Epidemiology of travelers' diarrhea in Thailand.
Current data on risk of travelers' diarrhea (TD) among visitors to Thailand largely comes from US military personnel, Peace Corps volunteers, or expatriates. We performed a 14-month systematic study of the incidence rate and characteristics of TD and a smaller study of etiology of the disease among visitors to Phuket and Chiang Mai. One randomly selected day each week from August 2005 until October 2006, data were collected from foreign tourists departing from airports serving Phuket and Chiang Mai. A separate subgroup of subjects with TD acquired in Phuket were invited to submit a stool sample for enteropathogens. Based on 22,401 completed questionnaires, the attack rate for TD was highest among residents from Australia or New Zealand (16%), while those from the United States and Europe had attack rates of 7% to 8%. Independent risk factors for the development of TD were eating outside the hotel and eating meat. In contrast, a history of drinking tap water and consuming ice cream were protective. In 56 subjects studied for etiology, Aeromonas spp were found in 8 subjects (14%), enterotoxigenic Escherichia coli (ETEC) or Vibrio spp each was found in 7 (13%) with O1 V. cholera (cholera) seen in one, mixed pathogens were found in 3 (5%), with no pathogen being detected in 33 (59%). Phuket and Chiang Mai should not be considered high-risk destinations for development of TD among US and European travelers to Thailand. In the study, Aeromonas, ETEC, and Vibrio spp were the most frequent enteropathogens identified.


A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation.
Selective autophagy of organelles is critical for cellular differentiation, homeostasis, and organismal health. Autophagy of the ER (ER-phagy) is implicated in human neuropathy but is poorly understood beyond a few autophagosomal receptors and remodelers. By using an ER-phagy reporter and genome-wide CRISPRi screening, we identified 200 high-confidence human ER-phagy factors. Two pathways were unexpectedly required for ER-phagy. First, reduced mitochondrial metabolism represses ER-phagy, which is opposite of general autophagy and is independent of AMPK. Second, ER-localized UFMylation is required for ER-phagy to repress the unfolded protein response via IRE1α. The UFL1 ligase is brought to the ER surface by DDRGK1 to UFMylate RPN1 and RPL26 and preferentially targets ER sheets for degradation, analogous to PINK1-Parkin regulation during mitophagy. Our data provide insight into the cellular logic of ER-phagy, reveal parallels between organelle autophagies, and provide an entry point to the relatively unexplored process of degrading the ER network.


Exploring the Link between the Germline and Somatic Genome in Cancer.
<b/> Carter and colleagues propose a systematic analysis of the germline and somatic genome in cancer. They identify interactions that occur between germline and somatic variants. This elucidates the function of the germline genome in the context of cancer risk and development. Cancer Discov; 7(4); 354-5. ©2017 AACRSee related article by Carter et al., p. 410.


Tracking by location and features: object correspondence across spatiotemporal discontinuities during multiple object tracking.
We examined whether surface feature information is utilized to track the locations of multiple objects. In particular, we tested whether surface features and spatiotemporal information are weighted according to their availability and reliability. Accordingly, we hypothesized that surface features should affect location tracking across spatiotemporal discontinuities. Three kinds of spatiotemporal discontinuities were implemented across five experiments: abrupt scene rotations, abrupt zooms, and a reduced presentation frame rate. Objects were briefly colored across the spatiotemporal discontinuity. Distinct coloring that matched spatiotemporal information across the discontinuity improved tracking performance as compared with homogeneous coloring. Swapping distinct colors across the discontinuity impaired performance. Correspondence by color was further demonstrated by more mis-selected distractors appearing in a former target color than distractors appearing in a former distractor color in the swap condition. This was true even when color never supported tracking and when participants were instructed to ignore color. Furthermore, effects of object color on tracking occurred with unreliable spatiotemporal information but not with reliable spatiotemporal information. Our results demonstrate that surface feature information can be utilized to track the locations of multiple objects. This is in contrast to theories stating that objects are tracked based on spatiotemporal information only. We introduce a flexible-weighting tracking account stating that spatiotemporal information and surface features are both utilized by the location tracking mechanism. The two sources of information are weighted according to their availability and reliability. Surface feature effects on tracking are particularly likely when distinct surface feature information is available and spatiotemporal information is unreliable.


Big³. Editorial.
To provide an editorial introduction into the 2014 IMIA Yearbook of Medical Informatics with an overview of the content, the new publishing scheme, and upcoming 25th anniversary. A brief overview of the 2014 special topic, Big Data - Smart Health Strategies, and an outline of the novel publishing model is provided in conjunction with a call for proposals to celebrate the 25th anniversary of the Yearbook. 'Big Data' has become the latest buzzword in informatics and promise new approaches and interventions that can improve health, well-being, and quality of life. This edition of the Yearbook acknowledges the fact that we just started to explore the opportunities that 'Big Data' will bring. However, it will become apparent to the reader that its pervasive nature has invaded all aspects of biomedical informatics - some to a higher degree than others. It was our goal to provide a comprehensive view at the state of 'Big Data' today, explore its strengths and weaknesses, as well as its risks, discuss emerging trends, tools, and applications, and stimulate the development of the field through the aggregation of excellent survey papers and working group contributions to the topic. For the first time in history will the IMIA Yearbook be published in an open access online format allowing a broader readership especially in resource poor countries. For the first time, thanks to the online format, will the IMIA Yearbook be published twice in the year, with two different tracks of papers. We anticipate that the important role of the IMIA yearbook will further increase with these changes just in time for its 25th anniversary in 2016.


[Sister chromatid exchanges in the cells of higher eukaryotes].
Experimental data on the influence of culture conditions on the frequency of sister chromatid exchange (SCE) are reviewed. Evidence is provided that spontaneous SCEs exist. Various methods for the identification of spontaneous SCEs are discussed.


Case Report and Clinical Reasoning: Fulminant Liver Failure and Invasive Aspergillosis Following Ocrelizumab Treatment in a 21 Year-Old Woman.
We present the case of a 21 year-old woman with newly diagnosed relapsing-remitting multiple sclerosis who is given a single dose of ocrelizumab and placed on moderate-dose steroids with subsequent development of hepatic failure who goes on to develop highly fulminant systemic and central nervous system (CNS) aspergillosis. Ocrelizumab has no documented association with aspergillus infection, and moderate-dose steroids less often lead to such fulminant disease, but liver failure is associated with often-fatal aspergillus infection. We emphasize that liver failure is an underrecognized immune dysregulated state that predisposes to bacterial and fungal infections and suggest changes in diagnostic reasoning that could be considered in patients with multiple modalities of immunosuppression.


Single-cell RNA-sequencing reports growth-condition-specific global transcriptomes of individual bacteria.
Bacteria respond to changes in their environment with specific transcriptional programmes, but even within genetically identical populations these programmes are not homogenously expressed1. Such transcriptional heterogeneity between individual bacteria allows genetically clonal communities to develop a complex array of phenotypes1, examples of which include persisters that resist antibiotic treatment and metabolically specialized cells that emerge under nutrient-limiting conditions2. Fluorescent reporter constructs have played a pivotal role in deciphering heterogeneous gene expression within bacterial populations3 but have been limited to recording the activity of single genes in a few genetically tractable model species, whereas the vast majority of bacteria remain difficult to engineer and/or even to cultivate. Single-cell transcriptomics is revolutionizing the analysis of phenotypic cell-to-cell variation in eukaryotes, but technical hurdles have prevented its robust application to prokaryotes. Here, using an improved poly(A)-independent single-cell RNA-sequencing protocol, we report the faithful capture of growth-dependent gene expression patterns in individual Salmonella and Pseudomonas bacteria across all RNA classes and genomic regions. These transcriptomes provide important reference points for single-cell RNA-sequencing of other bacterial species, mixed microbial communities and host-pathogen interactions.


On the elusive saddle-splay and splay-bend elastic constants of nematic liquid crystals.
The elastic behavior of nematics is commonly described in terms of the three so-called bulk deformation modes, i.e., splay, twist, and bend. However, the elastic free energy contains also other terms, often denoted as saddle-splay and splay-bend, which contribute, for instance, in confined systems. The role of such terms is controversial, partly because of the difficulty of their experimental determination. The saddle-splay (K24) and splay-bend (K13) elastic constants remain elusive also for theories; indeed, even the possibility of obtaining unambiguous microscopic expressions for these quantities has been questioned. Here, within the framework of Onsager theory with Parsons-Lee correction, we obtain microscopic estimates of the deformation free energy density of hard rod nematics in the presence of different director deformations. In the limit of a slowly changing director, these are directly compared with the macroscopic elastic free energy density. Within the same framework, we derive also closed microscopic expressions for all elastic coefficients of rodlike nematics. We find that the saddle-splay constant K24 is larger than both K11 and K22 over a wide range of particle lengths and densities. Moreover, the K13 contribution comes out to be crucial for the consistency of the results obtained from the analysis of the microscopic deformation free energy density calculated for variants of the splay deformation.


Sustained signaling by phospholipase C-gamma mediates nerve growth factor-triggered gene expression.
In contrast to conventional signaling by growth factors that requires their continual presence, a 1-min pulse of nerve growth factor (NGF) is sufficient to induce electrical excitability in PC12 cells due to induction of the peripheral nerve type 1 (PN1) sodium channel gene. We have investigated the mechanism for this triggered signaling pathway by NGF in PC12 cells. Mutation of TrkA at key autophosphorylation sites indicates an essential role for the phospholipase C-gamma (PLC-gamma) binding site, but not the Shc binding site, for NGF-triggered induction of PN1. In concordance with results with Trk mutants, drug-mediated inhibition of PLC-gamma activity also blocks PN1 induction by NGF. Examination of the kinetics of TrkA autophosphorylation indicates that triggered signaling does not result from sustained activation and autophosphorylation of the TrkA receptor kinase, whose phosphorylation state declines rapidly after NGF removal. Rather, TrkA triggers an unexpectedly prolonged phosphorylation and activation of PLC-gamma signaling that is sustained for up to 2 h. Prevention of the elevation of intracellular Ca2+ levels using BAPTA-AM results in a block of PN1 induction by NGF. Sustained signaling by PLC-gamma provides a means for differential neuronal gene induction after transient exposure to NGF.


Protocols for marker-free gene knock-out and knock-down in Kluyveromyces marxianus using CRISPR/Cas9.
There is increased interest in strain engineering in the food and industrial yeast Kluyveromyces marxianus and a number of CRISPR/Cas9 systems have been described and used by different groups. The methods that we developed allow for very rapid and efficient inactivation of target genes using the endogenous DNA repair mechanisms of the cell. The strains and plasmids that we use are freely available, and here we provide a set of integrated protocols to easily inactivate genes and to precisely integrate DNA fragments into the genome, for example for promoter replacement, allelic swaps or introduction of point mutations. The protocols use the Cas9/gRNA expression plasmid pUCC001 and Golden Gate assembly for molecular cloning of targeting sequences. A genome-wide set of target sequences is provided. Using these plasmids in wild-type strains or in strains lacking non-homologous end-joining (NHEJ) DNA repair, the first set of protocols explain how to introduce indels (NHEJ-mediated) or precise deletions (homology-dependent repair (HDR)-mediated) at precise targets. The second set of protocols describe how to swap a promoter or coding sequence to yield a reprogrammed gene. The methods do not require the use of dominant or auxotrophic marker genes and thus the strains generated are marker-free. The protocols have been tested in multiple K. marxianus strains, are straightforward and can be carried out in any molecular biology laboratory without specialized equipment.


Developing an ethics support tool for dealing with dilemmas around client autonomy based on moral case deliberations.
Moral Case Deliberations (MCDs) are reflective dialogues with a group of participants on their own moral dilemmas. Although MCD is successful as clinical ethics support (CES), it also has limitations. 1. Lessons learned from individual MCDs are not shared in order to be used in other contexts 2. Moral learning stays limited to the participants of the MCD; 3. MCD requires quite some organisational effort, 4. MCD deals with one individual concrete case. It does not address other, similar cases (it is case based). These limitations warrant research into complementary ways of providing CES to healthcare professionals. Our research objective was therefore to develop a low threshold CES tool based on a series of MCDs on autonomy in long-term care. We used a qualitative research design in which we analyzed the process and content of a series of MCDs, combined with reflections on the theoretical background of MCD. In total 28 MCDs (10 transcripts and 18 summary reports) were analyzed by means of a thematic content analysis. In various rounds of development, the results of the analysis were combined with theoretical reflections on CES. Consequently, the tool was evaluated in three focus groups and adjusted. The CES tool, called 'moral compass', guides the users through a series of six subsequent questions in order to methodically reflect on their concrete moral dilemma, in the form of a booklet of 23 pages. It combines a methodical element that encourages and structures a reflection process with a substantive element, including norms, values, options, strategies, and insights regarding dealing with client autonomy. By using data from a series of MCDs, combined with theoretical reflections on MCD, ethics support and moral learning, we developed a thematic, low-threshold CES tool that supports healthcare professionals in daily practice in dealing with moral questions regarding client autonomy. It integrates examples and insights from earlier MCDs on the same topic. The moral compass is not a replacement of, but can be used complementary to MCD. The feasibility and impact of the moral compass need to be investigated in an evaluative follow-up study. The methodology presented in this paper may be used to develop moral compasses on different topics in various healthcare organizations.


Physical chemistry of supersaturated solutions and implications for oral absorption.
Amorphous solid dispersion (ASD) formulations are widely used for delivery of poorly soluble drugs for dissolution enhancement and bioavailability improvement. When administered, ASDs often exhibit fast dissolution to yield supersaturated solutions. The physical chemistry of these supersaturated solutions is not well understood. This review will discuss the concepts of solubility, supersaturation, and the connection to membrane transport rate. Liquid-liquid phase separation (LLPS), which occurs when the amorphous solubility is exceeded, leading to solutions with interesting properties is extensively discussed as a phenomenon that is relevant to all enabling formulations. The multiple physical processes occurring during dissolution of the ASD and during oral absorption are analyzed. The beneficial reservoir effect of a system that has undergone LLPS is demonstrated, both experimentally and conceptually. It is believed that formulations that rapidly supersaturate and subsequently undergo LLPS, with maintenance of the supersaturation at this maximum value throughout the absorption process, i.e. those that exhibit "spring and plateau" behavior, will give superior performance in terms of absorption.


[Bacteremic pneumococcal pneumonia in adults admitted to a general hospital. Experience in 60 cases].
Bacteremic pneumococcal pneumonia (BPP) is a preventable disease with high morbimortality. To evaluate clinical aspects and mortality on BPP patients admitted to a Chilean regional hospital. We looked for adult patients with Streptococcus pneumoniae isolated from blood cultures between 2010 and 2014 years and reviewed clinical records of those who were admitted with pneumonia. We identified 70 BPP patients: 58% were men, mean age was 56 years, 30% were > 65 years, 70% with basic public health insurance, 26% were alcoholics, 86% had comorbidities. Only two patients were vaccinated against S. pneumoniae. CURB-65 severity index for community acquired pneumonia was > 3 in 37% of patients. Twenty-four patients were admitted to ICU, twenty required mechanical ventilation and twenty-four died (34%). Mortality was associated with an age over 65 years, presence of comorbidities and complications of pneumonia. A total of 22 serotypes of S. pneumoniae were identified, five of them (1,3,7F,14 y 9V) were present in 57% of cases. Elevated mortality of our BNN patients was associated with comorbidities and possibly with socio economic factors, which conditioned a late access to medical care.


Cytochrome P-450-mediated activation and irreversible binding of the antiestrogen tamoxifen to proteins in rat and human liver: possible involvement of flavin-containing monooxygenases in tamoxifen activation.
Tamoxifen (TXF), a triphenylethylene antiestrogen, is the major therapeutic agent for breast cancer. In rare cases, TXF treatment appears to increase incidence of endometrial cancer. Also in rats, TXF was found to induce hepatocellular carcinoma. Previous studies suggested that metabolism of TXF may contribute to its antiestrogenic and anticancer activity. The current study demonstrates a novel route of TXF metabolism. TXF is metabolized by rat and human liver microsomes into a reactive intermediate (txf*) which binds irreversibly to microsomal proteins. The binding requires NADPH and O2 and is inhibited by CO, inhibitors of P-450, and antibodies to rat NADPH-P450 reductase, indicating catalysis by P450. Phenobarbital treatment of rats markedly increases binding, suggesting the involvement of induced P450s. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of proteins from incubation of [14C] TXF with phenobarbital-treated microsomes exhibits a major radiolabeled zone which corresponds to a molecular weight of approximately 54,000, suggesting binding to a P-450. Cysteine and glutathione inhibited the binding of TXF without significantly affecting P-450-mediated metabolism of TXF, possibly by reacting with txf* or by competing for the same binding sites. Exposure of phenobarbital-treated microsomes and control-microsomes to 50 degrees C for 90 s, which inactivates the flavin-containing monooxygenase (FMO), diminished binding and pH 8.6 enhanced binding. Also, alternate FMO substrates inhibited binding. These findings indicate that P-450 and possibly FMO catalyze the reactions leading to the formation of txf*. However, incubations with single-labeled and dual-radiolabeled tamoxifen or with [14C]TXF-N-oxide demonstrated that monodesmethyl-TXF and TXF-N-oxide, the principal P-450 and FMO-mediated metabolites, respectively, are not on the major route of txf* formation, indicating that txf* could not be an aldehyde derived from tamoxifen nitrone. Thus, though the structure of txf* was not characterized, certain possibilities were excluded. Speculations on the structure of txf* and on its possible pharmacological and toxicological activity are presented.


Absorption Properties of Microgel-PVP Composite Nanofibers Made by Electrospinning.
The absorption and desorption of water, as well as the retention of certain molecules within a polymeric network, have special interest in a wide range of applications, including drug delivery, biosensing, chemical separation, catalysis, and optics. In this communication, we report the encapsulation by electrospinning of poly(N-isopropylacrylamide)-based monodisperse microgels within microfibers of crosslinked poly(vinylpyrrolidone), which is a hydrogel itself, up to concentrations of 40 wt.-% of the microgels. We present an optical characterization of these composite microfibers and quantify their absorbance, which can be as large as 17 times their de-swollen weight. Interestingly, this absorbance can be tuned by controlling the values of the temperature and the pH of the medium.


"Hey, I Got to Smoke Some Weed": Favorable Perceptions of Marijuana Use Among Non-College-Educated Young Adult Cigarette Smokers.
Introduction: As marijuana legalization progresses in the U.S., this study investigated the perceptions of marijuana use among non-college-educated young adult smokers. Methods: Twelve focus groups were conducted to explore themes related to marijuana and marijuana use among a racially and ethnically diverse sample of 75 young adult smokers (ages 18-29 years) with <4-year college education and <$90,000 annual household income living in the Washington, D.C. metropolitan area. Thematic content analysis was employed to analyze the transcripts. Data collection and analysis took place in 2017 and 2018, respectively. Results: Many participants reported smoking cigarettes to boost and maintain the psychoactive effect ("high") of smoking marijuana; some smoked marijuana to substitute frequent cigarette smoking. Participants generally stated that they believed marijuana smoking was healthier and less addictive than cigarette smoking; many preferred smoking marijuana over cigarettes. Participants also mentioned that cigarette smoking was stigmatized and not socially acceptable but marijuana smoking was "trendy" and "cool." Some reported that they smoked marijuana to cut down on cigarettes, although most were unsuccessful. Racial and ethnic differences in marijuana use were also identified. Discussion: Non-college-educated young adult smokers expressed largely favorable views towards smoking marijuana. Such positive views may lead to prolonged and escalated use of cigarettes and marijuana, resulting in exacerbated adverse health consequence of smoking both products as well as worsened outcomes of cigarette smoking cessation. Evidence-based messages are greatly needed to communicate the harm and risks of marijuana use and marijuana and tobacco co-use among this group.


Dynamic contrast-enhanced MRI and fractal characteristics of percolation clusters in two-dimensional tumor blood perfusion.
Dynamic contrast-enhanced magnetic resonance imaging (DE-MRI) of the tumor blood pool is used to study tumor tissue perfusion. The results are then analyzed using percolation models. Percolation cluster geometry is depicted using the wash-in component of MRI contrast signal intensity. Fractal characteristics are determined for each two-dimensional cluster. The invasion percolation model is used to describe the evolution of the tumor perfusion front. Although tumor perfusion can be depicted rigorously only in three dimensions, two-dimensional cases are used to validate the methodology. It is concluded that the blood perfusion in a two-dimensional tumor vessel network has a fractal structure and that the evolution of the perfusion front can be characterized using invasion percolation. For all the cases studied, the front starts to grow from the periphery of the tumor (where the feeding vessel was assumed to lie) and continues to grow toward the center of the tumor, accounting for the well-documented perfused periphery and necrotic core of the tumor tissue.


The Shape of Native Plant Cellulose Microfibrils.
Determining the shape of plant cellulose microfibrils is critical for understanding plant cell wall molecular architecture and conversion of cellulose into biofuels. Only recently has it been determined that these cellulose microfibrils are composed of 18 cellulose chains rather than 36 polymers arranged in a diamond-shaped pattern. This study uses density functional theory calculations to model three possible habits for the 18-chain microfibril and compares the calculated energies, structures, 13C NMR chemical shifts and WAXS diffractograms of each to evaluate which shape is most probable. Each model is capable of reproducing experimentally-observed data to some extent, but based on relative theoretical energies and reasonable reproduction of all variables considered, a microfibril based on 5 layers in a 34443 arrangement is predicted to be the most probable. A habit based on a 234432 arrangement is slightly less favored, and a 6 × 3 arrangement is considered improbable.


Telomerase activity and telomerase reverse transciptase (TERT) expression in ameloblastomas.
Telomerase activity is believed to be crucial for cell immortalization and cancerization, and is proven to be induced by c-myc protein. Telomerase reverse transcriptase (TERT) has been recently identified as a catalytic subunit of telomerase, whose expression is closely correlated with telomerase activity. We estimated telomerase activity by the telomeric repeat amplification protocol (TRAP) assay and examined the immunohistochemical expression of TERT and c-myc protein in 21 ameloblastoma tissues. All ameloblastoma samples were positive for telomerase activity, and TERT expression was detected in the nuclei of neoplastic cells but not in those of stromal cells. Numerous peripheral columnar or cuboidal cells, sporadic central polyhedral cells and some granular cells in ameloblastomas reacted with anti-TERT antibody. These results suggest that telomerase activity is associated with the oncogenesis or proliferative potential of odontogenic epithelium. The expression of c-myc protein showed a similar distribution pattern to that of TERT, suggesting that c-myc protein might induce telomerase activity in ameloblastomas.


Immediate breast reconstruction. A review.
In summary, immediate breast reconstruction has many advantages to the patients and to the surgeons who perform breast reconstruction. For the patients, it is less expensive, psychologically easier, and more convenient. For the surgeons, it facilitates the reconstruction and improves the aesthetic results. Oncologically, there is no reason not to perform immediate breast reconstruction unless the patient does not want it or the prognosis is so poor that any breast reconstruction is unwarranted. We generally offer immediate breast reconstruction to all patients with in situ, T1, or T2 breast cancers who are appropriate surgical candidates. We also offer it to selected patients with T3 breast cancers if the patients are good surgical candidates and are anxious to undergo immediate reconstruction. Skin-sparing mastectomy combined with immediate breast reconstruction has improved the quality of our results and the quality of our patients' lives. By helping our patients in this manner, it has increased the amount of pride we can take in our work and therefore the quality of our own lives as well.


[The use of computed and magnetic resonance tomography in the diagnosis of neoplasms of the pelvic bones and sacrum].
The experience of the computed tomography (CT) application in the pelvic bones and sacrum tumors diagnosis in 46 patients was summarized. The data obtained were defined more precisely using magnet-resonance tomography (MRT). MRT in contradistinction to permits to differentiate the soft tissues and reveal the tumoral invasion of dura mater and the spinal cord substance, the spinal cord nerves affection. Using CT it is possible to estimate more accurately the bone structure and tumoral elements, containing calcium.


Analysis and design of negative resistance oscillators using surface transverse wave-based single port resonators.
This practically oriented paper presents the fundamentals for analysis, optimization, and design of negative resistance oscillators (NRO) stabilized with surface transverse wave (STW)-based single-port resonators (SPR). Data on a variety of high-Q, low-loss SPR devices in the 900- to 2000-MHz range, suitable for NRO applications, are presented, and a simple method for SPR parameter extraction through Pi-circuit measurements is outlined. Negative resistance analysis, based on S-parameter data of the active device, is performed on a tuned-base, grounded collector transistor NRO, known for its good stability and tuning at microwave frequencies. By adding a SPR in the emitter network, the static transducer capacitance is absorbed by the circuit and is used to generate negative resistance only over the narrow bandwidth of the acoustic device, eliminating the risk of spurious oscillations. The analysis allows exact prediction of the oscillation frequency, tuning range, loaded Q, and excess gain. Simulation and experimental data on a 915-MHz fixed-frequency NRO and a wide tuning range, voltage-controlled STW oscillator, built and tested experimentally, are presented. Practical design aspects including the choice of transistor, negative feedback circuits, load coupling, and operation at the highest phase slope for minimum phase noise are discussed.


Exploration of the arrest peptide sequence space reveals arrest-enhanced variants.
Translational arrest peptides (APs) are short stretches of polypeptides that induce translational stalling when synthesized on a ribosome. Mechanical pulling forces acting on the nascent chain can weaken or even abolish stalling. APs can therefore be used as in vivo force sensors, making it possible to measure the forces that act on a nascent chain during translation with single-residue resolution. It is also possible to score the relative strengths of APs by subjecting them to a given pulling force and ranking them according to stalling efficiency. Using the latter approach, we now report an extensive mutagenesis scan of a strong mutant variant of the Mannheimia succiniciproducens SecM AP and identify mutations that further increase the stalling efficiency. Combining three such mutations, we designed an AP that withstands the strongest pulling force we are able to generate at present. We further show that diproline stretches in a nascent protein act as very strong APs when translation is carried out in the absence of elongation factor P. Our findings highlight critical residues in APs, show that certain amino acid sequences induce very strong translational arrest and provide a toolbox of APs of varying strengths that can be used for in vivo force measurements.


"It's so hard taking pills when you don't know what they're for": a qualitative study of patients' medicine taking behaviours and conceptualisation of medicines in the context of rheumatoid arthritis.
Patients with chronic illnesses are often required to take lifelong medication to alleviate symptoms and prevent disease progression. Many patients find it difficult to adhere to prescribed medication for various reasons, some of which may link to the way they conceptualise medicines and understand their illness and treatment. This study explores the medicine taking behaviours of patients presenting with Rheumatoid Arthritis (RA), a chronic inflammatory autoimmune disease. We focused particularly on patients' conceptualisation and understanding of medicines within this disease context, against a backdrop of scarce healthcare resources. We conducted semi-structured interviews with 18 female patients at a rheumatology clinic in South Africa, as well as a review of participants' medical records. We conducted a secondary analysis of the data using thematic analysis and framework analysis principles. Participants reported a range of medicine taking behaviours including self-medicating, adding complementary and alternative medicines (CAM) or traditional remedies, and sometimes acquiring prescribed medicines illegally. Participants provided insights into their understanding of what constitutes a medicine and what substances can be added to a prescribed regimen, which impacted on adherence. Importantly, the majority of participants demonstrated poor understanding of their illness, medications, regimens and dosage instructions. Medicine taking in the context of RA, within the studied demographic, is complex and appears strongly mediated by individual and contextual factors. Poor patient understanding, individual conceptualisation of medicines and medicine taking, and the availability of a range of additional medicines and remedies impact on adherence. Based on these findings, we make some suggestions for how healthcare providers can play a greater role in educating patients living with RA about medicines, CAM and traditional remedies, as well as medicine taking behaviours.


An immunoglobulin light chain from a lupus-prone mouse induces autoantibodies in normal mice.
Autoantibodies against the 70-kD U1 RNP nucleoprotein autoantigen and DNA were elicited in normal BALB/c mice with a purified Ig light chain. This light chain, derived from a lupus-prone MRL-lpr/lpr mouse, has two distinctive properties: it contains an idiotypic marker recognized by a monoclonal MRL-lpr/lpr anti-snRNP autoantibody, and the amino acid sequence of its third hypervariable region (CDR3) is homologous to a sequence in an antigenic region of the 70-kD U1 RNP polypeptide. The results demonstrate that an Ig idiotype that mimics an autoantigen can induce autoimmunization.


Collaborating with congregations: opportunities for financial services in the inner city.
In all economies, financial systems perform a basic set of functions, which include the need to pool resources, to save and borrow, to make payments, and to collect information. And yet, in rich and poor communities, the ways in which those needs are met differ greatly. In part, this is because traditional financial service firms have found it too expensive to serve poor neighborhoods. But it is possible to work with less traditional institutions to meet those needs. According to the authors, inner cities face two core impediments to financial services: lack of economies of scale and lack of good information. An inner-city investor with $500, for instance, does not warrant much attention from financial service firms. But 20,000 parishioners investing $500 apiece can collectively wield $10 million. By partnering with strong social organizations such as churches, financial institutions can benefit both themselves and investors. A lack of good information concerning credit histories--a common problem in poor communities--also makes low-income customers much less appealing to financial institutions. Churches can help close such information gaps by vouching for parishioners' reliability. There are certainly problems that come with mixing business and religion, as the authors concede. Ethical issues, trust issues, and issues of experience all come to mind. But understanding that functions need to dictate the structure of the financial service sector may be the first step toward achieving inner-city prosperity.


Influence of surface treatment of contaminated zirconia on surface free energy and resin cement bonding.
Influences of contamination and cleaning methods on the bonding of resin cement to zirconia ceramics were examined. Airborne particle-abraded zirconia (IPS e.max ZirCAD) specimens were contaminated with saliva and cleaned with tap water (SC) or by application of 37% phosphoric acid (PA), Ivoclean (IC), or additional airborne particle abrasion (AB). Specimens without contamination served as controls. After application of Monobond Plus to the surface of the specimens, resin cement was mixed and inserted into a mold. Surface free energies of the specimens were determined by measuring contact angles. Surface treatment and storage conditions significantly influenced bond strength, while there was no significant interaction between the two factors. Surface free energies of the SC and IC groups were significantly lower than those of the other groups. Additional AB of saliva-contaminated zirconia increased the strength of bonding with the resin cement as well as increased surface free energy.


[Some clinical and immunological aspects of female pulmonary tuberculosis].
Expression of activation markers, such as CD25, HLA-DR), Fas-AG, CD16), on the lymphocytes was studied in female patients with tuberculosis (n = 40) and healthy donors. The level of antituberculous antibodies was measured in parallel in the sera of these patients. The above parameters were examined in relation to the nature of the microflora detected in these patients. Nonspecific co-infection in patients with active tuberculosis is an additional factor of activation of the immune system and simultaneously a factor that enhances the involvement of cells in apoptosis.


Beta-defensin antibiotic peptides in the innate immunity of the buffalo: in vivo and in vitro studies.
Beta-defensin antimicrobial peptides are multifunctional biomolecules, which are a major component of the oxygen-independent microbicidal system of buffalo polymorphonuclear (PMN) cells. They have great potential for use as proteomic biomarkers of host cell responses in the presence of microbial agents. On purifying these peptides by RP-HPLC, four defensin peptides were revealed. The results from testing against Escherichia coli, Staphylococcus aureus, Streptococcus pyogenes, Candida albicans, Rinderpest Virus (RPV) and Newcastle Disease Virus (NDV), showed that the peptides possessed antimicrobial and antiviral activities. Minimum inhibitory concentration (MIC) values varied according to the peptide amounts and the exposure time. Furthermore, an increase in the levels of these cationic antimicrobial peptides was apparent in milk obtained from natural cases of mastitis, as compared to the levels in normal milk. MALDI-TOF-based amino acid sequencing confirmed the expression of two beta-defensins (LAP and BNBD-2) in mastitis milk. A comparison of peptide sequences revealed that buffalo LAP and BNBD-2 share 98.6% and 100% sequence identity, respectively, with those of cattle. In vitro, Bovine Viral Diarrhoea Virus (BVDV) infection was shown to induce the expression of the beta-defensin gene, as evidenced by the PCR amplification of cDNA with specific primers. The determination of the enhanced expression of beta-defensin peptides in mastitis milk and in PMN cells, can be considered as an advanced approach to the assessment of cellular and molecular responses to cell injury. It is hoped that in vitro studies on phagocytes such as PMN cells and other cell lines, will eventually replace the use of animals in elucidating the roles of these cytokines in response to microbe-derived cell damage. It will also be possible to use defensins as biomarkers to correlate failure in host cell defence systems with peptide heterogeneity.


Local inflammation alters the lung disposition of a drug loaded pegylated liposome after pulmonary dosing to rats.
The development of inhalable 'nanomedicines' based on biocompatible lipids and polymers is attracting increasing interest worldwide. Our understanding of how pulmonary inflammation impacts on lung distribution and clearance kinetics however, is limited. Similarly, there is limited information on how the inhaled delivery of biocompatible nanomaterials affects existing respiratory disease. We have addressed these knowledge gaps by describing and comparing the pulmonary pharmacokinetic behaviour of a 3H-labelled PEGylated liposome loaded with a model drug (ciprofloxacin) after intratracheal administration to healthy rats and rats with bleomycin-induced lung inflammation by following both 3H label and drug. Cell- and cytokine-based markers of lung inflammation were used to evaluate the response of healthy and inflamed lungs to the liposome. Liposomes were initially cleared more rapidly from inflamed lungs than from healthy lungs, but exhibited similar rates of lung clearance after 3 days. This was interesting given that mucociliary clearance was more efficient from healthy lungs, despite evidence of higher mucus retention in inflamed lungs and reduced association of the liposome with lung tissue. Although the plasma pharmacokinetics of ciprofloxacin did not differ between rats with healthy or inflamed lungs after pulmonary administration, the plasma pharmacokinetics of 3H-phosphatidylcholine suggested higher liposome bioavailability and more prolonged absorption from inflamed lungs. Concentrations of the pro-inflammatory cytokine IL-1β were increased in bronchoalveolar lavage fluid after a single pulmonary dose of liposomes to rats with inflamed lungs, but no other significant changes in lung inflammatory markers were identified in healthy or bleomycin-challenged rats.


The response of Fusarium oxysporum to dithane M-45 and Pseudomonas aeruginosa.
The interaction of the fungicide Dithane M-45 (active ingredient mancozeb), with Pseudomonas aeruginosa strain not sensitive to the compound, was studied. Pseudomonas aeruginosa produced a fungicidal compound inhibiting the growth of Fusarium oxysporum. Simultaneously Pseudomonas aeruginosa degraded the EBIS (ethyleneisothiocyaniane) formed from the spontaneous decomposition of the fungicide which is highly toxic for Fusarium oxysporum. When the fungicide was used as seed dressing together with the bacteria the inhibition of the fungus was reduced to the interaction of both fungicidal compounds.


Increase in luminal mast cell and epithelial damage may account for increased airway responsiveness after viral infection in dogs.
To elucidate the mechanisms of airway hyperresponsiveness induced by viral infection, we examined histologically and analyzed bronchoalveolar lavage (BAL) fluid using dogs infected with influenza C and noninfected control dogs. Airway responsiveness was assessed as inhaled acetylcholine concentration required to increase pulmonary resistance by 5 cm H2O/L/s (ACh PC). Airway responsiveness was determined before and 2 wk after virus or vehicle inoculation in infected and control dogs, and BAL and histologic studies were performed after the final challenge. Differential cell numbers and histamine concentration were determined in the BAL fluids of both groups. The ACh PC of control dogs did not change with the vehicle inoculation. However, that of infected dogs decreased two to five times as much as their initial value with viral infection. Histologic studies revealed diffuse epithelial damage in the central airways of infected dogs, but infiltrated cell counts within the airway tissue of both groups were not significantly different. From BAL analysis, mast cell number and the histamine concentration of infected dogs increased significantly compared with those of control dogs (3.1 +/- 0.4 x 10(5) versus 0.9 +/- 0.3 x 10(5) cells/ml and 7.3 +/- 1.7 versus 1.9 +/- 0.5 ng/ml, respectively). Luminal mast cell number and epithelial damage score in each dog was correlated with the increase in airway responsiveness. These findings indicate that airway inflammation in virus-induced hyperreactive dogs is characterized by epithelial damage and luminal increase in mast cells and related mediators, and these changes may be related to the appearance of virus-induced airway hyperreactivity.


Mortality and long term morbidity in esophageal atresia: the reduced impact of low birth weight and maturity on surgical outcome.
Progress in perinatal and postoperative techniques has reduced the prognostic role of traditional risk factors in esophageal atresia (EA). This paper reports on 75 cases of esophageal anomalies observed between 1992 and 2002 and followed after surgery from a minimum of six months to a maximum of ten years (mean five years). The impact on survival of birth weight, week of delivery, associated anomalies and need of ventilatory support at birth are discussed. Twenty-four patients were born before 37 weeks of gestation, 18 weighed less than 2000 g.; major anomalies affected 11 neonates, 23 cases required mechanical ventilation at birth. Seventy-four patients were operated on with a 90.6% survival rate; no deaths were related to surgical treatment. Three cases required reoperation for postoperative complications. Birth weight and week of delivery did not seem to influence outcome; this is affected by severe associated cardiovascular anomalies and the need of ventilation at birth. Follow up at 24 months on 51 patients, revealed respiratory problems in 12 cases and severe gastro-esophageal reflux in 16. This affected quality of life of EA patients and required long term medical attention; improvement with growth was observed. No correlation between perinatal conditions and late sequelae could be demonstrated in our series.


Impact of technological developments in drug-eluting stents on patient-focused outcomes: a pooled direct and indirect comparison of randomised trials comparing first- and second-generation drug-eluting stents.
To establish whether technological improvements in drug-eluting stent (DES) technology introduced in second-generation (G2) DES have contributed to improving patient-focused outcomes. We performed a systematic review of randomised clinical trials (RCT) comparing first-generation (G1) and G2 DES with a>9-month clinical follow-up. The primary endpoint for efficacy was ischaemia-driven target lesion revascularisation (ID-TLR); safety endpoints were all-cause death, myocardial infarction (MI) and stent thrombosis (ST). Sixteen RCTs involving 25,427 patients met eligibility criteria (17 comparisons). In these trials, paclitaxel (PES) and sirolimus (SES) were compared with everolimus (EES), zotarolimus (ZES) or biolimus A9 (BES) DES. G2 varied in metal alloy, strut thickness and type of drug-eluting matrix. Overall, G2 DES were associated with a 26% relative risk reduction (RRR) of MI (relative risk [RR]=0.74, 95% CI: 0.61-0.90, p=0.003) and ST (RR=0.70, 95% CI: 0.55-0.89, p=0.004), while no significant benefit was observed for ID-TLR and death. Use of 2G DES was associated with a significant reduction in the risk of ID-TLR (RR=0.66, 95% CI: 0.51-0.85, p=0.002), MI (RR=0.60, 95% CI: 0.49-0.72, p<0.001) and ST (RR=0.41, 95% CI: 0.26-0.65, p=0.001) when compared with PES. Strut thickness ≤91 µm in G2 DES was associated with a significantly lower risk of MI (RR=0.54, 95% CI: 0.51-0.86, p=0.002). The introduction of thinner stent struts and other technological improvements made in G2 DES technology have translated into better patient outcomes. Overall, the net benefit of G2 DES over G1 DES is expressed in terms of ID-TLR and ST risk reduction but it could be masked by heterogeneities in the use of G1 comparators and the use of non-inferiority study designs in RCTs.


Microfluidic Formulation of DNA-Loaded Multicomponent Lipid Nanoparticles for Gene Delivery.
In recent years, lipid nanoparticles (LNPs) have gained considerable attention in numerous research fields ranging from gene therapy to cancer immunotherapy and DNA vaccination. While some RNA-encapsulating LNP formulations passed clinical trials, DNA-loaded LNPs have been only marginally explored so far. To fulfil this gap, herein we investigated the effect of several factors influencing the microfluidic formulation and transfection behavior of DNA-loaded LNPs such as PEGylation, total flow rate (TFR), concentration and particle density at the cell surface. We show that PEGylation and post-synthesis sample concentration facilitated formulation of homogeneous and small size LNPs with high transfection efficiency and minor, if any, cytotoxicity on human Embryonic Kidney293 (HEK-293), spontaneously immortalized human keratinocytes (HaCaT), immortalized keratinocytes (N/TERT) generated from the transduction of human primary keratinocytes, and epidermoid cervical cancer (CaSki) cell lines. On the other side, increasing TFR had a detrimental effect both on the physicochemical properties and transfection properties of LNPs. Lastly, the effect of particle concentration at the cell surface on the transfection efficiency (TE) and cell viability was largely dependent on the cell line, suggesting that its case-by-case optimization would be necessary. Overall, we demonstrate that fine tuning formulation and microfluidic parameters is a vital step for the generation of highly efficient DNA-loaded LNPs.


Point defects in ZnO.
We have investigated intrinsic point defects in ZnO and extended this study to Li, Cu and Al impurity centres. Atomic and electronic structures as well as defect energies have been obtained for the main oxidation states of all defects using our embedded cluster hybrid quantum mechanical/molecular mechanical approach to the treatment of localised states in ionic solids. With these calculations we were able to explain the nature of a number of experimentally observed phenomena. We show that in zinc excess materials the energetics of zinc interstitial are very similar to those for oxygen vacancy formation. Our results also suggest assignments for a number of bands observed in photoluminescence and other spectroscopic studies of the material.


Expression of P-170 glycoprotein sensitizes lymphoblastoid CEM cells to mitochondria-mediated apoptosis.
Multidrug resistance caused by P-glycoprotein (P-170) is a phenomenon by which cells exposed to a single drug acquire resistance to other structurally and functionally unrelated drugs. This is a widespread phenomenon described in vivo in the management of infectious as well as non-infectious diseases. Several in vitro models have been developed in order to evaluate physiopathological properties of P-170. Among these are P-170-expressing variants of the human T-lymphoblastoid CEM cell line called VBL100. As a general rule, drug resistance normally results in resistance to apoptosis induction. By contrast, a paradoxical activity is exerted in this cell model by the cytokine tumour necrosis factor-alpha (TNF-alpha), which is capable of inducing apoptosis in P-170-expressing variants better than in wild-type (wt) cells. In the present study we partially address the mechanisms underlying this activity. In fact, the susceptibility of VBL100 cells to TNF-alpha appears to be specifically due to the depolarization of their mitochondrial membrane, a key factor for apoptotic induction. The same was observed with staurosporine, a specific mitochondrion-mediated proapoptotic chemical probe. Conversely, other proapoptotic stimuli, such as Fas/CD95 or the anti-cancer drug etoposide, did induce significant cell death in wild type cells only. Thus, schematically, mitochondrially dependent stimuli appeared to be more effective in VBL100-cell killing, while 'physiological' stimuli showed the opposite behaviour. Importantly, under steady-state conditions, VBL100 cells displayed per se a mitochondrial membrane hyperpolarization that appeared strictly related to their high susceptibility to specific apoptotic stimuli. In conclusion, the study of a well-established cell model such as that represented by the wt/VBL CEM lymphoid cell line seems to suggest that the multidrug resistance phenotype can specifically sensitize cells towards 'unphysiological', mitochondria-associated cell death cascade or, in the same fashion, it could shift cells from type I (mainly plasma membrane-associated) towards type II (mainly mitochondrial membrane-associated) phenotype.


Validation of cardiac echocardiography for measuring cardiac output to be applied for the multiple inert gas elimination technique.
The multiple inert gas elimination technique (MIGET) is being increasingly used in respiratory physiology and pathophysiology. Six inert gases are given as an intravenous infusion then measured in samples of expired air and mixed arterial and venous blood. This requires right-sided catheterization, a procedure that is sometimes ethically inappropriate. The present article reports a method in which inert gas levels in mixed venous blood were calculated, rather than measured, using Fick's law. Echocardiography was used to measure arterial inert gas levels and cardiac output. The method was validated in 11 men scheduled to undergo coronary bypass surgery. Cardiac output was either calculated based on biometrical (C) data or measured using four different methods in random order, namely Fick's law with oxygen (FiO2) or the inert gases (FiIG) as the tracers, thermodilution (TH), and echocardiography (E). Cardiac output values in L.min-1 (mean +/- SD) were as follows: C, 4.99 +/- 0.39; FiO2, 5.44 +/- 0.86; FiIG, 5.55 +/- 0.92; TH, 5.77 +/- 0.88; and E, 5.53 +/- 0.64. No significant differences were found among the four measured cardiac output values, of which the mean was 5.57 +/- 0.70 L/min, a value that was significantly higher than the calculated value. This difference is probably ascribable to the use of dopamine, dobutamine, or epinephrine in six of the 11 patients. A 1 L/min-1 cardiac output error, in either direction, was found to have a marked influence on the distribution of alveolar perfusion at various VA/Q ratios. Conversely, as expected, ventilation distribution was not influenced by cardiac output. In conclusion, echocardiography provides satisfactory cardiac output estimations using the MIGET except in patients with septal hypertrophy, subaortic membranes, a mitral valve prosthesis, or a mitral valve ring.


Highly Stretchable and Sensitive Strain Sensor with Porous Segregated Conductive Network.
Flexible strain sensors based on elastomeric conductive polymer composites (ECPCs) play an important role in wearable sensing electronics. However, the achievement of good conjunction between broad detection range and high sensitivity is still challenging. Herein, a highly stretchable and sensitive strain sensor was developed with the formation of porous segregated conductive network in the carbon nanotube/thermoplastic polyurethane composite via a facile and nontoxic compression-molding plus salt-leaching method. The strain sensor with porous segregated conductive network exhibited perfect combination of ultrawide sensing range (800% strain), large sensitivity (gauge factor of 356.4), short response time (180 ms) and recovery time (180 ms), as well as superior stability and durability. The integrated porous structure intensifies the deformation of segregated conductive network when tension strain is applied, which benefits enhancement of the sensitivity. Our sensor could monitor not only subtle oscillation and physiological signals but also energetic human motions efficiently, revealing promising potential applications in wearable motion monitoring systems. This work provides a unique and effective strategy for realizing ECPCs based strain sensors with excellent comprehensive sensing performances.


Post partum pneumomediastinum.
A 19-year-old primigravida had a normal vaginal delivery after a 90-minute second stage of labour. Within two hours she complained of dyspnoea and was noticed to have unusual swelling of the face and neck. The diagnosis of subcutaneous emphysema was confirmed by chest X-ray and pneumomediastinum was also detected. Uneventful recovery over four days followed conservative management, administration of oxygen and use of simple analgesics.


Association between anthropometric measures of obesity and subclinical atherosclerosis in Bangladesh.
Anthropometric measures such as waist-hip-ratio (WHR), waist-height-ratio (WHtR), waist circumference, Mid-upper arm circumference (MUAC), and upper thigh circumference, have been linked to the risk of cardiovascular disease (CVD). However, their relationships with subclinical atherosclerosis are unclear. Studies in normal-weight populations, especially in Asian countries where leanness is prevalent, are lacking. We conducted a cross-sectional study to assess the associations of WHR, WHtR, waist circumference, hip circumference, body mass index (BMI), MUAC and upper thigh circumference with carotid intima-media thickness (cIMT) among 562 middle-aged participants free of CVD in rural Bangladesh. After adjusting for age and sex, WHR and waist circumference but not BMI showed a positive significant association with cIMT. In multivariate analysis, each standard deviation (SD) increase of WHR (0.08) or WHtR (0.07) was associated with an 8.96 μm (95% CI, 1.12-16.81) or 11.45 μm (95%CI, 0.86-22.04) difference in cIMT, respectively, after controlling for age, sex, BMI, smoking status, education level, and systolic blood pressure (SBP). The associations of WHR and WHtR with cIMT were independent of the influence of other anthropometric measures. The associations of other anthropometric measures and cIMT were not apparent. In our relatively lean, healthy Asian population, WHR and WHtR appear to be better predictors of early atherosclerosis than other common surrogates of adiposity.


Comparative genomics of two 'Candidatus Accumulibacter' clades performing biological phosphorus removal.
Members of the genus Candidatus Accumulibacter are important in many wastewater treatment systems performing enhanced biological phosphorus removal (EBPR). The Accumulibacter lineage can be subdivided phylogenetically into multiple clades, and previous work showed that these clades are ecologically distinct. The complete genome of Candidatus Accumulibacter phosphatis strain UW-1, a member of Clade IIA, was previously sequenced. Here, we report a draft genome sequence of Candidatus Accumulibacter spp. strain UW-2, a member of Clade IA, assembled following shotgun metagenomic sequencing of laboratory-scale bioreactor sludge. We estimate the genome to be 80-90% complete. Although the two clades share 16S rRNA sequence identity of >98.0%, we observed a remarkable lack of synteny between the two genomes. We identified 2317 genes shared between the two genomes, with an average nucleotide identity (ANI) of 78.3%, and accounting for 49% of genes in the UW-1 genome. Unlike UW-1, the UW-2 genome seemed to lack genes for nitrogen fixation and carbon fixation. Despite these differences, metabolic genes essential for denitrification and EBPR, including carbon storage polymer and polyphosphate metabolism, were conserved in both genomes. The ANI from genes associated with EBPR was statistically higher than that from genes not associated with EBPR, indicating a high selective pressure in EBPR systems. Further, we identified genomic islands of foreign origins including a near-complete lysogenic phage in the Clade IA genome. Interestingly, Clade IA appeared to be more phage susceptible based on it containing only a single Clustered Regularly Interspaced Short Palindromic Repeats locus as compared with the two found in Clade IIA. Overall, the comparative analysis provided a genetic basis to understand physiological differences and ecological niches of Accumulibacter populations, and highlights the importance of diversity in maintaining system functional resilience.


[Interpersonal relations in groups of mentally ill and mentally healthy children].
Using the sociometric method supplemented by systematic observations, the authors studied the interpersonal relations in children's departments of mental and therapeutic hospitals. The subjective structures of choices were compared with the objectively forming interrelations. Mental patients showed a greater rigidity of these structures which remained unaltered even with the arrival of newcomers, which is explained by a relatively minor role played by such a factor as socialization. The nosological characteristics influenced the sociometric choices only indirectly, with the main structural factors being sex and age. The position of each patient in this structure was altered in parallel with the change in his or her mental status. Unlike the therapeutic department, characteristic of mentally ill patients was the limitation of choices by sex; they also differed by the fact that girls had two types of leaders.


[Effect of N-palmitoylethanolamine on energy-dependent transport of Ca2+ in vesicles of myometrium sarcolemma and their phospholipid composition].
N-palmitoylethanolamine (NPE) was studied for their effect on calcium pump of pig myometrium sarcolemma. NPE in concentration of 10 microM, stimulated by 28-46% Mg2+, ATP-dependent accumulation of Ca2+ in vesicles of plasmatic membrane of uterus myocytes taking absolutely no effect on passive release of this cation from them. NPE modified phospholipid composition of sarcolemma, causing the increase of percentage content of phosphatidylinositol (by 20.2%) and lysophosphatidylcholine (2.7 times). While NPE effects transport Ca2+, Mg(2+)-ATPase solubilized from plasmatic membrane and purified due to the method of affinity chromatography on calmodulin-sepharose 4B, no activating effect of NPE on the calcium pump was observed. And what is more, a weakly expressed tendency to inhibition (by 14-15%, respectively) of the rate of Ca2+, Mg(2+)-dependent enzymic hydrolysis of ATP has been revealed. It is supposed that the effect of NPE on active transmembrane transport of Ca2+ is an important link in the general mechanism of contraction-relax of the myometrium and is, apparently, connected with its modifying effect on the lipid composition of the sarcolemma.


Settlement size and fertility in the Nordic countries.
While the variation in childbearing patterns across countries and between socio-economic groups within a country has been studied in detail, less is known about the differences in fertility patterns across settlements within a country. Using aggregate and individual-level register data, we examine fertility variation across settlements in Denmark, Finland, Norway, and Sweden. We observe a significant variation in fertility level by settlement size in all four of these Nordic countries - the larger the settlement, the lower the fertility. Second, the variation in fertility level has decreased over time, but significant differences in fertility between settlements of different size persist. Third, the timing of childbearing also varies across settlements - the larger the settlement, the later the peak of fertility. Fourth, our analysis of parity-specific fertility in Sweden shows that the major socio-economic characteristics of women account for only a small portion of fertility variation across settlements.


Predictive factors of post-discharge surgical site infections among patients from a teaching hospital.
Surgical site infections (SSIs) often manifest after patients are discharged and are missed by hospital-based surveillance. We conducted a case-reference study nested in a prospective cohort of patients from six surgical specialties in a teaching hospital. The factors related to SSI were compared for cases identified during the hospital stay and after discharge. Among 3,427 patients, 222 (6.4%) acquired an SSI. In 138 of these patients, the onset of the SSI occurred after discharge. Neurological surgery and the use of steroids were independently associated with a greater likelihood of SSI diagnosis during the hospital stay. Our results support the idea of a specialty-based strategy for post-discharge SSI surveillance.


Using the interplay of magnetic guidance and controlled TGF-β release from protein-based nanocapsules to stimulate chondrogenesis.
Stimulating the proliferation and differentiation of chondrocytes for the regeneration of articular cartilage is a promising strategy, but it is currently ineffective. Although both physical stimulation and growth factors play important roles in cartilage repair, their interplay remains unclear and requires further investigation. In this study, we aimed to clarify their contribution using a magnetic drug carrier that not only can deliver growth factors but also provide an external stimulation to cells in the two-dimensional environment. We developed a nanocapsule (transforming growth factor-β1 [TGF-β1]-loaded magnetic amphiphilic gelatin nanocapsules [MAGNCs]; TGF-β1@MAGNCs) composed of hexanoic-anhydride-grafted gelatin and iron oxide nanoparticles to provide a combination treatment of TGF-β1 and magnetically induced physical stimuli. With the expression of Arg-Gly-Asp peptide in the gelatin, the TGF-β1@MAGNCs have an inherent affinity for chondrogenic ATDC5 cells. In the absence of TGF-β1, ATDC5 cells treated with a magnetic field show significantly upregulated Col2a1 expression. Moreover, TGF-β1 slowly released from biodegradable TGF-β1@ MAGNCs further improves the differentiation with increased expression of Col2a1 and Aggrecan. Our study shows the time-dependent interplay of physical stimuli and growth factors on chondrogenic regeneration, and demonstrates the promising use of TGF-β1@MAGNCs for articular cartilage repair.


Serum vitamin D and change in lipid levels over 5 y: The Atherosclerosis Risk in Communities study.
Deficiency of 25-hydroxyvitamin D (25[OH]D) is associated with increased risk for cardiovascular disease, perhaps mediated through dyslipidemia. Deficient 25(OH)D is cross-sectionally associated with dyslipidemia, but little is known about longitudinal lipid changes. The aim of this study was to determine the relationship of 25(OH)D deficiency to longitudinal lipid changes and risk for incident dyslipidemia. This was a longitudinal community-based study of 13 039 participants from the ARIC (Atherosclerosis Risk in Communities) study who had 25(OH)D and lipids measured at baseline (1990-1992) and lipids remeasured in 1993 to 1994 and 1996 to 1998. Mixed-effect models were used to assess the association of 25(OH)D and lipid trends after adjusting for clinical characteristics and for baseline or incident use of lipid-lowering therapy. Risk for incident dyslipidemia was determined for those without baseline dyslipidemia. Baseline mean ± SD age was 57 ± 6 y and 25(OH)D was 24 ± 9 ng/mL. Participants were 57% women, 24% black. Over a mean follow-up of 5.2 y, the fully adjusted average differences (95% confidence interval [CI]) comparing deficient (<20 ng/mL) to optimal (≥30 ng/mL) 25(OH)D were: total cholesterol (TC) -2.40 mg/dL (-4.21 to -0.60), high-density lipoprotein cholesterol (HDL-C) -3.02 mg/dL (-3.73 to -2.32) and the ratio of TC to HDL-C 0.18 (0.11-0.26). Those with deficient compared with optimal 25(OH)D had modestly increased risk for incident dyslipidemia in demographic-adjusted models (relative risk [RR], 1.19; 95% CI, 1.02-1.39), which was attenuated in fully adjusted models (RR, 1.12; 95% CI, 0.95-1.32). Deficient 25(OH)D was prospectively associated with lower TC and HDL-C and a greater ratio of TC to HDL-C after considering factors such as diabetes and adiposity. Further work including randomized controlled trials is needed to better assess how 25(OH)D may affect lipids and cardiovascular risk.


The effect of air pollution on infant mortality appears specific for respiratory causes in the postneonatal period.
To examine the association between individual lifetime measures of mean exposure to air pollution and postneonatal respiratory deaths, we have conducted a matched population-based case-control study covering all births registered in the Czech Republic from 1989 to 1991 that were linked to death records. For each case of infant death, we have randomly selected 20 controls from infants of the same sex born on the same day and alive when the case died. Exposure was assigned as the arithmetic mean of all 24-hour air pollution measurements in the district of residence of each case and control for the period between the birth and death of the index case. We used conditional logistic regression to estimate the effects of suspended particles, sulfur dioxide, and nitrogen oxides on risk of death in the neonatal and postneonatal period, controlling for maternal socioeconomic status and birth weight, birth length, and gestational age. There were 2,494 infant deaths with exposure data on at least one pollutant, 133 of them from respiratory causes. The effects of all pollutants were strongest in the postneonatal period and were specific for respiratory causes. For these, rate ratios for a 50 microg/m3 increase in particles, sulfur dioxide, and nitrogen oxides were 1.95 [95% confidence interval (CI) = 1.09-3.50], 1.74 (95% CI = 1.01-2.98), and 1.66 (95% CI = 0.98-2.81), respectively, after controlling for all covariates. Only particles showed a consistent association when all pollutants were entered in one model. We found no evidence of a relation between any pollutant and mortality from other causes. These results indicate that the effects of air pollution on infant mortality are specific for respiratory causes in the postneonatal period, are independent of socioeconomic factors, and are not mediated by birth weight or gestational age.


Effects of Propofol and Midazolam on the Inflammation of Lungs after Intravenous Endotoxin Administration in Rats.
Pulmonary complications are important sepsis (such as ARDS, diffuse pneumonia). Acute respiratory distress syndrome (ARDS) is characterized by the extensive migration of neutrophils into alveoli of the lungs. Propofol and midazolam are the most widely used agents for sedation in intensive care units. Aimed to investigate the effects of anaesthesia with propofol and midazolam on measured hemodynamic variables and neutrophil migration induced by Escherichia Coli endotoxin (ECE) in pulmonary viscera. Forty Sprague Dawley male rats were randomly assigned to four groups: Thiopental Sodium 30 mg/kg was administered intraperitoneally to anesthetize the rats. They were ventilated via tracheotomy. Femoral artery was cannulated for the measurement of continuous blood pressure and gases. Group C was the control. After the administration of 1 mL/kg 0.9% NaCL, infusion began at 1 mL/kg/h rate. In Group E 15 mg/kg lipopolysaccharide derived from ECE was administered iv. In Group PE, after a bolus dose of 10 mg/kg propofol and 15 mg/kg ECE, 10 mg/kg/h infusion was applied. In Group ME, after 0.1 mg/kg midazolam bolus dose and 15 mg/kg ECE administration, 0.1 mg/kg/h infusion was administered iv. Rats were sacrified by iv potassium chloride. The lungs were then removed, fixed in 10% buffered formalin for 3 days and embedded in paraffin. They were graded on a scale of 0-3 according to the aggregation of neutrophils. There was intense neutrophil migration in Group E (grade 2, 3). However, although mild neutrophil migration was obtained in 70% of the rat lungs in Group ME (grade 1, 2), it was recorded in only 30% of Group PE (grade 1). The sepsis model induced by ECE and compared with midazolam, propofol anaesthesia is associated with less neutrophil infiltration. In the light of the literature, propofol attenuate the free-radical-mediated lipid peroxidation and systemic inflammation in patients.


Optimal use of reminders: Metacognition, effort, and cognitive offloading.
Individuals frequently choose between accomplishing goals using unaided cognitive abilities or offloading cognitive demands onto external tools and resources. For example, in order to remember an upcoming appointment one might rely on unaided memory or create a reminder by setting a smartphone alert. Setting a reminder incurs both a cost (the time/effort to set it up) and a benefit (increased likelihood of remembering). Here we investigate whether individuals weigh such costs/benefits optimally or show systematic biases. In 3 experiments, participants performed a memory task where they could choose between (a) earning a maximum reward for each remembered item, using unaided memory; or (b) earning a lesser amount per item, using external reminders to increase the number remembered. Participants were significantly biased toward using external reminders, even when they had a financial incentive to choose optimally. Individual differences in this bias were stable over time, and predicted by participants' erroneous metacognitive underconfidence in their memory abilities. Bias was eliminated, however, when participants received metacognitive advice about which strategy was likely to maximize performance. Furthermore, we found that metacognitive interventions (manipulation of feedback valence and practice-trial difficulty) yielded shifts in participants' reminder bias that were mediated by shifts in confidence. However, the bias could not be fully attributed to metacognitive error. We conclude that individuals have stable biases toward using external versus internal cognitive resources, which result at least in part from inaccurate metacognitive evaluations. Finding interventions to mitigate these biases can improve individuals' adaptive use of cognitive tools. (PsycINFO Database Record (c) 2020 APA, all rights reserved).


Does the Numeric Rating Scale (NRS) represent the optimal tool for evaluating pain in the triage process of patients presenting to the ED? Results of a muticenter study.
Pain evaluation at triage in Emergency Department (ED) is fundamental, as it influences significantly patients color code determination. Different scales have been proposed to quantify pain but they are not always reliable. This study aims to determine a) how important is for triage nurses pain measurement b) reliability of Numeric Rating Scale (NRS), the most used instrument to evaluate pain in Italian EDs, because it frequently shows higher pain scores than others scales. End point 1: a questionnaire was administered to triage nurses in some hospitals of northern Italy. End point 2: 250 patients arriving at the ED referring pain have been evaluated using, randomly, either the NRS or a fake "30-50" scale. End point 1: Triage nurses acknowledge to modify frequently the referred pain intensity. This for several reasons: nurses think that patients may exaggerate to obtain a higher priority color code; they may be influenced by specific patients categories (non EU citizens, drugs-addicted, elderly); the pain score referred by patients is not correspondent to nurse perception. End point 2: Data show that the mean value obtained with NRS is significantly (p<0.05) higher that the mean obtained with the "30-50" scale. Manipulation on pain evaluation performed by nurses might result in a dangerous underestimation of this symptom. At the same time, the use of NRS seems to allow patients to exaggerate pain perception with consequent altered attribution of color code at triage.


Immune activation in HIV-infected African individuals. Italian-Ugandan AIDS cooperation program.
Immune activation induced by chronic infections, dietary limitations, and poor hygienic conditions is suggested to be present in African HIV infection and is at the basis of the hypothesis that HIV infection in Africa could be prevalently associated with immunopathogenetic mechanisms. Very limited data are nevertheless available supporting this theory, and in particular no data are reported on functional and phenotypic analyses performed on fresh peripheral blood mononuclear cells (PBMC) of African HIV-infected patients living in Africa. Immunological and virological parameters were analysed in fresh PBMC of HIV-infected African and Italian patients with advanced HIV disease and comparable CD4 and CD8 counts, sex, and age. Both functional (antigen- and mitogen-stimulated cytokine production) and phenotypic (activation markers; markers preferentially expressed by T helper (Th) type 2 cells or by memory and naive cells) analyses were performed. Results were compared with those of HIV-seronegative African and Italian controls. HIV plasma viraemia was analysed by competitive polymerase chain reaction (PCR) and branched DNA techniques. (1) The production of mitogen-stimulated IFN-gamma and TNF-alpha as well as the production of env peptide-stimulated IFN-gamma, TNF-alpha, and IL-10 are increased in African HIV infection; (2) the expression of activation and Th2-associated markers is augmented in African HIV infection as is the memory/naive ratio; (3) mitogen-stimulated IFN-gamma and IL-10 production, as well as the expression of activation and Th2-associated markers and the memory/naive ratio, are augmented in African compared with Italian controls; and (4) plasma viraemia is reduced in African compared with Italian HIV-infected individuals. These results, which are the first to be reported on fresh material from African HIV-infected patients living in Africa, indicate that HIV disease is associated with an abnormal immune hyperactivation and may be accompanied in these patients by lower loads of virus, and show that such activation is present even in HIV-seronegative controls.


Selection of Bacterial Mutants in Late Infections: When Vector Transmission Trades Off against Growth Advantage in Stationary Phase.
Bacterial infections are often composed of cells with distinct phenotypes that can be produced by genetic or epigenetic mechanisms. This phenotypic heterogeneity has proved to be important in many pathogens, because it can alter both pathogenicity and transmission. We studied how and why it can emerge during infection in the bacterium Xenorhabdus nematophila, a pathogen that kills insects and multiplies in the cadaver before being transmitted by the soil nematode vector Steinernema carpocapsae We found that phenotypic variants cluster in three groups, one of which is composed of lrp defective mutants. These mutants, together with variants of another group, have in common that they maintain high survival during late stationary phase. This probably explains why they increase in frequency: variants of X. nematophila with a growth advantage in stationary phase (GASP) are under strong positive selection both in prolonged culture and in late infections. We also found that the within-host advantage of these variants seems to trade off against transmission by nematode vectors: the variants that reach the highest load in insects are those that are the least transmitted.IMPORTANCE Pathogens can evolve inside their host, and the importance of this mutation-fueled process is increasingly recognized. A disease outcome may indeed depend in part on pathogen adaptations that emerge during infection. It is therefore important to document these adaptations and the conditions that drive them. In our study, we took advantage of the possibility to monitor within-host evolution in the insect pathogen X. nematophila We demonstrated that selection occurring in aged infection favors lrp defective mutants, because these metabolic mutants benefit from a growth advantage in stationary phase (GASP). We also demonstrated that these mutants have reduced virulence and impaired transmission, modifying the infection outcome. Beyond the specific case of X. nematophila, we propose that metabolic mutants are to be found in other bacterial pathogens that stay for many generations inside their host.


Investigation on the occurrence of Echinococcus multilocularis in Central Italy.
Recent studies on geographic distribution of Echinococcus multilocularis in Europe show that it has a wider range than previously thought. It is unclear, however, if the wider distribution is due to its recent spreading or to a lack of previous data from the new areas. Italy, previously considered E. multilocularis-free, is now part of these new areas: infected foxes (the main definitive host of the tapeworm) have been observed in a Northern Alpine territory. Thus, more surveys need to be done in other Italian regions in order to monitor the spreading of E. multilocularis. The aim of the present study was to look for this parasite in 283 foxes collected in an Apennine area of Central Italy by different diagnostic methods. The foxes were heavily parasitized by 11 helminthic genera, but none of the animals was infected by E. multilocularis neither by E. granulosus (harboured adult worms or their DNA). Low specificity was observed in commercially available ELISA kits for the detection of E. multilocularis antigens in the faeces. Molecular diagnostics were sensitive and specific for the detection and identification of tapeworm eggs in faeces, but less sensitive, although specific, to adult tapeworms in the intestinal content. Preliminarily, we can say that no E. multilocularis could be found in the study area. These data will enable us to follow temporal changes of the spatial distribution of the parasite in the study area of the Central Apennines. Due to its low specificity the ELISA kit for E. multilocularis coproantigens is not suitable for epidemiological surveys, whereas molecular diagnostics applied to faecal samples give useful results. Finally, absence of E. granulosus in foxes living in the endemic areas studied confirms the thought that this tapeworm prefers a different definitive host.


Multiply Quantized Vortices in Fermionic Superfluids: Angular Momentum, Unpaired Fermions, and Spectral Asymmetry.
We compute the orbital angular momentum L_{z} of an s-wave paired superfluid in the presence of an axisymmetric multiply quantized vortex. For vortices with a winding number |k|>1, we find that in the weak-pairing BCS regime, L_{z} is significantly reduced from its value ℏNk/2 in the Bose-Einstein condensation (BEC) regime, where N is the total number of fermions. This deviation results from the presence of unpaired fermions in the BCS ground state, which arise as a consequence of spectral flow along the vortex subgap states. We support our results analytically and numerically by solving the Bogoliubov-de Gennes equations within the weak-pairing BCS regime.


Inhaled salmeterol and/or fluticasone alters structure/function in a murine model of allergic airways disease.
The relationship between airway structural changes (remodeling) and airways hyperresponsiveness (AHR) is unclear. Asthma guidelines suggest treating persistent asthma with inhaled corticosteroids and long acting beta-agonists (LABA). We examined the link between physiological function and structural changes following treatment fluticasone and salmeterol separately or in combination in a mouse model of allergic asthma. BALB/c mice were sensitized to intraperitoneal ovalbumin (OVA) followed by six daily inhalation exposures. Treatments included 9 daily nebulized administrations of fluticasone alone (6 mg/ml), salmeterol (3 mg/ml), or the combination fluticasone and salmeterol. Lung impedance was measured following methacholine inhalation challenge. Airway inflammation, epithelial injury, mucus containing cells, and collagen content were assessed 48 hours after OVA challenge. Lungs were imaged using micro-CT. Treatment of allergic airways disease with fluticasone alone or in combination with salmeterol reduced AHR to approximately naüve levels while salmeterol alone increased elastance by 39% compared to control. Fluticasone alone and fluticasone in combination with salmeterol both reduced inflammation to near naive levels. Mucin containing cells were also reduced with fluticasone and fluticasone in combination with salmeterol. Fluticasone alone and in combination with salmeterol reduces airway inflammation and remodeling, but salmeterol alone worsens AHR: and these functional changes are consistent with the concomitant changes in mucus metaplasia.


Cytochrome P450 Inhibitors Reduce Creeping Bentgrass (Agrostis stolonifera) Tolerance to Topramezone.
Creeping bentgrass (Agrostis stolonifera L.) is moderately tolerant to the p-hydroxyphenylpyruvate dioxygenase-inhibiting herbicide topramezone. However, the contribution of plant metabolism of topramezone to this tolerance is unknown. Experiments were conducted to determine if known cytochrome P450 monooxygenase inhibitors 1-aminobenzotriazole (ABT) and malathion alone or in combination with the herbicide safener cloquintocet-mexyl influence creeping bentgrass tolerance to topramezone. Creeping bentgrass in hydroponic culture was treated with ABT (70 μM), malathion (70 μm and 1000 g ha(-1)), or cloquintocet-mexyl (70 μM and 1000 g ha(-1)) prior to topramezone (8 g ha(-1)) application. Topramezone-induced injury to creeping bentgrass increased from 22% when applied alone to 79 and 41% when applied with malathion or ABT, respectively. Cloquintocet-mexyl (70 μM and 1000 g ha(-1)) reduced topramezone injury to 1% and increased creeping bentgrass biomass and PSII quantum yield. Cloquintocet-mexyl mitigated the synergistic effects of ABT more than those of malathion. The effects of malathion on topramezone injury were supported by creeping bentgrass biomass responses. Responses to ABT and malathion suggest that creeping bentgrass tolerance to topramezone is influenced by cytochrome P450-catalyzed metabolism. Future research should elucidate primary topramezone metabolites and determine the contribution of cytochrome P450 monooxygenases and glutathione S-transferases to metabolite formation in safened and non-safened creeping bentgrass.


[An analysis of morbidity in those who worked in the cleanup of the aftermath of the Chernobyl accident].
Some aspects were studied of pathologies in those liquidators who sought to find out connection between health disorders and restorative work at the Chernobyl Power Plant through the Kiev Regional Expert Medical Counsel in 1990-1996. Those disorders in whose pathogenesis the radiation factor acts together with factors of nonradiation nature, namely of the nervous, cardiovascular systems, and digestive organs, rank first in the structure of pathologies during the first ten years of the postradiation period. The incidence rate of malignancies among those liquidators who had applied to the Council is on the increase. In the structure of oncopathologies prevalence, the leading place is taken up by tumours of digestive organs, respiratory system, and urogenital organs.


Vitamins D3 and D2 have marked but different global effects on gene expression in a rat oligodendrocyte precursor cell line.
Vitamin D deficiency increases the risk of developing multiple sclerosis (MS) but it is unclear whether vitamin D supplementation improves the clinical course of MS, and there is uncertainty about the dose and form of vitamin D (D2 or D3) to be used. The mechanisms underlying the effects of vitamin D in MS are not clear. Vitamin D3 increases the rate of differentiation of primary oligodendrocyte precursor cells (OPCs), suggesting that it might help remyelination in addition to modulating the immune response. Here we analyzed the transcriptome of differentiating rat CG4 OPCs treated with vitamin D2 or with vitamin D3 at 24 h and 72 h following onset of differentiation. Gene expression in differentiating CG4 cells in response to vitamin D2 or D3 was quantified using Agilent DNA microarrays (n = 4 replicates), and the transcriptome data were processed and analysed using the R software environment. Differential expression between the experimental conditions was determined using LIMMA, applying the Benjamini and Hochberg multiple testing correction to p-values, and significant genes were grouped into co-expression clusters by hierarchical clustering. The functional significance of gene groups was explored by pathway enrichment analysis using the clusterProfiler package. Differentiation alone changed the expression of about 10% of the genes at 72 h compared to 24 h. Vitamin D2 and D3 exerted different effects on gene expression, with D3 influencing 1272 genes and D2 574 at 24 h. The expression of the vast majority of these genes was either not changed in differentiating cells not exposed to vitamin D or followed the same trajectory as the latter. D3-repressed genes were enriched for Gene Ontology (GO) categories including transcription factors and the Notch pathway, while D3-induced genes were enriched for the Ras pathway. This study shows that vitamin D3, compared with D2, changes the expression of a larger number of genes in OLs. Identification of genes affected by D3 in OLs should help to identify mechanisms mediating its action in MS.


Inhibition of growth and purine-metabolizing enzymes of trypanosomid flagellates by N6-methyladenine.
N6-methyladenine (6-methylaminopurine [6-MA]), a plant growth regulator and a normal constituent of nucleic acids, has been found to inhibit the growth of Trypanosoma cruzi, Leishmania braziliensis, L. donovani, L. tarentolae, L. mexicana, and Crithidia fasciculata. The extent of growth inhibition in these organisms is related to the sensitivity of guanine deaminase (guanine aminohydrolase, EC 220.127.116.11), adenine deaminase (adenine aminohydrolase, EC 18.104.22.168), and adenosine hydrolase and phosphorylase. 6-MA was not an inhibitor of the purine phosphoribosyltransferases. Of the trypanosomid flagellates tested. Trypanosoma cruzi was most susceptible to 6-MA. Neither adenine deaminase (as found in the leishmaniae and C. fasciculata) nor adenosine deaminase (as found in mammalian cells) could be demonstrated in T. cruzi. Guanine deaminase, which is strikingly inhibited by 6-MA in T. cruzi, appears to play a major role in the purine salvage pathway of this organism, as judged from growth experiments and enzyme inhibition studies. Enzyme sensitivities to 6-MA vary greatly depending upon the organism. Rabbit liver guanine deaminase was shown to be insensitive to 6-MA at the concentrations used in this study.


Marmosets: A Neuroscientific Model of Human Social Behavior.
The common marmoset (Callithrix jacchus) has garnered interest recently as a powerful model for the future of neuroscience research. Much of this excitement has centered on the species' reproductive biology and compatibility with gene editing techniques, which together have provided a path for transgenic marmosets to contribute to the study of disease as well as basic brain mechanisms. In step with technical advances is the need to establish experimental paradigms that optimally tap into the marmosets' behavioral and cognitive capacities. While conditioned task performance of a marmoset can compare unfavorably with rhesus monkey performance on conventional testing paradigms, marmosets' social behavior and cognition are more similar to that of humans. For example, marmosets are among only a handful of primates that, like humans, routinely pair bond and care cooperatively for their young. They are also notably pro-social and exhibit social cognitive abilities, such as imitation, that are rare outside of the Apes. In this Primer, we describe key facets of marmoset natural social behavior and demonstrate that emerging behavioral paradigms are well suited to isolate components of marmoset cognition that are highly relevant to humans. These approaches generally embrace natural behavior, which has been rare in conventional primate testing, and thus allow for a new consideration of neural mechanisms underlying primate social cognition and signaling. We anticipate that through parallel technical and paradigmatic advances, marmosets will become an essential model of human social behavior, including its dysfunction in neuropsychiatric disorders.


Cardiovascular Pleiotropic Effects of Natriuretic Peptides.
Atrial natriuretic peptide (ANP) is a cardiac hormone belonging to the family of natriuretic peptides (NPs). ANP exerts diuretic, natriuretic, and vasodilatory effects that contribute to maintain water-salt balance and regulate blood pressure. Besides these systemic properties, ANP displays important pleiotropic effects in the heart and in the vascular system that are independent of blood pressure regulation. These functions occur through autocrine and paracrine mechanisms. Previous works examining the cardiac phenotype of loss-of-function mouse models of ANP signaling showed that both mice with gene deletion of ANP or its receptor natriuretic peptide receptor A (NPR-A) developed cardiac hypertrophy and dysfunction in response to pressure overload and chronic ischemic remodeling. Conversely, ANP administration has been shown to improve cardiac function in response to remodeling and reduces ischemia-reperfusion (I/R) injury. ANP also acts as a pro-angiogenetic, anti-inflammatory, and anti-atherosclerotic factor in the vascular system. Pleiotropic effects regarding brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were also reported. In this review, we discuss the current evidence underlying the pleiotropic effects of NPs, underlying their importance in cardiovascular homeostasis.


Brain volumes in late life: gender, hormone treatment, and estrogen receptor variants.
Structural imaging studies suggest gender differences in brain volumes; however, whether hormone treatment (HT) can protect against age-related structural changes remains unknown, and no prior neuroimaging study has investigated potential interactions between HT and estrogen receptor (ESR) polymorphisms. Magnetic resonance imaging was used to measure gray and white matter, hippocampal volume, corpus callosum, cerebrospinal fluid (CSF), total intracranial volume (ICV) and white matter lesions (WML) in 582 non-demented older adults. In multivariable analysis, when compared to women who had never used HT, men and women currently on treatment, but not past users, had significantly smaller ratios of gray matter to ICV and increased atrophy (CSF/ICV ratio). Hippocampal and white matter volume as well as the corpus callosum area were not significantly different across groups. ESR2 variants were not significantly associated with brain measures, but women with the ESR1 rs2234693 C allele had significantly smaller WML. Furthermore this association was modified by HT use. Our results do not support a beneficial effect of HT on brain volumes in older women, but suggest the potential involvement of ESR1 in WML.


Pressure effects on the structures and electronic properties of halide perovskite CsPbX3 (X = I, Br, Cl).
Cesium lead halide perovskites as ideal photovoltaic and optoelectronics materials have attracted more and more attention. Here, we investigated the structure and electronic properties of halide perovskite CsPbX3 (X = I, Br, Cl) by particle swarm optimization and first principles methods at hydrostatic pressure. For CsPbI3, the structure phases and corresponding phase transitions of non-perovskite orthorhombic Pnma (non-Pv-Pnma), monoclinic C2/m (C2/m-I), and another different monoclinic phase C2/m (C2/m-II) are found in the pressure range 0-120 GPa. The largest piezochromic effect in the perovskites can be predicted in CsPbI3 under a pressure below 10 GPa. The band gap is reduced under pressure and the C2/m-II phase becomes a metal under pressures larger than 65 GPa. For CsPbBr3 and CsPbCl3, the same phase sequence under pressure, i.e. from perovskite Pnma (Pv-Pnma), to non-Pv-Pnma, C2/m-I, and then to another orthorhombic Cmcm phase, is found. The newly discovered non-Pv-Pnma phase gives an excellent explanation of previous measurements at low pressure for CsPbBr3 and CsPbCl3. Furthermore, the calculations of electronic properties show that pressure is an effective means to tune the band gap. Our calculations and results extend the applications in photovoltaics and optoelectronics of halide perovskites.


GeneMANIA prediction server 2013 update.
GeneMANIA (http://www.genemania.org) is a flexible user-friendly web interface for generating hypotheses about gene function, analyzing gene lists and prioritizing genes for functional assays. Given a query gene list, GeneMANIA extends the list with functionally similar genes that it identifies using available genomics and proteomics data. GeneMANIA also reports weights that indicate the predictive value of each selected data set for the query. GeneMANIA can also be used in a function prediction setting: given a query gene, GeneMANIA finds a small set of genes that are most likely to share function with that gene based on their interactions with it. Enriched Gene Ontology categories among this set can sometimes point to the function of the gene. Seven organisms are currently supported (Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Mus musculus, Homo sapiens, Rattus norvegicus and Saccharomyces cerevisiae), and hundreds of data sets have been collected from GEO, BioGRID, IRefIndex and I2D, as well as organism-specific functional genomics data sets. Users can customize their search by selecting specific data sets to query and by uploading their own data sets to analyze.