chain. Such mutations hamper the activation of macrophages by a type 1 immune response and result in enhanced survival of intracellular pathogens. We here report two patients with unusual mycobacterial infections, both diagnosed with homozygous deleterious interferon-gamma receptor 1 gene mutations. Patient 1 became ill after Bacillus Calmette-Guérin vaccination at the age of 9 months and died at the age of 18 months. She carried a homozygous C71Y mutation in the extracellular part of the mature interferon-gamma receptor 1 protein, resulting in the lack of detectable protein expression and absence of interferon-gamma dependent signaling. Patient 2 became ill at the age of 3 years, is still alive at 19 years of age, and has suffered from five successive infection episodes with atypical mycobacteria. A homozygous splice-site mutation in intron 3 was identified, resulting in the deletion of exon 3 at the mRNA level and consequently a truncated interferon-gamma receptor 1 protein with absence of the transmembrane domain. Protein expression and interferon-gamma dependent signaling were not detectable.


Controlling the expression of rhizobial genes during nodule development with elements and an inducer of the lac operon.
A simple strategy was tested for imposing artificial regulation of rhizobial genes during nodule development. Isopropyl-β-d-1-thiogalactoside (IPTG) was added to liquid root media to sustain expression of rhizobial genes controlled by Escherichia coli lac promoter/operators and repressor gene lacI. Conversely, a rinsing protocol was devised to remove IPTG sufficiently that genes could be repressed after having been induced. gusA under this control exhibited clearly delineated expression and repression in both the determinate Rhizobium etli-Phaseolus vulgaris and the indeterminate Sinorhizobium meliloti-Medicago sativa symbioses. Apparently, IPTG was taken up in sufficiently undegraded concentrations that gene expression was derepressed even in interior portions of the nodule. Moreover, the rinsing protocol led to obvious repression of gusA. Importantly, no deleterious effects of IPTG on nodule development, infection, or nitrogen fixation were observed. An R. etli CE3 gene required for lipopolysaccharide O antigen and infection on bean was put under this control by means of a two-plasmid construct. When this construct was added to a strain with a null mutation in this gene, infection, nodule development, and nitrogenase activity all depended on the length of time before IPTG was rinsed from the roots after inoculation.


2018 EULAR recommendations for physical activity in people with inflammatory arthritis and osteoarthritis.
Regular physical activity (PA) is increasingly promoted for people with rheumatic and musculoskeletal diseases as well as the general population. We evaluated if the public health recommendations for PA are applicable for people with inflammatory arthritis (iA; Rheumatoid Arthritis and Spondyloarthritis) and osteoarthritis (hip/knee OA) in order to develop evidence-based recommendations for advice and guidance on PA in clinical practice. The EULAR standardised operating procedures for the development of recommendations were followed. A task force (TF) (including rheumatologists, other medical specialists and physicians, health professionals, patient-representatives, methodologists) from 16 countries met twice. In the first TF meeting, 13 research questions to support a systematic literature review (SLR) were identified and defined. In the second meeting, the SLR evidence was presented and discussed before the recommendations, research agenda and education agenda were formulated. The TF developed and agreed on four overarching principles and 10 recommendations for PA in people with iA and OA. The mean level of agreement between the TF members ranged between 9.8 and 8.8. Given the evidence for its effectiveness, feasibility and safety, PA is advocated as integral part of standard care throughout the course of these diseases. Finally, the TF agreed on related research and education agendas. Evidence and expert opinion inform these recommendations to provide guidance in the development, conduct and evaluation of PA-interventions and promotion in people with iA and OA. It is advised that these recommendations should be implemented considering individual needs and national health systems.


Zinc and silver glass polyalkenoate cements: an evaluation of their antibacterial nature.
A biofilm is an accumulation of micro-organisms and their extracellular products forming a structured community on a surface. Biofilm formation on medical devices has severe health consequences as bacteria growing in this lifestyle are tolerant to both host defence mechanisms and antibiotic therapies. However, silver and zinc ions inhibit the attachment and proliferation of immature biofilms. The objective of this study is to evaluate whether silver and zinc ions eluted from novel glass polyalkenoate cement (GPC) coatings have the ability to inhibit Methicillin-resistant Staphylococcus aureus (MRSA) in vivo. A silver and zinc-containing GPC coating was synthesised, deposited onto Ti6Al4V discs and placed in a specified amount of analytical water for 1, 7 and 30 days. The resulting elutes were collected and Atomic absorption spectroscopy was used to measure ion release. The elutes were injected into Galleria mellonella larvae infected with MRSA and the antibacterial properties of these elutes were evaluated in vivo. The majority of the zinc and silver ions were released within the first 24 h; this corresponded with the greatest degree of protection observed in infected larvae. Results were compared to a conventional in vitro model where identical elutes were incubated with MRSA on nutrient agar. These results were consistent with those observed in the larval model, demonstrating a reduction in bacterial viability when co-cultured with elutes for 2 h. This work confirms the promise of the Galleria mellonella as a model for the assessment of antimicrobial agents and demonstrates the capacity of novel silver and zinc-containing GPCs to retard the colonisation of MRSA.


Strategies for achieving healthy energy balance among African Americans in the Mississippi Delta.
Low-income African Americans who live in rural areas of the Deep South are particularly vulnerable to diseases associated with unhealthy energy imbalance. The Centers for Disease Control and Prevention (CDC) has suggested various physical activity strategies to achieve healthy energy balance. Our objective was to conduct formal, open-ended discussions with low-income African Americans in the Mississippi Delta to determine 1) their dietary habits and physical activity levels, 2) their attitudes toward CDC's suggested physical activity strategies, and 3) their suggestions on how to achieve CDC's strategies within their own environment. A qualitative method (focus groups) was used to conduct the study during 2005. Prestudy meetings were held with African American lay health workers to formulate a focus group topic guide, establish inclusion criteria for focus group participants, select meeting sites and times, and determine group segmentation guidelines. Focus groups were divided into two phases. All discussions and focus group meetings were held in community centers within African American neighborhoods in the Mississippi Delta and were led by trained African American moderators. Phase I focus groups identified the following themes: overeating, low self-esteem, low income, lack of physical exercise, unhealthy methods of food preparation, a poor working definition of healthy energy balance, and superficial knowledge of strategies for achieving healthy energy balance. Phase 2 focus groups identified a preference for social support-based strategies for increasing physical activity levels. Energy balance strategies targeting low-income, rural African Americans in the Deep South may be more effective if they emphasize social interaction at the community and family levels and incorporate the concept of community volunteerism.