Fostering futures: a preventive intervention program for school-age children in foster care.
Children in foster care have social and emotional problems at rates three to ten times higher than those found in the general population. During the elementary school years (i.e. 5-12 years), research indicates that disruptive behavior in children in care can negatively impact social, emotional and academic development, as well as placement stability. Evidenced-based interventions to improve children's behavior and reduce parenting stress are necessary. This pilot study augmented an existing evidenced-based intervention (i.e. the Incredible Years) developed for birth families for use with foster caregivers. Results from 18 families indicate that foster caregiver-reported conduct symptoms were significantly lower for children whose families participated in the treatment group. A similar trend was found for the overall externalizing behavior. No significant changes were identified in parenting attitudes and stress. Participants reported high levels of satisfaction and acceptability with the program and outcomes. These findings indicate that foster caregiver training should be examined in larger, randomized control trials.


Direct detection and differentiation of fastidious and nonfastidious adenoviruses in stools by using a specific nonradioactive probe.
Restriction fragments of fastidious human adenovirus type 41 (Ad41) were cloned in vector plasmid pBR322. A rapid and sensitive nonradioactive molecular-hybridization technique (M. Renz and C. Kurz, Nucleic Acids Res. 12:3435-3444, 1984) showed that one clone specifically detected fastidious Ad40 and Ad41 (subgenus F) without cross-hybridization with nonfastidious adenoviruses. This clone was mapped in a region of the Ad41 genome corresponding to early transcription unit E1B of Ad2. A number of DNAs from fastidious and nonfastidious adenoviruses were extracted, without cultivation, from stools of children with gastroenteritis and were hybridized with an Ad2 probe and with the cloned probe, allowing the differentiation of the two groups of viruses. This method could detect DNA quantities as low as 10 pg and should be particularly suitable for stool samples containing adenoviral DNA in amounts too low to be detected by staining with ethidium bromide.


Compensatory dynamics stabilize aggregate community properties in response to multiple types of perturbations.
Compensatory dynamics are an important suite of mechanisms that can stabilize community and ecosystem attributes in systems subject to environmental fluctuations. However, few experimental investigations of compensatory dynamics have addressed these mechanisms in systems of real-world complexity, and existing evidence relies heavily on correlative analyses, retrospective examination, and experiments in simple systems. We investigated the potential for compensatory dynamics to stabilize plankton communities in plankton mesocosm systems of real-world complexity. We employed four types of perturbations including two types of nutrient pulses, shading, and acidification. To quantify how communities responded to these perturbations, we used a measure of community-wide synchrony combined with spectral analysis that allowed us to assess timescale-specific community dynamics, for example, whether dynamics were synchronous at some timescales but compensatory at others. The 150-d experiment produced 32-point time series of all zooplankton taxa in the mesocosms. We then used those time series to evaluate total zooplankton biomass as an aggregate property and to evaluate community dynamics. For three of our four perturbation types, total zooplankton biomass was significantly less variable in systems with environmental variation than in constant environments. For the same three perturbation types, community-wide synchrony was much lower in fluctuating environments than in the constant environment, particularly at longer timescales (periods ≈ 60 d). Additionally, there were strong negative correlations between population temporal variances and the level of community-wide synchrony. Taken together, these results strongly imply that compensatory interactions between species stabilized total biomass in response to perturbations. Diversity did not differ significantly across either treatments or perturbation types, thus ruling out several classes of mechanisms driven by changes in diversity. We also used several pieces of secondary evidence to evaluate the particular mechanism behind compensatory responses since a wide variety of mechanisms are hypothesized to produce compensatory dynamics. We concluded that fluctuation dependent endogenous cycles that occur as a consequence of consumer-resource interactions in competitive communities were the most likely explanation for the compensatory dynamics observed in our experiment. As with our previous work, scale-dependent dynamics were also a key to understanding compensatory dynamics in these experimental communities.


Vane emargination of outer tail feathers improves flight manoeuvrability in streamerless hirundines, Hirundinidae.
Recent studies have suggested that the proximal part of the swallow (Hirundo rustica) tail streamer appears to aid turning flight, as expected if streamers evolved initially purely through natural selection for enhanced manoeuvrability. However, the evolution of slender aerodynamically advantageous streamers is also predicted by an alternative hypothesis, which suggests that such a trait could develop primarily to ameliorate the aerodynamic cost of a long size-dimorphic tail. To distinguish between these hypotheses, we have investigated for the effect on manoeuvrability of trimming the tips of the outer tail feathers into short streamers, without lengthening these feathers, in two streamerless hirundine species--the house martin (Delichon urbica) and the sand martin (Riparia riparia). This allowed us to examine the aerodynamic costs and benefits of streamers at an early evolutionary stage that predates elongation of the outermost tail feathers through female choice. We showed that such initial streamers enhance manoeuvrability in streamerless hirundines, confirming the findings of recent studies. However, in contrast to these studies, we showed that improved manoeuvrability resulting from streamers could arise before the outermost tail feathers have become elongated (e.g. owing to female choice). The occurrence of such an aerodynamic advantage depends on the ancestral shape of a forked tail. This provides support for the hypothesis that streamers, like those in the barn swallow, might evolve initially purely through natural selection for enhanced manoeuvrability.


The JNK/AP-1 pathway upregulates expression of the recycling endosome rab11a gene in B cells transformed by Theileria.
Lymphocyte transformation induced by Theileria parasites involves constitutive activation of c-Jun N-terminal kinase (JNK) and the AP-1 transcription factor. We found that JNK/AP-1 activation is associated with elevated levels of Rab11 protein in Theileria-transformed B cells. We show that AP-1 regulates rab11a promoter activity in B cells and that the induction of c-Jun activity in mouse fibroblasts also leads to increased transcription of the endogenous rab11a gene, consistent with it being an AP-1 target. Pharmacological inhibition of the JNK pathway reduced Rab11 protein levels and endosome recycling of transferrin receptor (TfR) and siRNA knockdown of JNK1 and Rab11A levels also reduced TfR surface expression. We propose a model, where activation of the JNK/AP-1 pathway during cell transformation might assure that the regulation of recycling endosomes is co-ordinated with cell-cycle progression. This might be achieved via the simultaneous upregulation of the cell cycle machinery (e.g. cyclin D1) and the recycling endosome regulators (e.g. Rab11A).


Proton pump inhibitor-induced neutropenia: possible cross-reactivity between omeprazole and pantoprazole.
Proton pump inhibitors (PPIs) are widely used drugs in the treatment or prophylaxis of peptic ulcer and gastro-oesophageal reflux disease. In addition to their well documented efficacy, these drugs are generally well tolerated with only rare serious adverse effects having been reported. Neutropenia and agranulocytosis are rare adverse events associated with PPI treatment. All previously published cases of isolated neutropenia have involved omeprazole, but leukopenia is labelled as a possible adverse effect in the summary of product characteristics of the other PPIs. In this report, we describe a case of omeprazole-induced neutropenia with further recurrence upon pantoprazole treatment. A 60-year-old man with chronic alcoholism and a medical history of pulmonary tuberculosis, untreated chronic C hepatitis, peripheral artery disease, chronic obstructive pulmonary disease and stable stage 3 chronic kidney disease was admitted with dehydration and malnutrition. Omeprazole 20 mg/day and sucralfate 3 g/day were started for diffuse gastritis on gastric endoscopy. While the patient's blood cell count had been within the normal range before this treatment, routine laboratory examination revealed moderate neutropenia (0.9 x 109/L) after 9 days of treatment. His blood cell count returned to the normal range after discontinuation of omeprazole and no further episodes of neutropenia were noted in the following months. One year later, oesophago-gastroscopy revealed a hiatal hernia with an extensive zone of Barrett's oesophagus. As the lesions did not improve with ranitidine and sucralfate therapy, the patient was started on pantoprazole 40 mg/day. His initial white blood cell count was normal, but moderate neutropenia (0.8 x 109/L) was again noted after only 2 days of pantoprazole treatment. Complete and further stable normalization was obtained within 3 days after replacement of pantoprazole with ranitidine. Toxic and immune-mediated mechanisms are the two commonly proposed mechanisms to explain the pathogenesis of drug-induced neutropenia. This report suggests that PPI-induced neutropenia is immune mediated and argues for a possible cross-reactivity between the two PPIs, as has already been described for PPI-induced hypersensitivity reactions. The report also indicates that patients with a history of neutropenia induced by one PPI may be at risk of recurrence of neutropenia if given another member of this drug class. In these patients, close haematological monitoring is proposed.


Comparative Analysis of the Regulatory T Cells Dynamics in Peripheral Blood in Human and Porcine Polytrauma.
Severely injured patients experience substantial immunological stress in the aftermath of traumatic insult, which often results in systemic immune dysregulation. Regulatory T cells (Treg) play a key role in the suppression of the immune response and in the maintenance of immunological homeostasis. Little is known about their presence and dynamics in blood after trauma, and nothing is known about Treg in the porcine polytrauma model. Here, we assessed different subsets of Treg in trauma patients (TP) and compared those to either healthy volunteers (HV) or data from porcine polytrauma. Peripheral blood was withdrawn from 20 TP with injury severity score (ISS) ≥16 at the admittance to the emergency department (ED), and subsequently on day 1 and at day 3. Ten HV were included as controls (ctrl). The porcine polytrauma model consisted of a femur fracture, liver laceration, lung contusion, and hemorrhagic shock resulting in an ISS of 27. After polytrauma, the animals underwent resuscitation and surgical fracture fixation. Blood samples were withdrawn before and immediately after trauma, 24 and 72 h later. Different subsets of Treg, CD4+CD25+, CD4+CD25+FoxP3+, CD4+CD25+CD127-, and CD4+CD25+CD127-FoxP3+ were characterized by flow cytometry. Absolute cell counts of leukocytes were significantly increasing after trauma, and again decreasing in the follow-up in human and porcine samples. The proportion of human Treg in the peripheral blood of TP admitted to the ED was lower when compared to HV. Their numbers did not recover until 72 h after trauma. Comparable data were found for all subsets. The situation in the porcine trauma model was comparable with the clinical data. In porcine peripheral blood before trauma, we could identify Treg with the typical immunophenotype (CD4+CD25+CD127-), which were virtually absent immediately after trauma. Similar to the human situation, most of these cells expressed FoxP3, as assessed by intracellular FACS stain. Despite minor percental differences in the recovery of Treg populations after trauma, our findings show a comparable decrease of Treg early after polytrauma, and strengthen the immunological significance of the porcine polytrauma model. Furthermore, the Treg subpopulation CD4+CD25+CD127- was characterized in porcine samples.


Recent development of balloon-occluded retrograde transvenous obliteration.
Gastric varices (GVs) are a major complication of portal hypertension in patients with liver cirrhosis. The mortality rate associated with the bleeding from GVs is not low. Balloon-occluded retrograde transvenous obliteration (BRTO) was first introduced by Kanagawa et al. as a treatment for isolated GVs in 1994. It has been performed most frequently in Asia, especially in Japan. Ethanolamine oleate was the original sclerosant used in the therapy. Since the late 2000s, BRTO using sodium tetradecyl sulfate foam or polidocanol foam as a sclerosant has been performed in many countries other than Japan. Then, early in the 2010s, modified BRTO techniques including vascular plug-assisted retrograde transvenous obliteration and coil-assisted retrograde transvenous obliteration were developed as an alternative treatment for GVs. This article provides a historical overview of BRTO using various sclerosants and modified BRTO techniques, such as plug-assisted retrograde transvenous obliteration and coil-assisted retrograde transvenous obliteration.


Systematic account of animal poisonings in Germany, 2012-2015.
A systematic retrospective study on animal poisonings in Germany (wildlife excluded) between January 2012 and December 2015 was conducted. Data were collected on animal exposure calls to German poison centres, poisoning cases presenting to the University of Veterinary Medicine, Hannover Small Animal and Equine Clinics, cases involving off-label use of veterinary medicinal products reported to the Federal Office of Consumer Protection and Food Safety and toxicological submissions to the Institute of Pharmacology, Toxicology, and Pharmacy, Faculty of Veterinary Medicine, Ludwig-Maximilians-University, Munich. Descriptive statistics were used to characterise animal type, exposure reason, type and substance, year/month of exposure, case severity and outcome. An evaluation of the data and data sources was also carried out. Variation in poisoning patterns was seen. However, dogs and cats were the most frequently reported species and medicinal products, pesticides and plants were consistently implicated as top causes of poisoning. Advantages and disadvantages were associated with each data source; bias was found to be an important consideration when evaluating poisoning data. This study provided useful information on animal poisonings in Germany and highlights the need for standardised approaches for the collection, evaluation and integration of poisoning data from multiple sources.


Managing genomic variant calling workflows with Swift/T.
Bioinformatics research is frequently performed using complex workflows with multiple steps, fans, merges, and conditionals. This complexity makes management of the workflow difficult on a computer cluster, especially when running in parallel on large batches of data: hundreds or thousands of samples at a time. Scientific workflow management systems could help with that. Many are now being proposed, but is there yet the "best" workflow management system for bioinformatics? Such a system would need to satisfy numerous, sometimes conflicting requirements: from ease of use, to seamless deployment at peta- and exa-scale, and portability to the cloud. We evaluated Swift/T as a candidate for such role by implementing a primary genomic variant calling workflow in the Swift/T language, focusing on workflow management, performance and scalability issues that arise from production-grade big data genomic analyses. In the process we introduced novel features into the language, which are now part of its open repository. Additionally, we formalized a set of design criteria for quality, robust, maintainable workflows that must function at-scale in a production setting, such as a large genomic sequencing facility or a major hospital system. The use of Swift/T conveys two key advantages. (1) It operates transparently in multiple cluster scheduling environments (PBS Torque, SLURM, Cray aprun environment, etc.), thus a single workflow is trivially portable across numerous clusters. (2) The leaf functions of Swift/T permit developers to easily swap executables in and out of the workflow, which makes it easy to maintain and to request resources optimal for each stage of the pipeline. While Swift/T's data-level parallelism eliminates the need to code parallel analysis of multiple samples, it does make debugging more difficult, as is common for implicitly parallel code. Nonetheless, the language gives users a powerful and portable way to scale up analyses in many computing architectures. The code for our implementation of a variant calling workflow using Swift/T can be found on GitHub at https://github.com/ncsa/Swift-T-Variant-Calling, with full documentation provided at http://swift-t-variant-calling.readthedocs.io/en/latest/.


Immobilization of organophosphate hydrolase on biocompatible gelatin pads and its use in removal of organophosphate compounds and nerve agents.
Bacterial organophosphate hydrolases (OPH) have been shown to hydrolyze structurally diverse group of organophosphate (OP) compounds and nerve agents. Due to broad substrate range and unusual catalytic properties, the OPH has successfully been used to develop eco-friendly strategies for detection and decontamination of OP compounds. However, their usage has failed to gain necessary acceptance, due to short half-life of the enzyme and loss of activity during process development. In the present study, we report a simple procedure for immobilization of OPH on biocompatible gelatin pads. The covalent coupling of OPH using glutaraldehyde spacer has been found to dramatically improve the enzyme stability. There is no apparent loss of OPH activity in OPH-gelatin pads stored at room temperature for more than six months. As revealed by a number of kinetic parameters, the catalytic properties of immobilized enzyme are found to be comparable to the free enzyme. Further, the OPH-gelatin pads effectively eliminate OP insecticide methyl parathion and nerve agent sarin.


Functional imaging of emotion reactivity in opiate-dependent borderline personality disorder.
Opiate dependence (OD) and borderline personality disorder (BPD), separately and together, are significant public health problems with poor treatment outcomes. BPD is associated with difficulties in emotion regulation, and brain-imaging studies in BPD individuals indicate differential activation in prefrontal cingulate cortices and their interactions with limbic regions. Likewise, a similar network is implicated in drug cue responsivity in substance abusers. The present, preliminary study used functional MRI to examine activation of this network in comorbid OD/BPD participants when engaged in an "oddball" task that required attention to a target in the context of emotionally negative distractors. Twelve male OD/BPD participants and 12 male healthy controls participated. All OD/BPD participants were taking the opiate replacement medication Suboxone, and a subset of participants was positive for substances of abuse on scan day. Relative to controls, OD/BPD participants demonstrated reduced activation to negative stimuli in the amygdala and anterior cingulate. Unlike previous studies that demonstrated hyperresponsivity in neural regions associated with affective processing in individuals with BPD versus healthy controls, comorbid OD/BPD participants were hyporesponsive to emotional cues. Future studies that also include BPD-only and OD-only groups are necessary to help clarify the individual and potentially synergistic effects of these two conditions.


Immediate Complications of Elective Newborn Circumcision.
To determine the incidence of immediate complications of elective newborn circumcision in 2 community teaching hospitals. We performed a retrospective chart review of all term neonates who had circumcision performed between August 2011 and December 2014 at 2 community hospitals in New York. Neonatal hospital records and subsequent inpatient and outpatient records were reviewed. We classified complications as minor, intermediate, and major. Out of a total of 1115 circumcisions, 1064 met inclusion criteria. There were 41 complications (3.9%), all involving hemorrhage. Sutures were used to control hemorrhage in 3 patients (0.3%). Local pressure or application of hemostatic chemical agents controlled bleeding in the remainder of patients. Bleeding was more common with the use of the Gomco clamp than with the Mogen clamp. Circumcisions performed with Gomco clamp represented 73.2% of the total complications compared with 26.8% with the Mogen clamp. There were no injuries to structures outside the prepuce or problems requiring medical treatment after discharge from the neonatal hospitalization. The most common immediate complication encountered during an elective neonatal circumcision was bleeding that required only pressure or topical thrombin to achieve hemostasis. Bleeding was more common with the use of the Gomco versus the Mogen clamp. To conclude, our data support the theory that elective infant circumcision can be performed safely in a hospital setting.


Differential Covariance: A New Method to Estimate Functional Connectivity in fMRI.
Measuring functional connectivity from fMRI recordings is important in understanding processing in cortical networks. However, because the brain's connection pattern is complex, currently used methods are prone to producing false functional connections. We introduce differential covariance analysis, a new method that uses derivatives of the signal for estimating functional connectivity. We generated neural activities from dynamical causal modeling and a neural network of Hodgkin-Huxley neurons and then converted them to hemodynamic signals using the forward balloon model. The simulated fMRI signals, together with the ground-truth connectivity pattern, were used to benchmark our method with other commonly used methods. Differential covariance achieved better results in complex network simulations. This new method opens an alternative way to estimate functional connectivity.


Novel insight into the agonistic mechanism of alefacept in vivo: differentially expressed genes may serve as biomarkers of response in psoriasis patients.
Alefacept is an LFA3-Ig fusion protein that binds to CD2 and is thought to inhibit T cell activation by antagonism of CD2 signaling or by lysis of CD2(+) cells. Alefacept is potential future therapeutic for organ transplant recipients or graft-vs-host disease and is an approved therapeutic for psoriasis vulgaris, which is a T cell-mediated inflammatory disease. However, alefacept improves psoriasis in only approximately 50% of patients treated for 12 wk. We studied the immunologic effects of alefacept in a group of psoriasis patients during treatment. We found that T cells, especially CD8(+) T cells, were rapidly decreased in the peripheral circulation. Decreases in circulating T cells were not associated with induced apoptosis. Unexpectedly, in addition to suppression of inflammatory genes, we found a marked induction of mRNAs for STAT1, IL-8, and monokine induced by IFN-gamma during the first day of treatment in PBMC. We confirmed the agonistic effects of alefacept in PBMC in vitro, which were similar to CD3/CD28 ligation on T cells. These data establish that alefacept activates gene expression programs in leukocytes and suggest that its therapeutic action may be as a mixed agonist/antagonist. Furthermore, responding patients to alefacept treatment show unique patterns of gene modulation. Whereas alefacept down-regulated TCRs CD3D and CD2 in responders, nonresponders reveal a higher expression of T cell activation genes such as CD69 in pretreatment PBMC. These finding suggest a potential basis for categorizing responders vs nonresponders at an early time point in treatment or before treatment of a broad range of proinflammatory diseases. This study 1) establishes alefacept as a novel CD2 agonist molecule for induction of leukocyte activation genes (prior work proposed its mechanism as a CD2 antagonist) and 2) that differential activation of genes may categorize clinical responders to this agent, critical for cost-effective use of this drug.


H2A.Z demarcates intergenic regions of the plasmodium falciparum epigenome that are dynamically marked by H3K9ac and H3K4me3.
Epigenetic regulatory mechanisms and their enzymes are promising targets for malaria therapeutic intervention; however, the epigenetic component of gene expression in P. falciparum is poorly understood. Dynamic or stable association of epigenetic marks with genomic features provides important clues about their function and helps to understand how histone variants/modifications are used for indexing the Plasmodium epigenome. We describe a novel, linear amplification method for next-generation sequencing (NGS) that allows unbiased analysis of the extremely AT-rich Plasmodium genome. We used this method for high resolution, genome-wide analysis of a histone H2A variant, H2A.Z and two histone H3 marks throughout parasite intraerythrocytic development. Unlike in other organisms, H2A.Z is a constant, ubiquitous feature of euchromatic intergenic regions throughout the intraerythrocytic cycle. The almost perfect colocalisation of H2A.Z with H3K9ac and H3K4me3 suggests that these marks are preferentially deposited on H2A.Z-containing nucleosomes. By performing RNA-seq on 8 time-points, we show that acetylation of H3K9 at promoter regions correlates very well with the transcriptional status whereas H3K4me3 appears to have stage-specific regulation, being low at early stages, peaking at trophozoite stage, but does not closely follow changes in gene expression. Our improved NGS library preparation procedure provides a foundation to exploit the malaria epigenome in detail. Furthermore, our findings place H2A.Z at the cradle of P. falciparum epigenetic regulation by stably defining intergenic regions and providing a platform for dynamic assembly of epigenetic and other transcription related complexes.


Midcycle administration of a progesterone synthesis inhibitor prevents ovulation in primates.
Progesterone receptors appear in granuloma cells of preovulatory follicles after the midcycle gonadotropin surge, suggesting important local actions of progesterone during ovulation in primates. Steroid reduction and replacement during the gonadotropin surge in macaques was used to evaluate the role of progesterone in the ovulatory process. Animals received gonadotropins to induce development of multiple preovulatory follicles, followed by human chorionic gonadotropin (hCG) administration (day 0) to promote oocyte (nuclear) maturation, ovulation, and follicular luteinization. On days 0-2, animals received no further treatment; a steroid synthesis inhibitor, trilostane (TRL); TRL + R5020; or TRL + dihydrotestosterone propionate (DHT). On day 3, ovulation was confirmed by counting ovulation sites and collecting oviductal oocytes. The meiotic status of oviductal and remaining follicular oocytes was evaluated. Peak serum estradiol levels, the total number of large follicles, and baseline serum progesterone levels at the time of hCG administration were similar in all animals. Ovulation sites and oviductal oocytes were routinely observed in controls. Ovulation was abolished in TRL. Progestin, but not androgen, replacement restored ovulation. Relative to controls, progesterone production was impaired for the first 6 days post-hCG in TRL, TRL + R5020, and TRL + DHT. Thereafter, progesterone remained low in TRL but recovered to control levels with progestin and androgen replacement. Similar percentages of mature (metaphase II) oocytes were collected among groups. Thus, steroid reduction during the gonadotropin surge inhibited ovulation and luteinization, but not reinitiation of oocyte meiotic maturation, in the primate follicle. The data are consistent with a local receptor-mediated role for progesterone in the ovulatory process.


The Mutational Landscape of Circulating Tumor Cells in Multiple Myeloma.
The development of sensitive and non-invasive "liquid biopsies" presents new opportunities for longitudinal monitoring of tumor dissemination and clonal evolution. The number of circulating tumor cells (CTCs) is prognostic in multiple myeloma (MM), but there is little information on their genetic features. Here, we have analyzed the genomic landscape of CTCs from 29 MM patients, including eight cases with matched/paired bone marrow (BM) tumor cells. Our results show that 100% of clonal mutations in patient BM were detected in CTCs and that 99% of clonal mutations in CTCs were present in BM MM. These include typical driver mutations in MM such as in KRAS, NRAS, or BRAF. These data suggest that BM and CTC samples have similar clonal structures, as discordances between the two were restricted to subclonal mutations. Accordingly, our results pave the way for potentially less invasive mutation screening of MM patients through characterization of CTCs.


Bioinformatics classification and functional analysis of PhoH homologs.
PhoH protein is a putative ATPase belonging to the phosphate regulon in Escherichia coli. EC-PhoH homologs are present in different organisms, but it is not clear if they are functionally related, besides nothing is known about their regulation. To distinguish true functional orthologs of EC-PhoH in different classes of bacteria and to identify their functional role in bacterial metabolic network we performed phylogenetic analysis of these proteins and comparative study of position and regulation of the related genes. Three groups of proteins were identified. Proteins of the first group (BS-PhoH orthologs) are present in most of bacteria and are proposed to be functionally linked to phospholipid metabolism and RNA modification. Proteins of the second group (BS-YlaK orthologs) are present in most of aerobes and Actinobacterial YlaK orthologs are shown to be members of a fatty acid beta-oxidation regulons. EC-PhoH orthologs are classified in a third group, specific for Enterobacteria. Functional role of PhoH homologs in the lipid and RNA metabolism and proposed interrelation of PhoH paralogs in one organism are discussed.


The relationship between fear and pain levels during needle procedures in children from the parents' perspective.
The primary objective was to determine the levels of and potential relationships between procedure-related fear and pain in children. Secondary objectives were to determine if there are associations between the child's age and sex, diagnostic group, time since diagnosis, time since last needle insertion, cortisol levels and the parent's fear level in relation to fear and pain. The child's level of pain and fear was reported by parents on 0-100 mm visual analogue scales (VAS). One hundred and fifty-one children were included consecutively when undergoing routine needle insertion into a subcutaneously implanted intravenous port. All children were subjected to one needle insertion following topical anaesthesia (EMLA) application. The effect of the child's age and sex, diagnostic group, time since diagnosis, time since last needle insertion, cortisol change levels and the parent's fear level, on fear and pain levels was investigated with multiple regression analysis. The needle-related fear level (VAS mean 28 mm) was higher than the needle-related pain level (VAS mean 17 mm) when topical anaesthesia is used according to parents' reports (n = 151, p < 0.001). With fear as the dependent variable, age and pain were significantly associated and explained 33% of the variance, and with pain as the dependent variable, fear, parents' fear and change in cortisol level were significantly associated and explained 38% of the variance. According to parents, children experienced more fear than pain during needle insertion when topical anaesthesia is used. Therefore, in addition to pain management, an extended focus on fear-reducing interventions is suggested for needle procedures.


Zyxin, a regulator of actin filament assembly, targets the mitotic apparatus by interacting with h-warts/LATS1 tumor suppressor.
The mitotic apparatus plays a pivotal role in dividing cells to ensure each daughter cell receives a full set of chromosomes and complement of cytoplasm during mitosis. A human homologue of the Drosophila warts tumor suppressor, h-warts/LATS1, is an evolutionarily conserved serine/threonine kinase and a dynamic component of the mitotic apparatus. We have identified an interaction of h-warts/LATS1 with zyxin, a regulator of actin filament assembly. Zyxin is a component of focal adhesion, however, during mitosis a fraction of cytoplasmic-dispersed zyxin becomes associated with h-warts/LATS1 on the mitotic apparatus. We found that zyxin is phosphorylated specifically during mitosis, most likely by Cdc2 kinase, and that the phosphorylation regulates association with h-warts/LATS1. Furthermore, microinjection of truncated h-warts/LATS1 protein, including the zyxin-binding portion, interfered with localization of zyxin to mitotic apparatus, and the duration of mitosis of these injected cells was significantly longer than that of control cells. These findings suggest that h-warts/LATS1 and zyxin play a crucial role in controlling mitosis progression by forming a regulatory complex on mitotic apparatus.


Heterosubtypic immunity to H7N9 influenza virus in isogenic guinea pigs after infection with pandemic H1N1 virus.
Heterosubtypic immunity is defined as immune-mediated (partial) protection against an influenza virus induced by an influenza virus of another subtype to which the host has not previously been exposed. This cross-protective effect has not yet been demonstrated to the newly emerging avian influenza A viruses of the H7N9 subtype. Here, we assessed the induction of protective immunity to these viruses by infection with A(H1N1)pdm09 virus in a newly developed guinea pig model. To this end, ten female 12-16 week old strain 2 guinea pigs were inoculated intratracheally with either A(H1N1)pdm09 influenza virus or PBS (unprimed controls) followed 4 weeks later with an A/H7N9 influenza virus challenge. Nasal swabs were taken daily and animals from both groups were sacrificed on days 2 and 7 post inoculation (p.i.) with A/H7N9 virus and full necropsies were performed. Nasal virus excretion persisted until day 7 in unprimed control animals, whereas only two out of seven H1N1pdm09-primed animals excreted virus via the nose. Infectious virus was recovered from nasal turbinates, trachea and lung of all animals at day 2 p.i., but titers were lower for H1N1pdm09-primed animals, especially in the nasal turbinates. By day 7 p.i., relatively high virus titers were found in the nasal turbinates of all unprimed control animals but infectious virus was isolated from the nose of only one of four H1N1pdm09-primed animals. Animals of both groups developed inflammation of variable severity in the entire respiratory tract. Viral antigen positive cells were demonstrated in the nasal epithelium of both groups at day 2. The bronchi(oli) and alveoli of unprimed animals showed a moderate to strong positive signal at day 2, whereas H1N1pdm09-primed animals showed only minimal positivity. By day 7, only viral antigen positive cells were found after H7N9 virus infection in the nasal turbinates and the lungs of unprimed controls. Thus infection with H1N1pdm09 virus induced partially protective heterosubtypic immunity to H7N9 virus in (isogenic) guinea pigs that could not be attributed to cross-reactive virus neutralizing antibodies.


OPRM1 SNP (A118G): involvement in disease development, treatment response, and animal models.
Endogenous opioids acting at mu-opioid receptors mediate many biological functions. Pharmacological intervention at these receptors has greatly aided in the treatment of acute and chronic pain, in addition to other uses. However, the development of tolerance and dependence has made it difficult to adequately prescribe these therapeutics. A common single nucleotide polymorphism (SNP), A118G, in the mu-opioid receptor gene can affect opioid function and, consequently, has been suggested to contribute to individual variability in pain management and drug addiction. Investigation into the role of A118G in human disease and treatment response has generated a large number of association studies across various disease states as well as physiological responses. However, characterizing the functional consequences of this SNP and establishing if it causes or contributes to disease phenotypes have been significant challenges. In this manuscript, we will review a number of association studies as well as investigations of the functional impact of this gene variant. In addition, we will describe a novel mouse model that was generated to recapitulate this SNP in mice. Evaluation of models that incorporate known human genetic variants into a tractable system, like the mouse, will facilitate the understanding of discrete contributions of SNPs to human disease.


Light availability and rhizobium variation interactively mediate the outcomes of legume-rhizobium symbiosis.
Nutrients, light, water, and temperature are key factors limiting the growth of individual plants in nature. Mutualistic interactions between plants and microbes often mediate resource limitation for both partners. In the mutualism between legumes and rhizobia, plants provide rhizobia with carbon in exchange for fixed nitrogen. Because partner quality in mutualisms is genotype-dependent, within-species genetic variation is expected to alter the responses of mutualists to changes in the resource environment. Here we ask whether partner quality variation in rhizobia mediates the response of host plants to changing light availability, and conversely, whether light alters the expression of partner quality variation. We inoculated clover hosts with 11 strains of Rhizobium leguminosarum that differed in partner quality, grew plants under either ambient or low light conditions in the greenhouse, and measured plant growth, nodule traits, and foliar nutrient composition. Light availability and rhizobium inoculum interactively determined plant growth, and variation in rhizobium partner quality was more apparent in ambient light. Our results suggest that variation in the costs and benefits of rhizobium symbionts mediate host responses to light availability and that rhizobium strain variation might more important in higher-light environments. Our work adds to a growing appreciation for the role of microbial intraspecific and interspecific diversity in mediating extended phenotypes in their hosts and suggests an important role for light availability in the ecology and evolution of legume-rhizobium symbiosis.


Spectral Identification in the Attogram Regime through Laser-Induced Emission of Single Optically Trapped Nanoparticles in Air.
Current trends in nanoengineering are bringing along new structures of diverse chemical compositions that need to be meticulously defined in order to ensure their correct operation. Few methods can provide the sensitivity required to carry out measurements on individual nano-objects without tedious sample pre-treatment or data analysis. In the present study, we introduce a pathway for the elemental identification of single nanoparticles (NPs) that avoids suspension in liquid media by means of optical trapping and laser-induced plasma spectroscopy. We demonstrate spectroscopic detection and identification of individual 25(±3.7) to 70(±10.5) nm in diameter Cu NPs stably trapped in air featuring masses down to 73±35 attograms. We found an increase in the absolute number of photons produced as size of the particles decreased; pointing towards a more efficient excitation of ensembles of only ca. 7×105 Cu atoms in the onset plasma.


A prospective study of transmission of Multidrug-Resistant Organisms (MDROs) between environmental sites and hospitalized patients-the TransFER study.
Hospital environmental surfaces are frequently contaminated by microorganisms. However, the causal mechanism of bacterial contamination of the environment as a source of transmission is still debated. This prospective study was performed to characterize the nature of multidrug-resistant organism (MDRO) transmission between the environment and patients using standard microbiological and molecular techniques. Prospective cohort study at 2 academic medical centers. A prospective multicenter study to characterize the nature of bacterial transfer events between patients and environmental surfaces in rooms that previously housed patients with 1 of 4 'marker' MDROs: methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Clostridium difficile, and MDR Acinetobacter baumannii. Environmental and patient microbiological samples were obtained on admission into a freshly disinfected inpatient room. Repeat samples from room surfaces and patients were taken on days 3 and 7 and each week the patient stayed in the same room. The bacterial identity, antibiotic susceptibility, and molecular sequences were compared between organisms found in the environment samples and patient sources. We enrolled 80 patient-room admissions; 9 of these patients (11.3%) were asymptomatically colonized with MDROs at study entry. Hospital room surfaces were contaminated with MDROs despite terminal disinfection in 44 cases (55%). Microbiological Bacterial Transfer events either to the patient, the environment, or both occurred in 12 patient encounters (18.5%) from the microbiologically evaluable cohort. Microbiological Bacterial Transfer events between patients and the environment were observed in 18.5% of patient encounters and occurred early in the admission. This study suggests that research on prevention methods beyond the standard practice of room disinfection at the end of a patient's stay is needed to better prevent acquisition of MDROs through the environment.


Epidemiological dynamics of Ebola outbreaks.
Ebola is a deadly virus that causes frequent disease outbreaks in the human population. In this study, we analyse its rate of new introductions, case fatality ratio, and potential to spread from person to person. The analysis is performed for all completed outbreaks and for a scenario where these are augmented by a more severe outbreak of several thousand cases. The results show a fast rate of new outbreaks, a high case fatality ratio, and an effective reproductive ratio of just less than 1.


Expression of nesfatin-1/NUCB2 in rodent digestive system.
To observe the regional distributions and morphological features of nesfatin-1/nucleobindin-2 (NUCB2) immunoreactive (IR) cells in the rodent digestive system. Paraffin-embedded sections of seven organs (pancreas, stomach, duodenum, esophagus, liver, small intestine and colon) dissected from sprague-dawley (SD) rats and imprinting-control-region (ICR) mice were prepared. The regional distributions of nesfatin-1/NUCB2 IR cells were observed by immunohistochemical staining. The morphological features of the nesfatin-1/NUCB2 IR cells were evaluated by hematoxylin and eosin (HE) staining. Fresh tissues of the seven organs were prepared for Western blotting to analyze the relative protein levels of NUCB2 in each organ. Immunohistochemical staining showed that the nesfatin-1/NUCB2 IR cells were localized in the central part of the pancreatic islets, the lower third and middle portion of the gastric mucosal gland, and the submucous layer of the duodenum in SD rats and ICR mice. HE staining revealed that the morphological features of nesfatin-1/NUCB2 IR cells were mainly islet cells in the pancreas, endocrine cells in the stomach, and Brunner's glands in the duodenum. Western blotting revealed that NUCB2 protein expression was higher in the pancreas, stomach and duodenum than in the esophagus, liver, small intestine and colon (P = 0.000). Nesfatin-1/NUCB2 IR cells are expressed in the pancreas, stomach and duodenum in rodents. These cells may play an important role in the physiological regulation of carbohydrate metabolism, gastrointestinal function and nutrient absorption.


Mixed anhydride complexes of rhodium(I) and ruthenium(II) - their synthesis and ligand rearrangements.
The coordination chemistry and solution behaviour of Rh(i) and Ru(ii) complexes derived from mixed anhydride ligands of carboxylic acids and phosphorus acids were explored. Similar to the free ligand systems, mixed anhydride complexes rearranged in solution via a number of pathways, with the pathway of choice dependent on the mixed anhydride employed, the auxiliary ligands present as well as the nature of the metal centre. Plausible mechanisms for some of the routes of rearrangement and by-product formation are proposed. Where stability allowed, new complexes were fully characterised, including solid state structures for four of the unrearranged mixed anhydride complexes and two of the interesting rearrangement products.


Aqueous-methanolic extract of sweet flag (Acorus calamus) possesses cardiac depressant and endothelial-derived hyperpolarizing factor-mediated coronary vasodilator effects.
This investigation was aimed to probe the pharmacological base of medicinal use of Acorus calamus in ischemic heart diseases. Effect on heart parameters was studied in isolated rabbit heart while coronary vasodilator effect was studied in isolated bovine coronary arterial rings, suspended in tissue baths filled with Krebs solution, maintained at 37°C, aerated with carbogen and responses were measured on PowerLab data acquisition system. In Langendorrf's perfused rabbit heart, the crude extract of Acorus calamus (Ac.Cr) at 0.01-10 mg/mL partially suppressed force of ventricular contractions (FVC), heart rate (HR) and coronary flow (CF). The ethylacetate fraction completely suppressed FVC, partially suppressed HR and CF, while the nHexane fraction exhibited similar effect on FVC and HR but increased CF, similar to methacholine and arachidonic acid. In bovine coronary arterial preparations, Ac.Cr caused inhibition of U46619 (20 nM)-precontractions, which was blocked in presence of increasing concentration of K(+) (4.8-20 mM), tetraethylammonium (1 μM) and SKF525A (10 μM), similar to arachidonic acid and methacholine, indicating K(+) channels activation and possible involvement of endothelial-derived hyperpolarizing factor (EDHF). Activity-directed fractionation revealed that EDHF-mediated activity is concentrated in the nHexane fraction. When tested against high K(+), the ethylacetate fraction was found more potent than parent crude extract and nHexane fraction. These data indicate that Ac.Cr mediates coronary vasodilator effect primarily through EDHF, responsible for the increase in CF, while the cardiac depressant effects may be due to the presence of additional cardiac depressant constituent(s), thus provides possible mechanistic basis to its medicinal use in ischemic heart diseases.


A systematic review and meta-analysis of changes in body weight in clinical trials of vegetarian diets.
In observational studies, vegetarians generally have lower body weights compared with omnivores. However, weight changes that occur when vegetarian diets are prescribed have not been well quantified. We estimated the effect on body weight when vegetarian diets are prescribed. We searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials for articles through December 31, 2013. Additional articles were identified from reference lists. We included intervention trials in which participants were adults, interventions included vegetarian diets of ≥4 weeks' duration without energy intake limitations, and effects on body weight were reported. Two investigators independently extracted data using predetermined fields. Estimates of body weight change, comparing intervention groups to untreated control groups, were derived using a random effects model to estimate the weighted mean difference. To quantify effects on body weight of baseline weight, sex, age, study duration, study goals, type of diet, and study authorship, additional analyses examined within-group changes for all studies reporting variance data. We identified 15 trials (17 intervention groups), of which 4 included untreated controls. Prescription of vegetarian diets was associated with a mean weight change of -3.4 kg (95% CI -4.4 to -2.4; P<0.001) in an intention-to-treat analysis and -4.6 kg (95% CI -5.4 to -3.8; P<0.001) in a completer analysis (omitting missing post-intervention values). Greater weight loss was reported in studies with higher baseline weights, smaller proportions of female participants, older participants, or longer durations, and in studies in which weight loss was a goal. Using baseline data for missing values, I(2) equaled 52.3 (P=0.10), indicating moderate heterogeneity. When missing data were omitted, I(2) equaled 0 (P=0.65), indicating low heterogeneity. Studies are relatively few, with variable quality. The prescription of vegetarian diets reduces mean body weight, suggesting potential value for prevention and management of weight-related conditions.


WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1-CUL4-ROC1 ligase.
Tuberous sclerosis (TSC) is an autosomal dominant disease characterized by hamartoma formation in various organs and is caused by mutations targeting either the TSC1 or TSC2 genes. TSC1 and TSC2 proteins form a functionally interdependent dimeric complex. Phosphorylation of either TSC subunit by different kinases regulates the function of TSC and represents a major mechanism to integrate various signals into a centralized cell growth pathway. The majority of disease-associated mutations targeting either TSC1 or TSC2 results in a substantial decrease in protein level, suggesting that protein turnover also plays a critical role in TSC regulation. Here we report that TSC2 protein binds to FBW5, a DDB1-binding WD40 (DWD) protein, and is recruited by FBW5 to the DDB1-CUL4-ROC1 E3 ubiquitin ligase. Overexpression of FBW5 or CUL4A promotes TSC2 protein degradation, and this is abrogated by the coexpression of TSC1. Conversely, depletion of FBW5, DDB1, or CUL4A/B stabilizes TSC2. Ddb1 or Cul4 mutations in Drosophila result in Gigas/TSC2 protein accumulation and cause growth defects that can be partially rescued by Gigas/Tsc2 reduction. These results indicate that FBW5-DDB1-CUL4-ROC1 is an E3 ubiquitin ligase regulating TSC2 protein stability and TSC complex turnover.


A Tubulin Binding Switch Underlies Kip3/Kinesin-8 Depolymerase Activity.
Kinesin-8 motors regulate the size of microtubule structures, using length-dependent accumulation at the plus end to preferentially disassemble long microtubules. Despite extensive study, the kinesin-8 depolymerase mechanism remains under debate. Here, we provide evidence for an alternative, tubulin curvature-sensing model of microtubule depolymerization by the budding yeast kinesin-8, Kip3. Kinesin-8/Kip3 uses ATP hydrolysis, like other kinesins, for stepping on the microtubule lattice, but at the plus end Kip3 undergoes a switch: its ATPase activity is suppressed when it binds tightly to the curved conformation of tubulin. This prolongs plus-end binding, stabilizes protofilament curvature, and ultimately promotes microtubule disassembly. The tubulin curvature-sensing model is supported by our identification of Kip3 structural elements necessary and sufficient for plus-end binding and depolymerase activity, as well as by the identification of an α-tubulin residue specifically required for the Kip3-curved tubulin interaction. Together, these findings elucidate a major regulatory mechanism controlling the size of cellular microtubule structures.


G protein-mediated neuronal DNA fragmentation induced by familial Alzheimer's disease-associated mutants of APP.
Missense mutations in the 695-amino acid form of the amyloid precursor protein (APP695) cosegregate with disease phenotype in families with dominantly inherited Alzheimer's disease. These mutations convert valine at position 642 to isoleucine, phenylalanine, or glycine. Expression of these mutant proteins, but not of normal APP695, was shown to induce nucleosomal DNA fragmentation in neuronal cells. Induction of DNA fragmentation required the cytoplasmic domain of the mutants and appeared to be mediated by heterotrimeric guanosine triphosphate-binding proteins (G proteins).


Panitumumab-Associated Encephalopathy after Accidental Intra-arterial Application through Dislocated Central Venous Access Device.
Acute central nervous system (CNS) toxicity and immune-related side effects are increasingly recognized with the use of monoclonal antibodies for cancer therapy. Here, we report a patient who developed of acute-onset encephalopathy and coma, which began shortly after administration of panitumumab for the treatment of metastatic colorectal cancer. Echocardiography revealed that the drug had been infused into the left cardiac ventricle via a dislocated central venous line. Diffusion-weighted magnetic resonance imaging disclosed multiple cortical hyperintensities, which were preferentially located in the frontal lobes. While the neurological condition improved within a few days, the patient died 4 weeks later. It seems likely that the administration of the antibody via the intra-arterial route contributed to the development of this condition. Toxic encephalopathy may be a hitherto unrecognized complication of panitumumab treatment and should be taken into consideration in patients developing CNS symptoms undergoing this therapy.


Oral haloperidol or risperidone treatment in rats: temporal effects on nerve growth factor receptors, cholinergic neurons, and memory performance.
First and second generation antipsychotics (FGAs and SGAs) ameliorate psychotic symptoms of schizophrenia, however, their chronic effects on information processing and memory function (i.e. key determinants of long term functional outcome) are largely unknown. In this rodent study the effects of different time periods (ranging from 2 weeks to 6 months) of oral treatment with the FGA, haloperidol (2.0 mg/kg/day), or the SGA, risperidone (2.5 mg/kg/day) on a water maze repeated acquisition procedure, the levels of nerve growth factor receptors, and two important cholinergic proteins, the vesicular acetylcholine transporter and the high affinity choline transporter were evaluated. The effects of the antipsychotics on a spontaneous novel object recognition procedure were also assessed during days 8-14 and 31-38 of treatment. Haloperidol (but not risperidone) was associated with impairments in water maze hidden platform trial performance at each of the time periods evaluated up to 45 days, but not when tested during days 83-90. In contrast, risperidone did not impair water maze task performance at the early time periods and it was actually associated with improved performance during the 83-90 day period. Both antipsychotics, however, were associated with significant water maze impairments during the 174-180 day period. Further, haloperidol was associated with decrements in short delay performance in the spontaneous novel object recognition task during both the 8-14 and 31-38 day periods of treatment, while risperidone was associated with short delay impairment during the 31-38 day time period. Both antipsychotics were also associated with time dependent alterations in the vesicular acetylcholine transporter, the high affinity choline transporter, as well as tyrosine kinase A, and p75 neurotrophin receptors in specific brain regions. These data from rats support the notion that while risperidone may hold some advantages over haloperidol, both antipsychotics can produce time-dependent alterations in neurotrophin receptors and cholinergic proteins as well as impairments in the performance of tasks designed to assess spatial learning and episodic memory.


Vegetarianism and cardiometabolic disease risk factors: Differences between South Asian and US adults.
Cardiometabolic diseases are increasing disproportionately in South Asia compared with other regions of the world despite high levels of vegetarianism. This unexpected discordance may be explained by differences in the healthfulness of vegetarian and non-vegetarian diets in South Asia compared with the United States. The aim of this study was to compare the food group intake of vegetarians with non-vegetarians in South Asia and the United States and to evaluate associations between vegetarianism and cardiometabolic disease risk factors (overweight/obesity, central obesity, diabetes, hypertension, high triacylglycerols, high low-density lipoprotein, low high-density lipoprotein, and high Framingham Heart Score). Using cross-sectional data from adults (age 20-69 y) in South Asia (Centre for Cardiometabolic Risk Reduction in South-Asia [CARRS] 2010-2011; N = 15 665) and the United States (National Health and Nutrition Examination Survey 2003-2006; N = 2159), adherence to a vegetarian diet was assessed using food propensity questionnaires. Multivariable logistic regression was used to estimate odds ratios and predicted margins (e.g., adjusted prevalence of the outcomes). One-third (33%; n = 4968) of adults in the South Asian sample were vegetarian compared with only 2.4% (n = 59) in the US sample. Among South Asians, vegetarians more frequently ate dairy, legumes, vegetables, fruit, desserts, and fried foods than non-vegitarians (all P < 0.05). Among Americans, vegetarians more frequently ate legumes, fruit, and whole grains, and less frequently ate refined cereals, desserts, fried foods, fruit juice, and soft drinks than non-vegetarians (all P < 0.05). After adjustment for confounders (age, sex, education, tobacco, alcohol, and also city in CARRS), South Asian vegetarians were slightly less frequently overweight/obese compared with non-vegetarians: 49% (95% confidence interval [CI], 45%-53%) versus 53% (95% CI, 51%-56%), respectively; whereas US vegetarians were considerably less frequently overweight/obese compared with non-vegetarians: 48% (95% CI, 32%-63%) versus 68% (95% CI, 65%-70%), respectively. Furthermore, US vegetarians were less likely to exhibit central obesity than non-vegetarians: 62% (95% CI, 43%-78%) versus 78% (95% CI, 76%-80%), respectively. There is greater divergence between vegetarian and non-vegetarian diets in the United States than in South Asia, and US vegetarians have more consistently healthier food group intakes than South Asian vegetarians. Vegetarians in both populations have a lower probability of overweight/obesity compared with non-vegetarians. The strength of this association may be stronger for US vegetarian diets, which were also protective against central obesity.


A2B adenosine receptor expression by myeloid cells is proinflammatory in murine allergic-airway inflammation.
Asthma is a chronic condition with high morbidity and healthcare costs, and cockroach allergens are an established cause of urban pediatric asthma. A better understanding of cell types involved in promoting lung inflammation could provide new targets for the treatment of chronic pulmonary disease. Because of its role in regulating myeloid cell-dependent inflammatory processes, we examined A(2B) R expression by myeloid cells in a cockroach allergen model of murine asthma-like pulmonary inflammation. Both systemic and myeloid tissue-specific A(2B) R deletion significantly decreased pulmonary inflammatory cell recruitment, airway mucin production, and proinflammatory cytokine secretion after final allergen challenge in sensitized mice. A(2B) R deficiency resulted in a dramatic reduction on Th2-type airways responses with decreased pulmonary eosinophilia without augmenting neutrophilia, and decreased lung IL-4, IL-5, and IL-13 production. Chemokine analysis demonstrated that eotaxin 1 and 2 secretion in response to repeated allergen challenge is myeloid cell A(2B) R dependent. In contrast, there were no differences in the levels of the CXC chemokines keratinocyte-derived chemokine and MIP-2 in the myeloid cell A(2B) R-deficient mice, strengthening A(2B) R involvement in the development of Th2-type airways inflammation. Proinflammatory TNF-α, IFN-γ, and IL-17 secretion were also reduced in systemic and myeloid tissue-specific A(2B) R deletion mouse lines. Our results demonstrate Th2-type predominance for A(2B) R expression by myeloid cells as a mechanism of development of asthma-like pulmonary inflammation.


Emerging Target Families: Intractable Targets.
The druggability of a target is defined by the likelihood of a certain target binding site to be amendable to functional modulation by a small molecule in vivo. Thus, druggability depends on the ability of the developed small molecule to reach the target site, the properties of the ligand binding pocket and our ability to develop chemical matter that efficiently interact with the drug binding site of interest. Historically enzymes have been the main drug targets because the inhibition of their activity can be easily assayed and catalytic centres are often attractive drug binding sites. However, despite considerable effort, a number of classical enzyme families have not been successfully targeted. More recently protein-protein interactions received considerable attention and several clinical inhibitors have now been developed. Despite the considerable progress made expanding target space, a large number of targets with a very strong rationale for targeting remain intractable. In the following chapter I will summarize progress made in developing inhibitors for challenging drug binding sites and emerging target families.


Detection and identification of common food-borne viruses with a tiling microarray.
Microarray hybridization based identification of viral genotypes is increasingly assuming importance due to outbreaks of multiple pathogenic viruses affecting humans causing wide-spread morbidity and mortality. Surprisingly, microarray based identification of food-borne viruses, one of the largest groups of pathogenic viruses, causing more than 1.5 billion infections world-wide every year, has lagged behind. Cell-culture techniques are either unavailable or time consuming for routine application. Consequently, current detection methods for these pathogens largely depend on polymerase chain reaction (PCR) based techniques, generally requiring an investigator to preselect the target virus of interest. Here we describe the first attempt to use the microarray as an identification tool for these viruses. We have developed methodology to synthesize targets for virus identification without using PCR, making the process genuinely sequence independent. We show here that a tiling microarray can simultaneously detect and identify the genotype and strain of common food-borne viruses in a single experiment.


Delayed open conversion following endovascular aortoiliac aneurysm repair: partial (or complete) endograft preservation as a useful adjunct.
The purpose of this study was to review our experience with delayed open conversion (>30 days) following endovascular aortoiliac aneurysm repair (EVAR) and to introduce the concept and advantages of endograft retention in this setting. From January 1992 to January 2003, a total of 386 EVARs using a variety of endografts were successfully deployed. Eleven (2.8%) patients required delayed conversion to open repair at an average of 30 months (range, 10-64). Data from all patients undergoing both EVAR and open conversion were prospectively collected. EVARs were performed using grafts made by Talent (4), Vanguard (2,) AneuRx (1), and Surgeon (4). Conversion to open repair (9 transabdominal, 1 retroperitoneal, 1 transabdominal plus thoracotomy) was performed for aneurysm rupture in 7 patients (4 type 1 endoleak, 2 type 2 endoleak, 1 aortoenteric fistula) and aneurysm enlargement in 4 patients (1 type 1 endoleak, 1 type 2 endoleak, 1 type 3 endoleak, 1 endotension). Patients with aneurysm rupture were treated on an emergent basis. Complete removal of the endograft with supraceliac cross-clamping was performed in two cases. One patient (rupture) did not survive the operation, and one patient (aortoenteric fistula) died 2 weeks postoperatively. In the remaining nine cases, the endograft was either completely (1) or partially (6) removed, or left in situ (2). Supraceliac balloon control (2), supraceliac clamping (1), suprarenal clamping (1), or infrarenal clamping (5) was used in these cases. All nine of these patients survived the operation. In one procedure in which the endograft was left intact (endotension), repair was accomplished by exposing the endograft and by placing a standard tube graft over it as a sleeve. In the second procedure in which the graft was left in situ (rupture), the graft was well incorporated, and bleeding lumbar arteries were oversewn and the sac was closed tightly over the endograft. In the remaining 7 cases, the endograft was transected and the proximal portion only (6) or the proximal and distal portions (1) were excised. All surviving patients continue to do well and remain without complications associated with the endograft remnant at a mean follow-up of 22 months (range, 3-56) from the time of open conversion and 46 months (range, 10-73) from the time of original EVAR. Open repair in the setting of a long-standing endograft offers several unique technical challenges but can be successfully accomplished in most patients. Preservation of all or part of the endograft is possible in many patients. This technique simplifies the operative approach and is preferred over complete endograft removal if possible.


Oncologic pharmacology: selected topics for critical care nurses.
Administration of multiple and complex medications is common in the intensive care setting, but the response of a patient with cancer to medications and the specific types of medications is a unique specialty practice. In this article, the author provides the experienced critical care nurse with a condensed overview of the most important nursing issues in pharmacologic therapy for patients with cancer. There is a discussion of physiologic variables that influence how patients with cancer respond to pharmaceutical agents. This is followed with detailed information about cancer chemotherapy, biotherapy, and antiemetic practices.


Which presenteeism measures are more sensitive to depression and anxiety?
Lost productivity from attending work when unwell, or "presenteeism", is a largely hidden cost of mental disorders in the workplace. Sensitive measures are needed for clinical and policy applications, however there is no consensus on the optimal self-report measure to use. This paper examines the sensitivity of four alternative measures of presenteeism to depression and anxiety in an Australian employed cohort. A prospective single-group study in ten call centres examined the association of presenteeism (presenteeism days, inefficiency days, Work Limitations Questionnaire, Stanford Presenteeism Scale) with Patient Health Questionnaire depression and anxiety syndromes. At baseline, all presenteeism measures were sensitive to differences between those with (N=69) and without (N=363) depression/anxiety. Only the Work Limitations Questionnaire consistently showed worse productivity as depression severity increased, and sensitivity to remission and onset of depression/anxiety over the 6-month follow-up (N=231). There was some evidence of individual depressive symptoms having a differential association with different types of job demands. The study findings may not generalise to other occupational settings with different job demands. We were unable to compare responders with non-responders at baseline due to anonymity. In this community sample the Work Limitations Questionnaire offered additional sensitivity to depression severity, change over time, and individual symptoms. The comprehensive assessment of work performance offers significant advantages in demonstrating both the individual and economic burden of common mental disorders, and the potential gains from early intervention and treatment.


The relevance of traditional knowledge systems for ethnopharmacological research: theoretical and methodological contributions.
Ethnopharmacology is at the intersection of the medical, natural, and social sciences. Despite its interdisciplinary nature, most ethnopharmacological research has been based on the combination of the chemical, biological, and pharmacological sciences. Far less attention has been given to the social sciences, including anthropology and the study of traditional knowledge systems. I reviewed the literature on traditional knowledge systems highlighting its potential theoretical and methodological contributions to ethnopharmacology. I discuss three potential theoretical contributions of traditional knowledge systems to ethnopharmacological research. First, while many plants used in indigenous pharmacopoeias have active compounds, those compounds do not always act alone in indigenous healing systems. Research highlights the holistic nature of traditional knowledge systems and helps understand plant's efficacy in its cultural context. Second, research on traditional knowledge systems can improve our understanding of how ethnopharmacological knowledge is distributed in a society, and who benefits from it. Third, research on traditional knowledge systems can enhance the study of the social relations that enable the generation, maintenance, spread, and devolution of cultural traits and innovations, including ethnopharmacological knowledge. At a methodological level, some ethnopharmacologists have used anthropological tools to understand the context of plant use and local meanings of health and disease. I discuss two more potential methodological contributions of research on traditional knowledge systems to ethnopharmacological research. First, traditional knowledge systems research has developed methods that would help ethnopharmacologists understand how people classify illnesses and remedies, a fundamental aspect of folk medicinal plant selection criteria. Second, ethnopharmacologists could also borrow methods derived from cultural consensus theory to have a broader look at intracultural variation and at the analysis of transmission and loss of traditional ethnopharmacological knowledge. Ethical considerations in the ethnopharmacology of the 21st century should go beyond the recognition of the Intellectual Property Rights or the acquisition of research permits, to include considerations on the healthcare of the original holders of ethnopharmacological knowledge. Ethnopharmacology can do more than speed up to recover the traditional knowledge of indigenous peoples to make it available for the development of new drugs. Ethnopharmacologists can work with health care providers in the developing world for the local implementation of ethnopharmacological research results.


Review and evaluation of electronic health records-driven phenotype algorithm authoring tools for clinical and translational research.
To review and evaluate available software tools for electronic health record-driven phenotype authoring in order to identify gaps and needs for future development. Candidate phenotype authoring tools were identified through (1) literature search in four publication databases (PubMed, Embase, Web of Science, and Scopus) and (2) a web search. A collection of tools was compiled and reviewed after the searches. A survey was designed and distributed to the developers of the reviewed tools to discover their functionalities and features. Twenty-four different phenotype authoring tools were identified and reviewed. Developers of 16 of these identified tools completed the evaluation survey (67% response rate). The surveyed tools showed commonalities but also varied in their capabilities in algorithm representation, logic functions, data support and software extensibility, search functions, user interface, and data outputs. Positive trends identified in the evaluation included: algorithms can be represented in both computable and human readable formats; and most tools offer a web interface for easy access. However, issues were also identified: many tools were lacking advanced logic functions for authoring complex algorithms; the ability to construct queries that leveraged un-structured data was not widely implemented; and many tools had limited support for plug-ins or external analytic software. Existing phenotype authoring tools could enable clinical researchers to work with electronic health record data more efficiently, but gaps still exist in terms of the functionalities of such tools. The present work can serve as a reference point for the future development of similar tools.


Remarkably enhanced photocatalytic activity of ordered mesoporous carbon/g-C₃N₄ composite photocatalysts under visible light.
Ordered mesoporous carbon/g-C3N4 (OMC/g-C3N4) composites with efficient photocatalytic activity under visible light irradiation were prepared by a facile heating method. The as-prepared OMC/g-C3N4 composites were thoroughly characterized by X-ray diffraction, Fourier transform infrared spectroscopy, elemental analyses, transmission electron microscopy with energy dispersion X-ray spectroscopy, N2 adsorption-desorption analysis, UV-vis diffuse reflectance spectroscopy and photoluminescence spectroscopy. The photocatalytic activities were evaluated by degrading Rhodamine B dye, and OMC/g-C3N4 composites exhibited much higher photocatalytic activities than pristine g-C3N4. Moreover, the catalysts retained good stability and the photodegradation efficiency hardly changed after five cycles. The degradation rate of the OMC/g-C3N4 photocatalyst was almost 10 times as high as that of the pristine g-C3N4, which indicated that OMC played an important role in the remarkable improvement of photocatalytic activity. The significant enhancement in photodegradation activity over the OMC/g-C3N4 catalyst could be ascribed to the combined effects coming from the enhanced visible light adsorption, enriched adsorption of the dye on the catalyst and subsequent efficient separation of photogenerated electrons and holes. In addition, a possible mechanism for the photodegradation process was proposed on the basis of active species scavenging experiments.


A behavioral and micro positron emission tomography imaging study in a rat model of hypothyroidism.
Hypothyroidism leads to somatic, neuropsychological, and psychiatric changes that are similar to depression. The mechanisms underlying the behavioral abnormalities in adult onset hypothyroidism remain ambiguous. Hypothyroidism was induced in adult male Wistar rats by the maintenance of 0.05% propylthiouracil (PTU) in drinking water for 5 weeks (hypothyroid group; HP group); control rats (CON group) received an equivalent amount of water. The open field and sucrose preference tests were employed, and the link between behavioral changes and brain glucose metabolism was evaluated using micro positron emission tomography imaging. The open field test revealed slightly decreased locomotor activity and significantly reduced rearing and defecation in the hypothyroid group. Hypothyroid rats were also characterized by decreased body weight, sucrose preference, and relative sucrose intake compared to control rats. Hypothyroidism induced reduced brain glucose metabolism in the bilateral motor cortex, the caudate putamen, the cortex cingulate, the nucleus accumbens, and the frontal association cortex. A decreased sucrose preference was positively correlated with metabolic glucose changes in the caudate putamen and the nucleus accumbens. The results indicate that the activity pattern in adult onset hypothyroidism is different from the activity pattern when hypothyroidism is induced in the developmental period of the central nervous system. Decreased sucrose preference in hypothyroid rats may be attributed to anhedonia. Furthermore, these findings suggest there may be a common mechanism underlying adult onset hypothyroidism and depression.


Social security: a program and policy history.
Many of the federal and state programs that provide income security to U.S. families have their roots in the Social Security Act (the Act) of 1935. This Act provided for unemployment insurance, old-age insurance, and means-tested welfare programs. The Great Depression was clearly a catalyst for the Social Security Act of 1935, and some of its provisions--notably the means-tested programs--were intended to offer immediate relief to families. However, the old-age insurance program-the precursor to today's Old-Age, Survivors, and Disability Insurance, or Social Security, program-was not designed specifically to deal with the economic crisis of that era. Indeed, monthly benefit payments, under the original Act, were not scheduled to begin until 1942. In addition, from the beginning, the Social Security program has embodied social insurance principles that were widely discussed even before the onset of the Great Depression. The first four decades of the Social Security program were, in general, ones of expansion. In fact, the program was expanded even before it became truly operational. In 1939, amendments added child, spouse, and survivor benefits to the retirement benefits authorized by the 1935 Act. Those amendments also allowed for monthly benefits to begin in 1940. Although the program was not changed substantially during the war years and the initial postwar period, the 1950s were a transformational decade in the program's history: benefit amounts were increased substantially, coverage under the program became close to universal, and a new disability insurance benefit was offered. The 1960s witnessed additional growth in Social Security, but the most important development in social insurance occurred in health insurance, with the creation of the Medicare program in 1965. Legislative actions in the 1970s had profound effects on the Social Security program and, indeed, set the stage for many of today's reform debates. Large benefit increases, a new benefit formula that was erroneously generous, and other changes in the early 1970s created a situation in which annual program costs, as a share of gross domestic product, increased during a 12-year period from about 3 percent to 5 percent. In 1977, amendments to the Act corrected the flawed benefit formula and made other changes in the financing of the system to shore up the program. Thus, the 1970s represent a watershed in the program's history-program growth gave way to increasing concerns about the program's finances. Those concerns were reflected in the amendments to the Act in 1983, which were the last major changes to the program. These amendments, based largely on recommendations from a commission chaired by Alan Greenspan, adjusted benefits and taxes to address pressing near-term financing problems faced by the system. Although the Greenspan Commission focused to a large extent on short-range issues, the resulting reforms have generated large surpluses in the program and the buildup of a substantial trust fund. However, the looming retirement of the baby boomers and several other demographic factors will, according to projections, result in the exhaustion of the trust fund by 2042.


Expanding molecular modeling and design tools to non-natural sidechains.
Protein-protein interactions encode the wiring diagram of cellular signaling pathways and their deregulations underlie a variety of diseases, such as cancer. Inhibiting protein-protein interactions with peptide derivatives is a promising way to develop new biological and therapeutic tools. Here, we develop a general framework to computationally handle hundreds of non-natural amino acid sidechains and predict the effect of inserting them into peptides or proteins. We first generate all structural files (pdb and mol2), as well as parameters and topologies for standard molecular mechanics software (CHARMM and Gromacs). Accurate predictions of rotamer probabilities are provided using a novel combined knowledge and physics based strategy. Non-natural sidechains are useful to increase peptide ligand binding affinity. Our results obtained on non-natural mutants of a BCL9 peptide targeting beta-catenin show very good correlation between predicted and experimental binding free-energies, indicating that such predictions can be used to design new inhibitors. Data generated in this work, as well as PyMOL and UCSF Chimera plug-ins for user-friendly visualization of non-natural sidechains, are all available at http://www.swisssidechain.ch. Our results enable researchers to rapidly and efficiently work with hundreds of non-natural sidechains.


Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia.
Despite the therapeutic efficacy of ibrutinib in chronic lymphocytic leukemia (CLL), complete responses are infrequent, and acquired resistance to Bruton agammaglobulinemia tyrosine kinase (BTK) inhibition is being observed in an increasing number of patients. Combination regimens that increase frequency of complete remissions, accelerate time to remission, and overcome single agent resistance are of considerable interest. We previously showed that the XPO1 inhibitor selinexor is proapoptotic in CLL cells and disrupts B-cell receptor signaling via BTK depletion. Herein we show the combination of selinexor and ibrutinib elicits a synergistic cytotoxic effect in primary CLL cells and increases overall survival compared with ibrutinib alone in a mouse model of CLL. Selinexor is effective in cells isolated from patients with prolonged lymphocytosis following ibrutinib therapy. Finally, selinexor is effective in ibrutinib-refractory mice and in a cell line harboring the BTK C481S mutation. This is the first report describing the combined activity of ibrutinib and selinexor in CLL, which represents a new treatment paradigm and warrants further evaluation in clinical trials of CLL patients including those with acquired ibrutinib resistance.


Inequalities in access to medical care by income in developed countries.
Most of the member countries of the Organization for Economic Cooperation and Development (OECD) aim to ensure equitable access to health care. This is often interpreted as requiring that care be available on the basis of need and not willingness or ability to pay. We sought to examine equity in physician utilization in 21 OECD countries for the year 2000. Using data from national surveys or from the European Community Household Panel, we extracted the number of visits to a general practitioner or medical specialist over the previous 12 months. Visits were standardized for need differences using age, sex and reported health levels as proxies. We measured inequity in doctor utilization by income using concentration indices of the need-standardized use. We found inequity in physician utilization favouring patients who are better off in about half of the OECD countries studied. The degree of pro-rich inequity in doctor use is highest in the United States and Mexico, followed by Finland, Portugal and Sweden. In most countries, we found no evidence of inequity in the distribution of general practitioner visits across income groups, and where it does occur, it often indicates a pro-poor distribution. However, in all countries for which data are available, after controlling for need differences, people with higher incomes are significantly more likely to see a specialist than people with lower incomes and, in most countries, also more frequently. Pro-rich inequity is especially large in Portugal, Finland and Ireland. Although in most OECD countries general practitioner care is distributed fairly equally and is often even pro-poor, the very pro-rich distribution of specialist care tends to make total doctor utilization somewhat pro-rich. This phenomenon appears to be universal, but it is reinforced when private insurance or private care options are offered.


Effect of renal denervation on the antinatriuretic response to morphine administration in conscious rats.
The effect of surgical denervation on the antinatriuretic response to morphine was assessed in conscious rats prepared with arterial and venous catheters and bladder cannulas. In sham-operated animals, morphine sulfate (4 mg/kg i.v. plus 2 mg/kg X hr) caused a marked reduction in sodium excretion (650 +/- 218 vs. 2394 +/- 265 nEq/100 g X min in vehicle-treated animals; P less than .05). Although glomerular filtration rate was reduced, fractional excretion of sodium, expressed as a percentage of the filtered load, was also markedly decreased by morphine (0.62 +/- 0.18 vs. 1.51 +/- 0.15% in the vehicle group; P less than .05). The changes in sodium excretion were readily reversed by naloxone. In rats subjected to the renal denervation procedure, morphine had no effect on sodium excretion (1614 +/- 261 vs. 1926 +/- 520 nEq/100 g X min) or on fractional sodium excretion (1.92 +/- 0.50 vs. 1.41 +/- 0.37%). However, glomerular filtration rate was reduced by morphine as in the sham-denervated rats. Blood pressure and heart rate were not significantly affected by morphine in either group. The results suggest that morphine enhances renal tubular sodium reabsorption, at least in part, by a mechanism dependent on intact renal nerves. Because there was no evidence of generalized sympathetic activation (as judged by blood pressure and heart rate changes), the effect may be selective for the renal innervation.


A Longitudinal Study on the Effects of Parental Monitoring on Adolescent Antisocial Behaviors: The Moderating Role of Adolescent Empathy.
In adolescence, youth antisocial behaviors reach a peak. Parents can use different strategies, such as parental solicitation and control, to monitor their children's activities and try to prevent or reduce their antisocial behaviors. However, it is still unclear if, and for which adolescents, these parental monitoring behaviors are effective. The aim of this study was to examine if the impact of parental solicitation and control on adolescent antisocial behaviors depends on adolescent empathy. In order to comprehensively address this aim, we tested the moderating effects of multiple dimensions (affective and cognitive) of both trait and state empathy. Participants were 379 Dutch adolescents (55.9% males) involved in a longitudinal study with their fathers and mothers. At T1 (conducted when adolescents were 17-year-old) adolescents filled self-report measures of antisocial behaviors and trait empathy during one home visit, while their state empathy was rated during a laboratory session. Furthermore, parents reported their own monitoring behaviors. At T2 (conducted 1 year later, when adolescents were 18-year-old), adolescents reported again on their antisocial behaviors. Moderation analyses indicated that both affective and cognitive state empathy moderated the effects of parental solicitation on adolescent antisocial behaviors. Results highlighted that solicitation had unfavorable effects on antisocial behaviors in adolescents with high empathy whereas the opposite effect was found for adolescents with low empathy. In contrast, neither state nor trait empathy moderated the effects of control on adolescent antisocial behaviors. Theoretical and practical implications of these findings are discussed.


Prevalence, Long-term Development, and Predictors of Psychosocial Consequences of False-Positive Mammography among Women Attending Population-Based Screening.
Cancer screening aims to detect cancer at an asymptomatic stage, although side effects from screening also occur. We investigated the prevalence, longitudinal development, and predictors of psychosocial consequences of false-positive breast cancer screening. Three hundred ninety-nine women with false-positive screening mammography responded to the Consequences of Screening-Breast Cancer (COS-BC) questionnaire immediately after a negative diagnosis (free from breast cancer) following recall examination(s) (baseline), and 6 and 12 months later. Age-matched controls (n = 499) with a negative mammogram responded to the COS-BC at the same occasions. Five COS-BC scales (Sense of dejection, Anxiety, Behavioral, Sleep, and Existential values) were used as outcome measures. Women with false-positive mammography had consistently higher prevalence of all five consequences compared with controls (P < 0.001). The prevalences decreased between baseline and 6 months (P < 0.001) but were stable between 6 and 12 months (P ≥ 0.136). Early recall profoundly predicted long-term consequences for all five outcomes (OR, 3.05-10.31), along with dissatisfaction with information at recall (OR, 2.28-2.56), being foreign-born (OR, 2.35-3.71), and lack of social support (OR, 1.13-1.25). This 1-year longitudinal study shows that women experience psychosocial consequences of false-positive screening mammography. Early recall should be performed cautiously, and provision of information as well as social support may reduce psychosocial consequences. Although delivery of population-based screening reduces breast cancer mortality, it also raises the issue of its impact on the psychosocial well-being of healthy women. Our findings identify predictors that can be targeted in future efforts to reduce the side effects of mammographic screening.


Serum NGF levels in children and adolescents with either Williams syndrome or Down syndrome.
The neurotrophin nerve growth factor (NGF) is a major regulator of peripheral and central nervous system development. Serum NGF was measured in normally developing control children (n=26) and in individuals affected by congenital syndromes associated with learning disability: either Williams syndrome (WS; n=12) or Down syndrome (DS; n=21). Participants were assessed at three distinct developmental stages: early childhood (2 to 6 years), childhood (8 to 12 years), and adolescence (14 to 20 years). A sample was taken only once from each individual. Serum NGF levels were markedly higher in participants with WS, than DS and control participants. In addition, different developmental profiles emerged in the three groups: while in normally developing individuals NGF levels were higher in early childhood than later on, children with WS showed constantly elevated NGF levels. When compared to control participants, those with DS showed lower NGF levels only during early childhood. Neuropsychological assessment confirmed previously reported differences among the three groups in the development of linguistic/cognitive abilities. Some features of individuals with WS, such as hyperacusis and hypertension, could be related to high-circulating NGF levels.


Efficient reactive Brownian dynamics.
We develop a Split Reactive Brownian Dynamics (SRBD) algorithm for particle simulations of reaction-diffusion systems based on the Doi or volume reactivity model, in which pairs of particles react with a specified Poisson rate if they are closer than a chosen reactive distance. In our Doi model, we ensure that the microscopic reaction rules for various association and dissociation reactions are consistent with detailed balance (time reversibility) at thermodynamic equilibrium. The SRBD algorithm uses Strang splitting in time to separate reaction and diffusion and solves both the diffusion-only and reaction-only subproblems exactly, even at high packing densities. To efficiently process reactions without uncontrolled approximations, SRBD employs an event-driven algorithm that processes reactions in a time-ordered sequence over the duration of the time step. A grid of cells with size larger than all of the reactive distances is used to schedule and process the reactions, but unlike traditional grid-based methods such as reaction-diffusion master equation algorithms, the results of SRBD are statistically independent of the size of the grid used to accelerate the processing of reactions. We use the SRBD algorithm to compute the effective macroscopic reaction rate for both reaction-limited and diffusion-limited irreversible association in three dimensions and compare to existing theoretical predictions at low and moderate densities. We also study long-time tails in the time correlation functions for reversible association at thermodynamic equilibrium and compare to recent theoretical predictions. Finally, we compare different particle and continuum methods on a model exhibiting a Turing-like instability and pattern formation. Our studies reinforce the common finding that microscopic mechanisms and correlations matter for diffusion-limited systems, making continuum and even mesoscopic modeling of such systems difficult or impossible. We also find that for models in which particles diffuse off lattice, such as the Doi model, reactions lead to a spurious enhancement of the effective diffusion coefficients.


The genes for mouse salivary androgen-binding protein (ABP) subunits alpha and gamma are located on chromosome 7.
We demonstrate that the previously described gene Androgen binding protein (Abp; Dlouhy and Karn, 1984) codes for the Alpha subunit of ABP and rename the locus Androgen binding protein alpha (Abpa). A study of recombinant inbred strains demonstrates that Abpa is located on chromosome 7 near Glucose phosphate isomerase-1 (Gpi-1). Biochemical and genetic evidence indicates the existence of another ABP subunit, Gamma, and its locus, Androgen binding protein gamma (Abpg), that is closely linked to Abpa. Although no polymorphism has yet been found for the previously described Beta subunit of ABP (Dlouhy and Karn, 1983; 1984), we suggest that it represents a third locus. Androgen binding protein beta (Abpb). ABP subunits appear to dimerize randomly and a model is presented demonstrating the origin of six ABP dimers in the salivas of AbpaaAbpga/AbpabAbpgb heterozygous mice. The results of cell-free translation studies in which the pre-ABP subunits are identified specifically by immunoprecipitation with anti-ABP antibody supports the idea that independent mRNAs code for the Alpha, Beta and Gamma subunits.


Epidemiology of Plasmodium malariae infection in Gambela, Ethiopia.
Malaria incidence and prevalence surveys were performed from December, 1967 to February, 1969 among the indigenous Nilotic inhabitants of Gambela, a small administrative centre in the western lowlands of Ethiopia. Entomological data suggested that malaria transmission was seasonal and this was consistent with monthly P. falciparum parasite rates. Monthly P. malariae parasite rates, however, were consistent with an hypothesis of homogeneity. The age-specific incidence of quartan malaria among 26 children zero to 11 years old at the start of study was examined at 28 day intervals over a 15-month period. The resulting data suggested that parasite acquisition was a slow process and an annual P. malariae incidence of 0.17 was derived. This statistic was supported by studies performed five years later: The incidence of P. malariae among 102 infants followed from birth up to 48 months of age was 0.16-0.20. An attempt was then made to account for the prevalence of P. malariae in terms of the entomological conditions observed in Gambela. Macdonald's formula for the sporozoite rate was used to derive hypothetical relative proportions of P. falciparum and P. malariae among the observed sporozoite-positive mosquito populations. About 4% of the sporozoite challenges were estimated to be of P. malariae. An hypothetical annual entomological P. malariae inoculation rate was then made by multiplying the number of observed sporozoite inoculations per person (approximately 10/year) by the proportion of them estimated to be of P. malariae. The annual P. malariae sporozoite challenge was thus estimated at 0.4 per person, in good agreement with the annual incidence estimates from parasite rates in children.


Mutations of the Rous sarcoma virus env gene that affect the transport and subcellular location of the glycoprotein products.
The envelope glycoproteins of Rous sarcoma virus (RSV), gp85 and gp37, are anchored in the membrane by a 27-amino acid, hydrophobic domain that lies adjacent to a 22-amino acid, cytoplasmic domain at the carboxy terminus of gp37. We have altered these cytoplasmic and transmembrane domains by introducing deletion mutations into the molecularly cloned sequences of a proviral env gene. The effects of the mutations on the transport and subcellular localization of the Rous sarcoma virus glycoproteins were examined in monkey (CV-1) cells using an SV40 expression vector. We found, on the one hand, that replacement of the nonconserved region of the cytoplasmic domain with a longer, unrelated sequence of amino acids (mutant C1) did not alter the rate of transport to the Golgi apparatus nor the appearance of the glycoprotein on the cell surface. Larger deletions, extending into the conserved region of the cytoplasmic domain (mutant C2), resulted in a slower rate of transport to the Golgi apparatus, but did not prevent transport to the cell surface. On the other hand, removal of the entire cytoplasmic and transmembrane domains (mutant C3) did block transport and therefore did not result in secretion of the truncated protein. Our results demonstrate that the C3 polypeptide was not transported to the Golgi apparatus, although it apparently remained in a soluble, nonanchored form in the lumen of the rough endoplasmic reticulum; therefore, it appears that this mutant protein lacks a functional sorting signal. Surprisingly, subcellular localization by internal immunofluorescence revealed that the C3 protein (unlike the wild type) did not accumulate on the nuclear membrane but rather in vesicles distributed throughout the cytoplasm. This observation suggests that the wild-type glycoproteins (and perhaps other membrane-bound or secreted proteins) are specifically transported to the nuclear membrane after their biosynthesis elsewhere in the rough endoplasmic reticulum.