Neural plasticity in functional and anatomical MRI studies of children with Tourette syndrome.
Tourette syndrome (TS) is a neuropsychiatric disorder with childhood onset characterized by chronic motor and vocal tics. The typical clinical course of an attenuation of symptoms during adolescence in parallel with the emerging self-regulatory control during development suggests that plastic processes may play an important role in the development of tic symptoms. We conducted a systematic search to identify existing imaging studies (both anatomical and functional magnetic resonance imaging [fMRI]) in young persons under the age of 19 years with TS. The final search resulted in 13 original studies, which were reviewed with a focus on findings suggesting adaptive processes (using fMRI) and plasticity (using anatomical MRI). Differences in brain activation compared to healthy controls during tasks that require overriding of prepotent responses help to understand compensatory pathways in children with TS. Along with alterations in regions putatively representing the origin of tics, deviations in several other regions most likely represent an activity-dependent neural plasticity that help to modulate tic severity, such as the prefrontal cortex, but also in the corpus callosum and the limbic system. Factors that potentially influence the development of adaptive changes in the brain of children with TS are age, comorbidity with other developmental disorders, medication use, IQ along with study-design or MRI techniques for acquisition, and analysis of data. The most prominent limitation of all studies is their cross-sectional design. Longitudinal studies extending to younger age groups and to children at risk for developing TS hopefully will confirm findings of neural plasticity in future investigations.


Single-shot, dual-wavelength digital holography based on polarizing separation.
We describe what we believe to be a new digital holographic configuration that can be utilized for both single-shot, dual-wavelength, off-axis geometry and imaging polarimetry. To get the feasibility of the single-shot, dual-wavelength, off-axis geometry, a sample with a nominal step height of 1.34 μm is used. Undesirable noises that strongly affect the measurement have been suppressed successfully by using a modified flat fielding method for the dual-wavelength scheme. And also, the experiment is conducted on a nanopattern sample on the basis of a single image acquisition to show the imaging polarimetry capability. The proposed scheme can provide a real-time solution for measuring three-dimensional objects having a high abrupt height difference with moderate accuracy. Furthermore, it can be used as a fast polarization imaging measurement tool.


Competing Risks of Mortality among Men with Biochemical Recurrence after Radical Prostatectomy.
Men with biochemical recurrence after radical prostatectomy need information on competing risks of mortality to inform prognosis and guide treatment. We quantified the risk of prostate cancer metastasis and mortality, and other cause mortality across key clinical predictors. We analyzed 1,225 men with biochemical recurrence after radical prostatectomy from 2001 to 2017 in the VA SEARCH database. Multivariable competing risks regression was used to identify predictors and quantify cumulative incidence of metastasis, prostate cancer specific mortality and other cause mortality. Recursive partitioning analysis was used to identify optimum variable cut points for prediction of prostate cancer specific mortality and other cause mortality. During a median followup of 5.6 years after biochemical recurrence (IQR 2.7-9.1), 243 (20%) men died of other causes and 68 (6%) died of prostate cancer. Multivariable competing risks regression showed that high D'Amico tumor risk and prostate specific antigen doubling time at biochemical recurrence less than 9 months were associated with metastasis and prostate cancer specific mortality (p ≤0.001). Ten-year prostate cancer specific mortality was 14% and 9% for those with high risk tumors and prostate specific antigen doubling time less than 9 months, respectively. Advanced age and worse comorbidity were associated with other cause mortality (p ≤0.001). Ten-year other cause mortality was higher among men 70 years old or older with any Charlson comorbidity (1-3+) (40% to 49%) compared to those with none (20%). Recursive partitioning analysis identified optimal variable cut points for prediction of prostate cancer specific mortality and other cause mortality, with 10-year prostate cancer specific mortality ranging from 3% to 59% and 10-year other cause mortality ranging from 17% to 50% across risk subgroups. Among men with biochemical recurrence after radical prostatectomy, there is significant heterogeneity in prognosis that can be explained by available clinical variables. Men in their 70s with any major comorbidity are 2 to 10 times more likely to die of other causes than of prostate cancer.


Current management and clinical outcomes for catheter ablation of atrioventricular nodal re-entrant tachycardia.
Historical studies of ablation of atrioventricular nodal re-entrant tachycardia (AVNRT) have shown high long-term success rates and low complication rates. The potential impact of several recent practice trends has not been described. This study aims to characterize recent clinical practice trends in AVNRT ablation and their associated success rates and complications. Patients undergoing initial ablation of AVNRT between 1 July 2005 and 30 June 2015 were included in this study. Patient demographics and procedural data were abstracted from procedure reports. Follow-up data, including AVNRT recurrence and complications, was evaluated through electronic medical record review. In total, 877 patients underwent catheter ablation for AVNRT. By the last recorded year, three-dimension (3D) electroanatomical mapping (EAM) was used in 36.2%, 43.2% included anaesthesia, and 23.1% utilized irrigated catheters. Long-term procedural success was 95.5%. The use of anaesthesia, 3D EAM, and irrigated ablation catheters were not associated with differences in success. The presence of an atrial 'echo' or 'AH' jump at the end of an acutely successful procedure was not associated with long-term recurrence (P = 0.18, P = 0.15, respectively). Complications, including AV block requiring a pacemaker (0.4%), were uncommon. In a large, contemporary cohort, catheter ablation for AVNRT remains highly successful with low complications rates. The increased use of anaesthesia as well as modern mapping and ablation tools were not associated with changes in clinical outcomes. Further prospective evaluation of such contemporary practices is warranted given the lack of evidence to support their escalating use.


A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis.
5'AMP-activated kinase (AMPK) constitutes a hub for cellular metabolic and growth control, thus representing an ideal therapeutic target for prostate cancers (PCas) characterized by increased lipogenesis and activation of mTORC1 pathway. However, whether AMPK activation itself is sufficient to block cancer cell growth remains to be determined. A small molecule screening was performed and identified MT 63-78, a specific and potent direct AMPK activator. Here, we show that direct activation of AMPK inhibits PCa cell growth in androgen sensitive and castration resistant PCa (CRPC) models, induces mitotic arrest, and apoptosis. In vivo, AMPK activation is sufficient to reduce PCa growth, whereas the allelic loss of its catalytic subunits fosters PCa development. Importantly, despite mTORC1 blockade, the suppression of de novo lipogenesis is the underpinning mechanism responsible for AMPK-mediated PCa growth inhibition, suggesting AMPK as a therapeutic target especially for lipogenesis-driven PCas. Finally, we demonstrate that MT 63-78 enhances the growth inhibitory effect of AR signaling inhibitors MDV3100 and abiraterone. This study thus provides a rationale for their combined use in CRPC treatment.


Within and between population variation for zinc and nickel accumulation in two species of Thlaspi (Brassicaceae).
In this study, the differences in zinc (Zn) and nickel (Ni) hyperaccumulation were investigated between three populations of Thlaspi pindicum together with genetic variation within populations of T. pindicum and Thlaspi alpinum var. sylvium, both serpentine endemics. Three experiments were conducted under standard conditions in hydroponic assay. Each experiment contained three treatments of metal: 100 microm Zn, 100 microm Ni, and combined 100/100 microm Zn/Ni. Genetic variation within populations was determined using maternal families. No genetic variation within populations was found for either Zn or Ni hyperaccumulation for both T. pindicum and T. alpinum var. sylvium, but differences were observed for both Zn and Ni hyperaccumulation between populations of T. pindicum. In combined Zn/Ni treatments, Zn inhibited Ni translocation in both species, which is unexpected considering that these species are serpentine endemics and well known Ni hyperaccumulators. The lack of genetic variation for metal hyperaccumulation is possibly due to inbreeding. Since Zn hyperaccumulation is not manifested in the field, inadvertent uptake of Zn is a plausible hypothesis for its preferential uptake.


Breastfeeding knowledge, attitude and practice among school teachers in Abha female educational district, southwestern Saudi Arabia.
Inadequate knowledge, or inappropriate practice, of breastfeeding may lead to undesirable consequences. The aim of this study was to assess breastfeeding knowledge, attitude and practice (KAP) among female teachers in the Abha Female Educational District and identify factors that may affect breastfeeding practice in the study population. A cross-sectional study using a self-administered questionnaire was conducted among school teachers in Abha Female Educational District during the months of April to June, 2011. Breastfeeding KAP of participants who had at least one child aged five years or younger at the time of the study were assessed using a self-administered questionnaire, based on their experience with the last child. A total of 384 women made up of 246 (61.1%) primary-, 89 (23.2%) intermediate- and 49 (12.8%) high-school teachers participated in the study. One hundred and nineteen participants (31%) started breastfeeding their children within one hour of delivery, while exclusive breastfeeding for 6 months was reported only by 32 (8.3%) participants. Insufficient breast milk and work related problems were the main reasons given by 169 (44%) and 148 (38.5%) of participants, respectively, for stopping breastfeeding before two years. Only 33 participants (8.6%) had attended classes related to breastfeeding. However, 261 participants (68%) indicated the willingness to attend such classes, if available, in future pregnancies. This study revealed that breast milk insufficiency and adverse work related issues were the main reasons for a very low rate of exclusive breastfeeding among female school teachers in Abha female educational district, Saudi Arabia. A very low rate of attending classes addressing the breastfeeding issues during pregnancy, and an alarming finding of a high percentage of babies receiving readymade liquid formula while still in hospital, were also brought out by the present study. Such findings, if addressed comprehensively by health care providers and decision-makers, will lead to the improvement of breastfeeding practices in the study community.


OECI TuBaFrost tumor biobanking.
OECI TuBaFrost harbors a complete infrastructure for the exchange of frozen tumor samples between European countries. OECI TuBaFrost consists of: * A code of conduct on how to exchange human residual samples in Europe, * A central database application accessible over the Internet (www.tubafrost.org) where data can be uploaded and searched from samples that can be selected and ordered, * Access rules with incentives for collectors, * Standardization needed to enable the analysis of high quality samples derived from different centers, * Virtual Microscopy to support sample selection with difficult pathology. The entire infrastructure was, after completion, which was entirely financed by the European Commission, implemented in the OECI. But so far it has not been used to its capacity. A recent survey held amongst the OECI members shed light on the causes. The main conclusion is that all responders see OECI TuBaFrost as a good platform for exchange of samples, however, the biggest bottleneck found was that potential users are too unfamiliar with the communication between their own biobank tracking system and the TuBaFrost central database application. Therefore, new future plans are drawn. In addition, new infrastructure plans have been developed and the first preparatory steps have been set. For biobanks the BBMRI project has started aiming for Pan-European Biobanking and Biomolecular Resources Research Infrastructure.


Perspectives for Ag2S NIR-II nanoparticles in biomedicine: from imaging to multifunctionality.
Research on near-infrared (NIR) bioimaging has progressed very quickly in the past few years, as fluorescence imaging is reaching a credible implementation as a preclinical technique. The applications of NIR bioimaging in theranostics have contributed to its increasing impact. This has brought about the development of novel technologies and, simultaneously, of new contrast agents capable of acting as efficient NIR optical probes. Among these probes, Ag2S nanoparticles (NPs) have attracted increasing attention due to their temperature-sensitive NIR-II emission, which can be exploited for deep-tissue imaging and thermometry, and their heat delivery capabilities. This multifunctionality makes Ag2S NPs ideal candidates for theranostics. This review presents a critical analysis of the synthesis routes, properties and optical features of Ag2S NPs. We also discuss the latest and most remarkable achievements enabled by these NPs in preclinical imaging and theranostics, together with a critical assessment of their potential to face forthcoming challenges in biomedicine.


Multiple sclerosis in the UK: service use, costs, quality of life and disability.
Multiple sclerosis (MS) is a chronic condition that affects quality of life (QOL), leads to disability and requires ongoing care inputs. Few studies have examined the impact of QOL, disability and demographic characteristics on treatment costs. To investigate the links between service use, costs, QOL and disability for people with MS. A cross-sectional study was conducted in people with MS who were members of the Multiple Sclerosis Society of Great Britain and Northern Ireland. A questionnaire, consisting of sociodemographic questions, the Client Service Receipt Inventory, EQ-5D and Guy's Neurological Disability Scale (GNDS), was sent to 4000 members of the Society. Service and lost employment costs were calculated. Regression models were developed to identify the participant characteristics that were associated with costs, QOL and disability. All costs are presented in year 2006-7 values. Questionnaires were returned by 1942 members (48.9%). The mean (SD) EQ-5D QOL score was 0.41 (0.34), whilst the GNDS disability score was 20.8 (8.9). The mean (SD) service cost over the preceding 6 months was pound8397 ( pound10,404), and most of this (71.6%) was due to informal care. Only a small amount of cost (8.1%) was due to the use of disease-modifying drugs and drugs for spasticity. Lost employment costs amounted to a mean of pound4240. Higher costs were associated with higher levels of disability and lower levels of health-related QOL. This study showed that MS participants had high levels of service use, and that QOL was low in comparison with other conditions. There were significant associations between costs, QOL and disability.


[Pain evaluation in neonatology.].
The study of pain has seen a great development in the last decades, making evaluation and intervention a growing concern among health professionals. The objective of pain evaluation should be to provide accurate data to determine the actions that should be taken to relieve or abolish it and, at the same time, to evaluate the efficacy of those actions. The objective of this review was to discuss the methods used to evaluate pain in neonatology, since treatment strategies used without systematic pain evaluation are not effective or adequate. A widely accepted, easy to apply and uniform technique to evaluate pain in children, especially newborns and infants, that can be used in all situations does not exist. Before trusting the accuracy of the data, it is necessary that health professionals trust the instruments used to collect the data. Several indicators can be used to evaluate, quantify, and qualify the painful stimulus and, when analyzed as a set, allow the discrimination between pain and non-painful stimuli. Although the objective standardization of measuring pain severity is desirable, it does not exist. Measurement of pain in this age group is done by assessing physiological (heart rate, respiratory rate, blood pressure, and etc.) and behavioral (facial expression, posture, and vocalization or verbalization) parameters using evaluation scales, each one with its advantages and limitations. The current concern with better methods to measure and evaluate pain contributed to increase the sensitivity of health professionals regarding the nature of painful experiences. Pain should be valued as the fifth vital sign and evaluated in a systemized manner, including in newborns.


Additional benefit of ¹⁸F-fluorodeoxyglucose integrated positron emission tomography/computed tomography in the staging of oesophageal cancer.
¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET) has been shown to improve the accuracy of staging in oesophageal cancer. We assessed the benefit of PET/CT over conventional staging and determined if tumour histology had any significant impact on PET/CT findings. A retrospective cohort study, reviewing the results from 200 consecutive patients considered suitable for radical treatment, undergoing routine PET/CT staging comparing the results from CT and endoscopic ultrasound, as well as multi-disciplinary team records. Adenocarcinoma and squamous cell carcinoma were compared for maximum Standardised Uptake Value (SUV(max)), involvement of local lymph nodes and distant metastases. PET/CT provided additional information in 37 patients (18.5%) and directly altered management in 34 (17%): 22 (11%) were upstaged; 15 (7.5%) were downstaged, 12 of whom (6%) received radical treatment. There were 11 false negatives (5.5%) and 1 false positive (0.5%). SUV(max) was significantly lower for adenocarcinoma than squamous cell carcinoma (median 9.1 versus 13.5, p = 0.003). Staging with PET/CT offers additional benefit over conventional imaging and should form part of routine staging for oesophageal cancer. Adenocarcinoma and squamous cell carcinoma display significantly different FDG-avidity.


Systematic review and meta-analysis of different dietary approaches to the management of type 2 diabetes.
There is evidence that reducing blood glucose concentrations, inducing weight loss, and improving the lipid profile reduces cardiovascular risk in people with type 2 diabetes. We assessed the effect of various diets on glycemic control, lipids, and weight loss. We conducted searches of PubMed, Embase, and Google Scholar to August 2011. We included randomized controlled trials (RCTs) with interventions that lasted ≥6 mo that compared low-carbohydrate, vegetarian, vegan, low-glycemic index (GI), high-fiber, Mediterranean, and high-protein diets with control diets including low-fat, high-GI, American Diabetes Association, European Association for the Study of Diabetes, and low-protein diets. A total of 20 RCTs were included (n = 3073 included in final analyses across 3460 randomly assigned individuals). The low-carbohydrate, low-GI, Mediterranean, and high-protein diets all led to a greater improvement in glycemic control [glycated hemoglobin reductions of -0.12% (P = 0.04), -0.14% (P = 0.008), -0.47% (P < 0.00001), and -0.28% (P < 0.00001), respectively] compared with their respective control diets, with the largest effect size seen in the Mediterranean diet. Low-carbohydrate and Mediterranean diets led to greater weight loss [-0.69 kg (P = 0.21) and -1.84 kg (P < 0.00001), respectively], with an increase in HDL seen in all diets except the high-protein diet. Low-carbohydrate, low-GI, Mediterranean, and high-protein diets are effective in improving various markers of cardiovascular risk in people with diabetes and should be considered in the overall strategy of diabetes management.


Manual versus target-controlled infusion remifentanil administration in spontaneously breathing patients.
The combination of propofol-remifentanil for procedural deep sedation in spontaneously breathing patients is characterized by the frequent incidence of side effects, especially respiratory depression. These side effects may be due to either the drug combination or the drug delivery technique. Target-controlled infusion (TCI) might optimize drug delivery. In this prospective, randomized, double-blind study in patients undergoing elective colonoscopy, we thus tried to answer two questions: first, if adding remifentanil to propofol surpasses the disadvantages of the combination of these two products, and second, if administration of remifentanil via TCI decreases the incidence of side effects, compared to manually controlled administration. Patients undergoing elective colonoscopy were randomly assigned to receive remifentanil via manually controlled continuous infusion (MCI) (0.125 microg x kg(-1) x min(-1) for 2 min followed by a continuous infusion of 0.05 microg x kg(-1) x min(-1)), TCI remifentanil (1 ng/mL), or placebo (normal saline either as TCI or manual infusion of equivalent rate). All patients received TCI propofol, adjusted to a target concentration level that provided deep sedation in which patients were not responsive to verbal commands, but maintained spontaneous ventilation without assistance. Significantly more patients in the placebo group showed movement, cough and hiccup, which transiently interfered with the examination. There were no clinically significant differences in hemodynamic or recovery variables among all groups. Remifentanil administered via TCI resulted in a decrease in propofol requirements. The incidence of hypopnea and apnea was less frequent when remifentanil was administered via TCI compared to MCI (TCI n = 7, MCI n = 16, P < 0.05). The combination of remifentanil and propofol for deep sedation in spontaneously breathing patients, offered better conditions for colonoscopy than propofol used as a single drug. Remifentanil administered via TCI resulted in a decrease in propofol dosing and in a lower incidence in apnea and respiratory depression (TCI n = 7, MCI n = 16, P < 0.05), compared to manually controlled administration of remifentanil.


Essential domains of Anaplasma phagocytophilum invasins utilized to infect mammalian host cells.
Anaplasma phagocytophilum causes granulocytic anaplasmosis, an emerging disease of humans and domestic animals. The obligate intracellular bacterium uses its invasins OmpA, Asp14, and AipA to infect myeloid and non-phagocytic cells. Identifying the domains of these proteins that mediate binding and entry, and determining the molecular basis of their interactions with host cell receptors would significantly advance understanding of A. phagocytophilum infection. Here, we identified the OmpA binding domain as residues 59 to 74. Polyclonal antibody generated against a peptide spanning OmpA residues 59 to 74 inhibited A. phagocytophilum infection of host cells and binding to its receptor, sialyl Lewis x (sLe(x)-capped P-selectin glycoprotein ligand 1. Molecular docking analyses predicted that OmpA residues G61 and K64 interact with the two sLe(x) sugars that are important for infection, α2,3-sialic acid and α1,3-fucose. Amino acid substitution analyses demonstrated that K64 was necessary, and G61 was contributory, for recombinant OmpA to bind to host cells and competitively inhibit A. phagocytophilum infection. Adherence of OmpA to RF/6A endothelial cells, which express little to no sLe(x) but express the structurally similar glycan, 6-sulfo-sLe(x), required α2,3-sialic acid and α1,3-fucose and was antagonized by 6-sulfo-sLe(x) antibody. Binding and uptake of OmpA-coated latex beads by myeloid cells was sensitive to sialidase, fucosidase, and sLe(x) antibody. The Asp14 binding domain was also defined, as antibody specific for residues 113 to 124 inhibited infection. Because OmpA, Asp14, and AipA each contribute to the infection process, it was rationalized that the most effective blocking approach would target all three. An antibody cocktail targeting the OmpA, Asp14, and AipA binding domains neutralized A. phagocytophilum binding and infection of host cells. This study dissects OmpA-receptor interactions and demonstrates the effectiveness of binding domain-specific antibodies for blocking A. phagocytophilum infection.


Advances in random matrix theory, zeta functions, and sphere packing.
Over four hundred years ago, Sir Walter Raleigh asked his mathematical assistant to find formulas for the number of cannonballs in regularly stacked piles. These investigations aroused the curiosity of the astronomer Johannes Kepler and led to a problem that has gone centuries without a solution: why is the familiar cannonball stack the most efficient arrangement possible? Here we discuss the solution that Hales found in 1998. Almost every part of the 282-page proof relies on long computer verifications. Random matrix theory was developed by physicists to describe the spectra of complex nuclei. In particular, the statistical fluctuations of the eigenvalues ("the energy levels") follow certain universal laws based on symmetry types. We describe these and then discuss the remarkable appearance of these laws for zeros of the Riemann zeta function (which is the generating function for prime numbers and is the last special function from the last century that is not understood today.) Explaining this phenomenon is a central problem. These topics are distinct, so we present them separately with their own introductory remarks.


Gunshot injuries of the spine--a review of 49 cases managed at the Groote Schuur Acute Spinal Cord Injury Unit.
The Acute Spinal Injury Unit, relocated from Conradie Hospital to Groote Schuur Hospital in mid-2003, admitted 162 patients in the first year of its existence. A large number of these injuries were the result of interpersonal violence, particularly gunshot wounds. To review patients with gunshot injuries to the spine, with reference to neurological injury, associated injuries, need for surgery and complications. A comprehensive database is maintained to collect data on all spinal injury admissions. These data, as well as case notes and X-rays, were reviewed for all gunshot spine patients admitted to the Acute Spinal Injury Unit over a year. Forty-nine patients were identified. Thirty-eight were male and 11 female with an average age of 27.5 years (range 15-51 +/- 8.53). The average stay in the acute unit was 30 (4-109 +/- 28) days. The spinal injury was complete in 38 and incomplete in 8, with 3 having no neurological deficit. The level was cervical in 13, thoracic in 24 and lumbar in 12. Only 9 patients improved neurologically. The spine was considered stable in 43 cases. Stabilisation was performed in the 6 unstable cases. The bullets were removed in 11 cases as they were in the canal. There were 55 significant associated injuries, viz. 14 haemo-pneumothoraces, 16 abdominal visceral injuries, 3 vascular injuries, 4 injuries of the brachial plexus and 3 of the oesophagus, 2 tracheal injuries, 1 soft palate injury and 11 non-spinal fractures. Complications included 3 deaths and discitis in 3 cases, pneumonia in 6 and pressure sores in 6. Gunshot injuries of the spine are a prevalent and resource-intensive cause of paralysis. There is a high incidence of permanent severe neurological deficit, but usually the spine remains mechanically stable. Most of the management revolves around the associated injuries and consequences of the neurological deficit.


Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition.
T cell recognition of minor histocompatibility antigens (mHags) underlies allogeneic immune responses that mediate graft-versus-host disease and the graft-versus-leukemia effect following stem cell transplantation. Many mHags derive from single amino acid polymorphisms in MHC-restricted epitopes, but our understanding of the molecular mechanisms governing mHag immunogenicity and recognition is incomplete. Here we examined antigenic presentation and T-cell recognition of HA-1, a prototypic autosomal mHag derived from single nucleotide dimorphism (HA-1(H) versus HA-1(R)) in the HMHA1 gene. The HA-1(H) peptide is restricted by HLA-A2 and is immunogenic in HA-1(R/R) into HA-1(H) transplants, while HA-1(R) has been suggested to be a "null allele" in terms of T cell reactivity. We found that proteasomal cleavage and TAP transport of the 2 peptides is similar and that both variants can bind to MHC. However, the His>Arg change substantially decreases the stability and affinity of HLA-A2 association, consistent with the reduced immunogenicity of the HA-1(R) variant. To understand these findings, we determined the structure of an HLA-A2-HA-1(H) complex to 1.3A resolution. Whereas His-3 is accommodated comfortably in the D pocket, incorporation of the lengthy Arg-3 is predicted to require local conformational changes. Moreover, a soluble TCR generated from HA-1(H)-specific T-cells bound HA-1(H) peptide with moderate affinity but failed to bind HA-1(R), indicating complete discrimination of HA-1 variants at the level of TCR/MHC interaction. Our results define the molecular mechanisms governing immunogenicity of HA-1, and highlight how single amino acid polymorphisms in mHags can critically affect both MHC association and TCR recognition.


PNPLA3 polymorphism increases risk for and severity of chronic hepatitis C liver disease.
To examine the association of PNPLA3 polymorphisms in chronic hepatitis C patients and development of liver disease spectrum. Literature was searched systematically from PubMed/MEDLINE, EMBASE, and Cochrane search engines for full-length articles written in English that examined PNPLA3 polymorphism in chronic hepatitis C (CHC) patients. Studies evaluating the association of PNPLA3 polymorphism spectrum (fatty liver, steatohepatitis, cirrhosis, and hepatocellular carcinoma) of CHC were included. Pooled data are reported as OR with 95%CI. Our study endpoint was the risk of the entire liver disease spectrum including: Steatosis/fatty liver, cirrhosis, and hepatocellular carcinoma in CHC patients with PNPLA3 polymorphisms. Of 380 studies identified, a total of 53 studies were included for full-text review. Nineteen on chronic hepatitis C were eligible for analysis. Pooled ORs for rs738409 GG compared to CC and CG among patients with fatty liver was 2.214 (95%CI: 1.719-2.853). ORs among advanced fibrosis/cirrhosis were 1.762 (95%CI: 1.258-2.468). Similar odds ratios among hepatocellular carcinoma patients were 2.002 (95%CI: 1.519-2.639). Pooled ORs for rs738409 GG and CG compared to CC among patients with fatty liver were 1.750 (95%CI: 1.542-1.986). Pooled ORs for advanced fibrosis/cirrhosis patients were 1.613 (95%CI: 1.211-2.147). All analyses were homogenous and without publication bias except one. The associations were maintained after adjusting for publication bias and heterogeneity. PNPLA3 polymorphisms have strong association with increased risk and severity of the liver disease spectrum in CHC patients.


PELP1--a novel estrogen receptor-interacting protein.
PELP1 (proline-, glutamic acid-, and leucine-rich protein-1) is a novel estrogen receptor (ER)-interacting protein that has been implicated to be important for mediation of both the genomic and nongenomic signaling of 17beta-estradiol (E2). PELP1 contains ten nuclear receptor-interacting boxes (LXXLL motifs), which allow it to interact with ER and other nuclear hormone receptors, a zinc finger, a glutamic acid-rich domain, and two proline-rich domains. The proline-rich regions contain several consensus PXXP motifs, which allow PELP1 to couple the ER with SH3 domain-containing kinase signaling proteins, such as Src and PI3K P85 regulatory subunit. PELP1 is expressed in many different brain regions, including the hippocampus, hypothalamus, and cerebral cortex. Further work has demonstrated that PELP1 is colocalized with ER-alpha in neurons in various brain regions. PELP1 is primarily expressed in neurons, with some expression also observed in glia. Subcellular localization studies revealed that PELP1 is highly localized in the cell nucleus of neurons, with some cytoplasm localization as well, and PELP1 is also localized at synaptic sites. Work in other tissues has demonstrated that PELP1 is critical for nongenomic and genomic signaling by E2, as PELP1 knockdown studies significantly attenuates E2-induced activation of ERK and Akt signaling pathways, and inhibits E2 genomic transcriptional effects on gene expression in breast cancer cells. Preliminary studies in the brain, suggests that similar roles may exist for PELP1 in the brain, but this remains to be established, and further work to characterize the precise roles and functions of PELP1 in the brain are needed.


Carbon irradiated semi insulating GaAs for photoconductive terahertz pulse detection.
We report here a photoconductive material for THz detection with sub-picosecond carrier lifetime made by C(12) (Carbon) irradiation on commercially available semi-insulating (SI) GaAs. We are able to reduce the carrier lifetime of SI-GaAs down to sub-picosecond by irradiating it with various irradiation dosages of Carbon (C(12)) ions. With an increase of the irradiation dose from ~10(12) /cm(2) to ~10(15) /cm(2) the carrier lifetime of SI-GaAs monotonously decreases to 0.55 picosecond, whereas that of usual non-irradiated SI-GaAs is ~70 picosecond. This decreased carrier lifetime has resulted in a strong improvement in THz pulse detection compared with normal SI-GaAs. Improvement in signal to noise ratio as well as in detection bandwidth is observed. Carbon irradiated SI-GaAs appears to be an economical alternative to low temperature grown GaAs for fabrication of THz devices.


Acupuncture for subacute stroke rehabilitation: a Sham-controlled, subject- and assessor-blind, randomized trial.
Any adjunctive therapy that may reduce persistent disability after stroke should be considered. Acupuncture is used for this purpose, but there is conflicting evidence on its effectiveness. Patients with a recent (<4 weeks) episode of stroke were randomized to receive 12 sessions of either real or sham acupuncture during 2 weeks. The primary outcome was the change in Barthel activities of daily living score at the end of treatment. Secondary outcome measures included National Institutes of Health Stroke Scale score, motoricity index, and quality of life (EQ-5D [ EuroQoL-5 Dimensional form] and EQ-VAS [EuroQoL-Visual Analog Scale]). Assessments were carried out by blinded physicians. A total of 116 patients (56 in the real acupuncture group and 60 in the sham group) were randomized, and 98 (real, 48; sham, 50) completed treatment and the 2-week assessment. Patient blinding by means of the sham acupuncture device was successful. Acupuncture was well tolerated except for 1 seizure during a real acupuncture session. The improvements in the Barthel scores were 4 points (interquartile range [IQR], 0-8) vs 3 points (IQR, 0-7) in the real and sham acupuncture groups, respectively (P = .38). The secondary outcome measures also essentially showed no significant effect of acupuncture. Post hoc analysis by baseline severity showed a greater improvement in leg function in the subgroup with baseline Barthel score less than the median (median score, 6): 22 points (IQR, 0-37) vs 0 [corrected] points (IQR, 0-4) in the acupuncture and sham control groups, respectively (P = .02). Acupuncture is not superior to sham treatment for recovery in activities of daily living and health-related quality of life after stroke, although there may be a limited effect on leg function in more severely affected patients.


Economic vulnerability and payment for research participation.
There has been significant analysis of the ethical and regulatory issues involved with paying research participants, but less attention has been focused specifically on paying economically vulnerable individuals and the unique challenges it may present. This is important, as individuals of lower socio-economic standing are present in all disease groups and study populations. Moreover, clinical research is often conducted in economically under-developed locales, such as lower- or middle-income countries as well as impoverished locales of otherwise wealthy nations (such as, for example, rural Appalachia in the United States). Is it ethical to offer payment in such contexts? What are the ethical considerations relevant for determining payment rates and practices to individuals who are economically vulnerable? We offer an analysis of these issues, focusing on four unique areas of concern: (1) whether the risk of undue influence is greater for economically vulnerable individuals than for wealthier ones; (2) whether payment unacceptably raises the risk of 'unjust influence' or disproportionate representation of poor people in clinical research; (3) the positive reasons in favor of paying economically vulnerable people that stem from the ethical value of fairness; and (4) appropriate compensation rates for economically vulnerable populations. Our analysis supports the position that payment to economically vulnerable populations is ethically justified and indeed desirable when certain conditions are met.


School environments and physical activity: The development and testing of an audit tool.
The aim of this study was to develop, test, and employ an audit tool to objectively assess the opportunities for physical activity within school environments. A 44 item tool was developed and tested at 92 primary schools in the county of Norfolk, England, during summer term of 2007. Scores from the tool covering 6 domains of facility provision were examined against objectively measured hourly moderate to vigorous physical activity levels in 1868 9-10 year old pupils attending the schools. The tool was found to have acceptable reliability and good construct validity, differentiating the physical activity levels of children attending the highest and lowest scoring schools. The characteristics of school grounds may influence pupil's physical activity levels.


Intended and unintended pregnancies worldwide in 2012 and recent trends.
Periodic estimation of the incidence of global unintended pregnancy can help demonstrate the need for and impact of family planning programs. We draw upon multiple sources of data to estimate pregnancy incidence by intention status and outcome at worldwide, regional, and subregional levels in 2012 and to assess recent trends using previously published estimates for 2008 and 1995. We find that 213 million pregnancies occurred in 2012, up slightly from 211 million in 2008. The global pregnancy rate decreased only slightly from 2008 to 2012, after declining substantially between 1995 and 2008. Eighty-five million pregnancies, representing 40 percent of all pregnancies, were unintended in 2012. Of these, 50 percent ended in abortion, 13 percent ended in miscarriage, and 38 percent resulted in an unplanned birth. The unintended pregnancy rate continued to decline in Africa and in the Latin America and Caribbean region. If the aims of the London Summit on Family Planning are carried out, the incidence of unwanted and mistimed pregnancies should decline in the coming years.


Nebraska dental professional's procedures and opinions related to infectious diseases.
Based on the findings of this study, the following specific strategic recommendations are offered: 1. Offer continuing education courses throughout the state at reasonable fees. The courses should emphasize recognition of AIDS related lesions and infectious diseases, aseptic techniques/infectious disease control, AIDS, Hepatitis B, and infections/antibiotics. In addition, continuing education courses in the area of medical history taking methods should be offered to teach methods of inquiring about sexual and drug-use histories. 2. Establish a state resource center for information regarding infectious diseases. This could, perhaps, be a cooperative venture with the Department of Health, the Nebraska Dental Association, and the College of Dentistry. There is a need to gather, interpret and disseminate periodic updates on infectious disease research. This venture should also focus on developing literature for practitioners with consistent information about infection control regulations and guidelines. 3. Either through continuing education courses or through the information resource center, provide instruction on realistic assessment of the risk of infectious disease transmission in dentistry. 4. Develop a public relations campaign to educate the public about infection control policies in dentistry, what is being done to protect the public. 5. A research effort should be undertaken to determine the discrepancy between self-reported infection control practices and observed infection control practices. This could be accomplished through patient and dentist surveys, interviews, and/or observations. 6. Establish a confidential HIV blood screening program for health care providers.


The prevalence of alcohol consumption and heavy drinking among people with HIV in the United States: results from the HIV Cost and Services Utilization Study.
To establish population-based estimates of the prevalence of any alcohol consumption and heavy drinking among individuals who tested positive for human immunodeficiency virus (HIV) and to identify the factors associated with alcohol consumption and heavy drinking in this population. Data from the HIV Cost and Services Utilization Study (HCSUS), a national probability survey of HIV-infected adults receiving medical care in the U.S. in early 1996 (N = 2,864: 2,017 men, 847 women), were used to estimate the prevalence of any alcohol consumption and heavy drinking. Logistic regression was used to identify independent influences of sociodemographic, health status, and substance use variables on alcohol consumption and heavy drinking. Approximately 53% of persons in care for HIV reported drinking alcohol in the preceding month and 8% were classified as heavy drinkers. Of those who drank, 15% were heavy drinkers. The odds of heavy drinking were significantly higher among users of cocaine or heroin and significantly lower among the better educated and those with an AIDS-defining illness. Alcohol consumption is common among people in care for HIV, with rates of heavy drinking almost twice those found in the general population. Heavy drinking is especially higher among individuals with lower educational levels and users of cocaine or heroin.


Changes in the mother-child relationship during the transition to adulthood for youth with autism spectrum disorders.
We examined whether exiting high school was associated with changes in the mother-child relationship. Participants were 170 mothers of youth with ASD who were part of our larger longitudinal study and who exited high school during the study; data were collected four times over 7 years. Results indicated improvement in the mother-child relationship while in high school; however, improvement in all indices slowed or stopped after exit. Mothers of youth with ASD without an intellectual disability (ID) and who had more unmet service needs evidenced the least improvement after exit. Our findings provide further evidence that the years after high school exit are a time of increased risk, especially for those with ASD without ID and whose families are under-resourced.


Glutamate modulates neurotransmission in the submucosal plexus of guinea-pig small intestine.
Effects of glutamate on synaptic transmission in the submucosal plexus of guinea-pig small intestine were studied with intracellular electrophysiological recording methods. Glutamate suppressed stimulus-evoked slow excitatory postsynaptic potentials (EPSPs) and increased the amplitude of slow inhibitory postsynaptic potentials (IPSPs) in submucosal neurons. The actions of glutamate were mimicked by the group I metabotropic glutamate receptor (mGluRs) agonist DHPG, but not by the group II agonist S-4C3HPG, the group III agonist L-AP4, or selective agonists for ionotropic glutamate receptors (iGluRs). Glutamate actions were suppressed by the selective group I mGluRs antagonist S-4CPG, but not by group II and III mGluRs antagonist CPPG or iGluRs antagonists. Glutamate suppressed substance P- and 5-HT-evoked slow EPSP-like responses and potentiated norepinephrine-induced slow IPSP-like responses. The results suggest that group I mGluRs mediate glutamate-induced suppression of slow EPSPs and potentiation of slow IPSPs in S-type uniaxonal submucosal neurons.


Computing the various pathways of penicillin synthesis and their molar yields.
More than 80 years after its discovery, penicillin is still a widely used and commercially highly important antibiotic. Here, we analyse the metabolic network of penicillin synthesis in Penicillium chrysogenum based on the concept of elementary flux modes. In particular, we consider the synthesis of the invariant molecular core of the various subtypes of penicillin and the two major ways of incorporating sulfur: transsulfuration and direct sulfhydrylation. 66 elementary modes producing this invariant core are obtained. These show four different yields with respect to glucose, notably ½, 2/5, 1/3, and 2/7, with the highest yield of ½ occurring only when direct sulfhydrylation is used and α-aminoadipate is completely recycled. In the case of no recycling of this intermediate, we find the maximum yield to be 2/7. We compare these values with earlier literature values. Our analysis provides a systematic overview of the redundancy in penicillin synthesis and a detailed insight into the corresponding routes. Moreover, we derive suggestions for potential knockouts that could increase the average yield.


MIPSTR: a method for multiplex genotyping of germline and somatic STR variation across many individuals.
Short tandem repeats (STRs) are highly mutable genetic elements that often reside in regulatory and coding DNA. The cumulative evidence of genetic studies on individual STRs suggests that STR variation profoundly affects phenotype and contributes to trait heritability. Despite recent advances in sequencing technology, STR variation has remained largely inaccessible across many individuals compared to single nucleotide variation or copy number variation. STR genotyping with short-read sequence data is confounded by (1) the difficulty of uniquely mapping short, low-complexity reads; and (2) the high rate of STR amplification stutter. Here, we present MIPSTR, a robust, scalable, and affordable method that addresses these challenges. MIPSTR uses targeted capture of STR loci by single-molecule Molecular Inversion Probes (smMIPs) and a unique mapping strategy. Targeted capture and our mapping strategy resolve the first challenge; the use of single molecule information resolves the second challenge. Unlike previous methods, MIPSTR is capable of distinguishing technical error due to amplification stutter from somatic STR mutations. In proof-of-principle experiments, we use MIPSTR to determine germline STR genotypes for 102 STR loci with high accuracy across diverse populations of the plant A. thaliana. We show that putatively functional STRs may be identified by deviation from predicted STR variation and by association with quantitative phenotypes. Using DNA mixing experiments and a mutant deficient in DNA repair, we demonstrate that MIPSTR can detect low-frequency somatic STR variants. MIPSTR is applicable to any organism with a high-quality reference genome and is scalable to genotyping many thousands of STR loci in thousands of individuals.


Nanoelectronic programmable synapses based on phase change materials for brain-inspired computing.
Brain-inspired computing is an emerging field, which aims to extend the capabilities of information technology beyond digital logic. A compact nanoscale device, emulating biological synapses, is needed as the building block for brain-like computational systems. Here, we report a new nanoscale electronic synapse based on technologically mature phase change materials employed in optical data storage and nonvolatile memory applications. We utilize continuous resistance transitions in phase change materials to mimic the analog nature of biological synapses, enabling the implementation of a synaptic learning rule. We demonstrate different forms of spike-timing-dependent plasticity using the same nanoscale synapse with picojoule level energy consumption.


Optimal out-of-band correction for multispectral remote sensing.
In this paper, an optimal out-of-band (OOB) correction transform (OOBCT) for dealing with onboard Visible/Infrared Imaging Radiometer Suite (VIIRS) OOB effects is proposed. This paper addresses the OOB response issue without consideration of the impact of other error sources on the correction processing. The OOBCT matrix is derived by minimizing an objective function of error summation between the expected and realistic recovered band-averaged spectral radiances. Using the VIIRS filter transmittance functions for all multiband sensors obtained from prelaunch laboratory measurements and a simulated dataset obtained from Airborne Visible InfraRed Imaging Spectrometer (AVIRIS) hyperspectral data, the OOBCT matrix is numerically computed. The processing of the OOB correction is straightforward and can be performed by a product between the OOBCT matrix and a measured multispectral image vector. The experimental results with both AVIRIS and Hyperspectral Imager for the Coastal Ocean datasets demonstrate that the ratios of average errors of recovered band-averaged spectral radiances divided by the measured radiances with the OOB responses are less than 4%. The average values of the relative errors for all pixels and bands indicate that the OOBCT method outperforms the works reported in literature.


Activation of Rho is required for ligand-independent oncogenic signaling by a mutant epidermal growth factor receptor.
Mutations in the epidermal growth factor receptor have been identified in several human tumor types, including gliomas. These receptor mutants have deletions in their extracellular ligand-binding domains and are, therefore, no longer regulated by ligand, resulting in constitutive activation of the receptor kinase. These mutants have been proposed to transduce oncogenic signals via ligand-independent signaling pathways. Avian viral homologues of these oncogenic epidermal growth factor receptors exhibit structurally homologous deletions and form tumors in chickens. One such mutant, S3v-ErbB, transforms fibroblasts in vitro, and transformation has been correlated with the formation of a novel tyrosine phosphoprotein complex. V-ErbB-mediated complex formation and transformation have been shown to occur independently of Ras activation. The major aims of this study are to further characterize this ligand-independent v-ErbB oncogenic signaling pathway. Here we show that both v-ErbB-mediated phosphoprotein complex formation and transformation are inhibited by a dominant negative mutant of Rho. This inhibition is specific for dominant negative Rho; dominant negative mutants of Rac and Cdc42 have no effect on transformation or on tyrosine phosphorylation of the phosphoprotein complex. Based on these observations, we propose that S3v-ErbB stimulates a Rho-dependent tyrosine kinase, resulting in complex formation and ultimately oncogenic transformation.


Tetrathiafulvalene-calix[4]pyrrole: a versatile synthetic receptor for electron-deficient planar and spherical guests.
The first tetrakis-tetrathiafulvalene-calix[4]pyrrole (TTF-C[4]P) was reported in 2004. Early on it and related π-extended TTF-C[4]Ps were found to function as both anion receptors and as hosts for planar electron deficient neutral guests, including nitroaromatic explosives. Anion binding was found to occur with a 1 : 1 binding stoichiometry and to stabilise the cone C[4]P conformation, whereas planar electron deficient guests were bound in a cooperative 1 : 2 fashion to the 1,3-alternate conformer. Addition of strongly complexing anions was found to trigger release of the electron deficient guests concurrent with a conformational change to the cone form. Subsequent studies led to the discovery of anion-induced complexation with C60, and the finding that the resulting complexes would support fast photoinduced electron transfer events. Synthetic advances then led to the preparation of nonsymmetric TTF-C[4]Ps where a single moiety organises the receptor in either the 1,3-alternate conformation or the partial cone conformation, thus modifying both selectivity and sensitivity. TTF-C[4]P-based stimulus responsive systems, that rely on anions and cations as controlling inputs, have also been developed and studied in recent years. This review provides a summary of TTF-C[4]P-related chemistry.


A framework for identifying carbon hotspots and forest management drivers.
Spatial analyses of ecosystem system services that are directly relevant to both forest management decision making and conservation in the subtropics are rare. Also, frameworks that identify and map carbon stocks and corresponding forest management drivers using available regional, national, and international-level forest inventory datasets could provide insights into key forest structural characteristics and management practices that are optimal for carbon storage. To address this need we used publicly available USDA Forest Service Forest Inventory and Analysis data and spatial analyses to develop a framework for mapping "carbon hotspots" (i.e. areas of significantly high tree and understory aboveground carbon stocks) across a range of forest types using the state of Florida, USA as an example. We also analyzed influential forest management variables (e.g. forest types, fire, hurricanes, tenure, management activities) using generalized linear mixed modeling to identify drivers associated with these hotspots. Most of the hotspots were located in the northern third of the state some in peri-urban areas, and there were no identifiable hotspots in South Florida. Forest silvicultural treatments (e.g. site preparation, thinning, logging, etc) were not significant predictors of hotspots. Forest types, site quality, and stand age were however significant predictors. Higher site quality and stand age increased the probability of forests being classified as a hotspot. Disturbance type and time since disturbance were not significant predictors in our analyses. This framework can use globally available forest inventory datasets to analyze and map ecosystems service provision areas and bioenergy supplies and identify forest management practices that optimize these services in forests.


Eosinophilia With Hepatic Mass and Abnormal Liver Function Tests: An Unusual Presentation of Chronic Myeloid Leukemia.
Chronic myeloid leukemia (CML) is a chronic myeloproliferative neoplasm characterized by excess granulocytes at different stages of maturation and the presence of BCR-ABL1 fusion gene or Philadelphia chromosome. Absolute eosinophilia, basophilia, and monocytosis are not uncommon in CML. However, a rare entity called eosinophilic variant of CML (eoCML) can present with eosinophilia without excess neutrophils or basophils. Here, we report a rare and unusual case of eoCML presenting as a liver mass with abnormal liver function tests, which has not been reported in the literature so far.


Exploring Stereotypes of Athletes With a Disability: A Behaviors From Intergroup Affect and Stereotypes Map Comparison.
Identifying as a regular exerciser has been found to effectively alter stereotypes related to warmth and competence for adults with a physical disability; however, it remains unclear how sport participation can influence this trend. Therefore, this study aimed to examine warmth and competence perceptions of adults with a physical disability portrayed as elite and nonelite athletes relative to other athletic and nonathletic subgroups of adults with and without a physical disability in the context of the stereotype content model. Using survey data from able-bodied participants (N = 302), cluster analyses were applied to a behaviors from intergroup affect and stereotypes map for displaying the intersection of warmth and competence perceptions. The results demonstrated that adults with a physical disability who are described as elite athletes (i.e., Paralympians) are clustered with high warmth and high competence, similar to their able-bodied athletic counterparts (i.e., Olympians). The findings suggest that perceiving athletic and elite sport statuses for adults with a physical disability may counter the stereotypes commonly applied to this group.


Factors affecting public access defibrillator placement decisions in the United Kingdom: A survey study.
This study aimed to understand current community PAD placement strategies and identify factors which influence PAD placement decision-making in the United Kingdom (UK). Individuals, groups and organisations involved in PAD placement in the UK were invited to participate in an online survey collecting demographic information, facilitators and barriers to community PAD placement and information used to decide where a PAD is installed in their experiences. Survey responses were analysed through descriptive statistical analysis and thematic analysis. There were 106 included responses. Distance from another PAD (66%) and availability of a power source (63%) were most frequently used when respondents are deciding where best to install a PAD and historical occurrence of cardiac arrest (29%) was used the least. Three main themes were identified influencing PAD placement: (i) the relationship between the community and PADs emphasising community engagement to create buy-in; (ii) practical barriers and facilitators to PAD placement including securing consent, powering the cabinet, accessibility, security, funding, and guardianship; and (iii) 'risk assessment' methods to estimate the need for PADs including areas of high footfall, population density and type, areas experiencing health inequalities, areas with delayed ambulance response and current PAD provision. Decision-makers want to install PADs in locations that maximise impact and benefit to the community, but this can be constrained by numerous social and infrastructural factors. The best location to install a PAD depends on local context; work is required to determine how to overcome barriers to optimal community PAD placement.


Rhodium-Catalyzed [3 + 2] Annulation of Cyclic N-Acyl Ketimines with Activated Olefins: Anticancer Activity of Spiroisoindolinones.
The rhodium(III)-catalyzed redox-neutral coupling reaction of N-acyl ketimines generated in situ from 3-hydroxyisoindolinones with various activated olefins is described. This approach leads to the synthesis of bioactive spiroisoindolinone derivatives in moderate to high yields. In the case of internal olefins such as maleimides, maleates, fumarates, and cinnamates, spiroindanes were obtained by the [3 + 2] annulations reaction. In sharp contrast, acrylates and quinones displayed the β-H elimination followed by Prins-type cyclization furnishing spiroindenes. The synthetic compounds were evaluated for in vitro anticancer activity against androgen-sensitive human prostate adenocarcinoma cells (LNCaP), human prostate adenocarcinoma cells (DU145), human endometrial adenocarcinoma cells (Ishikawa), human breast cancer cell (MCF-7), and triple negative human breast cancer cells (MDA-MB-231). Notably, quinone-containing spiroindenes displayed potent anticancer activity about 2- to 3-fold stronger than that of anticancer agent doxorubicin.


Phylogenomics of Lophotrochozoa with Consideration of Systematic Error.
Phylogenomic studies have improved understanding of deep metazoan phylogeny and show promise for resolving incongruences among analyses based on limited numbers of loci. One region of the animal tree that has been especially difficult to resolve, even with phylogenomic approaches, is relationships within Lophotrochozoa (the animal clade that includes molluscs, annelids, and flatworms among others). Lack of resolution in phylogenomic analyses could be due to insufficient phylogenetic signal, limitations in taxon and/or gene sampling, or systematic error. Here, we investigated why lophotrochozoan phylogeny has been such a difficult question to answer by identifying and reducing sources of systematic error. We supplemented existing data with 32 new transcriptomes spanning the diversity of Lophotrochozoa and constructed a new set of Lophotrochozoa-specific core orthologs. Of these, 638 orthologous groups (OGs) passed strict screening for paralogy using a tree-based approach. In order to reduce possible sources of systematic error, we calculated branch-length heterogeneity, evolutionary rate, percent missing data, compositional bias, and saturation for each OG and analyzed increasingly stricter subsets of only the most stringent (best) OGs for these five variables. Principal component analysis of the values for each factor examined for each OG revealed that compositional heterogeneity and average patristic distance contributed most to the variance observed along the first principal component while branch-length heterogeneity and, to a lesser extent, saturation contributed most to the variance observed along the second. Missing data did not strongly contribute to either. Additional sensitivity analyses examined effects of removing taxa with heterogeneous branch lengths, large amounts of missing data, and compositional heterogeneity. Although our analyses do not unambiguously resolve lophotrochozoan phylogeny, we advance the field by reducing the list of viable hypotheses. Moreover, our systematic approach for dissection of phylogenomic data can be applied to explore sources of incongruence and poor support in any phylogenomic data set. [Annelida; Brachiopoda; Bryozoa; Entoprocta; Mollusca; Nemertea; Phoronida; Platyzoa; Polyzoa; Spiralia; Trochozoa.].


Comparison of Predictors and Mortality Between Bloodstream Infections Caused by ESBL-Producing Escherichia coli and ESBL-Producing Klebsiella pneumoniae.
OBJECTIVETo compare the epidemiology, clinical characteristics, and mortality of patients with bloodstream infections (BSI) caused by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (ESBL-EC) versus ESBL-producing Klebsiella pneumoniae (ESBL-KP) and to examine the differences in clinical characteristics and outcome between BSIs caused by isolates with CTX-M versus other ESBL genotypesMETHODSAs part of the INCREMENT project, 33 tertiary hospitals in 12 countries retrospectively collected data on adult patients diagnosed with ESBL-EC BSI or ESBL-KP BSI between 2004 and 2013. Risk factors for ESBL-EC versus ESBL-KP BSI and for 30-day mortality were examined by bivariate analysis followed by multivariable logistic regression.RESULTSThe study included 909 patients: 687 with ESBL-EC BSI and 222 with ESBL-KP BSI. ESBL genotype by polymerase chain reaction amplification of 286 isolates was available. ESBL-KP BSI was associated with intensive care unit admission, cardiovascular and neurological comorbidities, length of stay to bacteremia >14 days from admission, and a nonurinary source. Overall, 30-day mortality was significantly higher in patients with ESBL-KP BSI than ESBL-EC BSI (33.7% vs 17.4%; odds ratio, 1.64; P=.016). CTX-M was the most prevalent ESBL subtype identified (218 of 286 polymerase chain reaction-tested isolates, 76%). No differences in clinical characteristics or in mortality between CTX-M and non-CTX-M ESBLs were detected.CONCLUSIONSClinical characteristics and risk of mortality differ significantly between ESBL-EC and ESBL-KP BSI. Therefore, all ESBL-producing Enterobacteriaceae should not be considered a homogeneous group. No differences in outcomes between genotypes were detected.CLINICAL TRIALS IDENTIFIERClinicalTrials.gov. Identifier: NCT01764490.Infect Control Hosp Epidemiol 2018;39:660-667.


Human subject protection in India - is it adequate?
India's experience in clinical trials is shorter in time than that of the developed countries but as in everything else in the current globalizing environment, business compulsions characterized by compressed timelines are strong persuaders to catch up. Most global pharmaceutical and biotechnology organizations include India in their strategic plans, Immediate implementation of aspects that attract benefit are an urgent necessity. Technical and ethical issues that remain unresolved constrain India from reaching its deserved potential. To take fullest advantage of the current inflow of clinical trials, India must adopt, without delay, an all-inclusive approach and invest in a widespread and comprehensive GCP-compliance programme taking into account India-related cultural and socioeconomic issues. The initiative should not be allowed to flag. Government, the pharmaceutical and biotechnological research industries, the medical and pharmacy profession including relevant training institutes, the media and the public have a stake in such investment. The programme should involve assessing gaps in current clinical trial compliance measures and possible solutions, set the field for rectification and ensure implementation through mandate and penalty as feasible.


QM/MM analysis suggests that Alkaline Phosphatase (AP) and nucleotide pyrophosphatase/phosphodiesterase slightly tighten the transition state for phosphate diester hydrolysis relative to solution: implication for catalytic promiscuity in the AP superfamily.
Several members of the Alkaline Phosphatase (AP) superfamily exhibit a high level of catalytic proffciency and promiscuity in structurally similar active sites. A thorough characterization of the nature of transition state for different substrates in these enzymes is crucial for understanding the molecular mechanisms that govern those remarkable catalytic properties. In this work, we study the hydrolysis of a phosphate diester, MpNPP(-), in solution, two experimentally well-characterized variants of AP (R166S AP, R166S/E322Y AP) and wild type Nucleotide pyrophosphatase/phosphodiesterase (NPP) by QM/MM calculations in which the QM method is an approximate density functional theory previously parametrized for phosphate hydrolysis (SCC-DFTBPR). The general agreements found between these calculations and available experimental data for both solution and enzymes support the use of SCC-DFTBPR/MM for a semiquantitative analysis of the catalytic mechanism and nature of transition state in AP and NPP. Although phosphate diesters are cognate substrates for NPP but promiscuous substrates for AP, the calculations suggest that their hydrolysis reactions catalyzed by AP and NPP feature similar synchronous transition states that are slightly tighter in nature compared to that in solution, due in part to the geometry of the bimetallic zinc motif. Therefore, this study provides the first direct computational support to the hypothesis that enzymes in the AP superfamily catalyze cognate and promiscuous substrates via similar transition states to those in solution. Our calculations do not support the finding of recent QM/MM studies by López-Canut and co-workers, who suggested that the same diester substrate goes through a much looser transition state in NPP/AP than in solution, a result likely biased by the large structural distortion of the bimetallic zinc site in their simulations. Finally, our calculations for different phosphate diester orientations and phosphorothioate diesters highlight that the interpretation of thio-substitution experiments is not always straightforward.


Musicians: Larks, Owls or Hummingbirds?
Previous studies have shown an association between morning and evening types and creative thinking. Musicians are creative individuals and the purpose of the current research was to examine whether musicians are significantly more evening types than non-musicians. The total sample included 835 participants (n women = 353; n men = 482), with a mean age of 28.0 years (SD = 10.4). The group of musicians consisted of 600 participants (n women = 168; n men = 432) with a mean age of 29.1 years (SD = 11.2). The group of non-musicians consisted of 233 participants (n women = 184; n men = 49) with a mean age of 25.3 years (SD = 7.4). Participants were recruited via an online forum, and chronotypes were assessed using the self-report Horne & Ostberg's Morningness-Eveningness Questionnaire (MEQ). We found that performance musicians had significantly lower MEQ scores compared to non-performance musicians, and musicians who composed had the lowest MEQ scores across the whole sample. This indicates that musicians, particularly composing musicians had a tendency towards eveningness. These findings are discussed in relation to theories on chronobiology, creativity, and cognitive psychology.


Computational and experimental analysis reveals a novel Src family kinase in the C. elegans genome.
The complete genomes of a number of organisms have already been sequenced. However, the vast majority of annotated genes are derived by gene prediction methods. It is important to not only validate the predicted coding regions but also to identify genes that may have been missed by these programs. We searched the entire C.elegans genomic sequence database maintained by the Sanger Center using human c-Src sequence in a TBLASN search. We have confirmed one of the predicted regions by isolation of a cDNA and carried out a phylogenetic analysis of Src kinase family members in the worm, fly and several vertebrate species. Our analysis identified a novel tyrosine kinase in the C.elegans genome that contains functional features typical of the Src family kinases that we have designated as Src-1. The open reading frame contains a conserved N-terminal myristoylation site and a tyrosine residue within the C-terminus that is crucial for regulating the activity of Src kinases. Our phylogenetic analysis of Src family members from C. elegans, Drosophila and other higher organisms revealed a relationship among Src kinases from C. elegans and Drosophila.


Impact of the Microbiome on the Immune System.
Higher organisms are all born with general immunity as well as with, increasingly, more specific immune systems. All immune mechanisms function with the intent of aiding the body in defense against infection. Internal and external factors alike have varying effects on the immune system, and the immune response is tailored specifically to each one. Accompanying the components of the human innate and adaptive immune systems are the other intermingling systems of the human body. Increasing understanding of the body's immune interactions with other systems has opened new avenues of study, including that of the microbiome. The microbiome has become a highly active area of research over the last 10 to 20 years since the NIH began funding the Human Microbiome Project (HMP), which was established in 2007. Several publications have focused on the characterization, functions, and complex interplay of the microbiome as it relates to the rest of the body. A dysfunction between the microbiome and the host has been linked to various diseases including cancers, metabolic deficiencies, autoimmune disorders, and infectious diseases. Further understanding of the microbiome and its interaction with the host in relation to diseases is needed in order to understand the implications of microbiome dysfunction and the possible use of microbiota in the prevention of disease. In this review, we have summarized information on the immune system, the microbiome, the microbiome's interplay with other systems, and the association of the immune system and the microbiome in diseases such as diabetes and colorectal cancer.


Design and flight results of the VHF/UHF communication system of Longjiang lunar microsatellites.
As a part of China's Chang'e-4 lunar far side mission, two lunar microsatellites for low frequency radio astronomy, amateur radio and education, Longjiang-1 and Longjiang-2, were launched as secondary payloads on 20 May 2018 together with the Queqiao L2 relay satellite. On 25 May 2018, Longjiang-2 successfully inserted itself into a lunar elliptical orbit of 357 km × 13,704 km, and became the smallest spacecraft which entered lunar orbit with its own propulsion system. The satellite carried the first amateur radio communication system operating in lunar orbit, which is a VHF/UHF software defined radio (SDR) designed for operation with small ground stations. This article describes and evaluates the design of the VHF/UHF radio and the waveforms used. Flight results of the VHF/UHF radio are also presented, including operation of the radio, performance analysis of downlink signals and the first lunar orbit UHF very-long-baseline interferometry (VLBI) experiment.


Psychostimulant prescribing trends in a paediatric population in Ireland: a national cohort study.
Psychotropic paediatric prescribing trends are increasing internationally. The aim of this study is to examine the prevalence and secular trends in psychotropic prescribing in Irish children and adolescents between 2002 and 2011. Data was obtained from the Irish General Medical Services (GMS) scheme pharmacy claims database from the Health Service Executive Primary Care Reimbursement Services (HSE-PCRS). Prescribing rates per 1000 eligible population and associated 95% confidence intervals (CIs) were calculated across years (2002-2011), age groups (0-4, 5-11, 12-15 years) and gender. Rates of concomitant prescriptions for psycholeptics and antidepressants were also examined. The total expenditure costs were calculated and expressed as a percentage of the cost of all prescriptions for this age group (≤ 15 years). In 2002, 3.77/1000 GMS population (95% CI: 3.53-4.01) received at least one psychostimulant prescription and this rate increased to 8.63/1000 GMS population (95% CI: 8.34-8.92) in 2011. Methylphenidate was the most frequently prescribed psychostimulant. For both males and females the prevalence of medication use was highest among the 12-15 year old group. On average, a psycholeptic medication was prescribed to 8% of all psychostimulant users and an antidepressant was concomitantly prescribed on average to 2%. Total expenditure rose from €89,254 in 2002 to €1,532,016 in 2011. The rate and cost of psychostimulant prescribing among GMS children and adolescents in Ireland increased significantly between 2002 and 2011. Further research is necessary to assess the safety, efficacy and economic impact of concomitant psychotropic prescribing in this population.


The use of fixed-mixture insulins in clinical practice.
Pre-mixed insulins currently represent about 40% of the world market in human insulin. Despite the fact that many patients are being treated with these insulin formulations, there are surprisingly few data about fixed mixtures and comparisons with other administration schedules. The main advantages of using a pre-mixed preparation over a self-mixed insulin are increased accuracy of dosage, efficacy and patient convenience. These benefits may lead to increased compliance resulting in better long-term control of the disease. Insulin mixtures are used by a wide variety of patients with type-1 and type-2 diabetes. Pre-mixed insulins also appear to be useful in elderly and adolescent patients with diabetes, although there are few published data on patients in these groups. It is likely that, in the future, fixed mixtures containing rapid-acting insulin analogues, such as insulin lispro, and possibly newly formulated intermediate-acting insulin analogues, such as neutral protamine lispro, may allow further improvements in both metabolic control and patient convenience.


A heavy metal baseline score predicts outcome in acute myeloid leukemia.
Despite abundant epidemiological data linking metals to leukemia and other cancers, baseline values of toxic and essential metals in patients with leukemia and the clinical impact of these metals remain unknown. Thus, we sought to quantify metal values in untreated patients with acute myeloid leukemia (AML) and controls and determine the impact of metal values on AML patients' survival. Serum samples from patients with untreated AML and controls at Hospices Civils de Lyon were analyzed and compared for trace metals and copper isotopic abundance ratios with inductively coupled plasma mass spectrometry. Survival analysis was performed as a function of metal values, and a multi-metal score was developed for patients with AML. Serum samples were collected from 67 patients with untreated AML and 94 controls. Most patients had intermediate-risk cytogenetics (63.1%) without FLT3 internal tandem duplication mutations (75.6%) or NPM1 mutations (68.1%). Most metal values differed significantly between AML and control groups. Patients with lower magnesium and higher cadmium values had the worst survival rates, with only 36% surviving at 6 months (P = .001). The adverse prognostic effect of this combination was maintained on multivariate analysis. Based on this, we developed a novel metal score, which accounts for multiple relative abnormalities in the values of five toxic and five essential metals. Patients with a higher metal score had significantly worse survival, which was maintained on multivariate analysis (P = .03). This baseline metal scoring system was also prognostic when we applied it to a separate population of front-line AML patients.


[Metal poisoning].
Metals are amongst the oldest toxic substances known to man. In today's industrialized world the sources of exposure to metals are ubiquitous both in the field of work and from polluted water, foodstuffs and the environment. Their toxicity is characterized by the metallic element in question, but this is modified by the type of compound, whether organic or inorganic, and its characteristics of hydrosolubility and liposolubility, which determines its toxicokinetics and thus the possibilities of it reaching its targets. The biomolecules most affected by metals are the proteins with enzymatic activity, which is why their pathology is multisystemic. The principal systems affected are the gastrointestinal, central and peripheral neurological, haematic and renal. Some metallic compounds are carcinogenic. Metals's treatment is conditioned by their chemical reactivity. They can be deactivated and eliminated by the administering of chelating agents that produce complex molecules, which are non-toxic and can be excreted. The principal chelating agents are: BAL (British Anti-Lewisite or dimercaprol) DMPS (2,3-Dimercapto-1-propanesulfonic Acid) and DMSA (meso-2,3-Dimercaptosuccinic or Succimer), EDTA, Penicilamine (b,b-dimethylcysteine) and Deferoxamine. Toxicokinetic characteristics, mechanism of action, clinical picture and treatment of some of the most relevant metals and metalloids: lead, mercury and arsenic, are considered.


Converging patterns of uptake and hydraulic redistribution of soil water in contrasting woody vegetation types.
We used concurrent measurements of soil water content and soil water potential (Psi(soil)) to assess the effects of Psi(soil) on uptake and hydraulic redistribution (HR) of soil water by roots during seasonal drought cycles at six sites characterized by differences in the types and amounts of woody vegetation and in climate. The six sites included a semi-arid old-growth ponderosa pine (Pinus ponderosa Dougl. ex P. Laws & C. Laws) forest, a moist old-growth Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco) forest, a 24-year-old Douglas-fir forest and three Brazilian savanna sites differing in tree density. At all of the sites, HR was confined largely to the upper 60 cm of soil. There was a common threshold relationship between the relative magnitude of HR and Psi(soil) among the six study sites. Below a threshold Psi(soil) of about -0.4 MPa, overnight recharge of soil water storage increased sharply, and reached a maximum value of 80-90% over a range of Psi(soil) from ~ -1.2 to -1.5 MPa. Although amounts of water hydraulically redistributed to the upper 60 cm of soil were relatively small (0 to 0.4 mm day(-1)), they greatly reduced the rates of seasonal decline in Psi(soil). The effectiveness of HR in delaying soil drying diminished with increasing sapwood area per ground area. The relationship between soil water utilization and Psi(soil) in the 20-60-cm layer was nearly identical for all six sites. Soil water utilization varied with a surrogate measure of rhizosphere conductance in a similar manner at all six sites. The similarities in relationships between Psi(soil) and HR, soil water utilization and relative rhizosphere conductance among the six sites, suggests that, despite probable differences in maximum rooting depth and density, there was a convergence in biophysical controls on soil water utilization and redistribution in the upper soil layers where the density of finer roots is greatest.


On-chip hydrodynamic chromatography separation and detection of nanoparticles and biomolecules.
For the first time, on-chip planar hydrodynamic chromatography is combined with UV absorption detection. This technique is suitable for size characterization of synthetic polymers, biopolymers, and particles. Possible advantages of an on-chip hydrodynamic chromatography system over conventional techniques, such as size exclusion chromatography, and field-flow fractionation are fast analysis, high efficiency, reduced solvent consumption, and easy temperature control. The hydrodynamic separations are performed in a planar configuration realized in fused silica using a mixture of fluorescent and nonfluorescent polystyrene particles with sizes ranging from 26 to 155 nm. The planar chip configuration consists of a 1-microm-high, 0.5-mm-wide, and 69-mm-long channel, an integrated 150-pL injection structure, and a 30-microm-deep and 30-microm-wide detection cell, suitable for UV absorption detection. By combination of the separation data obtained in the new fused-silica chip with those obtained using a previously presented planar hydrodynamic chromatography chip, which was realized using silicon and glass microtechnology, a description of the retention and dispersion behavior of planar hydrodynamic chromatography is obtained. Especially the influence of the sidewalls on the dispersion is investigated. Furthermore a hydrodynamic separation within 70 s of several biopolymers is shown in the glass-silicon chip.


Revealing the power of the natural red pigment lycopene.
By-products derived from food processing are attractive source for their valuable bioactive components and color pigments. These by-products are useful for development as functional foods, nutraceuticals, food ingredients, additives, and also as cosmetic products. Lycopene is a bioactive red colored pigment naturally occurring in plants. Industrial by-products obtained from the plants are the good sources of lycopene. Interest in lycopene is increasing due to increasing evidence proving its preventive properties toward numerous diseases. In vitro, in vivo and ex vivo studies have demonstrated that lycopene-rich foods are inversely associated to diseases such as cancers, cardiovascular diseases, diabetes, and others. This paper also reviews the properties, absorption, transportation, and distribution of lycopene and its by-products in human body. The mechanism of action and interaction of lycopene with other bioactive compounds are also discussed, because these are the crucial features for beneficial role of lycopene. However, information on the effect of food processing on lycopene stability and availability was discussed for better understanding of its characteristics.


Exogenous peptide YY3-36 and Exendin-4 further decrease food intake, whereas octreotide increases food intake in rats after Roux-en-Y gastric bypass.
Patients show an elevated postprandial satiety gut hormone release after Roux-en-Y Gastric bypass (gastric bypass). The altered gut hormone response appears to have a prominent role in the reduction of appetite and body weight (BW) after gastric bypass. Patients with insufficient BW loss after gastric bypass have an attenuated postprandial gut hormone response in comparison with patients who lost an adequate amount of BW. The effects of additional gut hormone administration after gastric bypass are unknown. The effects of peripheral administration of peptide YY3-36 (PYY3-36; 300 nmol kg(-1)), glucagon-like peptide-1 (GLP-1) analogue Exendin-4 (20 nmol kg(-1)) and somatostatin analogue octreotide (10 μg kg(-1)) on feeding and BW were evaluated in rats after gastric bypass. Gastric bypass rats weighed (P<0.01) and ate less on postoperative day 5 (P<0.001) and thereafter, whereas postprandial plasma PYY and GLP-1 levels were higher compared with sham-operated controls (P<0.001). Administration of both PYY3-36 and Exendin-4 led to a further decrease in food intake in bypass rats compared with saline treatment (P=0.02 and P<0.0001, respectively). Similar reduction in food intake was observed in sham rats (P=0.02 and P<0.001, respectively). Exendin-4 treatment resulted in a significant BW loss in bypass (P=0.03) and sham rats (P=0.04). Subsequent treatment with octreotide led to an increase in food intake in bypass (P=0.007), but not in sham rats (P=0.87). Peripheral administration of PYY3-36 and Exendin-4 reduces short-term food intake, whereas octreotide increases short-term food intake in rats after gastric bypass. The endogenous gut hormone response after gastric bypass can thus potentially be further enhanced by additional exogenous therapy with pharmacological doses of gut hormones in patients with insufficient weight loss or weight regain after surgery.


Motion in microfluidic ratchets.
The ubiquitous random motion of mesoscopic active particles, such as cells, can be "rectified" or directed by embedding the particles in systems containing local and periodic asymmetric cues. Incorporated on lab-on-a-chip devices, these microratchet-like structures can be used to self-propel fluids, transport particles, and direct cell motion in the absence of external power sources. In this Focus article we discuss recent advances in the use of ratchet-like geometries in microfluidics which could open new avenues in biomedicine for applications in diagnosis, cancer biology, and bioengineering.


Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy.
The combination of intravital microscopy and animal models of disease has propelled studies of disease mechanisms and treatments. However, many disorders afflict tissues inaccessible to light microscopy in live subjects. Here we introduce cellular-level time-lapse imaging deep within the live mammalian brain by one- and two-photon fluorescence microendoscopy over multiple weeks. Bilateral imaging sites allowed longitudinal comparisons within individual subjects, including of normal and diseased tissues. Using this approach, we tracked CA1 hippocampal pyramidal neuron dendrites in adult mice, revealing these dendrites' extreme stability and rare examples of their structural alterations. To illustrate disease studies, we tracked deep lying gliomas by observing tumor growth, visualizing three-dimensional vasculature structure and determining microcirculatory speeds. Average erythrocyte speeds in gliomas declined markedly as the disease advanced, notwithstanding significant increases in capillary diameters. Time-lapse microendoscopy will be applicable to studies of numerous disorders, including neurovascular, neurological, cancerous and trauma-induced conditions.


Regulation of major acute-phase plasma proteins by hepatocyte-stimulating factors of human squamous carcinoma cells.
Human squamous carcinoma (COLO-16) cells release factors which specifically stimulate the synthesis of major acute-phase plasma proteins in human and rodent hepatic cells. Anion exchange, hydroxyapatite, lectin, and gel chromatography of conditioned medium of COLO-16 cells result in separation into three distinct forms of hepatocyte-stimulating factors (designated HSF-I, HSF-II, and HSF-III) with apparent molecular weights of 30,000, 50,000 and 70,000, respectively. None of the preparations contains detectable amounts of thymocyte-stimulating activity. Each of the three HSF forms stimulates the accumulation of mRNA for alpha 1-antichymotrypsin in the human hepatoma cell line, HepG2. When the same factors were added to primary cultures of adult rat hepatocytes, the expression of the same set of plasma proteins was modulated as by nonfractionated medium. The hormonally induced accumulation of mRNA for acute phase proteins is qualitatively comparable to that occurring in the liver of inflamed rats. Unlike in human cells, in rat liver cells dexamethasone acts additively and synergistically with HSFs. The only functional difference between the three HSF forms lies in the level of maximal stimulation. HSF-I represents the predominant form produced by normal human keratinocytes and closely resembles in molecular size and isoelectric point the activity produced by activated peripheral blood monocytes while the larger molecular weight forms are more prevalent in human as well as mouse squamous carcinoma cells. The observation that HSFs from different sources elicit essentially the same pleiotropic response in hepatic cells led to the hypothesis that the species-specific reaction of adult liver cells to inflammatory stimuli is pre-programmed and that the function of any HSF is to trigger and tune the execution of this fixed cellular process.


Liming can decrease legume crop yield and leaf gas exchange by enhancing root to shoot ABA signalling.
To meet future requirements for food production, sustainable intensive agricultural systems need to optimize nutrient availability to maximize yield, traditionally achieved by maintaining soil pH within an optimal range (6-6.5) by applying lime (calcium carbonate). However, a field trial that applied recommended liming rates to a sandy loam soil (increasing soil pH from 5.5 to 6.2) decreased pod yield of field bean (Vicia faba L. cv. Fuego) by ~30%. Subsequent pot trials, with liming that raised soil pH to 6.3-6.7, reduced stomatal conductance (g(s)) by 63, 26, and 59% in V. faba, bean (Phaseolus vulgaris), and pea (Pisum sativum), respectively. Furthermore, liming reduced shoot dry biomass by 16-24% in these species. Ionomic analysis of root xylem sap and leaf tissue revealed a decrease in phosphorus concentration that was correlated with decreased g(s): both reductions were partially reversed by adding superphosphate fertilizer. Further analysis of pea suggests that leaf gas exchange was reduced by a systemic increase (roots, xylem sap, and leaves) in the phytohormone abscisic acid (ABA) in response to lime-induced suboptimal plant phosphorus concentrations. Supplying synthetic ABA via the transpiration stream to detached pea leaves, at the same xylem sap concentrations induced by liming, decreased transpiration. Furthermore, the g(s) of the ABA-deficient mutant pea wilty was unresponsive to liming, apparently confirming that ABA mediates some responses to low phosphorus availability caused by liming. This research provides a detailed mechanistic understanding of the physiological processes by which lime application can limit crop yields, and questions the suitability of current liming recommendations.


IL-7 receptor α expressing B cells act proinflammatory in collagen-induced arthritis and are inhibited by sympathetic neurotransmitters.
The sympathetic nervous system (SNS) as well as the interleukin (IL)-7/IL-7 receptor (IL-7R) system play a role in the pathogenesis of arthritis. However, the target cells and mechanisms involved are not fully resolved. The goal of this study was to determine if B cells are influenced by IL-7 and to investigate the possible interplay between the SNS and the IL-7/IL-7R system on B cells in arthritis. Collagen type II-induced arthritis (CIA) in DBA1 mice. ELISA to determine specific anti-CII antibodies. Fluorescence activated cell sorting (FACS) analysis to determine IL-7R+ cells and intracellular phosphorylated signal transducer and activator of transcription 5 (pSTAT5). Immunohistochemistry to show IL-7R+ B cells in rheumatoid arthritis (RA) and osteoarthritis (OA) synovial tissue. IL-7 stimulated IL-7R+ mature B cells act proinflammatory (increased clinical score, increased anticollagen type II antibodies) after cell transfer in CIA. The sympathetic neurotransmitter norepinephrine abrogates this effect. Expression of IL-7Rα is increased when B cells are activated (anti-CD40 or lipopolysaccharide) in vitro and stimulating the IL-7R induces intracellular accumulation of pSTAT5. α- And β-adrenergic agonists show no influence on expression levels of IL-7R on activated B cells; however, intracellular IL-7R downstream signalling is abrogated via the β2-adreonceptor (β2AR) agonist terbutaline. IL-7R and β2AR are also expressed on B cells in synovial tissue from RA and OA patients. These data indicate that IL7R+ B cells have a proinflammatory role in arthritis which can be inhibited by the sympathetic neurotransmitter norepinephrine via inhibition of IL-7R signalling.


The effects of single and mixed infections of Apicystis bombi and deformed wing virus in Bombus terrestris.
Many pollinators are currently suffering from declines, diminishing their gene pool and increasing their vulnerability to parasites. Recently, an increasing diversity of parasites has been recorded in bumblebees, yet for many, knowledge of their virulence and hence the risk their presence poses, is lacking. The deformed wing virus (DWV), known to be ubiquitous in honey bees, has now been detected in bumblebees. In addition, the neogregarine Apicystis bombi has been discovered to be more prevalent than previously thought. Here, we assess for the first time the lethal and sublethal effects of these parasites during single and mixed infections of worker bumblebees (Bombus terrestris). Fifteen days after experimental exposure, 22% of bees exposed to A. bombi, 50% of bees exposed to DWV and 86% of bees exposed to both parasites had died. Bumblebees that had ingested A. bombi had increased sucrose sensitivity (SS) and a lower lipid:body size ratio than control bees. While dual infected bumblebees showed no increase in SS. Overall, we find that A. bombi exhibits both lethal and sublethal effects. DWV causes lethal effect and may reduce the sub lethal effects imposed by A. bombi. The results show that both parasites have significant, negative effects on bumblebee health, making them potentially of conservation concern.


Modified cognitive behavioral therapy (M-CBT) for cocaine dependence: Development of treatment for cognitively impaired users and results from a Stage 1 trial.
Cognitive impairments are associated with poor outcomes when treating cocaine dependent patients, but behavioral interventions to mitigate this impact have not been developed. In this Stage 1A/1B treatment development study, several compensatory strategies (e.g., content repetition, daily logs, diaries, visual presentation) were combined to create a modified cognitive behavioral therapy (M-CBT) for treating cocaine dependence. Initially, a select group of therapists, neuropsychology experts, and patients were asked to provide input on early drafts of the treatment manual and companion patient workbook. After an uncontrolled small trial (N = 15) and two rounds of manual development (Stage 1A), a pilot randomized clinical trial (N = 102) of cocaine dependent outpatients with and without cognitive impairments was conducted (Stage 1B). Participants were randomized to M-CBT (N = 52) or CBT (N = 50). Both treatments were individually delivered over 12 weeks with assessments conducted at baseline, end-of-treatment, and 3-month follow-up. The primary outcome was frequency of cocaine use, measured by number of days used in the prior 7 days. Participants in the two treatment groups did not differ significantly on drug use reduction or retention in treatment. However, among participants who completed at least 9 weeks of treatment, those in M-CBT showed a trend toward greater reduction in cocaine use compared to those in the CBT group. M-CBT is feasible for impaired and nonimpaired cocaine dependent participants. However, M-CBT treatment did not show significant superiority over standard CBT in the present sample. (PsycINFO Database Record (c) 2018 APA, all rights reserved).