Improved Outcome of High-Grade, Early 1-Stage Endometrioid Endometrial Carcinoma With Adjuvant Chemotherapy and Radiotherapy: Comparison of 2 Treatment Strategies.
Patients with high-grade endometrioid endometrial carcinoma have a high risk of recurrence, even in early stage. To determine the benefit of a more aggressive adjuvant treatment approach, different treatment strategies of 2 referral centers were compared. Outcome of all patients with International Federation of Gynecology and Obstetrics IB and II high-grade endometrioid endometrial carcinoma treated between 2008 and 2012, at the Gynecological Oncology Center South (GOCS) were compared with patients treated at the British Columbia Cancer Agency (BCCA). All patients underwent primary surgical treatment. Adjuvant treatment consisted of radiotherapy dependent on final pathology (GOCS), or adjuvant chemotherapy and pelvic radiotherapy (BCCA). A total of 116 patients were treated at the GOCS (n = 61) and BCCA (n = 55). Patient cohorts were comparable for clinicopathological factors, except for age at diagnosis and lymphadenectomy. Radiotherapy was applied in 70.5% at the GOCS compared with 100% at the BCCA. All BCCA patients received chemotherapy compared with 3.3% at GOCS. The BCCA treatment strategy resulted in a significant reduced recurrence rate when compared with GOCS, 10.9% and 36.1%, respectively. There was no significant difference in the recurrence rate between patients with (n = 48) and without a lymphadenectomy (n = 68). Yet, numbers are relatively low. Because most recurrences were distant 78.6% (22/28), adjuvant chemotherapy resulted in reduced disease-related mortality. Adjuvant chemotherapy and radiotherapy in early-stage high-grade endometrioid endometrial carcinoma results in improved disease-specific and overall survival compared to radiotherapy alone. Yet, due to the relatively low numbers, validation of these findings is needed in large prospective trials.


[Improved diagnosis of early cerebral infarct by the combined use of diffusion and perfusion].
To evaluate the feasibility and the diagnostic efficacy of multislice diffusion-weighted and perfusion imaging in addition to FLAIR-TSE, T2w-GraSE and MR-angiography in the diagnosis of acute stroke. 18 patients with acute stroke were examined at 1.5 Tesla (Gyroscan ACS-NT, Philips Medical Systems) within 6 (n = 9) and 6-48 (n = 9) hours, respectively, and followed at regular intervals. For diffusion imaging we used a multislice multishot EPI-SE sequence with navigator echo correction and cardiac gating. Perfusion imaging was done by means of a FFE-EPI sequence after bolus injection of Gd-DTPA. The diagnostic value of diffusion-weighted and perfusion imaging was significantly higher compared with FLAIR-TSE (p = 0.0023) and GraSE (p = 0.0012) during the first 6 hours. With FLAIR-TSE and GraSE first pathologic changes were seen after 4 hours. We detected perfusion deficit (rCBV < 10%) and a corresponding drop of the ADC in all infarcts larger than 1 cm in diameter. Within the area of low rCBV the combined analysis of diffusion and perfusion imaging allows to identify an infarct region with characteristics of a penumbra and one with characteristics of the infarct core. TTP was increased in the surrounding tissue. However, parts of this area were rarely included in the infarct. The final extension of the untreated infarct, as revealed by computed tomography, corresponded well to the perfusion deficit. Early ischaemic cerebral infarcts can be diagnosed with diffusion and perfusion imaging before pathological changes are visualized with other imaging modalities. The combined use may allow to distinguish the infarct core from surrounding, potentially salvageable tissue.


A novel PrECOG (PrE0901) dose-escalation trial using eltrombopag: enhanced platelet recovery during consolidation therapy in acute myeloid leukemia.
High-dose cytarabine (HiDAC) consolidation for acute myeloid leukemia (AML) induces transient profound myelosuppression and potential morbidity/mortality. PrE0901 was a phase I multi-center trial evaluating the safety/toxicity of eltrombopag in AML patients receiving HiDAC consolidation. We used a standard 3 + 3 design employing a unique dose-escalation/de-escalation strategy. One hundred four patients were screened, 54 declined participation, 35 were deemed medically ineligible, and 14 were treated on study. Three patients were treated in cohorts 1-4 and two were treated in cohort 5. Eltrombopag + HiDAC was well-tolerated and no dose-limiting toxicities were observed. Median time to platelet recovery of all patients treated was 22.5 (range 16-43) days. Observationally, eltrombopag 150 mg once daily starting on day 3 of consolidation demonstrated the fastest and most consistent platelet recovery (median 19 days). Further investigation is needed to define the optimal role, dose, and schedule of eltrombopag in the treatment of chemotherapy associated myelosuppression.


Epacadostat Shows Value in Two SCCHN Trials.
In the ECHO-202/KEYNOTE-037 and ECHO-204 trials reported at the 2017 Annual Meeting of the American Society of Clinical Oncology, patients with squamous cell carcinoma of the head and neck responded well to the combinations of epacadostat plus pembrolizumab and epacadostat plus nivolumab. An IDO1 inhibitor, epacadostat also demonstrated promising activity in combination with the PD-1 checkpoint inhibitors in other solid tumors, including melanoma, urothelial carcinoma, renal cell carcinoma, and non-small cell lung cancer.


[Surgical treatment for aortic valve endocarditis combined with bacterial meningitis and vertebral osteomyelitis;report of a case].
A 59-year-old man was referred to our hospital with disturbance of consciousness. Bacterial meningitis was diagnosed by a spinal tap, and penicillin sensitive Streptococcus pneumonia was detected by blood culture. Magnetic resonance imaging revealed a vertebral osteomyelitis. Treatment with antibiotics was started immediately. Four days after admission, congestive heart failure suddenly occurred. Echocardiography showed mobile vegetation on the aortic valve, and severe regurgitation. As acute heart failure could not be controlled, the aortic valve was replaced by ATS 22AP valve on the 7th day after admission. Antibiotic therapy was continued for 8 weeks. The postoperative course was uneventful.


Utility of ribotyping, restriction endonuclease analysis and pulsed-field gel electrophoresis to discriminate between isolates of Neisseria gonorrhoeae of serovar IA-2 which require arginine, hypoxanthine or uracil for growth.
Neisseria gonorrhoeae isolates that require arginine--i.e., either citrulline (C), or ornithine (O)--uracil (U) and hypoxanthine (H) have generally been considered to be similar when characterised by auxotype, serovar and plasmid content. The MICs of penicillin, tetracycline, erythromycin, spectinomycin, cefoxitin and ceftriaxone for 552 isolates belonging to serovar IA-2 with these phenotypes were found to be similar. Therefore, restriction fragment length polymorphism analysis of rRNA genes (ribotyping), restriction enzyme (RE) analysis of chromosomal DNA, and pulsed-field gel electrophoresis (PFGE) were evaluated to determine whether these isolates could be distinguished by molecular methods. A subset of 27 isolates of N. gonorrhoeae that were OUH-requiring, CUH-requiring or OH-requiring, belonged to serovar IA-2 and carried a 2.6-MDa plasmid, were selected for further study. Based on the RE analysis of SmaI-digested genomic DNA, the 27 isolates fell into a single RE pattern, five ribotypes and 17 PFGE profiles which did not correlate with the specific arginine-requiring subtypes of these isolates. Each ribotype varied by the presence of only a single fragment, which was of a different size in each pattern, and 17 (63%) of the 27 isolates belonged to ribotype I. PFGE yielded the highest level of discrimination with 17 different profiles.


Comprehensive learning and adaptive teaching: Distilling multi-modal knowledge for pathological glioma grading.
The fusion of multi-modal data, e.g., pathology slides and genomic profiles, can provide complementary information and benefit glioma grading. However, genomic profiles are difficult to obtain due to the high costs and technical challenges, thus limiting the clinical applications of multi-modal diagnosis. In this work, we investigate the realistic problem where paired pathology-genomic data are available during training, while only pathology slides are accessible for inference. To solve this problem, a comprehensive learning and adaptive teaching framework is proposed to improve the performance of pathological grading models by transferring the privileged knowledge from the multi-modal teacher to the pathology student. For comprehensive learning of the multi-modal teacher, we propose a novel Saliency-Aware Masking (SA-Mask) strategy to explore richer disease-related features from both modalities by masking the most salient features. For adaptive teaching of the pathology student, we first devise a Local Topology Preserving and Discrepancy Eliminating Contrastive Distillation (TDC-Distill) module to align the feature distributions of the teacher and student models. Furthermore, considering the multi-modal teacher may include incorrect information, we propose a Gradient-guided Knowledge Refinement (GK-Refine) module that builds a knowledge bank and adaptively absorbs the reliable knowledge according to their agreement in the gradient space. Experiments on the TCGA GBM-LGG dataset show that our proposed distillation framework improves the pathological glioma grading and outperforms other KD methods. Notably, with the sole pathology slides, our method achieves comparable performance with existing multi-modal methods. The code is available at https://github.com/CUHK-AIM-Group/MultiModal-learning.


Crossing the threshold of ultrafast laser writing in bulk silicon.
An important challenge in the field of three-dimensional ultrafast laser processing is to achieve permanent modifications in the bulk of silicon and narrow-gap materials. Recent attempts by increasing the energy of infrared ultrashort pulses have simply failed. Here, we establish that it is because focusing with a maximum numerical aperture of about 1.5 with conventional schemes does not allow overcoming strong nonlinear and plasma effects in the pre-focal region. We circumvent this limitation by exploiting solid-immersion focusing, in analogy to techniques applied in advanced microscopy and lithography. By creating the conditions for an interaction with an extreme numerical aperture near 3 in a perfect spherical sample, repeatable femtosecond optical breakdown and controllable refractive index modifications are achieved inside silicon. This opens the door to the direct writing of three-dimensional monolithic devices for silicon photonics. It also provides perspectives for new strong-field physics and warm-dense-matter plasma experiments.Ultrafast laser processing is a versatile three-dimensional photonic structuring method but it has been limited to wide band gap materials like glasses. Here, Chanal et al. demonstrate direct refractive-index modification in the bulk of silicon by extreme localization of the energy deposition.


[Clinico-biochemical characteristics of persons with borderline arterial hypertension].
Clinico-biochemical investigation of 76 persons with borderline arterial hypertension (BAH) aged 15 to 64 and 60 controls with assessment of some parameters of lipid, carbohydrate and water-salt metabolism was carried out. Gustatory sensitivity to sodium chloride was studied. Differences in the levels of these indices were revealed in patients with BAH with relation to the presence or absence of basal changes on ECG and fundus of the eye; there were also some differences in risk factors in BAH and essential hypertension.


New approaches for imaging and therapy of solid cancer.
Radionuclide therapy is a systemic treatment that aims to deliver cytotoxic radiation to cancer cells. Due to their properties, antibodies have been considered as suitable agent for the delivery of therapeutic radioisotopes, radioimmunotherapy (RIT). This article gives an overview of new approaches for imaging and therapy of solid cancer with particular attention to strategies to enhance treatment success. Examples of increased antibody uptake by targeting stromal constituent of tumor microenvironment such as fibronectin (FN) an important tumor-associated angiogenesis targeting agent, with specifically designed antibody format will be provided. Strategies oriented to identify patients most likely to benefit from RIT including identification of radiosensitivity profiles, in vivo target identification by teragnostic approach and better prediction of dosimetric estimates would be presents. Combination regimens such as with chemo-radiotherapy and immunotherapy would be also discussed as an approach to enhance RIT success.


5alpha,8alpha-epidioxysterols from a Formosan sponge, Axinyssa sp.
One new 5alpha,8alpha-epidioxysterol, 3-acetylaxinysterol (1), along with one known sterol, axinysterol (2), were isolated from a Formosan sponge, Axinyssa sp.. The structures of the compounds were determined by spectroscopic methods and the absolute configuration of 2 was further confirmed by single-crystal X-ray diffraction analysis for the first time. Compound 2 exhibited significant cytotoxicity against K562 and Molt 4 cancer cell lines.


Neuroendocrine neoplasm update: toward universal nomenclature.
Neuroendocrine neoplasia is described in almost every tissue, either in the pure endocrine organs, the nerve structures or in the so-called diffuse neuroendocrine system. The current nomenclature contains time-honored, widely accepted definitions; however, it is different according to anatomical sites. Diverse definitions may generate confusion and non-standard patient management. The International Agency for Research on Cancer - World Health Organization (IARC-WHO) proposed a framework for universal classification of neuroendocrine neoplasia. Evidence indicates that neuroendocrine cancer is composed by cells with a distinctive phenotype characterized by the expression of general and specific neuroendocrine markers. The neuroendocrine phenotype is indicated as descriptor of a unique cancer category, now recommended for all organs as neuroendocrine neoplasm. Evidence indicates that neuroendocrine neoplasia may be well or poorly differentiated, with diverse incidence and prevalence in different organs. It is proposed that the well-differentiated neoplasm is universally defined as neuroendocrine tumor (NET) and the poorly differentiated as neoplasm neuroendocrine carcinoma (NEC). Evidence indicates that a cancer grading tool based on a proliferation measure by mitotic count, Ki67 % and/or necrosis assessment is useful to predict NET patient behavior. It is proposed to utilize this tool for grading NET universally, with site-specific cut-offs to be defined. It is also acknowledged that significant biological site-specific differences exist. It is recommended that current pathology reports contain this classification together with the current traditional classifiers. This IARC-WHO common classification framework for neuroendocrine neoplasm aims at uniformizing nomenclature toward different organs and at fostering the definition of a similar site-specific gene signature.


Proteasome beta-type subunits: unequal roles of propeptides in core particle maturation and a hierarchy of active site function.
The 26 S proteasome is a large eukaryotic protease complex acting in ubiquitin-mediated degradation of abnormal and many short-lived, regulatory proteins. Its cylinder-shaped 20 S proteolytic core consists of two sets, each of seven different alpha and beta-type subunits arranged into two outer alpha-rings surrounding two inner beta-rings. The beta-rings form a central chamber with a total of six proteolytically active centers located in the beta1, beta2 and beta5 subunits. Activation of these subunits occurs during late assembly stages through intramolecular precursor autolysis removing propeptides attached to Thr1, which then serves as N-terminal nucleophile in substrate hydrolysis. This maturation entails intermolecular cleavage of propeptides residing in two of the non-active beta-type subunits, beta6 and beta7. In yeast, deletion of the beta5/Pre2 propeptide was shown to be lethal by preventing assembly of the core particle, while its expression as a separate entity restored growth. We investigated the role of the yeast beta1/Pre3, beta2/Pup1 and beta7/Pre4 propeptides by expressing the mature subunit moieties without propeptides as C-terminal fusions to ubiquitin. In all cases, viable strains could be generated. Deletion of the beta1/Pre3 and beta7/Pre4 propeptides did not affect cell growth, but deletion of the beta2/Pup1 propeptide led to poor growth, which was partially restored by co-expression of the free propeptide. Gain of proteolytic activity of beta1/Pre3 and beta2/Pup1 was abolished or drastically reduced, respectively, if their respective propeptides were not N-terminally bound. We detected N -alpha-acetylation at Thr1 of beta1/Pre3 as cause for its inactivation. Thus, one role for the propeptides of active beta-type subunits might be to protect the mature subunits catalytic Thr1 alpha-amino group from acetylation. The beta2/Pup1 propeptide was, in addition, required for efficient 20 S proteasome maturation, as revealed by the accumulation of beta7/Pre4 precursor and intermediate processing forms upon expression of mature beta2/Pup1. Finally, growth phenotypes resulting from expression of active site mutated beta-type subunits uncoupled from their propeptides allowed us to deduce the hierarchy of the importance of individual subunit activities for proteasomal function as follows: beta5/Pre2>>beta2/Pup1>/=beta1/Pre3.


Role of NF-Y in in vivo regulation of the gamma-globin gene.
The duplicated CCAAT box is required for gamma gene expression. We report here that the transcriptional factor NF-Y is recruited to the duplicated CCAAT box in vivo. A mutation of the duplicated CCAAT box that severely disrupts the NF-Y binding also reduces the accessibility level of the gamma gene promoter, affects the assembly of basal transcriptional machinery, and increases the recruitment of GATA-1 to the locus control region (LCR) and the proximal promoter and the recruitment of transcription cofactor CBP/p300 to the LCR. These findings suggest that recruitment of NF-Y to the duplicated CCAAT box plays a role in the chromatin opening of the gamma gene promoter as well as in the communication between the gamma gene promoter and the LCR.


The roadmap for allergology in Europe: The subspecialty of allergology as "stop-over" on the way to a full specialty. An EAACI position statement.
The vision of European Academy of Allergy and Clinical Immunology (EAACI) and the Union of European Medical Specialists Section and Board on allergology is to promote and to establish a full specialty of allergology in all European countries. In many European countries, a full specialty does not exist. In those countries, organ-based (sub)specialists or paediatricians and internists with an expertise in allergology may deliver allergy care. There are no generally accepted requirements for the training of subspecialists available. To fill the gap between the need and availability of experienced and accredited physicians who can deliver optimal care to the allergic patients, the EAACI Specialty Committee proposes the minimal requirements for training and certification of subspecialists in allergology. This paper describes the required theoretical knowledge, skills, competences and training facilities (staff and institution). The subspecialist as described in this paper should ideally show the necessary competence in providing good quality care to patients in an environment lacking those full specialists in allergology or tertiary care paediatric subspecialists in allergy.


Phenolic compounds in field horsetail (Equisetum arvense L.) as natural antioxidants.
In this paper, the study of antioxidant activity and phenolic composition of three different extracts (EtOAc, n-BuOH and H(2)O) of field horsetail (Equisetum arvense L.) is presented. The antioxidant activity has been evaluated measuring the total reducing power (expressed by Ascorbate Equivalent Antioxidant Capacity - AEAC), inhibition of lipid peroxidation, and free radical scavenging capacity (RSC) towards 2,2-diphenyl-1-picrylhydrazyl (DPPH radical) and nitric oxide (NO), respectively. In addition, the total flavonoid content (TFC) and phenolic constituents of each extract have been determined. The results obtained show that the highest RSC regarding both DPPH and NO radicals is expressed by EtOAc extract (EC(50)=2.37 microg/mL and EC(50)=90.07 microg/mL, respectively), and the lowest by H(2)O extract (EC(50)=37.2 microg/mL and EC(50)>333.33 microg/mL, respectively). n-BuOH extract showed the highest total reducing power (AEAC=13.40 microg/mL). Differences in the phenolic composition of examined extracts are found comparing the HPLC chemical profiles. Although, isoquercitrin is the main flavonoid in both EtOAc and n-BuOH extracts, a considerable amount of di-E-caffeoyl-meso-tartaric acid was presented in the n-BuOH extract. In H(2)O extract high content of phenolic acids and low percentage of flavonoids were detected.


Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging.
The bacterium Helicobacter pylori is the causative agent for peptic ulcer disease. Bacterial adherence to the human gastric epithelial lining is mediated by the fucosylated Lewis b (Leb) histo-blood group antigen. The Leb-binding adhesin, BabA, was purified by receptor activity-directed affinity tagging. The bacterial Leb-binding phenotype was associated with the presence of the cag pathogenicity island among clinical isolates of H. pylori. A vaccine strategy based on the BabA adhesin might serve as a means to target the virulent type I strains of H. pylori.


Texture classification using discrete Tchebichef moments.
In this paper, a method to characterize texture images based on discrete Tchebichef moments is presented. A global signature vector is derived from the moment matrix by taking into account both the magnitudes of the moments and their order. The performance of our method in several texture classification problems was compared with that achieved through other standard approaches. These include Haralick's gray-level co-occurrence matrices, Gabor filters, and local binary patterns. An extensive texture classification study was carried out by selecting images with different contents from the Brodatz, Outex, and VisTex databases. The results show that the proposed method is able to capture the essential information about texture, showing comparable or even higher performance than conventional procedures. Thus, it can be considered as an effective and competitive technique for texture characterization.


Noninvasive Stimulation of the Ventromedial Prefrontal Cortex Enhances Pleasant Scene Processing.
Depressive patients typically show biased attention towards unpleasant and away from pleasant emotional material. Imaging studies suggest that dysfunctions in a distributed neural network, including the ventromedial prefrontal cortex (vmPFC), are associated with this processing bias. Accordingly, changes in vmPFC activation should mediate changes in processing of emotional stimuli. Here, we investigated the effect of inhibitory and excitatory transcranial direct current stimulation (tDCS) of the vmPFC on emotional scene processing in two within-subject experiments using functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). Both studies showed that excitatory relative to inhibitory tDCS amplifies processing of pleasant compared to unpleasant scenes in healthy participants. This modulatory effect occurred in a distributed network including sensory and prefrontal cortex regions and was visible during very early to late processing stages. Findings are discussed with regard to neurophysiological models of emotional processing. The convergence of stimulation effects across independent groups of healthy participants and complementary neuroimaging methods (fMRI, MEG) provides a basis for further investigation of a potentially therapeutic use of this novel stimulation approach in patients with depression or other affective disorders.


Development of a Method for Fucoxanthin Production Using the Haptophyte Marine Microalga Pavlova sp. OPMS 30543.
The natural pigment fucoxanthin has attracted global attention because of its superior antioxidant properties. The haptophyte marine microalgae Pavlova spp. are assumed to be promising industrial fucoxanthin producers as their lack of a cell wall could facilitate the commercialization of cultured cells as a whole food. This study screened promising Pavlova strains with high fucoxanthin content to develop an outdoor cultivation method for fucoxanthin production. Initial laboratory investigations of P. pinguis NBRC 102807, P. lutheri NBRC 102808, and Pavlova sp. OPMS 30543 identified OPMS 30543 as having the highest fucoxanthin content. The culture conditions were optimized for OPMS 30543. Compared with f/2 and Walne's media, the use of Daigo's IMK medium led to the highest biomass production and highest fucoxanthin accumulation. The presence of seawater elements in Daigo's IMK medium was necessary for the growth of OPMS 30543. OPMS 30543 was then cultured outdoors using acrylic pipe photobioreactors, a plastic bag, an open tank, and a raceway pond. Acrylic pipe photobioreactors with small diameters enabled the highest biomass production. Using an acrylic pipe photobioreactor with 60-mm diameter, a fucoxanthin productivity of 4.88 mg/L/day was achieved in outdoor cultivation. Thus, this study demonstrated the usefulness of Pavlova sp. OPMS 30543 for fucoxanthin production in outdoor cultivation.


[Static and dynamic components of length-dependent regulation of contraction of the atrial and ventricular myocardium].
The influence of changes in length of the frog isolated atrium and ventriculus upon the isometric twitches was investigated. The length-tension relationship of the first contraction following the step of stretch was independent of the inotropic agents (Ca20+, adrenaline). The stretch to 0,35 induced the 5.04 +/- 051 fold increment of active tension in ventriculus and 1.75 +/- 0.12-fold increment of active tension in atrium. The length-tension relationship of the first contraction seems to depend on the degree of myofilaments overlapping A long-lasting transition-process occurred after step of deformation. The influence of inotropic agents upon the length tension relationship was shown for steady state contractions. An additional effect of activation by the length in normal solution was estimated for ventriculus as 22 +/- 5% and for atrium as 30 +/- 7%. The data suggest that the steady component-myofilament overlapping and dynamic component-calcium activations by the length change may participate in heterometric regulation of myocardial contractions.


A Bilayer 2D-WS2/Organic-Based Heterojunction for High-Performance Photodetectors.
Two-dimensional (2D) tungsten disulfide (WS2) has inspired great efforts in optoelectronics, such as in solar cells, light-emitting diodes, and photodetectors. However, chemical vapor deposition (CVD) grown 2D WS2 domains with the coexistence of a discontinuous single layer and multilayers are still not suitable for the fabrication of photodetectors on a large scale. An emerging field in the integration of organic materials with 2D materials offers the advantages of molecular diversity and flexibility to provide an exciting aspect on high-performance device applications. Herein, we fabricated a photodetector based on a 2D-WS2/organic semiconductor materials (mixture of the (Poly-(N, N'-bis-4-butylphenyl-N, N'-bisphenyl) benzidine and Phenyl-C61-butyric acid methyl ester (Poly-TPD/PCBM)) heterojunction. The application of Poly-TPD/PCBM organic blend film enhanced light absorption, electrically connected the isolated WS2 domains, and promoted the separation of electron-hole pairs. The generated exciton could sufficiently diffuse to the interface of the WS2 and the organic blend layers for efficient charge separation, where Poly-TPD was favorable for hole carrier transport and PCBM for electron transport to their respective electrodes. We show that the photodetector exhibited high responsivity, detectivity, and an on/off ratio of 0.1 A/W, 1.1 × 1011 Jones, and 100, respectively. In addition, the photodetector showed a broad spectral response from 500 nm to 750 nm, with a peak external quantum efficiency (EQE) of 8%. Our work offers a facile solution-coating process combined with a CVD technique to prepare an inorganic/organic heterojunction photodetector with high performance on silicon substrate.


An evaluation of the effects of lowering blood alcohol concentration limits for drivers on the rates of road traffic accidents and alcohol consumption: a natural experiment.
Drink driving is an important risk factor for road traffic accidents (RTAs), which cause high levels of morbidity and mortality globally. Lowering the permitted blood alcohol concentration (BAC) for drivers is a common public health intervention that is enacted in countries and jurisdictions across the world. In Scotland, on Dec 5, 2014, the BAC limit for drivers was reduced from 0·08 g/dL to 0·05 g/dL. We therefore aimed to evaluate the effects of this change on RTAs and alcohol consumption. In this natural experiment, we used an observational, comparative interrupted time-series design by use of data on RTAs and alcohol consumption in Scotland (the interventional group) and England and Wales (the control group). We obtained weekly counts of RTAs from police accident records and we estimated weekly off-trade (eg, in supermarkets and convenience stores) and 4-weekly on-trade (eg, in bars and restaurants) alcohol consumption from market research data. We also used data from automated traffic counters as denominators to calculate RTA rates. We estimated the effect of the intervention on RTAs by use of negative binomial panel regression and on alcohol consumption outcomes by use of seasonal autoregressive integrated moving average models. Our primary outcome was weekly rates of RTAs in Scotland, England, and Wales. This study is registered with ISRCTN, number ISRCTN38602189. We assessed the weekly rate of RTAs and alcohol consumption between Jan 1, 2013, and Dec 31, 2016, before and after the BAC limit came into effect on Dec 5, 2014. After the reduction in BAC limits for drivers in Scotland, we found no significant change in weekly RTA rates after adjustment for seasonality and underlying temporal trend (rate ratio 1·01, 95% CI 0·94-1·08; p=0.77) or after adjustment for seasonality, the underlying temporal trend, and the driver characteristics of age, sex, and socioeconomic deprivation (1·00, 0·96-1·06; p=0·73). Relative to RTAs in England and Wales, where the reduction in BAC limit for drivers did not occur, we found a 7% increase in weekly RTA rates in Scotland after this reduction in BAC limit for drivers (1·07, 1·02-1·13; p=0·007 in the fully-adjusted model). Similar findings were observed for serious or fatal RTAs and single-vehicle night-time RTAs. The change in legislation in Scotland was associated with no change in alcohol consumption, measured by per-capita off-trade sales (-0·3%, -1·7 to 1·1; p=0·71), but a 0·7% decrease in alcohol consumption measured by per-capita on-trade sales (-0·7%, -0·8 to -0·5; p<0·0001). Lowering the driving BAC limit to 0·05 g/dL from 0·08 g/dL in Scotland was not associated with a reduction in RTAs, but this change was associated with a small reduction in per-capita alcohol consumption from on-trade alcohol sales. One plausible explanation is that the legislative change was not suitably enforced-for example with random breath testing measures. Our findings suggest that changing the legal BAC limit for drivers in isolation does not improve RTA outcomes. These findings have significant policy implications internationally as several countries and jurisdictions consider a similar reduction in the BAC limit for drivers. National Institute for Health Research Public Health Research Programme.


Fibroblast Growth Factor 2-A Review of Stabilisation Approaches for Clinical Applications.
Basic fibroblast growth factor (FGF)-2 has been shown to regulate many cellular functions including cell proliferation, migration, and differentiation, as well as angiogenesis in a variety of tissues, including skin, blood vessel, muscle, adipose, tendon/ligament, cartilage, bone, tooth, and nerve. These multiple functions make FGF-2 an attractive component for wound healing and tissue engineering constructs; however, the stability of FGF-2 is widely accepted to be a major concern for the development of useful medicinal products. Many approaches have been reported in the literature for preserving the biological activity of FGF-2 in aqueous solutions. Most of these efforts were directed at sustaining FGF-2 activity for cell culture research, with a smaller number of studies seeking to develop sustained release formulations of FGF-2 for tissue engineering applications. The stabilisation approaches may be classified into the broad classes of ionic interaction modification with excipients, chemical modification, and physical adsorption and encapsulation with carrier materials. This review discusses the underlying causes of FGF-2 instability and provides an overview of the approaches reported in the literature for stabilising FGF-2 that may be relevant for clinical applications. Although efforts have been made to stabilise FGF-2 for both in vitro and in vivo applications with varying degrees of success, the lack of comprehensive published stability data for the final FGF-2 products represents a substantial gap in the current knowledge, which has to be addressed before viable products for wider tissue engineering applications can be developed to meet regulatory authorisation.


Artificial light-driven ion pump for photoelectric energy conversion.
Biological light-driven ion pumps move ions against a concentration gradient to create a membrane potential, thus converting sunlight energy directly into an osmotic potential. Here, we describe an artificial light-driven ion pump system in which a carbon nitride nanotube membrane can drive ions thermodynamically uphill against an up to 5000-fold concentration gradient by illumination. The separation of electrons and holes in the membrane under illumination results in a transmembrane potential which is thought to be the foundation for the pumping phenomenon. When used for harvesting solar energy, a sustained open circuit voltage of 550 mV and a current density of 2.4 μA/cm2 can reliably be generated, which can be further scaled up through series and parallel circuits of multiple membranes. The ion transport based photovoltaic system proposed here offers a roadmap for the development of devices by using simple, cheap, and stable polymeric carbon nitride.


Genetic Variants in Epigenetic Pathways and Risks of Multiple Cancers in the GAME-ON Consortium.
Background: Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, and may be influenced by the genetic background.Methods: In a subsets (ASSET) meta-analytic approach, we investigated associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas using 51,724 cases and 52,001 controls. False discovery rate-corrected P values (q values < 0.05) were considered statistically significant.Results: Among 162,887 imputed or genotyped variants in 555 candidate genes, SNPs in eight genes were associated with risk of more than one cancer type. For example, variants in BABAM1 were confirmed as a susceptibility locus for squamous cell lung, overall breast, estrogen receptor (ER)-negative breast, and overall prostate, and overall serous ovarian cancer; the most significant variant was rs4808076 [OR = 1.14; 95% confidence interval (CI) = 1.10-1.19; q = 6.87 × 10-5]. DPF1 rs12611084 was inversely associated with ER-negative breast, endometrioid ovarian, and overall and aggressive prostate cancer risk (OR = 0.93; 95% CI = 0.91-0.96; q = 0.005). Variants in L3MBTL3 were associated with colorectal, overall breast, ER-negative breast, clear cell ovarian, and overall and aggressive prostate cancer risk (e.g., rs9388766: OR = 1.06; 95% CI = 1.03-1.08; q = 0.02). Variants in TET2 were significantly associated with overall breast, overall prostate, overall ovarian, and endometrioid ovarian cancer risk, with rs62331150 showing bidirectional effects. Analyses of subpathways did not reveal gene subsets that contributed disproportionately to susceptibility.Conclusions: Functional and correlative studies are now needed to elucidate the potential links between germline genotype, epigenetic function, and cancer etiology.Impact: This approach provides novel insight into possible pleiotropic effects of genes involved in epigenetic processes. Cancer Epidemiol Biomarkers Prev; 26(6); 816-25. ©2017 AACR.


Template engaged synthesis of hollow ceria-based composites.
Hollow ceria-based composites, which consist of noble metal nanoparticles or metal oxides as a secondary component, are being studied extensively for potential applications in heterogeneous catalysis. This is due to their unique features, which exhibit the advantages of a hollow structure (e.g. high surface area and low weight), and also integrate the properties of ceria and noble metals/metal oxides. More importantly, the synergistic effect between constituents in hollow ceria-based composites has been demonstrated in various catalytic reactions. In this feature article, we summarize the state-of-the-art in the synthesis of hollow ceria-based composites, including traditional hard-templates and more recently, sacrificial-template engaged strategies, highlighting the key role of selected templates in the formation of hollow composites. In addition, the catalytic applications of hollow ceria-based composites are briefly surveyed. Finally, challenges and perspectives on future advances of hollow ceria-based composites are outlined.


RAC1 nitration at Y32 IS involved in the endothelial barrier disruption associated with lipopolysaccharide-mediated acute lung injury.
Acute lung injury (ALI), a devastating illness induced by systemic inflammation e.g., sepsis or local lung inflammation e.g., COVID-19 mediated severe pneumonia, has an unacceptably high mortality and has no effective therapy. ALI is associated with increased pulmonary microvascular hyperpermeability and alveolar flooding. The small Rho GTPases, RhoA and Rac1 are central regulators of vascular permeability through cytoskeleton rearrangements. RhoA and Rac1 have opposing functional outcome: RhoA induces an endothelial contractile phenotype and barrier disruption, while Rac1 stabilizes endothelial junctions and increases barrier integrity. In ALI, RhoA activity is increased while Rac1 activity is reduced. We have shown that the activation of RhoA in lipopolysaccharide (LPS)-mediated ALI, is dependent, at least in part, on a single nitration event at tyrosine (Y)34. Thus, the purpose of this study was to determine if the inhibition of Rac1 is also dependent on its nitration. Our data show that Rac1 inhibition by LPS is associated with its nitration that mass spectrometry identified as Y32, within the switch I region adjacent to the nucleotide-binding site. Using a molecular modeling approach, we designed a nitration shielding peptide for Rac1, designated NipR2 (nitration inhibitor peptide for the Rho GTPases 2), which attenuated the LPS-induced nitration of Rac1 at Y32, preserves Rac1 activity and attenuates the LPS-mediated disruption of the endothelial barrier in human lung microvascular endothelial cells (HLMVEC). Using a murine model of ALI induced by intratracheal installation of LPS we found that NipR2 successfully prevented Rac1 nitration and Rac1 inhibition, and more importantly attenuated pulmonary inflammation, reduced lung injury and prevented the loss of lung function. Together, our data identify a new post-translational mechanism of Rac1 inhibition through its nitration at Y32. As NipR2 also reduces sepsis induced ALI in the mouse lung, we conclude that Rac1 nitration is a therapeutic target in ALI.


Dependency of polychlorinated biphenyl and polycyclic aromatic hydrocarbon bioaccumulation in Mya arenaria on both water column and sediment bed chemical activities.
The bioaccumulation of polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) by the filter-feeding soft-shell clam Mya arenaria was evaluated at three sites near Boston (MA, USA) by assessing the chemical activities of those hydrophobic organic compounds (HOCs) in the sediment bed, water column, and organisms. Polyethylene samplers were deployed to measure the activities of HOCs in the water column. Sediment activities were assessed by normalizing concentrations with sediment-water sorption coefficient values, including adsorption to black carbon in addition to absorption by organic carbon. Likewise, both lipids and proteins were considered in biota-water partition coefficients used to estimate chemical activities in the animals. Chemical activities of PAHs in M. arenaria were substantially less than those of the corresponding bed sediments in which they lived. In contrast, chemical activities of PCBs in M. arenaria often were greater than or equal to activities in the corresponding bed sediments. Activities of PAHs, such those of pyrene, in the water column were undersaturated relative to the sediment. However, some PCBs, such as congener 52, had higher activities in the water column than in the sediment. Tissue activities of pyrene generally were in between the sediment and water column activities, whereas activity of PCB congener 52 was nearest to water column activities. These results suggest that attempts to estimate bioaccumulation by benthic organisms should include interactions with both the bed sediment and the water column.


Aging phenomena during phase separation in fluids: decay of autocorrelation for vapor-liquid transitions.
We performed molecular dynamics simulations to study relaxation phenomena during vapor-liquid transitions in a single component Lennard-Jones system. Results from two different overall densities are presented: one in the neighborhood of the vapor branch of the coexistence curve and the other being close to the critical density. The nonequilibrium morphologies, growth mechanisms and growth laws in the two cases are vastly different. In the low density case growth occurs via diffusive coalescence of droplets in a disconnected morphology. On the other hand, the elongated structure in the higher density case grows via advective transport of particles inside the tube-like liquid domains. The objective in this work has been to identify how the decay of the order-parameter autocorrelation, an important quantity to understand aging dynamics, differs in the two cases. In the case of the disconnected morphology, we observe a very robust power-law decay, as a function of the ratio of the characteristic lengths at the observation time and at the age of the system, whereas the results for the percolating structure appear rather complex. To quantify the decay in the latter case, unlike the standard method followed in a previous study, here we have performed a finite-size scaling analysis. The outcome of this analysis shows the presence of a strong preasymptotic correction, while revealing that in this case also, albeit in the asymptotic limit, the decay follows a power-law. Even though the corresponding exponents in the two cases differ drastically, this study, combined with a few recent ones, suggests that power-law behavior of this correlation function is rather universal in coarsening dynamics.


Simulating structural and thermodynamic properties of carcinogen-damaged DNA.
A pair of stereoisomeric covalent adducts to guanine in double-stranded DNA, derived from the reaction of mutagenic and tumorigenic metabolites of benzo[a]pyrene, have been well characterized structurally and thermodynamically. Both high-resolution NMR solution structures and an array of thermodynamic data are available for these 10S (+)- and 10R (-)-trans-anti -[BP]-N(2)-dG adducts in double-stranded deoxyoligonucleotides. The availability of experimentally well-characterized duplexes containing these two stereoisomeric guanine adducts provides an opportunity for evaluating the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method for computing thermodynamic properties from molecular dynamics ensembles. We have carried out 3-ns molecular dynamics simulations, using NMR solution structures as the starting models for the 10S (+)- and 10R (-)-trans-anti-dG adducts in a DNA duplex 11-mer using AMBER 6.0. We employed the MM-PBSA method to compute the free energies, enthalpies, and entropies of the two adducts. Our complete thermodynamic analysis agrees quite well with the full experimental thermodynamic characterization of these adducts, showing essentially equal stabilities of the two adducts. We also calculated the nuclear Overhauser effect (NOE) distances from the molecular dynamics trajectories, and compared them against the experimental NMR-derived NOE distances. Our results showed that the simulated structures are in good agreement with the NMR experimental NOE data. Furthermore, the molecular dynamics simulations provided new structural and biological insights. Specifically, the puzzling observation that the BP aromatic ring system in the 10S (+)-trans-anti-dG adduct is more exposed to the aqueous solvent than the 10R (-)-trans-anti-dG adduct, is rationalized in terms of the adduct structures. The structural and thermodynamic features of these stereoisomeric adducts are also discussed in relation to their reported low susceptibilities to nucleotide excision repair.


Detection of four Plasmodium species in blood from humans by 18S rRNA gene subunit-based and species-specific real-time PCR assays.
There have been reports of increasing numbers of cases of malaria among migrants and travelers. Although microscopic examination of blood smears remains the "gold standard" in diagnosis, this method suffers from insufficient sensitivity and requires considerable expertise. To improve diagnosis, a multiplex real-time PCR was developed. One set of generic primers targeting a highly conserved region of the 18S rRNA gene of the genus Plasmodium was designed; the primer set was polymorphic enough internally to design four species-specific probes for P. falciparum, P. vivax, P. malarie, and P. ovale. Real-time PCR with species-specific probes detected one plasmid copy of P. falciparum, P. vivax, P. malariae, and P. ovale specifically. The same sensitivity was achieved for all species with real-time PCR with the 18S screening probe. Ninety-seven blood samples were investigated. For 66 of them (60 patients), microscopy and real-time PCR results were compared and had a crude agreement of 86% for the detection of plasmodia. Discordant results were reevaluated with clinical, molecular, and sequencing data to resolve them. All nine discordances between 18S screening PCR and microscopy were resolved in favor of the molecular method, as were eight of nine discordances at the species level for the species-specific PCR among the 31 samples positive by both methods. The other 31 blood samples were tested to monitor the antimalaria treatment in seven patients. The number of parasites measured by real-time PCR fell rapidly for six out of seven patients in parallel to parasitemia determined microscopically. This suggests a role of quantitative PCR for the monitoring of patients receiving antimalaria therapy.


Rumor-Related and Exclusive Behavior Coverage in Internet News Reports Following the 2009 H1N1 Influenza Outbreak in Japan.
We sought to elucidate news article reporting of adverse public psychosocial behaviors, in particular, rumor-related coverage (eg, panic, demagoguery) and exclusive behavior coverage (negative behaviors, eg, discrimination, bullying) during the 2009 influenza A (H1N1) influenza pandemic in Japan. We examined 154 Internet news-site articles reporting adverse public psychosocial responses in the first 60 days of the outbreak. Rumor-related coverage and exclusive behavior coverage were dichotomously coded as included or not. Moreover, we assessed whether or not health information (eg, coping methods, virus toxicity information) or emphasis on information quality (eg, importance of information, cautions about overreactions) were simultaneously reported. Rumor-related coverage (n=120, 77.9%) was less likely to simultaneously report public health information (eg, toxicity information, health support information, and cautions about overreactions; P<.05). Conversely, exclusive behavior coverage (n=41, 26.6%) was more likely to report public health information (P<.05). Rumor-related coverage was less likely to have accompanying public health information, whereas exclusive behavior coverage was more likely to include it. During public health crises, it is essential to understand that rumors and exclusive behaviors have adverse effects on the public and that accompanying public health information may help people take proactive coping actions.


Structure and magnetism of a binuclear Cu(II) pyrophosphate: transition to a 3D magnetic behaviour studied by single crystal EPR.
A binuclear Cu(II) compound [Cu2(bpa)2(P2O7)(H2O)2]·2.5H2O, 1, (bpa = 2,2'-bipyridylamine), with pairs of Cu(II) ions bridged by one pyrophosphate tetra-anion, was synthesized and crystallized. Its triclinic structure was determined by single-crystal X-ray diffraction. Electron paramagnetic resonance (EPR) spectra of single crystal samples of 1 were recorded for a fixed orientation of the magnetic field (B0) as a function of temperature (T) between 4.7 and 293 K, and at T = 4.7, 50 and 293 K, as a function of the orientation of B0. Below ∼8 K, the spectra are assigned to two types of mononuclear crystal defects hyperfine-coupled to one copper and two nitrogen nuclei. The g-matrices and hyperfine couplings at these T provide information about the structures of these defects. Above 10 K, the spectrum is dominated by the response of the bulk binuclear Cu(II) material, showing hyperfine interactions with two copper nuclei, collapsing to a single peak above 18 K when the units are magnetically connected, and the magnetic behaviour becomes 3D. We attribute the results above 10 K to the interplay of an AFM intrabinuclear exchange interaction J0 = -28(3) cm(-1) (defined as Hex = -J0S1·S2), and three orders of magnitude weaker exchange coupling with average magnitude |J1| ≥ 0.022 cm(-1) between Cu(II) ions in neighbouring binuclear units. The interplays between structure, exchange couplings, magnetic dimension and spin dynamics in the binuclear compound are discussed. A previously unreported situation, where the structure of the spectra arising from the anisotropic spin-spin interaction term (D) within the binuclear unit is averaged out, but the forbidden half field transition is not, is observed and explained.


Serum enzymes and isoenzymes in the diagnosis and differential diagnosis of myocardial ischemia and necrosis.
Diagnosis of injury to the myocardium is facilitated by information on the activities of creatine kinase (EC 126.96.36.199) MB isoenzyme (CK-MB) and lactate dehydrogenase (EC 184.108.40.206) isoenzyme 1 in serum, thee isoenzymes being present in higher activities in the myocardium than in other tissues or in normal serum. The temporal relationships of these isoenzymes, total creatine kinase, total lactate dehydrogenase, and aspartate aminotransferase (EC 126.96.36.199) are highly sensitive and specific for acute injury to the heart, particularly acute myocardial infarction. Chronic heart diseases, electric cardioversion for heart rhythm disturbances, coronary catheterization, and exercise usually do not produce increases of CK-MB, although abnormal aspartate aminotransferase, creatine kinase, lactate dehydrogenase, and lactate dehydrogenase isoenzyme 1 activities are seen in some individuals. Many other causes of increased activities of these enzymes and isoenzymes in serum are unrelated to injury to the heart. Because CK-MB is present in the skeletal muscle in low activities, substantial injury to skeletal muscle can increase CK-MB activities in the blood to abnormal values. Pulmonary embolism can mimic myocardial infarction in its clinical presentation. In patients with an accurately known time of onset of symptoms and serial enzyme analysis every 12 h during the first 48 h, acute myocardial infarction can be distinguished from pulmonary embolism by determinations of creatine kinase, CK-MB, aspartate aminotransferase, and lactate dehydrogenase isoenzyme 1 in serum.


[Cholinergic deficiency syndrome as an indicator for the cholinesterase inhibitors].
Cholinesterase inhibitors are licensed for the treatment of dementia in Alzheimer's disease. In clinical practice, these drugs have little effect on the cognitive symptoms of dementia. Several studies report a beneficial effect of cholinesterase inhibitors on neuropsychiatric symptoms. We hypothesise that symptoms such as the impairment of attention and concentration, anxiety, restlessness and hallucinations, delineate a specific central cholinergic deficiency syndrome. It is postulated that this syndrome crosses boundaries of nosological entities and occurs in various neurodegenerative diseases. Symptoms resulting from cholinergic deficiency might be a much better target for treatment than cognitive deficits.


Bioelectronic measurement and feedback control of molecules in living cells.
We describe an electrochemical measurement technique that enables bioelectronic measurements of reporter proteins in living cells as an alternative to traditional optical fluorescence. Using electronically programmable microfluidics, the measurement is in turn used to control the concentration of an inducer input that regulates production of the protein from a genetic promoter. The resulting bioelectronic and microfluidic negative-feedback loop then serves to regulate the concentration of the protein in the cell. We show measurements wherein a user-programmable set-point precisely alters the protein concentration in the cell with feedback-loop parameters affecting the dynamics of the closed-loop response in a predictable fashion. Our work does not require expensive optical fluorescence measurement techniques that are prone to toxicity in chronic settings, sophisticated time-lapse microscopy, or bulky/expensive chemo-stat instrumentation for dynamic measurement and control of biomolecules in cells. Therefore, it may be useful in creating a: cheap, portable, chronic, dynamic, and precise all-electronic alternative for measurement and control of molecules in living cells.


Phenology and photosynthetic traits of short shoots and long shoots in Betula grossa.
Leaf phenology, growth irradiance (i.e., photosynthetic photon flux (PPF) at the leaf surface) and photosynthetic capacity (A(area); measured at a PPF of 1000 micro mol m(-2) s(-1) and expressed on a leaf area basis) were investigated in early leaves (ELs) and late leaves (LLs) of Betula grossa Siebold & Zucc. trees. Early leaves first appeared on morphologically distinct long shoots and short shoots. The appearance of ELs, which was restricted to the bud break period, was followed by the successive appearance of LLs on long shoots only. Late leaves appeared successively until the middle of the growing season. Late leaves started to abscise around the middle of the growing season, whereas ELs on both long and short shoots did not abscise until near the end of the growing season. Solar irradiance was higher at the surface of LLs of late appearance than at the surface of either LLs of early appearance or ELs. Solar irradiance at the surface of ELs decreased after LLs appeared. In both long and short shoots, A(area) of ELs increased and then remained stable for 65-80 days before starting to decrease. Although A(area) was higher in LLs than in ELs for a short time in August, it started to decrease earlier in LLs than in ELs. Area-based nitrogen concentration (N(area)) was higher in LLs than in ELs after August. Although N(area) decreased slowly in ELs after August, it did not decrease in LLs. In both ELs and LLs, A(area)/N(area) decreased with time. The crown was thus characterized by a rapidly growing surface with young LLs having high A(area) and by shaded inner parts with ELs having stable low A(area).


From Childhood Trauma to Adult Dissociation: The Role of PTSD and Alexithymia.
The mechanism of how childhood trauma leads to increased risk for adult dissociation is not sufficiently understood. We sought to investigate the predicting effects and the putatively mediating roles of PTSD and alexithymia on the path from childhood trauma to adult dissociation. A total of 666 day-clinic outpatients were administered the Childhood Trauma Questionnaire (CTQ), the Toronto Alexithymia Scale (TAS-20), the Posttraumatic Diagnostic Scale (PDS), and the Dissociative Experiences Scale (DES) and controlled for sex, age, and the Global Symptom Index (GSI). Linear regression analyses and mediation analyses were applied. Independent predictive effects on dissociation were found for childhood trauma, alexithymia and PDS, even after adjusting for GSI. Effects of childhood neglect on dissociation were slightly stronger than of abuse. Alexithymia did not mediate the path from childhood trauma to dissociation. Mediation by PDS was specific for childhood abuse, with all PTSD symptom clusters being significantly involved. Childhood abuse and neglect are important predictors of dissociation. While the effects of abuse are mediated by PTSD, the mechanism of how neglect leads to dissociation remains unclear. The results further support the predictive value of alexithymia for adult dissociation above and beyond the effects of childhood trauma, PTSD, and GSI scores.


Why religion is nothing special but is central.
It is proposed that explaining religion in evolutionary terms is a misleading enterprise because religion is an indissoluble part of a unique aspect of human social organization. Theoretical and empirical research should focus on what differentiates human sociality from that of other primates, i.e. the fact that members of society often act towards each other in terms of essentialized roles and groups. These have a phenomenological existence that is not based on everyday empirical monitoring but on imagined statuses and communities, such as clans or nations. The neurological basis for this type of social, which includes religion, will therefore depend on the development of imagination. It is suggested that such a development of imagination occurred at about the time of the Upper Palaeolithic 'revolution'.


VAP-RELATED SUPPRESSORS OF TOO MANY MOUTHS (VST) family proteins are regulators of root system architecture.
Root system architecture (RSA) is a key factor in the efficiency of nutrient capture and water uptake in plants. Understanding the genetic control of RSA will be useful in minimizing fertilizer and water usage in agricultural cropping systems. Using a hydroponic screen and a gel-based imaging system, we identified a rice (Oryza sativa) gene, VAP-RELATED SUPPRESSOR OF TOO MANY MOUTHS1 (OsVST1), which plays a key role in controlling RSA. This gene encodes a homolog of the VAP-RELATED SUPPRESSORS OF TOO MANY MOUTHS (VST) proteins in Arabidopsis (Arabidopsis thaliana), which promote signaling in stomata by mediating plasma membrane-endoplasmic reticulum contacts. OsVST1 mutants have shorter primary roots, decreased root meristem size, and a more compact RSA. We show that the Arabidopsis VST triple mutants have similar phenotypes, with reduced primary root growth and smaller root meristems. Expression of OsVST1 largely complements the short root length and reduced plant height in the Arabidopsis triple mutant, supporting conservation of function between rice and Arabidopsis VST proteins. In a field trial, mutations in OsVST1 did not adversely affect grain yield, suggesting that modulation of this gene could be used as a way to optimize RSA without an inherent yield penalty.


Cell- and subunit-specific mechanisms of CNG channel ciliary trafficking and localization in C. elegans.
Primary cilia are ubiquitous sensory organelles that concentrate transmembrane signaling proteins essential for sensing environmental cues. Mislocalization of crucial ciliary signaling proteins, such as the tetrameric cyclic nucleotide-gated (CNG) channels, can lead to cellular dysfunction and disease. Although several cis- and trans-acting factors required for ciliary protein trafficking and localization have been identified, whether these mechanisms act in a protein- and cell-specific manner is largely unknown. Here, we show that CNG channel subunits can be localized to discrete ciliary compartments in individual sensory neurons in C. elegans, suggesting that channel composition is heterogeneous across the cilium. We demonstrate that ciliary localization of CNG channel subunits is interdependent on different channel subunits in specific cells, and identify sequences required for efficient ciliary targeting and localization of the TAX-2 CNGB and TAX-4 CNGA subunits. Using a candidate gene approach, we show that Inversin, transition zone proteins, intraflagellar transport motors and a MYND-domain protein are required to traffic and/or localize CNG channel subunits in both a cell- and channel subunit-specific manner. We further find that TAX-2 and TAX-4 are relatively immobile in specific sensory cilia subcompartments, suggesting that these proteins undergo minimal turnover in these domains in mature cilia. Our results uncover unexpected diversity in the mechanisms that traffic and localize CNG channel subunits to cilia both within and across cell types, highlighting the essential contribution of this process to cellular functions.


Fe L-edge XAS studies of K4[Fe(CN)6] and K3[Fe(CN)6]: a direct probe of back-bonding.
Distinct spectral features at the Fe L-edge of the two compounds K3[Fe(CN)6] and K4[Fe(CN)6] have been identified and characterized as arising from contributions of the ligand pi orbitals due to metal-to-ligand back-bonding. In addition, the L-edge energy shifts and total intensities allow changes in the ligand field and effective nuclear charge to be determined. It is found that the ligand field term dominates the edge energy shift. The results of the experimental analysis were compared to BP86 DFT calculations. The overall agreement between the calculations and experiment is good; however, a larger difference in the amount of pi back-donation between Fe(II) and Fe(III) is found experimentally. The analysis of L-edge spectral shape, energy shift, and total intensity demonstrates that Fe L-edge X-ray absorption spectroscopy provides a direct probe of metal-to-ligand back-bonding.


Cellular Decision Making by Non-Integrative Processing of TLR Inputs.
Cells receive a multitude of signals from the environment, but how they process simultaneous signaling inputs is not well understood. Response to infection, for example, involves parallel activation of multiple Toll-like receptors (TLRs) that converge on the nuclear factor κB (NF-κB) pathway. Although we increasingly understand inflammatory responses for isolated signals, it is not clear how cells process multiple signals that co-occur in physiological settings. We therefore examined a bacterial infection scenario involving co-stimulation of TLR4 and TLR2. Independent stimulation of these receptors induced distinct NF-κB dynamic profiles, although surprisingly, under co-stimulation, single cells continued to show ligand-specific dynamic responses characteristic of TLR2 or TLR4 signaling rather than a mixed response, comprising a cellular decision that we term "non-integrative" processing. Iterating modeling and microfluidic experiments revealed that non-integrative processing occurred through interaction of switch-like NF-κB activation, receptor-specific processing timescales, cell-to-cell variability, and TLR cross-tolerance mediated by multilayer negative feedback.


Insights into alternative splicing of sarcomeric genes in the heart.
Driven by rapidly evolving technologies in next-generation sequencing, alternative splicing has emerged as a crucial layer in gene expression, greatly expanding protein diversity and governing complex biological processes in the cardiomyocyte. At the core of cardiac contraction, the physical properties of the sarcomere are carefully orchestrated through alternative splicing to fit the varying demands on the heart. By the recent discovery of RBM20 and RBM24, two major heart and skeletal muscle-restricted splicing factors, it became evident that alternative splicing events in the heart occur in regulated networks rather than in isolated events. Analysis of knockout mice of these splice factors has shed light on the importance of these fundamental processes in the heart. In this review, we discuss recent advances in our understanding of the role and regulation of alternative splicing in the developing and diseased heart, specifically within the sarcomere. Through various examples (titin, myomesin, troponin T, tropomyosin and LDB3) we illustrate how alternative splicing regulates the functional properties of the sarcomere. Finally, we evaluate opportunities and obstacles to modulate alternative splicing in therapeutic approaches for cardiac disease.


The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance.
Glioblastoma remains one of the most lethal types of cancer, and is the most common brain tumour in adults. In particular, tumour recurrence after surgical resection and radiation invariably occurs regardless of aggressive chemotherapy. Here, we provide evidence that the transcription factor ZEB1 (zinc finger E-box binding homeobox 1) exerts simultaneous influence over invasion, chemoresistance and tumourigenesis in glioblastoma. ZEB1 is preferentially expressed in invasive glioblastoma cells, where the ZEB1-miR-200 feedback loop interconnects these processes through the downstream effectors ROBO1, c-MYB and MGMT. Moreover, ZEB1 expression in glioblastoma patients is predictive of shorter survival and poor Temozolomide response. Our findings indicate that this regulator of epithelial-mesenchymal transition orchestrates key features of cancer stem cells in malignant glioma and identify ROBO1, OLIG2, CD133 and MGMT as novel targets of the ZEB1 pathway. Thus, ZEB1 is an important candidate molecule for glioblastoma recurrence, a marker of invasive tumour cells and a potential therapeutic target, along with its downstream effectors.


Direct, genome-wide assessment of DNA mutations in single cells.
DNA mutations are the inevitable consequences of errors that arise during replication and repair of DNA damage. Because of their random and infrequent occurrence, quantification and characterization of DNA mutations in the genome of somatic cells has been difficult. Random, low-abundance mutations are currently inaccessible by standard high-throughput sequencing approaches because they cannot be distinguished from sequencing errors. One way to circumvent this problem and simultaneously account for the mutational heterogeneity within tissues is whole genome sequencing of a representative number of single cells. Here, we show elevated mutation levels in single cells from Drosophila melanogaster S2 and mouse embryonic fibroblast populations after treatment with the powerful mutagen N-ethyl-N-nitrosourea. This method can be applied as a direct measure of exposure to mutagenic agents and for assessing genotypic heterogeneity within tissues or cell populations.


Ex vivo biomechanical evaluation of pigeon (Columba livia) cadaver intact humeri and ostectomized humeri stabilized with caudally applied titanium locking plate or stainless steel nonlocking plate constructs.
OBJECTIVE To evaluate mechanical properties of pigeon (Columba livia) cadaver intact humeri versus ostectomized humeri stabilized with a locking or nonlocking plate. SAMPLE 30 humeri from pigeon cadavers. PROCEDURES Specimens were allocated into 3 groups and tested in bending and torsion. Results for intact pigeon humeri were compared with results for ostectomized humeri repaired with a titanium 1.6-mm screw locking plate or a stainless steel 1.5-mm dynamic compression plate; the ostectomized humeri mimicked a fracture in a thin cortical bone. Locking plates were secured with locking screws (2 bicortical and 4 monocortical), and nonlocking plates were secured with bicortical nonlocking screws. Constructs were cyclically tested nondestructively in 4-point bending and then tested to failure in bending. A second set of constructs were cyclically tested non-destructively and then to failure in torsion. Stiffness, strength, and strain energy of each construct were compared. RESULTS Intact specimens were stiffer and stronger than the repair groups for all testing methods, except for nonlocking constructs, which were significantly stiffer than intact specimens under cyclic bending. Intact bones had significantly higher strain energies than locking plates in both bending and torsion. Locking and nonlocking plates were of equal strength and strain energy, but not stiffness, in bending and were of equal strength, stiffness, and strain energy in torsion. CONCLUSIONS AND CLINICAL RELEVANCE Results for this study suggested that increased torsional strength may be needed before bone plate repair can be considered as the sole fixation method for avian species.


Metallothionein-I overexpression alters brain inflammation and stimulates brain repair in transgenic mice with astrocyte-targeted interleukin-6 expression.
Transgenic expression of IL-6 in the CNS under the control of the GFAP gene promoter, glial fibrillary acidic protein-interleukin-6 (GFAP-IL-6) mice, raises an inflammatory response and causes significant brain damage. However, the results obtained in the GFAP-IL-6 mice after a traumatic brain injury, such as a cryolesion, demonstrate a neuroprotective role of IL-6. Thus, the GFAP-IL-6 mice showed faster tissue repair and decreased oxidative stress and apoptosis compared with control litter-mate mice. The neuroprotective factors metallothionein-I+II (MT-I+II) were upregulated by the cryolesion to a higher extent in the GFAP-IL-6 mice, suggesting that they could be related to the neuroprotection afforded by the transgenic expression of IL-6. To examine this possibility, we have crossed GFAP-IL-6 mice with transgenic mice overexpressing MT-I (TgMT), producing double transgenic GFAP-IL-6 TgMT mice. The results obtained after cryolesion in GFAP-IL-6 TgMT mice, as well as in TgMT mice, consistently supported the idea that the increased MT-I+II levels observed in GFAP-IL-6 mice are a fundamental and important mechanism for coping with brain damage. Accordingly, MT-I overexpression regulated the inflammatory response, decreased oxidative stress and apoptosis significantly, and increased brain tissue repair in comparison with either GFAP-IL-6 or control litter-mate mice. Overall, the results demonstrate that brain MT-I+II proteins are fundamental neuroprotective factors.


Predictors of changes in gait performance over four years in persons with late effects of polio.
Reduced gait performance is common in persons with late effects of polio. To identify predictors of change in gait performance over four years in persons with late effects of polio. Gait performance was assessed annually in 51 ambulatory persons (mean age 64 years, SD 6) by the Timed "Up & Go" (TUG), Comfortable and Fast Gait Speed (CGS, FGS), and 6-Minute Walk Test (6MWT). Isokinetic knee extensor and flexor muscle strength was measured with a Biodex dynamometer. Mixed Linear Models were used to analyze changes in gait performance and to identify any predictors of change among the covariates gender, age, body mass index, time with new symptoms, baseline reduction in gait performance and knee muscle strength. There were significant linear effects over time (reduction per year) for three gait performance tests; CGS (0.8%; p < 0.05), FGS (1.7%; p < 0.001), and 6MWT (0.7%; p < 0.05) with significant random effects for all tests. The strongest predictor of a change in gait performance was the individual variations in the knee flexor strength (p < 0.001). The small gradual reduction in gait performance over time in persons with late effects of polio is primarily determined by the individual variations in the knee flexor strength.


mTOR kinase inhibitor AZD8055 enhances the immunotherapeutic activity of an agonist CD40 antibody in cancer treatment.
mTOR is a central mediator of cancer cell growth, but it also directs immune cell differentiation and function. On this basis, we had explored the hypothesis that mTOR inhibition can enhance cancer immunotherapy. Here, we report that a combination of αCD40 agonistic antibody and the ATP-competitive mTOR kinase inhibitory drug AZD8055 elicited synergistic antitumor responses in a model of metastatic renal cell carcinoma. In contrast to the well-established mTOR inhibitor rapamycin, AZD8055 increased the infiltration, activation, and proliferation of CD8(+) T cells and natural killer cells in liver metastatic foci when combined with the CD40 agonist. AZD8055/αCD40-treated mice also display an increased incidence of matured macrophages and dendritic cells compared with that achieved in mice by αCD40 or AZD8055 treatment alone. We found that the combination treatment also increased macrophage production of TNFα, which played an indispensable role in activation of the observed antitumor immune response. Levels of Th1 cytokines, including interleukin 12, IFN-γ, TNFα, and the Th1-associated chemokines RANTES, MIG, and IP-10 were each elevated significantly in the livers of mice treated with the combinatorial therapy versus individual treatments. Notably, the AZD8055/αCD40-induced antitumor response was abolished in IFN-γ(-/-) and CD40(-/-) mice, establishing the reliance of the combination therapy on host IFN-γ and CD40 expression. Our findings offer a preclinical proof of concept that, unlike rapamycin, the ATP-competitive mTOR kinase inhibitor AZD8055 can contribute with αCD40 treatment to trigger a restructuring of the tumor immune microenvironment to trigger regressions of an established metastatic cancer.


[Management of pyelonephritis in childhood: medical treatment (author's transl)].
Authors point out worth of a rational treatment in urinary tract infections, based on the accomplishment of general standards, correction of predisposing conditions, antimicrobic treatment, long term observation and intime cooperation among Pediatric, Nephropediatric and Urologic physicians in the close surveyance of these patients.


Familial dilated cardiomyopathy: a transverse and longitudinal clinical and echocardiographic study.
The familial occurrence of hypertrophic cardiomyopathy is well known; familial dilated cardiomyopathy has so far received less attention. Ten families with two or more members affected by dilated cardiomyopathy were studied by echocardiography. In 3 out of 10 families, a transverse study extended to even apparently healthy subjects was carried out, which included a total of 45 subjects. In 19 out of the 45, dilated cardiomyopathy (either symptomatic or asymptomatic) was diagnosed at echocardiography. Three more relatives, already dead of the disease, were identified through hospital records. A clinical and echocardiographic longitudinal study, lasting up to 11 years, was carried out in 5 of the 10 families. During the follow-up, 8 out of 19 patients who, at first examination were affected by dilated cardiomyopathy, died, one improved, 3 remained in stable condition and 7 were lost at follow-up. One of two patients who presented echocardiographic findings suggestive of border-line dilated cardiomyopathy returned to normality and the other developed dilated cardiomyopathy. The clinical and echocardiographic findings in our patients, and in their relatives, suggest the possibility that idiopathic dilated cardiomyopathy may be a multifactorial disease in which genetic factors might play a variable role.


Developing adolescent-specific health state values for economic evaluation: an application of profile case best-worst scaling to the Child Health Utility 9D.
The way that health is measured and valued is fundamental to economic evaluation. To date, adult health state values have been routinely used in the calculation of QALYs for the economic evaluation of healthcare treatment and preventive programmes, including those targeted at adolescents. The main objective of this study was to apply profile case best-worst scaling (BWS) discrete-choice experiment (DCE) methods to obtain adolescent-specific values for the Child Health Utility 9D (CHU9D), a new generic preference-based measure of health-related quality of life developed specifically for application in cost-effectiveness analyses of treatments and interventions targeted at young people. A secondary aim was to assess the feasibility of a web-based method of data collection for the valuation of health states defined by the CHU9D. A web-based survey was developed including the CHU9D instrument and a series of BWS DCE questions. Specifically, respondents were asked to indicate the best and worst attribute levels from a series of ten health states defined by the CHU9D, presented one at a time. The survey was administered to a community-based sample of consenting adolescents (n = 590) aged 11-17 years. A conditional logistic regression model was applied to estimate values (part-worth utilities) for each level of the nine attributes relating to the CHU9D. A marginal utility matrix was then estimated to generate an adolescent-specific scoring algorithm on the full health = 1 and dead = 0 scale required for the calculation of QALYs. The results indicate that participants were able to readily choose 'best' and 'worst' attribute levels for the CHU9D health states. Large differences in value were found between the first and fifth levels (indicating 'no problems' and 'severe problems', respectively) for all nine attributes relating to the CHU9D. In general, there was little differentiation between the middle levels of all attributes indicating only limited additional value for adolescents of moving between these levels. Comparison of the adolescent-specific algorithm and the existing adult scoring algorithm for the CHU9D revealed some significant differences in values for identical health states, which may have important implications for the application of the CHU9D to value adolescent treatment and service programmes particularly for mental health. In general, adolescents appeared to place more weight upon the CHU9D attributes relating to mental health (worried, sad and annoyed) than would be implied by application of the existing algorithm based upon adult values. This study provides preliminary indications that there may be potentially important and systematic differences in the valuations attached to identical health states by adolescents in comparison with adult population groups. The study findings lend support to the potential future application of profile case BWS DCE methods to undertake large-scale health state valuation studies directly with young adolescent population samples and provide support for the feasibility and acceptability of a web-based mode of administration for this purpose.


Relationship of 25-hydroxyvitamin D with all-cause and cardiovascular disease mortality in older community-dwelling adults.
Vitamin D deficiency is associated with cardiovascular disease, osteoporosis, poor muscle strength, falls, fractures and mortality. Although older adults are at a higher risk of vitamin D deficiency, the relationship of serum 25-hydroxyvitamin D (25(OH)D) with all-cause and cardiovascular disease mortality has not been well characterized in the elderly. We hypothesized that low serum 25(OH)D levels predicted mortality in older adults. Serum 25(OH)D as well as all-cause and cardiovascular disease mortality were examined in 1006 adults, aged > or =65 years, who participated in the InCHIANTI (Invecchiare in Chianti, Aging in the Chianti Area) study, a population-based, prospective cohort study of aging in Tuscany, Italy. Serum 25(OH)D levels were measured at the time of enrollment in 1998-1999, and participants were followed up for mortality. During 6.5 years of follow-up, 228 (22.7%) participants died, of whom 107 died due to cardiovascular diseases. Compared with participants in the highest quartile of serum 25(OH)D (>26.5 ng/ml) (to convert to nmol/l, multiply by 2.496), those in the lowest quartile (<10.5 ng/ml) had increased risk of all-cause mortality (Hazard Ratio (H.R.) 2.11, 95% Confidence Interval (95% C.I.): 1.22-3.64, P=0.007) and cardiovascular disease mortality (H.R. 2.64, 95% C.I.: 1.14-4.79, P=0.02), in multivariate Cox proportional hazards models that adjusted for age, sex, education, season, physical activity and other potential confounders. Older community-dwelling adults with low serum 25(OH)D levels are at higher risk of all-cause and cardiovascular disease mortality.


Attenuated cardiovascular response to sympathetic system activation during exercise in patients with dialysis-induced hypotension.
We wished to investigate potential causes of dialysis-induced hypotension (DIH), including the attenuated cardiovascular response to sympathetic system activation during exercise and myocardial dysfunction. This study included 26 end-stage renal disease (ESRD) patients with DIH, 30 ESRD patients without DIH (Non-DIH), and 30 control subjects. Each patient was evaluated with echocardiography and a symptom-limited treadmill stress test. The chronotropic index (CRI), heart rate recovery (HRR), systolic blood pressure response to exercise (SBP response), and tissue Doppler systolic myocardial velocities were calculated. The HRR and velocities were reduced in dialysis patients compared to controls; however, they were similar in patients with and without DIH. Patients with DIH had the lowest CRI compared to the Non-DIH group (0.62 ± 0.15 vs. 0.73 ± 0.17, p = 0.020) and controls (0.62 ± 0.15 vs. 0.86 ± 0.11, p < 0.001). Similarly, patients with DIH had the lowest SBP response values compared to the Non-DIH (34.88 ± 15.01 vs. 55.67 ± 25.42, p = 0.002) and controls (34.88 ± 15.01 vs. 59.70 ± 23.04, p < 0.001). Patients with DIH have inadequate sympathetic activity of the cardiovascular system during exercise and impaired left ventricular systolic function. Both factors could contribute to the development of hypotension during hemodialysis.


An RbAp48-like gene regulates adult stem cells in planarians.
Retinoblastoma-associated proteins 46 and 48 (RbAp46 and RbAp48) are factors that are components of different chromatin-modelling complexes, such as polycomb repressive complex 2, the activity of which is related to epigenetic gene regulation in stem cells. To date, no direct findings are available on the in vivo role of RbAp48 in stem-cell biology. We recently identified DjRbAp48 - a planarian (Dugesia japonica) homologue of human RBAP48 - expression of which is restricted to the neoblasts, the adult stem cells of planarians. In vivo silencing of DjRbAp48 induces lethality and inability to regenerate, even though neoblasts proliferate and accumulate after wounding. Despite a partial reduction in neoblast number, we were always able to detect a significant number of these cells in DjRbAp48 RNAi animals. Parallel to the decrease in neoblasts, a reduction in the number of differentiated cells and the presence of apoptotic-like neoblasts were detectable in RNAi animals. These findings suggest that DjRbAp48 is not involved in neoblast maintenance, but rather in the regulation of differentiation of stem-cell progeny. We discuss our data, taking into account the possibility that DjRbAp48 might control the expression of genes necessary for cell differentiation by influencing chromatin architecture.


Hazard analysis and critical control point evaluation of school food programs in Bahrain.
Hazard analyses were conducted in six food preparation sites and 16 school canteens in the State of Bahrain. Sandwiches made with cheese, meat, eggs, liver, and beef burgers were prepared in small shops or a bakery outside schools. Foods were cooked between 4 and 5 A.M. Time-temperature exposure during cooking was adequate to kill vegetative microbes and their spores, but potential for recontamination existed from the hands of food workers, utensils, and cloths and sponges used for wiping. All foods were left at room temperature before they were transported in vans to schools where they were also kept at room temperature between 17 degrees C and 41 degrees C. Air temperature inside the canteens during this investigation was between 18.5 and 28 degrees C with a relative humidity of 65 to 70%. Hazard analyses, which included observation of operations inside school canteens and sites of food preparation, measuring temperatures, and interviewing workers and consumers (teachers, students) were carried out. Hazards were primarily associated with preparation of foods long before they were consumed, physical touching of products, and holding foods at room temperature after preparation. Holding foods at room temperature would have allowed germination of bacterial spores and multiplication of microbes. Reheating of foods was not practiced. Health promoters must be aware of these hazards and need to educate food workers, administrators, and the public on the methods of prevention.


Commissioning of a clinical pencil beam scanning proton therapy unit for ultra-high dose rates (FLASH).
The purpose of this work was to provide a flexible platform for FLASH research with protons by adapting a former clinical pencil beam scanning gantry to irradiations with ultra-high dose rates. PSI Gantry 1 treated patients until December 2018. We optimized the beamline parameters to transport the 250 MeV beam extracted from the PSI COMET accelerator to the treatment room, maximizing the transmission of beam intensity to the sample. We characterized a dose monitor on the gantry to ensure good control of the dose, delivered in spot-scanning mode. We characterized the beam for different dose rates and field sizes for transmission irradiations. We explored scanning possibilities in order to enable conformal irradiations or transmission irradiations of large targets (with transverse scanning). We achieved a transmission of 86% from the cyclotron to the treatment room. We reached a peak dose rate of 9000 Gy/s at 3 mm water equivalent depth, along the central axis of a single pencil beam. Field sizes of up to 5 × 5 mm2 were achieved for single-spot FLASH irradiations. Fast transverse scanning allowed to cover a field of 16 × 1.2 cm2 . With the use of a nozzle-mounted range shifter, we are able to span depths in water ranging from 19.6 to 37.9 cm. Various dose levels were delivered with precision within less than 1%. We have realized a proton FLASH irradiation setup able to investigate continuously a wide dose rate spectrum, from 1 to 9000 Gy/s in single-spot irradiation as well as in the pencil beam scanning mode. As such, we have developed a versatile test bench for FLASH research.


Population-level effects of fitness costs associated with repressible female-lethal transgene insertions in two pest insects.
Genetic control strategies offer great potential for the sustainable and effective control of insect pests. These strategies involve the field release of transgenic insects with the aim of introducing engineered alleles into wild populations, either permanently or transiently. Their efficacy can therefore be reduced if transgene-associated fitness costs reduce the relative performance of released insects. We describe a method of measuring the fitness costs associated with transgenes by analyzing their evolutionary trajectories when placed in competition with wild-type alleles in replicated cage populations. Using this method, we estimated lifetime fitness costs associated with two repressible female-lethal transgenes in the diamondback moth and olive fly as being acceptable for field suppression programs. Furthermore, using these estimates of genotype-level fitness costs, we were able to project longer-term evolutionary trajectories for the transgenes investigated. Results from these projections demonstrate that although transgene-associated fitness costs will ultimately cause these transgenes to become extinct, even when engineered lethality is repressed, they may persist for varying periods of time before doing so. This implies that tetracycline-mediated transgene field persistence in these strains is unlikely and suggests that realistic estimates of transgene-associated fitness costs may be useful in trialing 'uncoupled' gene drive system components in the field.


Is Sex Good for Your Brain? A National Longitudinal Study on Sexuality and Cognitive Function among Older Adults in the United States.
Using a life course approach, we examined how sexuality is related to cognitive function for partnered older adults. We utilized longitudinal data from two rounds of the National Social Life, Health, and Aging Project (NSHAP) to analyze 1,683 respondents. Cognitive function was measured using a continuous Montreal Cognitive Assessment (MoCA) score. We considered both sexual frequency and sexual quality (i.e., physical pleasure, emotional satisfaction). We estimated cross-lagged models to consider the potential reciprocal relationship between sexuality and cognitive function. Results indicated that sexuality was not related to later cognitive function in the total sample, but the pattern varied by age and gender. For adults aged 62-74, better sexual quality (i.e., feelings of physical pleasure and emotional satisfaction) was related to better cognitive functioning, while for those aged 75-90, more frequent sex was related to better cognitive functioning. Feelings of physical pleasure were related to better cognitive functioning for men but not women. There was no evidence of cognitive functioning being related to later sexuality. The findings highlight the importance of age and gender in modifying the link between sexuality and cognition in later life.


Effects of high hydrostatic pressure processing on embryonation of Toxocara canis eggs.
Toxocara canis is a zoonotic nematode parasite that can be transmitted to humans by food or water contaminated with T. canis eggs from infected dog feces. High-pressure processing (HPP) is a useful alternative to thermal treatments to eliminate pathogens from foods. Most of the research on HPP has focused on prokaryotes, but little is known about its effects on eukaryotic organisms. We evaluated the ability of HPP to affect embryonation of T. canis eggs to test the hypothesis that HPP treatment can delay development of T. canis eggs. Efficacy of HPP was determined by using an embryonation assay on T. canis eggs from naturally infected puppies. For each treatment, 2500 T. canis eggs in tap water were placed in sealable plastic bags and subjected to 138-400 megapascals (MPa; 1 MPa=10 atm=147 psi) for 60 s in a commercial HPP unit. We found that treatment with 300 or 400 MPa for 60 s killed 100% of eggs using embryonation as the standard. Treatment with 250, 241, and 207 MPa was less effective and killed 80%, 56%, and 8% of eggs, respectively. Results from this study suggest that HPP may be a useful treatment to protect foods from T. canis contamination.


KSRP modulation of GAP-43 mRNA stability restricts axonal outgrowth in embryonic hippocampal neurons.
The KH-type splicing regulatory protein (KSRP) promotes the decay of AU-rich element (ARE)-containing mRNAs. Although KSRP is expressed in the nervous system, very little is known about its role in neurons. In this study, we examined whether KSRP regulates the stability of the ARE-containing GAP-43 mRNA. We found that KSRP destabilizes this mRNA by binding to its ARE, a process that requires the presence of its fourth KH domain (KH4). Furthermore, KSRP competed with the stabilizing factor HuD for binding to these sequences. We also examined the functional consequences of KSRP overexpression and knockdown on the differentiation of primary hippocampal neurons in culture. Overexpression of full length KSRP or KSRP without its nuclear localization signal hindered axonal outgrowth in these cultures, while overexpression of a mutant protein without the KH4 domain that has less affinity for binding to GAP-43's ARE had no effect. In contrast, depletion of KSRP led to a rise in GAP-43 mRNA levels and a dramatic increase in axonal length, both in KSRP shRNA transfected cells and neurons cultured from Ksrp(+/-) and Ksrp(-/-) embryos. Finally we found that overexpression of GAP-43 rescued the axonal outgrowth deficits seen with KSRP overexpression, but only when cells were transfected with GAP-43 constructs containing 3' UTR sequences targeting the transport of this mRNA to axons. Together, our results suggest that KSRP is an important regulator of mRNA stability and axonal length that works in direct opposition to HuD to regulate the levels of GAP-43 and other ARE-containing neuronal mRNAs.


Linkage disequilibrium mapping of a breast cancer susceptibility locus near RAI/PPP1R13L/iASPP.
Previous results have suggested an association of the region of 19q13.3 with several forms of cancer. In the present study, we investigated 27 public markers within a previously identified 69 kb stretch of chromosome 19q for association with breast cancer by using linkage disequilibrium mapping. The study groups included 434 postmenopausal breast cancer cases and an identical number of individually matched controls. Studying one marker at a time, we found a region spanning the gene RAI (alias PPP1R13L or iASPP) and the 5' portion of XPD to be associated with this cancer. The region corresponds to a haplotype block, in which there seems to be very limited recombination in the Danish population. Studying combinations of markers, we found that two to four neighboring markers gave the most consistent and strongest result. The haplotypes with strongest association with cancers were located in the gene RAI and just 3' to the gene. Coinciding peaks were seen in the region of RAI in groups of women of different age. In a follow-up to these results we sequenced 10 cases and 10 controls in a 44 kb region spanning the peaks of association. This revealed 106 polymorphisms, many of which were not in the public databases. We tested an additional 44 of these for association with disease and found a new tandem repeat marker, called RAI-3'd1, located downstream of the transcribed region of RAI, which was more strongly associated with breast cancer than any other marker we have tested (RR = 2.44 (1.41-4.23, p = 0.0008, all cases; RR = 6.29 (1.49-26.6), p = 0.01, cases up to 55 years of age). We expect the marker RAI-3'd1 to be (part of) the cause for the association of the chromosome 19q13.3 region's association with cancer.


Structural Relaxation and Recovery: A Dielectric Approach.
We compare structural relaxation and structural recovery dynamics for molecular glass-formers, both measured by dielectric techniques in the regime of linear responses. It is emphasized that structural recovery restores ergodicity, whereas structural relaxation or α-processes characterize fluctuations of the system in equilibrium (and thus do not involve a change of structure within experimental resolution). Evidence is provided that structural recovery is linked to rate exchange and thus is distinct from structural relaxation dynamics, even in the limit of small perturbations. As a consequence, structural recovery is somewhat slower and more exponential than the equilibrium dynamics as derived, for instance, from low field dielectric relaxation experiments. This contrasts the standard assumption inherent in models of physical aging, which assume the identity of both responses if measured in the limit of a small perturbation. Typical experiments associated with physical aging and scanning calorimetry involve nonlinear responses and are thus even more complex.


Quality of life in fibromyalgia patients with craniomandibular disorders.
Fibromyalgia (FM) is a rheumatic disease which affects fibrous tissues and muscles; it is characterized by chronic pain and it is often associated with craniomandibular disorders (CMD). 31 patients were assessed from March 2012 to October 2012 through the administration of specific questionnaires and following neurologic and gnatologic assessment. A relevant corre-lation between FM and CMD emerges from the present study, as 80.6% of our patients report CMD symptoms with high prevalence of myofascial pain (84%). Multivariate regression analysis revealed that the patients in the present study did not differ in score of quality of life questionnaires from patients with fibromyalgia. The neuropathic pain diagnostic question-naire (DN4) scores were positively affected by belonging to group II of Research Diagnostic Criteria of Temporomandibular Disorders (RDC/ TDM) classification, suggesting the possibility of a neuropathic component in chronic pain in this CMD group, as already speculated in our study on the correlation between burning mouth syndrome and CMD and by other au-thors in studies on chronic low back pain. However, further clinic and instrumental studies are needed in order to test this as-sumption.