Noise-constrained switching times for heteroclinic computing.
Heteroclinic computing offers a novel paradigm for universal computation by collective system dynamics. In such a paradigm, input signals are encoded as complex periodic orbits approaching specific sequences of saddle states. Without inputs, the relevant states together with the heteroclinic connections between them form a network of states-the heteroclinic network. Systems of pulse-coupled oscillators or spiking neurons naturally exhibit such heteroclinic networks of saddles, thereby providing a substrate for general analog computations. Several challenges need to be resolved before it becomes possible to effectively realize heteroclinic computing in hardware. The time scales on which computations are performed crucially depend on the switching times between saddles, which in turn are jointly controlled by the system's intrinsic dynamics and the level of external and measurement noise. The nonlinear dynamics of pulse-coupled systems often strongly deviate from that of time-continuously coupled (e.g., phase-coupled) systems. The factors impacting switching times in pulse-coupled systems are still not well understood. Here we systematically investigate switching times in dependence of the levels of noise and intrinsic dissipation in the system. We specifically reveal how local responses to pulses coact with external noise. Our findings confirm that, like in time-continuous phase-coupled systems, piecewise-continuous pulse-coupled systems exhibit switching times that transiently increase exponentially with the number of switches up to some order of magnitude set by the noise level. Complementarily, we show that switching times may constitute a good predictor for the computation reliability, indicating how often an input signal must be reiterated. By characterizing switching times between two saddles in conjunction with the reliability of a computation, our results provide a first step beyond the coding of input signal identities toward a complementary coding for the intensity of those signals. The results offer insights on how future heteroclinic computing systems may operate under natural, and thus noisy, conditions.


INNERVATION OF THE LATERAL CILIA IN THE MUSSEL. MYTILUS EDULIS L.
With the use of standard dissection, electron microscopic and histochemical fluorescence techniques branchial nerve fibers have been traced from the visceral ganglion to the ciliated epithelium of the gill in the mussel, Mytilus edulis. Hitherto underscribed nerve fibers have been shown to lie adjacent to gill filaments and to penetrate the fibrous basal lamina under the gill epithelium. Nerve fibers have been observed subjacent to postlateral. ciliated lateral and frontal cells. Homologous lateral ciliated cells have been demonstrated to be connected by septate junctions. The localization of 5-HT in the branchial nerve within the gill epithelium has been studied by means of histochemical fluorescence. Severing the branchial nerve or intramuscular injections of reserpine depleted the 5-HT in the gill. Intramuscular injections of nialamide resulted in an increase of specific fluorscence.


Phase transition of the susceptible-infected-susceptible dynamics on time-varying configuration model networks.
We present a degree-based theoretical framework to study the susceptible-infected-susceptible (SIS) dynamics on time-varying (rewired) configuration model networks. Using this framework on a given degree distribution, we provide a detailed analysis of the stationary state using the rewiring rate to explore the whole range of the time variation of the structure relative to that of the SIS process. This analysis is suitable for the characterization of the phase transition and leads to three main contributions: (1) We obtain a self-consistent expression for the absorbing-state threshold, able to capture both collective and hub activation. (2) We recover the predictions of a number of existing approaches as limiting cases of our analysis, providing thereby a unifying point of view for the SIS dynamics on random networks. (3) We obtain bounds for the critical exponents of a number of quantities in the stationary state. This allows us to reinterpret the concept of hub-dominated phase transition. Within our framework, it appears as a heterogeneous critical phenomenon: observables for different degree classes have a different scaling with the infection rate. This phenomenon is followed by the successive activation of the degree classes beyond the epidemic threshold.


EORTC Cancer in the Elderly Task Force guidelines for the use of colony-stimulating factors in elderly patients with cancer.
Increasing age is not, in itself, a contraindication to cancer chemotherapy. Myelosuppression, however, a common adverse consequence of the administration of many standard-dose chemotherapy regimens to both young and elderly patients with cancer, increases with age. The risk of development of febrile neutropenia may contribute to a reluctance to administer chemotherapy in the elderly patient population. We conducted a detailed literature search (1992-2002) to derive evidence-based conclusions on the value of prophylactic colony-stimulating factor (CSF) administration in elderly patients receiving chemotherapy. Sufficient evidence allows us to affirm that prophylactic granulocyte colony-stimulating factor (G-CSF) reduces the incidence of chemotherapy-induced neutropenia, febrile neutropenia and infections in elderly patients receiving myelotoxic chemotherapy for non-Hodgkin's lymphoma (NHL), small-cell lung cancer (SCLC) or urothelial tumours. Lack of available trial data does not allow similar conclusions to be drawn for other cancers studied, but it is likely that similar benefits would accrue from the use of prophylactic G-CSF. There is insufficient evidence to extend this recommendation to include the use of granulocyte-macrophage colony-stimulating factor (GM-CSF). There are insufficient data available to allow the evaluation of the impact of prophylactic CSF on the incidence of toxic deaths in elderly patients with cancer and this is a crucial question for geriatric oncology practice. There is no evidence in elderly patients that the delivery of standard-dose chemotherapy on schedule improves efficacy measures. The data show that febrile neutropenic events are more likely to occur during the first and second cycles of chemotherapy, thus prophylactic measures should be considered early in the course of treatment. Furthermore, since systematic dose reduction can impact on outcome, primary prophylactic use of G-CSF for all elderly patients receiving curative myelotoxic chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or CHOP-like) is indicated and we suggest a risk-adapted strategy with primary prophylactic G-CSF administration in high-risk patients. Dose intensification, through dose interval reduction, facilitated by prophylactic G-CSF, improved survival in elderly patients with some specific diseases. There is a need for further well-designed studies to identify the elderly patients who will benefit most from prophylactic G-CSF. To achieve this, we strongly urge the design of and participation in further trials.


Pain Assessment and Management in Critically ill Intubated Patients in Jordan: A Prospective Study.
The purpose of this study was to describe: (1) pain indicators used by nurses and physicians to assess pain, (2) pain management interventions (pharmacological and non-pharmacological) used by nurses, and (3) indicators used by nurses to verify pain intervention effectiveness. A total of 301 medical records of currently admitted patients from six different ICUs in Jordan were reviewed using a data collection instrument developed by Gélinas et al. (2004) Pain-related indicators were classified into non-observable (patient's self-reports of pain) and observable (physiological and behavioral) categories. Only 105 (35%) of a total 301 reviewed medical records contained pain assessment data. From these medical records, 15 pain episodes were collected altogether. Observable indicators documented 98% of the 115 pain episodes. Patients' self-reports of pain were documented only 1.7% of the time. In 78% and 46% of the 115 pain episodes, pharmacological and nonpharmacological interventions for pain management were documented, respectively. Only 37% of the pain episodes were reassessed with self- report (1%) and observable indicators (36%) to determine the effectiveness of the interventions. Pain documentation for assessment, management, and reassessment was lacking and needs improvement.


Novel N-mustard-benzimidazoles/benzothiazoles Hybrids, Synthesis and Anticancer Evaluation.
Bendamustine, an N-mustard-benzoimidazole hybrid conjugate, was recently approved for the treatment of chronic lymphocytic leukemia. However, the short half-life of bendamustine may limit its clinical applications. The purpose of this study is to design and synthesize compounds with a more favorable pharmacokinetic profile. We synthesized a series of hybrid molecules comprising a phenyl N-mustard moiety and benzothiazole or benzimidazole scaffold linked via a urea linker and evaluated their antitumor activity and plasma stability. We revealed that these agents exhibited significant cytotoxicity against a panel of human lymphoblastic leukemia and human solid tumor cells in culture. Human lymphoblastic leukemia CCRM-CEM cells were the most sensitive to the tested compounds. In general, the new hybrids were as potent as cisplatin, but significantly more cytotoxic than bendamustine. Phenyl N-mustard-benzothiazole compound 27d and phenyl N-mustardbenzimidaloe compound 32b possessed significant cytotoxicity and led to apoptotic death in the treated tumor cells. These two agents were able to induce DNA interstrand cross-linking and arrested cell cycle progression at the G2/M phase. Furthermore, we showed that these new hybrids were more chemically stable than bendamustine in rat plasma. Our results suggest that conjugation of phenyl N-mustard pharmacophore at C6 of benzimidazole or at C8 of the benzothiazole ring via a urea linker is likely an approach to increase the chemical stability and bioavailability. Highlights ⇒ Series of benzimidazoles and benzothiazoles linked to N-mustard were synthesized. ⇒ The newly synthesized derivatives induced DNA interstrand cross-links. ⇒ These derivatives induced cell cycle arrest in the G2/M phase and triggered apoptosis in H460 cells. ⇒ The new compounds are more cytotoxic than bendamustine. ⇒ The new compounds were chemically more stable than bendamustine in rat plasma.


Ynamides: versatile tools in organic synthesis.
Ynamides display an exceptionally fine balance between stability and reactivity. They also offer unique and multiple opportunities for the inclusion of nitrogen-based functionalities into organic molecules, and are emerging as especially useful and versatile building blocks for organic synthesis. Recent breakthroughs in the preparation of these substrates have revitalized interest in nitrogen-substituted alkynes, and the beginning of the 21st century has witnessed an ever-increasing number of publications reporting the development of new reactions or synthetic sequences starting from ynamides. This Review highlights major developments in this area.


Host-pathogen interactions in bovine mammary epithelial cells and HeLa cells by Staphylococcus aureus isolated from subclinical bovine mastitis.
Staphylococcus aureus is a common pathogen that causes subclinical bovine mastitis due to several virulence factors. In this study, we analyzed S. aureus isolates collected from the milk of cows with subclinical mastitis that had 8 possible combinations of bap, icaA, and icaD genes, to determine their capacity to produce biofilm on biotic (bovine primary mammary epithelial cells and HeLa cells) and abiotic (polystyrene microplates) surfaces, and their ability to adhere to and invade these cells. We also characterized isolates for microbial surface components recognizing adhesive matrix molecules (MSCRAMM) and agr genes, and for their susceptibility to cefquinome sulfate in the presence of biofilm. All isolates adhered to and invaded both cell types, but invasion indexes were higher in bovine primary mammary epithelial cells. Using tryptic soy broth + 1% glucose on abiotic surfaces, 5 out of 8 isolates were biofilm producers, but only the bap+icaA+icaD+ isolate was positive in Dulbecco's Modified Eagle's medium. The production of biofilm on biotic surfaces occurred only with this isolate and only on HeLa cells, because the invasion index for bovine primary mammary epithelial cells was too high, making it impossible to use these cells in this assay. Of the 5 biofilm producers in tryptic soy broth + 1% glucose, 4 presented with the bap/fnbA/clfA/clfB/eno/fib/ebpS combination, and all were protected from cefquinome sulfate. We found no predominance of any agr group. The high invasive potential of S. aureus made it impossible to observe biofilm in bovine primary mammary epithelial cells, and we concluded that cells with lower invasion rates, such as HeLa cells, were more appropriate for this assay.


Renal gluconeogenesis.
Gluconeogenesis, the de novo formation of glucose from non-carbohydrate precursors, is confined to the proximal convoluted and proximal straight tubules of the mammalian kidney. Compared to liver, renal gluconeogenesis has different substrate requirements and responds to different regulatory stimuli. Stimuli in kidney include starvation, metabolic acidosis, glucocorticoid treatment, and, possibly, PTH and catecholamines. Regulation of gluconeogenic flux occurs at three or four key enzyme sites, particularly phosphoenolpyruvate carboxykinase (PEPCK) and fructose 1,6-bisphosphatase. Interest has focused on the relation among H+, Ca2+, and cyclic AMP in the hormonal regulation of gluconeogenesis. The importance of other putative regulators including fructose 2,6-bisphosphate remains to be determined.


SELECTION FOR NATIVE CHARACTERS IN HYBRIDS BETWEEN TWO LOCALLY ADAPTED PLANT SUBSPECIES.
Gene exchange between locally adapted plant populations can have significant evolutionary consequences, including changes in genetic diversity, introduction of adaptive or maladaptive traits, disruptive of coadaptive gene complexes, and the creation of new ecotypes or even species. The potential for introgression between divergent populations will depend on the strength of selection against nonnative characters. Morphologically variable F2 hybrids of two Gilia capitata subspecies were used to evaluate the strength of phenotypic selection and the response to selection in the home habitats of each subspecies. At both sites, traits diagnostic of the subspecies were subject to significant phenotypic selection, probably mediated by direct selection on unmeasured correlated characters. Phenotypic selection favored native morphologies in all but a single case; leaf shape of one subspecies was favored in both habitats. The strength of selection varied between sites, with one site selecting more strongly against nonnative characters. Offspring of the F2 hybrids showed a significant evolutionary response to selection when grown in a common environment. Evolution was in the direction of similarity with the subspecies native to the site where selection was imposed. This result reveals that native character states are adaptive and suggests that selection will maintain native morphologies even after a substantial influx of genes from an ecologically and morphologically distinct, and locally adapted subspecies.


Bio-electrosprayed living composite matrix implanted into mouse models.
We show that composite de novo structures can be generated using bio-electrosprays. Mouse lung fibroblasts are bio-electrosprayed directly with a biopolymer to form cell-bearing matrices, which are viable even when implanted subcutaneously into murine hosts. Generated cell-bearing matrices are assessed in-vitro and found to undergo all expected cellular behaviour. Subsequent in-vivo studies demonstrate the implanted living matrices integrating as expected with the surrounding microenvironment. The in-vitro and in-vivo studies elucidate and validate the ability for either bio-electrosprays or cell electrospinning to form a desired living architecture for undergoing investigation for repairing, replacing and rejuvenating damaged and/or ageing tissues.


Palmoplantar keratoderma, pseudo-ainhum and knuckle pads in an African patient: A case report.
Hereditary palmoplantar keratoderma is a rare heterogenous group of genodermatoses characterised by hyperkeratosis of the palms and soles. Genetic alterations affecting proteins of the keratin cytoskeleton, cornified cell envelope, desmosomes and gap junction proteins have been implicated in the pathogenesis of inherited palmoplantar keratoderma. Reports of palmoplantar keratoderma in the African population are scarce. Herein, we report a case of a 29-year-old HIV-infected African female, who presented to a tertiary hospital with complaints of a painful left fourth toe, secondary to a constriction band. Her background history is significant for prior constriction bands involving her toes, some of which progressed to auto-amputations and childhood-onset thickening of the palmoplantar skin. Examination revealed diffuse transgrediens palmoplantar keratoderma with associated clinical findings of pseudo-ainhum and knuckle pads. A systemic workup was non-contributory. Next-generation sequencing genetic testing detected two variants of undetermined significance in gap junction protein beta 4, a connexin-encoding gene, and in the rhomboid 5 homolog 2 gene. Her phenotype remains discordant with our genetic findings. Her clinical features are instead consistent with overlapping phenotypes of gap junction protein beta 2-related connexin disorders: Vohwinkel syndrome and Bart-Pumphrey syndrome. Our case underlines the genetic heterogeneity of palmoplantar keratoderma and the diagnostic challenges it presents. Our patient required surgical amputation of the affected toe and is receiving ongoing dermatological management. Early recognition, appropriate referral and management are required to avert the debilitating consequences of mutilating keratoderma and improve the quality of life.


An exceptional overall survival using bevacizumab beyond progression in a patient with non-small cell lung cancer.
Non-small cell lung cancer (NSCLC) is the most common malignancy and the leading cause of cancer death worldwide. In this report, we describe a patient with NSCLC who was treated with continuation of Bevacizumab (Bev) beyond progression to first-line Bev-based chemotherapy. The prolonged treatment with Bev by continuing the inhibition of VEGF beyond first-progression has a strong rationale. Nevertheless, few data exist regarding the efficacy and safety of Bev beyond first line of chemotherapy progression in NSCLC patients. Further studies including a large number of patients are needed, in order to select patients who could benefit from this approach.


Resiliency Improvements in Medical Emergency Staff in Burn Missions: A Qualitative Study in an Iranian Context.
Medical emergency staff complete understanding of the nature of resiliency in burn events is a prerequisite for improving the quality of clinical service delivery in pre-hospital burn events. The present study aimed to describe resiliency in view of medical emergency staff in burn events. The present qualitative study was performed using a content analysis method. In total, 18 Iranian emergency care personnel participated in the study. A purposeful sampling method was applied until reaching data saturation. Data was collected using semi-structured interviews and field observations. Afterwards, data was analyzed by face content analysis. By analyzing 456 primary codes, four main concepts including: 1) scene safety/security, 2) effective clinical decision making, 3) self-efficacy and 4) religious support were extracted through content analysis from experiences of pre-hospital emergency personnel during burn care. Different factors affect resiliency improvements in medical emergency staff and consequently the quality of pre-hospital burn care. This study showed that various factors such as scene security/safety, effective decision making, self-efficacy and religious support are effective in the improvement of resiliency and the quality of pre-hospital emergency care.


Changes in the prevalence of subgingival enteric rods, staphylococci and yeasts after treatment with penicillin and erythromycin.
The changes in the balance of microbial flora in the periodontium after antibiotic treatment were investigated in a blind study. The prevalence of gram-negative enteric rods, staphylococci and yeasts was followed before and during penicillin or erythromycin treatment of 72 periodontitis patients without periodontal cleaning. The prevalence of subgingival coagulase-positive staphylococci increased significantly following systemic penicillin therapy. After systemic erythromycin therapy, the prevalence of subgingival gram-negative enteric rods increased. Ten of 24 (42%) patients receiving systemic penicillin therapy developed clinical evidence of periodontal abscesses. In the absence of conventional mechanical cleaning, systemic administration of penicillin and erythromycin antibiotic to patients with pre-existing periodontitis may lead to periodontal superinfection with opportunistic organisms.


Barriers to participation in a randomized controlled trial of Qigong exercises amongst cancer survivors: lessons learnt.
Clinical trials on cancer subjects have one of the highest dropout rates. Barriers to recruitment range from patient-related, through institutional-related to staff-related factors. This paper highlights the low response rate and the recruitment barriers faced in our Qigong exercises trial. The Qigong trial is a three-arm trial with a priori power size of 114 patients for 80% power. The University Malaya Medical Centre database showed a total of 1,933 patients from 2006-2010 and 751 patients met our inclusion criteria. These patients were approached via telephone interview. 131 out of 197 patients attended the trial and the final response rate was 48% (n=95/197). Multiple barriers were identified, and were regrouped as patient- related, clinician-related and/or institutional related. A major consistent barrier was logistic difficulty related to transportation and car parking at the Medical Centre. conclusions: All clinical trials must pay considerable attention to the recruitment process and it should even be piloted to identify potential barriers and facilitators to reduce attrition rate in trials.


Effectiveness of Tai Chi Exercise Program on Sleep, Quality of Life, and Physical Performance in Postmenopausal Working Women.
Menopause being an unavoidable time in every woman's life brings up various challenges. Inevitable changes in body systems affect the life of a woman permanently. The symptoms constitute the postmenopausal syndrome which further affects the quality of life (QOL). Women spend most of the time working during the menopausal transition period and also during postmenopause. The discussion of symptoms is still considered a taboo. Exercise intervention to reduce the symptoms related to menopause which can show a positive impact on health status and work needs to be incorporated. Tai Chi exercise intervention was given for 8 weeks to the women who achieved natural menopause and were included in the study (n = 76). They were assessed for sleep, QOL, and physical performance before and after the intervention. A significant difference was observed in all the outcomes after 8 weeks of intervention (Sleep Quality Scale (SQS)-t = 7.57, P = 0.0001; WHOQOL-BREF-t = 7.56, P = 0.0001; and Physical Performance Test PPT-t = 19.93, P = 0.0001). The results were consistent due to the active participation and high adherence rate of the individuals to the protocol. Our study revealed that besides being low velocity and low impact exercise, Tai Chi was a safe and effective mode of treatment in postmenopausal working women. In this group approach sessions were interactive and improved socialization skills because it was conducted in a community setting minimum equipment's and greater feasibility. Hence, this could also be incorporated in different age group population.


The function and evolution of male and female genitalia in Phyllophaga Harris scarab beetles (Coleoptera: Scarabaeidae).
Genitalia diversity in insects continues to fuel investigation of the function and evolution of these dynamic structures. Whereas most studies have focused on variation in male genitalia, an increasing number of studies on female genitalia have uncovered comparable diversity among females, but often at a much finer morphological scale. In this study, we analysed the function and evolution of male and female genitalia in Phyllophaga scarab beetles, a group in which both sexes exhibit genitalic diversity. To document the interaction between male and female structures during mating, we dissected flash-frozen mating pairs from three Phyllophaga species and investigated fine-scale morphology using SEM. We then reconstructed ancestral character states using a species tree inferred from mitochondrial and nuclear loci to elucidate and compare the evolutionary history of male and female genitalia. Our dissections revealed an interlocking mechanism of the female pubic process and male parameres that appears to improve the mechanical fit of the copulatory position. The comparative analyses, however, did not support coevolution of male and female structures and showed more erratic evolution of the female genitalia relative to males. By studying a group that exhibits obvious female genitalic diversity, we were able to demonstrate the relevance of female reproductive morphology in studies of male genital diversity.


Temperature-dependent deliquescent and efflorescent properties of methanesulfonate sodium studied by ATR-FTIR spectroscopy.
Modeling of aerosols and cloud formation processes in the marine boundary layer (MBL) require extensive data on hygroscopic properties of relevant methanesulfonate particles, which are currently scarce. In this work, methanesulfonate sodium (CH3SO3Na, MSA-Na), the most abundant methanesulfonate salt, was selected, and its deliquescent and efflorescent properties at temperatures relevant to the lower troposphere were studied using an ATR-FTIR flow system. To validate the approach, we investigated hygroscopic properties of NaCl particles, and our measured deliquescent relative humidity (DRH) and efflorescent relative humidity (ERH) of the NaCl particles obtained from the changes in integrated absorbance of water peaks in infrared spectra agreed with literature data well. We then reported DRH and ERH of MSA-Na particles as a function of temperature for the first time using both the changes in integrated absorbance of water peaks and the changes in peak position and shape of CH3SO3(-) symmetric and asymmetric vibrational modes. Our experiments showed that MSA-Na particles present quite different temperature-dependent hygroscopic behaviors from NaCl. Both the DRH and ERH of MSA-Na particles increase with decreasing temperatures. Due to the significant differences in temperature-dependent DRH and ERH, NaCl particles, if processed in MBL by methanesulfonic acid, are expected to deliquesce slightly earlier during a hydration process but effloresce at a much earlier stage during a dehydration process, especially at lower temperatures. This could considerably influence phase, size, and water content of sea salt aerosols and consequently their reactivity, lifetime, and impacts on atmospheric chemistry and climate systems.


Aqueous misdirection in thyroid eye disease.
Secondary glaucoma in thyroid eye disease (TED) is attributed either to raised episcleral venous pressure or to mechanical compression induced trabecular meshwork damage by mucopolysaccharide deposition. While the mechanism for raised intraocular pressure (IOP) in TED is largely mechanical and is often evident during its active stage, our case presented with aqueous misdirection in the left eye during the inactive stage. Appropriate diagnostic tests should be ordered to diagnose cause of raised IOP, which would help determine appropriate treatment for the cause for secondary glaucoma in TED.


Lobomycosis. An electronmicroscopic, histochemical and immunologic study.
A 73-year-old woman from Guyana had nodular keloidal lesions on her face which had persisted for 56 years. A biopsy of the lesion revealed lobomycosis, a rare fungal infection. Microscopically, numerous fungi were seen in giant cells and macrophages. The macrophages had abundant pink reticulated cytoplasm. These macrophages in lobomycosis, considered by some in the past to be granular myoblastoma cells, were rich in glycoproteins and appeared to be "Gaucher-like cells" in electronmicrographs. Further, a transition of macrophages containing organisms to Gaucher-like cells was noted. Antibodies to the fungus were demonstrated in the patient's serum by counter immunoelectrophoresis and indirect immunofluorescence studies. We postulate that the Gaucher-like cells formed because of the inability of host macrophages to digest glycoproteins in the capsule of this unusual fungus.


An Unconventional Zwitterionic Bolaamphiphile Containing PEG as Spacer Chain: Surface Tension and Self-Assembly Behavior.
Monolayer lipid membrane formation based on self-assembly of bolaamphiphiles containing hydrophobic spacer are well-established in the literature, but monolayer vesicle formation by so-called hydrophilic poly(ethylene glycol) (PEG) spacer has not been reported to date. Here, a novel l-cysteine-derived bolaamphiphile with PEG as spacer has been developed and characterized. The interfacial properties and the solution behavior of the amphiphile were investigated in pH 7.0 at 25 °C. The self-assembly properties of the bolaamphiphile in aqueous buffer were investigated by using different techniques, such as surface tensiometry, fluorescence spectroscopy, UV-vis spectroscopy, isothermal titration calorimetry, dynamic light scattering, transmission electron microscopy, and atomic force microscopy. Surprisingly, despite having so-called polar spacer in between two polar head groups, it exhibits formation of microstructures in aqueous buffer as well as in water at 25 °C. The molecule undergoes self-organization leading to the formation of monolayer vesicles with hydrodynamic diameters between 100 and 250 nm in a wide range of concentration. The thermodynamic parameters clearly suggest that the aggregate formation is mainly driven by the hydrophobic effect. The monolayer vesicles were found to form at a very low concentration (≥0.63 mM) and within a wide pH range (2-10). The vesicles exhibit excellent shelf life at physiological temperature.


Endothelial to Mesenchymal Transition in Cardiovascular Disease: JACC State-of-the-Art Review.
Endothelial to mesenchymal transition (EndMT) is a process whereby an endothelial cell undergoes a series of molecular events that lead to a change in phenotype toward a mesenchymal cell (e.g., myofibroblast, smooth muscle cell). EndMT plays a fundamental role during development, and mounting evidence indicates that EndMT is involved in adult cardiovascular diseases (CVDs), including atherosclerosis, pulmonary hypertension, valvular disease, and fibroelastosis. Therefore, the targeting of EndMT may hold therapeutic promise for treating CVD. However, the field faces a number of challenges, including the lack of a precise functional and molecular definition, a lack of understanding of the causative pathological role of EndMT in CVDs (versus being a "bystander-phenomenon"), and a lack of robust human data corroborating the extent and causality of EndMT in adult CVDs. Here, we review this emerging but exciting field, and propose a framework for its systematic advancement at the molecular and translational levels.


Rabies surveillance in the United States during 2017.
OBJECTIVE To describe rabies and rabies-related events occurring during 2017 in the United States. DESIGN Cross-sectional analysis of passive surveillance data. ANIMALS All animals submitted for laboratory diagnosis of rabies in the United States during 2017. PROCEDURES State and territorial public health departments provided data on animals submitted for rabies testing in 2017. Data were analyzed temporally and geographically to assess trends in domestic and sylvatic animal rabies cases. RESULTS During 2017, 52 jurisdictions reported 4,454 rabid animals to the CDC, representing a 9.3% decrease from the 4,910 rabid animals reported in 2016. Of the 4,454 cases of animal rabies, 4,055 (91.0%) involved wildlife species. Relative contributions by the major animal groups were as follows: 1,433 (32.2%) bats, 1,275 (28.6%) raccoons, 939 (21.1%) skunks, 314 (7.0%) foxes, 276 (6.2%) cats, 62 (1.4%) dogs, and 36 (0.8%) cattle. There was a 0.4% increase in the number of samples submitted for testing in 2017, compared with the number submitted in 2016. Two human rabies deaths were reported in 2017, compared with none in 2016. CONCLUSIONS AND CLINICAL RELEVANCE The overall number of reported cases of animal rabies has decreased over time. Laboratory testing of animals suspected to be rabid remains a critical public health function and continues to be a cost-effective method to directly influence human rabies postexposure prophylaxis recommendations.


Evaluation of plaque characteristics in coronary artery patients with impaired glucose tolerance through optical coherence tomography.
With the adoption of optical coherence tomography (OCT), this study targets the impacts on plaque characteristics brought about by impaired glucose tolerance (IGT) in patients with coronary artery disease. For this study, 150 patients with coronary artery disease were recruited. Regarding glycosylated hemoglobin (HbAlc), the patients were sectioned into normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetes mellitus (DM) groups. Coronary angiography (CAG) and OCT were conducted for 150 patients. There were 186 plaques discovered in 150 patients (37, 40, 44, and 65 in the NGT, IFG, IGT, and DM groups, respectively). Compared to the NGT group, the lipid core size, which is presented as the average angle of the lipid arc, was markedly larger in the IFG,IGT and DM groups ( 135.7 ± 32.7 Ê, 161.2 ± 55.7 Ê, 162.5 ± 55.8 Ê, and 170.2 ± 59.7 Ê, respectively, all P values< 0.05). Meanwhile, the fibrous cap over the lipid core in the NGT group was remarkably thicker than that in the IFG, IGT, and DM groups (115.7 ± 47.7 μm vs. 77.7 ± 23.5 μm, 75.1 ± 23.2 µm, 71.2 ± 22.1 µm, all P values<0.05). Coronary plaques in coronary artery patients with NDT are more stable than in those with IGT and DM.


Defining the cross-sectional anatomy important to interscalene brachial plexus block with magnetic resonance imaging.
Interscalene brachial plexus block is a useful technique to provide anesthesia and analgesia for the shoulder and proximal upper extremity. The initial needle direction at the interscalene groove has been described as being "perpendicular to the skin in every plane" (1). A cross-sectional (axial) approach may offer a more easily conceptualized directed needle placement. The purpose of this study is to define the cross-sectional anatomy and idealized needle angles important to interscalene brachial plexus block. Following IRB approval, 50 patients were studied. Cross-sectional volume coil T1-weighted magnetic resonance images (MRI) were obtained from 50 patients undergoing cervical region imaging for other reasons. At the interscalene groove, a simulated needle path to contact the ventral rami or trunks of the brachial plexus was approximated at the level of C6 or C6-C7 interspace. The angle of this needle path intersecting the sagittal plane was recorded for each patient. The mean angle of the simulated needle path relative to sagittal plane was determined to be 61.1 +/- 6.1 degrees (range, 50-78 degrees). In 13 of 50 (26%) MRI scans, the cervical nerve roots were not visualized at the level of C6 and were measured at the C6-C7 level. These findings suggest initial needle placement at the interscalene groove should be angled less perpendicularly relative to the sagittal plane than is often observed. A cross-sectional approach enables more practical visualization of initial needle placement. A more accurate initial needle placement may minimize the number of needle passes necessary to contact the nerve roots, thereby more efficiently obtaining a successful block.


New concepts in medical bacteriology.
Traditional tests employed in a clinical microbiology laboratory for speciation of bacteria rely upon the presence of one or more gene products (biochemical profile) from a population of bacterial cells. These traits have been stable over a relatively long period of time, and the techniques have served us well. Current technology allows for modification and potential improvement of this system. By chemically separating DNA strands and employing recombinant DNA techniques, direct identification of bacteria becomes possible. These methods can be adapted directly to the clinical setting. In addition, specific gene products yield clinical disease; monoclonal antibodies directed against these products may speciate a bacterium indirectly through a unique gene product. Specific gene products also provide markers for epidemiologic investigation. All these technologies should find frequent clinical application in the next several years. The discoveries a century ago that germs cause infection and that different germs cause different infections prompted the development of a system of taxonomy for pathogenic microbes. It then became apparent that the identity of the germ infecting a patient could tell us more about his or her diagnosis and prognosis than could all of the clinical skills accumulated up to that time.


Diabetes Update: Risk Factors, Screening, Diagnosis, and Prevention of Type 2 Diabetes.
Type 2 diabetes (T2D) is the result of insulin resistance. Significant differences are noted in the prevalence of T2D among races. Screening recommendations vary by subspecialty society. Asian Americans should be screened for T2D at a lower body mass index (BMI) (ie, 23 kg/m2) than other racial groups. Risk factors for T2D include high-risk ethnicity, obesity, taking of certain drugs (including statins), and gestational diabetes. Health disparities and genetics also influence risk of T2D, although these complexities continue to be poorly understood. Lifestyle changes, weight loss, and increased exercise are proven to decrease the risk of T2D. There also is strong evidence that bariatric surgery reduces the risk. Current debate focuses on whether BMI should continue to be used to determine candidacy for bariatric surgery, or whether patients at risk of T2D with nonobese BMIs also might benefit from these procedures.


ValTrendsDB: bringing Protein Data Bank validation information closer to the user.
Structures in PDB tend to contain errors. This is a very serious issue for authors that rely on such potentially problematic data. The community of structural biologists develops validation methods as countermeasures, which are also included in the PDB deposition system. But how are these validation efforts influencing the structure quality of subsequently published data? Which quality aspects are improving, and which remain problematic? We developed ValTrendsDB, a database that provides the results of an extensive exploratory analysis of relationships between quality criteria, size and metadata of biomacromolecules. Key input data are sourced from PDB. The discovered trends are presented via precomputed information-rich plots. ValTrendsDB also supports the visualization of a set of user-defined structures on top of general quality trends. Therefore, ValTrendsDB enables users to see the quality of structures published by selected author, laboratory or journal, discover quality outliers, etc. ValTrendsDB is updated weekly. Freely accessible at http://ncbr.muni.cz/ValTrendsDB. The web interface was implemented in JavaScript. The database was implemented in C++. Supplementary data are available at Bioinformatics online.


Single cell and tissue-transcriptomic analysis of murine bladders reveals age- and TNFα-dependent but microbiota-independent tertiary lymphoid tissue formation.
Aging has multifaceted effects on the immune system, but how aging affects tissue-specific immunity is not well-defined. Bladder diseases characterized by chronic inflammation are highly prevalent in older women, but mechanisms by which aging promotes these pathologies remain unknown. Tissue transcriptomics of unperturbed, young and aged bladders identified a highly altered immune landscape as a fundamental feature of the aging female bladder. Detailed mapping of immune cells using single cell RNA-sequencing revealed novel subsets of macrophages and dendritic cells and unique changes to the immune repertoire in the aged bladder. B and T cells are highly enriched in aged bladders and spontaneously form organized bladder tertiary lymphoid tissues (bTLTs). Naïve, activated, and germinal center B cells and IgA+ plasma cells are found within bTLT and associated with increased urinary IgA concentrations. bTLTs form with increasing age and their formation is dependent on TNFα. Microbiota are not required to form bTLT, as aged germfree mice also harbor them. Thus, bTLTs require age-dependent TNFα but are independent of the microbiota. Our results indicate that chronic, age-associated inflammation underlies a fundamental alteration to the bladder and establishes a resource for further investigation of the bladder immune system in homeostasis, aging, and disease.


Viscosity of xanthan gum solutions at low shear rates.
The viscosity of xanthan gum solutions in the low shear region was investigated with the aid of a Couette instrument. All solutions were highly pseudoplastic . Solutions containing 0.3-0.5% of the gum exhibited a highly ordered phase at very low shear. Viscosity, the degree of pseudoplasticity , and the value of the transition from soft gel to pseudoplastic behavior were directly related to gum concentration. The effect of the addition of a salt on viscosity depended on the xanthan gum concentration. The viscosity of a 0.3% xanthan gum solution was practically unaffected by the salts. Higher gum concentrations exhibited a viscosity increase when salt was present. Concentrations less than 0.3% exhibited a viscosity decrease in the presence of a salt. All viscosity effects seemed to reach limiting values at approximately 10(-3) to 3.3 X 10(-3) N salt. No major differences were observed between sodium chloride, calcium chloride, and sodium citrate in their influence on xanthan gum viscosity.


Ultrasensitive Gas Sensors Based on Vertical Graphene Nanowalls/SiC/Si Heterostructure.
Gas sensors, which play an important role in the safety of human life, cover a wide range of applications including intelligent systems and detection of harmful and toxic gases. It is known that graphene is an ideal and attractive candidate for gas sensing due to its high surface area and excellent mechanical, electrical, optical, and thermal properties. However, in order to fully realize its potential as a commercial gas sensor, demand for a graphene-based device of low-limit detection, high sensitivity, and fast response time needs to be met. Here, we demonstrate a metal/insulator/semiconductor (MIS) based gas sensor consisting of as-grown epitaxial graphene nanowalls (EGNWs)/silicon carbide (SiC)/silicon (Si) structure. The unique edge dominant three-dimensional (3D) EGNWs based MIS device achieved an extraordinarily low limit of detection (0.5 ppm) and unprecedented sensitivity (82 μA/ppm/cm2 for H2) with a fast response of shorter than 500 ms. These unique properties of our MIS device are attributed to the abundance of vertically oriented nanographitic edges and structural defects that act as extra-favorable adsorption sites and exhibit fast electron-transfer kinetics through the edges. Our experimental findings can pave the way for the realization of high-performance 3D graphene-based gas sensor devices.


Regaining control over opioid use? The potential application of auricular transcutaneous vagus nerve stimulation to improve opioid treatment in China.
Opioid use disorder (OUD) is a critical problem in China and is accompanied by depression and deficits in cognitive control. In China, the most successful intervention for OUD is the community drug rehabilitation where methadone maintenance treatment (MMT) plays a key role. Even though methadone for the treatment of OUD can be helpful, it can cause severe somatic side-effects, which limit its effectivity. Even worse, it can have detrimental effects on cognitive control, which is crucial to regain control over drug intake. Here, we consider the potential use of auricular transcutaneous vagus nerve stimulation (atVNS) as an addition to MMT for opioid withdrawal treatment. Compared to other non-invasive brain stimulation methods, atVNS also targets the locus coeruleus (LC) important for noradrenaline (NA) synthesis. NA is an essential neurotransmitter impacted in opioid withdrawal and also critically involved in cognitive control processes. Its ADD-ON to MMT might be a useful mean to improve mood and enhance cognitive control processes impacted in OUD. We discuss the translational advantages of atVNS in China such as the cultural acceptance of the modality of treatment similar to electroacupuncture. Additionally, the wearability of the ear electrode and at-home self-administration without intense medical supervision makes of atVNS a useful tool to enhance clinical and cognitive outcomes especially in everyday life situation. We discuss how atVNS can be integrated in tele-medical health approaches allowing that innovative treatments can widely be disseminated and continued even in situations of restricted medical access.


Dynamic Arterial Elastance in Predicting Arterial Pressure Increase After Fluid Challenge During Robot-Assisted Laparoscopic Prostatectomy: A Prospective Observational Study.
During robot-assisted laparoscopic prostatectomy, specific physiological conditions such as carbon dioxide insufflation and the steep Trendelenburg position can alter the cardiac workload and cerebral hemodynamics. Inadequate arterial blood pressure is associated with hypoperfusion, organ damage, and poor outcomes. Dynamic arterial elastance (Ea) has been proposed to be a useful index of fluid management in hypotensive patients. We therefore evaluated whether dynamic Ea can predict a mean arterial pressure (MAP) increase ≥ 15% after fluid challenge during pneumoperitoneum and the steep Trendelenburg position.We enrolled 39 patients receiving robot-assisted laparoscopic prostatectomy. Fluid challenge was performed with 500 mL colloids in the presence of preload-dependent conditions and arterial hypotension. Patients were classified as arterial pressure responders or arterial pressure nonresponders according to whether they showed an MAP increase ≥15% after fluid challenge. Dynamic Ea was defined as the ratio between the pulse pressure variation and stroke volume variation. Receiver operating characteristic curve analysis was performed to assess the arterial pressure responsiveness after fluid challenge during robot-assisted laparoscopic prostatectomy.Of the 39 patients, 17 were arterial pressure responders and 22 were arterial pressure nonresponders. The mean dynamic Ea before fluid challenge was significantly higher in arterial pressure responders than in arterial pressure nonresponders (0.79 vs 0.61, P < 0.001). In receiver operating characteristic curve analysis, dynamic Ea showed an area under the curve of 0.810. The optimal cut-off value of dynamic Ea for predicting an MAP increase of ≥ 15% after fluid challenge was 0.74.Dynamic Ea can predict an MAP increase ≥ 15% after fluid challenge during robot-assisted laparoscopic prostatectomy. This result suggests that evaluation of arterial pressure responsiveness using dynamic Ea helps to maintain an adequate arterial blood pressure and to improve perioperative outcomes in preload-dependent patients receiving robot-assisted laparoscopic prostatectomy under pneumoperitoneum and in the steep Trendelenburg position.


Circular dichroism of a tilted U-shaped nanostructure.
The circular dichroism (CD) effect plays an important role in biological detection, analytical chemistry, and plasmonic sensing. Tilted 3D structures can generate CD signals under normal illumination. However, fabricating tilted 3D structures is complex and expensive. In this study, we fabricate a tilted U-shaped nanostructure (TUSN) on a polystyrene (PS) nanosphere through the glancing angle deposition method. One branch of the U-shaped nanostructure is tilted by raising a sheet of SiO2 on the PS nanosphere. And the CD signal of the TUSN is enhanced because the phase difference increases with increasing thickness of the SiO2 sheet. This work proposes a method for fabricating tilted nanostructures and elucidates the mechanism of the CD effect for future research.


Characterization of virucidal agents in activated sludge.
A comprehensive study was carried out to determine the properties of agents responsible for loss of virus infectivity in mixed-liquor suspended solids (MLSS) of activated sludge. Initial experiments revealed that model enteric viruses (poliovirus-1 and rotavirus SA-11) were irreversibly inactivated in MLSS and released their RNA genomes. Enteric viruses belonging to other genera (echovirus-12, coxsackievirus A13, reovirus-3) were also shown to lose infectivity in MLSS. Although the virucidal activity decreased at reduced temperatures, MLSS still retained significant activity at 4 degrees C. The virucidal agents in MLSS were stable for months at 4 degrees C, but their activity decreased approximately 50% during 4 days of aeration at 26 degrees C. Primary effluent, the nutrient source for activated sludge, also contained virucidal activity. After centrifugation of MLSS, almost all virucidal activity was found in the particulate fraction because of inhibitory substances retained in the supernatant fraction. Decreasing or increasing the solids concentration of the particulate fraction did not increase the virucidal activity of the fraction. The effects of heat and antibiotics on the virucidal activity of MLSS, coupled with the finding that the activity can be produced in autoclaved primary effluent seeded with MLSS, strongly support the conclusion that microorganisms are responsible for this activity. Attempts to characterize the virucidal microbial components of MLSS indicated that treatments that resulted in the inactivation or removal of microorganisms also caused a loss of virucidal activity. Thus, it appears that the virucidal components of microorganisms are either short-lived or active only while bound to the organisms themselves.


Two Cases of Thyrotoxicosis and Euglycemic Diabetic Ketoacidosis Under Sodium-glucose Transport Protein 2 Inhibitor Treatment.
Thyrotoxicosis and sodium-glucose transport protein 2 inhibitors (SGLT2is) are associated with the induction of euglycemic diabetic ketoacidosis (euDKA). We herein report two cases of euDKA in patients with diabetes mellitus wherein both thyrotoxicosis and SGLT2i treatment were the underlying causes. One patient developed thyrotoxicosis during the course of type 2 diabetes mellitus, whereas the other patient was suspected of developing slowly progressive insulin-dependent diabetes mellitus during the course of Graves' disease. Although such cases are rare, there is some concern that similar cases may occur because of the increased frequency of SGLT2i use in recent years.


The effects of antipsychotic therapy on serum lipids: a comprehensive review.
The purpose of this paper is to review the literature since 1970 documenting the effects of antipsychotic agents on serum lipids, including a discussion of possible mechanisms for the observed phenomena, the clinical significance and recommendations for monitoring hyperlipidemia during antipsychotic therapy. High-potency conventional antipsychotics (e.g., haloperidol) and the atypical antipsychotics, ziprasidone, risperidone and aripiprazole, appear to be associated with lower risk of hyperlipidemia. Low-potency conventional antipsychotics (e.g., chlorpormazine, thioridazine) and the atypical antipsychotics, quetiapine, olanzapine and clozapine, are associated with higher risk of hyperlipidemia. Possible hypotheses for lipid dysregulation include weight gain, dietary changes and the development of glucose intolerance. Given the multiple cardiovascular risk factors seen in patients with schizophrenia, great care must be exercised in the choice of antipsychotic therapy to minimize the medical burden of additional risk imposed by hyperlipidemia. It is recommended that a lipid panel be obtained at baseline in all patients with schizophrenia, annually thereafter for patients on agents associated with lower risk of hyperlipidemia and quarterly in patients on agents associated with higher risk for hyperlipidemia. All patients with persistent dyslipidemia should be referred for lipid-lowering therapy or switched to a less lipid-offending antipsychotic agent.


A family of juvenile proximal spinal muscular atrophy with dominant inheritance.
A family with juvenile proximal spinal muscular atrophy with dominant inheritance and complete penetrance is reported. The disease occurred in three generations and showed high variations in the age of onset and progression among the affected members. A characteristic feature was the constant involvement of facial nuclei.


Best practice in the management of clinical coding services: Insights from a project in the Republic of Ireland, Part 2.
This is the second of two articles about best practice in the management of coding services. The best practice project was part of a year-long project conducted in the Republic of Ireland to review the quality of the Hospital Inpatient Enquiry data for its use in activity-based funding. The four methods used to address the best practice aspect of the project were described in detail in Part 1. The results included in this article are those relating to the coding manager's background, preparation and style, clinical coder (CC) workforce adequacy, the CC workforce structure and career pathway, and the physical and psychological work environment for the clinical coding service. Examples of best practice were found in the study hospitals but there were also areas for improvement. Coding managers would benefit from greater support in the form of increased opportunities for management training and a better method for calculating CC workforce numbers. A career pathway is needed for CCs to progress from entry to expert CC, mentor, manager and quality controller. Most hospitals could benefit from investment in infrastructure that places CCs in a physical environment that tells them they are an important part of the hospital and their work is valued.


Changes in Gait Characteristics During and Immediately After the 6-Minute Walk Test in Persons With Multiple Sclerosis: A Systematic Review.
There is limited information about gait patterns during prolonged walking in people with multiple sclerosis (PwMS). The aim of this review was to report on gait metrics during and immediately after the 6-Minute Walk Test (6MWT) in PwMS with different levels of disability. The systematic search was performed in 3 databases (PubMed, Web of Science, and SCOPUS) using keywords related to multiple sclerosis and 6MWT. Studies that reported on quantitative gait outcomes before and after the 6MWT or multiple time points during the 6MWT were included. The Hedges g effect size (ES) was calculated to determine the magnitude of change in each gait parameter. Fourteen studies (n = 534 PwMS; n = 166 healthy controls) were eligible. Five studies investigated gait parameters prior to and immediately after the 6MWT. Nine studies collected gait measures during the 6MWT. Speed (ES = -0.43 to 0.19), cadence (ES = -0.46 to 0.16), step length (ES = -0.46 to 0.14), stability (ES = -0.35 to 0.33), and regularity (ES = -0.25 to -0.15) decreased in most studies. In the majority of included studies, step time (ES = 0 to 0.35), stance period (ES = 0.12 to 0.58), double support phase (ES = 0.03 to 0.62), variability (ES = -0.19 to 1.13), and asymmetry (ES = -0.79 to 0.62) increased following the 6MWT. The kinetic and kinematic (mainly in dorsiflexion angle [ES = -0.08 to -0.36]) features of gait were also negatively changed after 6 minutes of walking. Walking speed, cadence, step length, stride length, and stride time after 6MWT at a comfortable speed all increased. Changes in the majority of spatiotemporal parameters were more pronounced in PwMS with moderate-to-severe disability compared with PwMS with mild disability. Most quantitative gait parameters deteriorated during the 6MWT, especially in PwMS with moderate-to-severe disability. The deterioration of gait patterns should be considered when designing therapeutic interventions to increase sustained walking capacity.


Treatment of SSRI-resistant depression: a meta-analysis comparing within- versus across-class switches.
Two broad treatment options exist for switching antidepressants for depressed patients who fail to respond to a selective serotonin reuptake inhibitor (SSRI): either a second course of SSRI therapy or a different class of antidepressants. The goal of the present work was to conduct a meta-analysis of studies comparing these two switch strategies. Several sources were searched for randomized clinical trials comparing these two switch strategies. Data from four clinical trials (n = 1496) were combined using a random-effects model. Patients randomized to switch to a non-SSRI antidepressant (bupropion, mirtazapine, venlafaxine) were more likely to experience remission than patients switched to a second SSRI (risk ratio = 1.29, p = .007). Pooled remission rates were 28% (for non-SSRIs) and 23.5% (for SSRIs). There was also a nonsignificant trend (p = .1) in the rate of discontinuation due to intolerance favoring the within-class switch strategy (risk ratio = 1.23). There was no difference in response rates between the two treatment groups. These results suggest a modest yet statistically significant advantage in remission rates when switching patients with SSRI-resistant depression to a non-SSRI rather than an SSRI antidepressant. With the number needed to treat (NNT) statistic as one indicator of clinical significance, nearly 22 SSRI nonresponders would need to be switched to a non-SSRI rather than a second SSRI antidepressant to obtain one additional remitter. This difference falls well below the mark of NNT = 10 suggested by the United Kingdom's National Institute of Clinical Excellence but nonetheless might be of public health relevance given the large number of SSRI-resistant patients switched to an SSRI versus a non-SSRI antidepressant.


Proprotein convertase subtilisin/kexin type 9 (PCSK9) and metabolic syndrome components among young adult females.
Occurrence of metabolic syndrome (MetS) in the United Arab Emirates (UAE) is rising steadily, with subsequent increase in the prevalence of type 2 diabetes and cardiovascular disease (CVD). Recent studies have shown that PCSK9 plays a substantial role in atherogenic dyslipidemia. Hence, the aim of this study was to assess level of PCSK9 and its relationship with MetS components among young adult females. This study was carried out on 137 adult females over 18 years of age residing in the UAE. Subjects were categorized into two groups according to waist circumferences (WC): normal (<80cm; n=41) and large (≥80cm; n=96). Anthropometric and biochemical parameters in the fasting state (glucose, insulin, lipid profile, and PCSK9) were determined using conventional techniques. Homeostasis model assessment of insulin resistance (HOMA-IR) and MetS scores were calculated as appropriate. PCSK9 was lower in subjects with large WC compared to normal WC (p=0.016). PCSK9 correlated negatively with measures of obesity (p<0.05), and positively with IR (r=0.425, p<0.001). Multiple linear regression analysis revealed that the strongest predictor of PCSK9 was IR (B=6.213; p<0.001), followed by WC (B=-2.488; p<0.001) and triglycerides (B=0.897; p=0.013). Results from this study demonstrate that PCSK9 correlates with some components of metabolic syndrome and central obesity in young females. Such findings support the suggestion of using PCSK9 inhibitors in the management of MetS to modify risk for development of CVD.


Effects of LHRH on copulatory behavior and locomotor activity in sexually inexperienced male rats.
To determine whether luteinizing hormone-releasing hormone (LHRH) contributes to the sexual behavior and locomotor activity of sexually inexperienced male rats, subcutaneous injections of LHRH (500 ng) were given to males. The males showed significant facilitation of a few aspects of sexual behavior 2h after LHRH injection, compared with saline-injected controls. However, the locomotor activity of males injected with LHRH showed no significant change. These results may indicate that LHRH mechanisms play a direct role in the normal regulation of sexual arousal of male behavior in rats.


Alcoholism in the families of family practice outpatients.
As part of a screening process for alcoholism, 147 patients at a university-based family practice center were each asked to complete two tests: the Michigan Alcohol Screening Test (MAST) concerning themselves and a modified MAST concerning their families. Charts of patients with positive results for family alcoholism were reviewed for presenting complaints, ongoing medical problems, and recognition or mention of family alcoholism by the physician. Over 34 percent (50) of patients had definite alcoholism problems in their families. Women were more likely than men to have a positive family MAST (37.7 percent women vs 24.4 percent men, P less than .001), whereas men were more likely to be alcoholic (34.1 percent men vs 10.4 percent women, P less than .001). Nearly 40 percent of patients with a positive family MAST had complaints that could be attributed to the family disruption of alcoholism, and another 20.8 percent had medical problems that might be exacerbated by stress, but use of alcohol by a family member was mentioned in only 12.5 percent (5/40) of charts reviewed.


[Epidemiology of tuberculosis in the Amur region].
Since 1991, the tuberculosis epidemiological situation has become worse: its morbidity has increased from 36.4 in 1990 to 60.6 in 1994 and mortality has grown from 5.3 in 1990 to 11.3 in 1994 and 22.2 in 1995 per 100,000. There has been a rise in destructive and fibrous-and-cavernous tuberculoses in the pattern of morbidity. The efficiency of treatment has drastically decreased. The basic principles in the deterioration of the epidemiological situation are socioeconomic conditions, inadequate financing of antituberculous measures.


2D Early Transition Metal Carbides (MXenes) for Catalysis.
MXenes, a bourgeoning class of 2D transition metal carbides, are of considerable interest in catalysis due to their rich surface chemistry, tunable electronic structures, and thermal stability. Here, recent conceptual advances in applying MXenes and their nanocomposites in (photo)electrocatalysis and conventional heterogeneous catalysis are highlighted. In addition, the nature of active sites in the MXene-based catalysts are discussed and the significance and challenges in the future development of catalysts using MXenes as the platforms are summarized.


Key roles for MED1 LxxLL motifs in pubertal mammary gland development and luminal-cell differentiation.
Mediator recently has emerged as a central player in the direct transduction of signals from transcription factors to the general transcriptional machinery. In the case of nuclear receptors, in vitro studies have shown that the transcriptional coactivator function of the Mediator involves direct ligand-dependent interactions of the MED1 subunit, through its two classical LxxLL motifs, with the receptor AF2 domain. However, despite the strong in vitro evidence, there currently is little information regarding in vivo functions of the LxxLL motifs either in MED1 or in other coactivators. Toward this end, we have generated MED1 LxxLL motif-mutant knockin mice. Interestingly, these mice are both viable and fertile and do not exhibit any apparent gross abnormalities. However, they do exhibit severe defects in pubertal mammary gland development. Consistent with this phenotype, as well as loss of the strong ligand-dependent estrogen receptor (ER)alpha-Mediator interaction, expression of a number of known ERalpha-regulated genes was down-regulated in MED1-mutant mammary epithelial cells and could no longer respond to estrogen stimulation. Related, estrogen-stimulated mammary duct growth in MED1-mutant mice was also greatly diminished. Finally, additional studies show that MED1 is differentially expressed in different types of mammary epithelial cells and that its LxxLL motifs play a role in mammary luminal epithelial cell differentiation and progenitor/stem cell determination. Our results establish a key nuclear receptor- and cell-specific in vivo role for MED1 LxxLL motifs, through Mediator-ERalpha interactions, in mammary gland development.


Effects of surfactant characteristics on drug availability from suppositories.
The addition of surfactants to suppository formulations is referred to in the scientific literature, but their effects on drug availability remain uncertain. Surfactants are reported to improve drug dispersion into hard fatty excipients, to increase the spreading of the melted suppository on the rectal mucosa leading to a greater contact surface, to reduce the viscosity of the molten mass and to reduce the pathway of drug particles to the interface. In the present study a systematic investigation based on tensiometric and rheological methods was carried out to evaluate the effects of nonionic surfactants with different HLBs (hydrophilic-lipophilic-balance) on drug availability and to clarify the possible mechanisms involved in the release process. The relationship between the melted suppositories and a membrane simulating the rectal barrier were investigated in the course of the in vitro release test by measuring their energy characteristics. At the same time, the potential influences of such interactions on drug release were investigated in suppositories formulated with different kinds and concentrations of surfactant additives. Drug availability was influenced not only by the interaction between the suppository and the rectal membrane but also by the interaction between surfactant, lipophilic excipient and suspended drug particles. Such interactions appear to greatly influence drug release from suppositories, which, in turn, is the main parameter determining drug availability.


Impact of donor-specific antibodies on long-term graft survival with pediatric liver transplantation.
In a previous paper, we reported a high prevalence of donor-specific antibody (DSA) in pediatric patients with chronic rejection and expressed the need for confirmation of these findings in a larger cohort. To clarify the importance of DSAs on long-term graft survival in a larger cohort of pediatric patients. We performed a retrospective analysis of 123 pediatric liver transplantation (LT) recipients who participated in yearly follow-ups including Luminex testing for DSA at our center. The cohort was split into two groups according to the DSA status (DSA-positive n = 54, DSA-negative n = 69). Groups were compared with regard to liver function, biopsy findings, graft survival, need for re-LT and immunosuppressive medication. DSA-positive pediatric patients showed a higher prevalence of chronic rejection (P = 0.01), fibrosis (P < 0.001) and re-transplantation (P = 0.018) than DSA-negative patients. Class II DSAs particularly influenced graft survival. Alleles DQ2, DQ7, DQ8 and DQ9 might serve as indicators for the risk of chronic rejection and/or allograft fibrosis. Mean fluorescence intensity levels and DSA number did not impact graft survival. Previous episodes of chronic rejection might lead to DSA development. DSA prevalence significantly affected long-term liver allograft performance and liver allograft survival in our cohort of pediatric LT. Screening for class II DSAs in combination with assessment of protocol liver biopsies for chronic antibody-mediated rejection improved early identification of patients at risk of graft loss.


Neuronal C/EBPβ/AEP pathway shortens life span via selective GABAnergic neuronal degeneration by FOXO repression.
The age-related cognitive decline of normal aging is exacerbated in neurodegenerative diseases including Alzheimer's disease (AD). However, it remains unclear whether age-related cognitive regulators in AD pathologies contribute to life span. Here, we show that C/EBPβ, an Aβ and inflammatory cytokine-activated transcription factor that promotes AD pathologies via activating asparagine endopeptidase (AEP), mediates longevity in a gene dose-dependent manner in neuronal C/EBPβ transgenic mice. C/EBPβ selectively triggers inhibitory GABAnergic neuronal degeneration by repressing FOXOs and up-regulating AEP, leading to aberrant neural excitation and cognitive dysfunction. Overexpression of CEBP-2 or LGMN-1 (AEP) in Caenorhabditis elegans neurons but not muscle stimulates neural excitation and shortens life span. CEBP-2 or LGMN-1 reduces daf-2 mutant-elongated life span and diminishes daf-16-induced longevity. C/EBPβ and AEP are lower in humans with extended longevity and inversely correlated with REST/FOXO1. These findings demonstrate a conserved mechanism of aging that couples pathological cognitive decline to life span by the neuronal C/EBPβ/AEP pathway.


BRCA1 mutations in women with familial or early-onset breast cancer and BRCA2 mutations in familial cancer in Estonia.
The aim of this study was to identify BRCA1 and BRCA2 mutations in the Estonian population. We analyzed genetic data and questionnaire from 64 early-onset (< 45 y) breast cancer patients, 47 familial cases (patients with breast or ovarian cancer and a case of these cancers in the family), and 33 predictive cases (patients without breast or ovarian cancer, with a family history of such diseases) from Estonia for mutations in the BRCA1 gene. A sub-set of familial cases and predictive cases were also analyzed for mutations in the BRCA2 gene. For mutation detection, we used the Polymerase Chain Reaction-Single Stranded Conformation Polymorphism Heteroduplex Analysis (PCR-SSCP-HD), followed by direct DNA sequencing. We identified three clinically important mutations in the BRCA1 gene, including seven occurrences of the c.5382insC mutation, three of c.4154delA, and one instance of c.3881_3882delGA. We also detected six polymorphisms: c.2430T>C, c.3232A>G, c.4158A>G, c.4427T>C, c.4956A>G, and c.5002T>C. Four sequence alterations were detected in introns: c.560+64delT, c.560+ [36-38delCTT, 52-63del12], c.666-58delT, and c.5396+60insGTATTCCACTCC. In the BRCA2 gene, two clinically important mutations were found: c.9610C>T and c.6631delTTAAATG. Additionally, two alterations (c.7049G>T and c.7069+80delTTAG) with unknown clinical significance were detected. In our dataset, the overall frequency of clinically important BRCA1 mutations in early-onset patients, familial cases, and predictive testing was 7.6% (144 cases, 11 mutation carriers). Pathogenic mutations were identified in 4 of the 64 early-onset breast cancer cases (6.3%). In familial cases, clinically important mutations in the BRCA1 gene were found in 6 of the 47 individuals analyzed (12.8%). In predictive cases, 1 clinically important mutation was detected in 33 individuals studied (3%). The occurrence of clinically important mutations in BRCA2 in familial cases of breast cancer was 2 of the 16 individuals analyzed (12.5%).


Qualitative and quantitative differences in normal vaginal flora of conventionally reared mice, rats, hamsters, rabbits, and dogs.
We examined quantitatively the vaginal flora of conventionally reared mice, rats, hamsters, rabbits and dogs, species that are widely used as laboratory animals. Vaginal specimens were examined according to the method of analyzing intestinal flora (Mitsuoka's procedure). The total number of bacteria (aerobes and anaerobes) and the prevalence of specific bacteria were determined. The total number of bacteria was highest during estrus and lowest during diestrus or anestrus in mice, rats, hamsters, and dogs. The most predominant bacteria during estrus were streptococci in mice; gram-negative rods (GNR), streptococci, and members of the family Bacteroidaceae in rats; GNR, Bacteroidaceae and gram-positive anaerobic cocci in hamsters, and Bacteroidaceae in dogs. The increase in the total number of bacteria during estrus was caused by an increase of predominant bacteria in the vagina. Aerobes were more predominant than anaerobes in mice, and number of aerobes was comparable to that of anaerobes in rats and dogs. On the other hand, in hamsters, anaerobes were more predominant than aerobes and the total number of bacteria was highest among the laboratory animals (mice, rats, hamsters, rabbits, and dogs). However, in rabbits, bacteria were not isolated from about 90% of the vaginal specimens. Rabbits do not have cyclic reproductive stages and are usually in precoital status in the laboratory. In precoital rabbits, vaginal epithelium manifests few signs of secretion. Therefore, we suspect that the vaginal environment in precoital rabbits is comparable to that during diestrus or anestrus in mice, rats, hamsters, and dogs. These results suggest that the vaginal flora of laboratory animals is influenced by the estrous cycle, and probably by mucous secretion. Our data imply that vaginal flora differ among laboratory animals species, and researchers need to take into consideration the estrous cycle of laboratory animals when studying their vaginal flora.


New, improved analysis of correlation ECE data to accurately determine turbulent electron temperature spectra and magnitudes (invited).
Turbulent electron temperature fluctuation measurement using a correlation electron cyclotron emission (CECE) radiometer has become an important diagnostic for studying energy transport in fusion plasmas, and its use is widespread in tokamaks (DIII-D, ASDEX Upgrade, Alcator C-Mod, Tore Supra, EAST, TCV, HL-2A, etc.). The CECE diagnostic typically performs correlation analysis between two closely spaced (within the turbulent correlation length) ECE channels that are dominated by uncorrelated thermal noise emission. This allows electron temperature fluctuations embedded in the thermal noise to be revealed and fluctuation level and spectra determined. We have demonstrated a new, improved CECE coherency-based analysis for calculating the temperature fluctuation frequency spectrum and level, which has been verified both numerically through the simulation of synthetic ECE radiometer data and through analysis of experimental data from the CECE system on DIII-D. The new formulation places coherency-based analysis on a firm foundational footing and corrects some currently published methodologies. This new method accurately accounts for bias error in the coherence function and correctly calculates noise levels for a fixed data record length. It provides excellent accuracy in determining temperature fluctuation level (e.g., <10% error) even for a small realization number in the ensemble average. The method also has a smaller uncertainty (i.e., error bar) in the power spectrum when compared to the more standard cross-power method when evaluated at low coherency. Direct calculation of system noise level using correlation between randomized intermediate frequency signals is recommended.


Mast cells as a possible source of Haemophilus influenzae-induced changes in plasma and lung histamine levels.
Histidine decarboxylase activity and histamine levels of peritoneal mast cells were enhanced 4 days after intraperitoneal Haemophilus influenzae vaccination of rats. Incubation of the cells with propranolol (3.4 x 10(-4) M) resulted in histamine release and an increased histidine decarboxylase activity. Histidine decarboxylase activity and histamine release were more increased in the presence of propranolol in mast cells obtained from H. influenzae-vaccinated rats. An increased mediator release is also suggested by the increase of the number of peritoneal eosinophils. These data might explain the earlier observed enhanced plasma and lung histamine levels in H. influenzae-vaccinated rats.


Automatic, high-speed, high-precision acquisition scheme with QPD for the Taiji program.
Most of the space gravitational wave detection missions, such as the Taiji program, use space-based laser interferometer to sense the gravitational waves. However, to obtain the interference signal, the inter-satellite laser acquisition scheme is firstly required to establish the laser link. Traditional acquisition sensors are CCD cameras, which cause a serious heating problem and call for high alignment precision. To avoid these questions, a high-speed, high-precision, fully automatic acquisition scheme with quadrant photodetectors (QPD) is proposed in this paper. Incoherent measurement method of the QPD is introduced to fulfill high-speed acquisition, while a dedicated imaging system is involved for automatic acquisition. Also, an improved differential power sensing (DPS) signal is developed. Combined with the down-sampling algorithm and the match filter algorithm, the acquisition scheme can achieve 1 µrad resolution with total scanning time less than 220 s.


Molecular pathogenesis of infections caused by Legionella pneumophila.
The genus Legionella contains more than 50 species, of which at least 24 have been associated with human infection. The best-characterized member of the genus, Legionella pneumophila, is the major causative agent of Legionnaires' disease, a severe form of acute pneumonia. L. pneumophila is an intracellular pathogen, and as part of its pathogenesis, the bacteria avoid phagolysosome fusion and replicate within alveolar macrophages and epithelial cells in a vacuole that exhibits many characteristics of the endoplasmic reticulum (ER). The formation of the unusual L. pneumophila vacuole is a feature of its interaction with the host, yet the mechanisms by which the bacteria avoid classical endosome fusion and recruit markers of the ER are incompletely understood. Here we review the factors that contribute to the ability of L. pneumophila to infect and replicate in human cells and amoebae with an emphasis on proteins that are secreted by the bacteria into the Legionella vacuole and/or the host cell. Many of these factors undermine eukaryotic trafficking and signaling pathways by acting as functional and, in some cases, structural mimics of eukaryotic proteins. We discuss the consequences of this mimicry for the biology of the infected cell and also for immune responses to L. pneumophila infection.


Molecular epidemiology of Campylobacter jejuni isolates from wild-bird fecal material in children's playgrounds.
In many countries relatively high notification rates of campylobacteriosis are observed in children under 5 years of age. Few studies have considered the role that environmental exposure plays in the epidemiology of these cases. Wild birds inhabit parks and playgrounds and are recognized carriers of Campylobacter, and young children are at greater risk of ingesting infective material due to their frequent hand-mouth contact. We investigated wild-bird fecal contamination in playgrounds in parks in a New Zealand city. A total of 192 samples of fresh and dried fecal material were cultured to determine the presence of Campylobacter spp. Campylobacter jejuni isolates were also characterized by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST), and the profiles obtained were compared with those of human isolates. C. jejuni was isolated from 12.5% of the samples. MLST identified members of clonal complexes ST-45, ST-682, and ST-177; all of these complexes have been recovered from wild birds in Europe. PFGE of ST-45 isolates resulted in profiles indistinguishable from those of isolated obtained from human cases in New Zealand. Members of the ST-177 and ST-682 complexes have been found in starlings (Sturnus vulgaris) in the United Kingdom, and these birds were common in playgrounds investigated in New Zealand in this study. We suggest that feces from wild birds in playgrounds could contribute to the occurrence of campylobacteriosis in preschool children. Further, the C. jejuni isolates obtained in this study belonged to clonal complexes associated with wild-bird populations in the northern hemisphere and could have been introduced into New Zealand in imported wild garden birds in the 19th century.


Human Staufen1 associates to miRNAs involved in neuronal cell differentiation and is required for correct dendritic formation.
Double-stranded RNA-binding proteins are key elements in the intracellular localization of mRNA and its local translation. Staufen is a double-stranded RNA binding protein involved in the localised translation of specific mRNAs during Drosophila early development and neuronal cell fate. The human homologue Staufen1 forms RNA-containing complexes that include proteins involved in translation and motor proteins to allow their movement within the cell, but the mechanism underlying translation repression in these complexes is poorly understood. Here we show that human Staufen1-containing complexes contain essential elements of the gene silencing apparatus, like Ago1-3 proteins, and we describe a set of miRNAs specifically associated to complexes containing human Staufen1. Among these, miR-124 stands out as particularly relevant because it appears enriched in human Staufen1 complexes and is over-expressed upon differentiation of human neuroblastoma cells in vitro. In agreement with these findings, we show that expression of human Staufen1 is essential for proper dendritic arborisation during neuroblastoma cell differentiation, yet it is not necessary for maintenance of the differentiated state, and suggest potential human Staufen1 mRNA targets involved in this process.


Idiopathic thrombocytopenic purpura in childhood, Langerhans cell histiocytosis in adulthood: More than a chance association?
Described herein, a case of Langerhans cell histiocytosis (LCH) in an adult with Idiopathic Thrombocytopenic Purpura (ITP) diagnosed at age ten. She presented with cranial diabetes insipidus, later developed hypogonadotrophic hypogonadism and multiple cervical lympadenopathy from which histopathology of excisional biopsy confirmed LCH. Magnetic resonance imaging showed thickened pituitary stalk. Association of ITP and LCH is unknown but the question of LCH presenting as isolated thrombocytopenia in childhood only to be discovered in adulthood when there was pituitary and bone involvement remains. It reemphasizes the need for high index of suspicion and the challenges in diagnosing LCH at the outset.


Effect of cardiopulmonary bypass on circulating concentrations of leucocyte elastase and free radical activity.
Circulating concentrations of leucocyte elastase and free radical activity were measured in 11 adults undergoing cardiopulmonary bypass. In all patients the bypass procedure was associated with pronounced changes in plasma elastase concentrations, and peak enzyme concentrations correlated closely with the duration of bypass (r = 0.91, p less than 0.001). Serial measurement of octadeca-9, 11-dienoic acid, a non-peroxide marker of free radical activity, showed significant changes only in the plasma free fatty acid fraction, suggesting a direct relation to the action of heparin rather than to the bypass procedure as such. These studies support the hypothesis that neutrophil activation plays a central role in the organ dysfunction that may complicate cardiopulmonary bypass and suggest that elastase release rather than free radical generation may be the appropriate marker of the event.


Tomato (Solanum lycopersicum L.) accumulation and allergenicity in response to nickel stress.
Vegetables represent a major source of Ni exposure. Environmental contamination and cultural practices can increase Ni amount in tomato posing significant risk for human health. This work assesses the tomato (Solanum lycopersicum L.) response to Ni on the agronomic yield of fruits and the related production of allergens. Two cultivars were grown in pots amended with Ni 0, 30, 60, 120, and 300 mg kg-1, respectively. XRF and ICP-MS analyses highlighted the direct increase of fruit Ni content compared to soil Ni, maintaining a stable biomass. Leaf water content increased at Ni 300 mg kg-1. Total protein content and individual allergenic components were investigated using biochemical (RP-HPLC and N-terminal amino acid sequencing) and immunological (inhibition tests of IgE binding by SPHIAa assay on the FABER testing system) methodologies. Ni affected the fruit tissue concentration of pathogenesis-related proteins and relevant allergens (LTP, profilin, Bet v 1-like protein and TLP). This study elucidates for the first time that tomato reacts to exogenous Ni, uptaking the metal while changing its allergenic profiles, with potential double increasing of exposure risks for consumers. This evidence highlighted the importance of adequate choice of low-Ni tomato cultivars and practices to reduce Ni uptake by potentially contaminated matrices.


LocalSCF method for semiempirical quantum-chemical calculation of ultralarge biomolecules.
A linear-scaling semiempirical method, LocalSCF, has been proposed for the quantum-chemical calculations of ultralarge molecular systems by treating the large-scale molecular task as a variational problem. The method resolves the self-consistent field task through the finite atomic expansion of weakly nonorthogonal localized molecular orbitals. The inverse overlap matrix arising from the nonorthogonality of the localized orbitals is approximated by preserving the first-order perturbation term and applying the second-order correction by means of a penalty function. This allows for the separation of the orbital expansion procedure from the self-consistent field optimization of linear coefficients, thereby maintaining the localized molecular orbital size unchanged during the refinement of linear coefficients. Orbital normalization is preserved analytically by the variation of virtual degrees of freedom, which are orthogonal to the initial orbitals. Optimization of linear coefficients of localized orbitals is performed by a gradient procedure. The computer program running on a commodity personal computer was applied to the GroEL-GroES chaperonin complex containing 119,273 atoms.


What happened after the clinical trials: long-term safety and efficacy of ustekinumab in daily clinical practice.
Ustekinumab has been investigated in patients with psoriasis by randomized clinical trials. There are few data on ustekinumab use under 'real life' conditions outside long-term registries. The aim of our study was to evaluate the efficacy and safety of ustekinumab as a long-term therapy in real life. We retrospectively analyzed the data of 71 patients who had been treated with ustekinumab up to 2 years. Efficacy data were analyzed both by 'as treated' and 'intention to treat-last observation carried forward'. A significant improvement in the Psoriasis Area and Severity Index score was observed at 4 weeks and further improvements were observed throughout the treatment. Adverse events were generally mild. In routine administration ustekinumab seems to be more efficient than reported by randomized clinical trials. Our results are encouraging and can answer the patients' biggest concern on whether ustekinumab is an effective and safe drug for long-term use.


Rho GTPases: Novel Players in the Regulation of the DNA Damage Response?
The Ras-related C3 botulinum toxin substrate 1 (Rac1) belongs to the family of Ras-homologous small GTPases. It is well characterized as a membrane-bound signal transducing molecule that is involved in the regulation of cell motility and adhesion as well as cell cycle progression, mitosis, cell death and gene expression. Rac1 also adjusts cellular responses to genotoxic stress by regulating the activity of stress kinases, including c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38 kinases as well as related transcription factors. Apart from being found on the inner side of the outer cell membrane and in the cytosol, Rac1 has also been detected inside the nucleus. Different lines of evidence indicate that genotoxin-induced DNA damage is able to activate nuclear Rac1. The exact mechanisms involved and the biological consequences, however, are unclear. The data available so far indicate that Rac1 might integrate DNA damage independent and DNA damage dependent cellular stress responses following genotoxin treatment, thereby coordinating mechanisms of the DNA damage response (DDR) that are related to DNA repair, survival and cell death.


Essential Role of Couplings between Hearing Nonlinearities.
Hopf-type nonlinearities have been recently found to be the basic mechanism of the mammalian cochlear response. Physiology requires that these nonlinearities be coupled. By suitably implementing a biomorphic coupling scheme of cochlear nonlinearities, we obtain a simple cochlea model that faithfully reproduces measured basilar membrane response, validating the utility of the Hopf amplifier concept. Our results demonstrate that the correct coupling between nonlinearities is as important as the nonlinearities themselves.


Geographical Accessibility of the Referral Networks in France. Intermediate Results from the IGéAS Research Program.
Rare cancer patients face lower survival and experience delays in diagnosis and therapeutic mismanagement. Considering the specificities of rare cancers, referral networks have been implemented in France to improve the management and survival of patients. The IGéAS research program aims to assess the networks' ability to reduce inequalities. Data analysis of the IGéAS cohort (n = 20,590, sarcoma diagnosed between 2011 and 2014) by gathering medical data and geographical index will identify risk factors associated with the belated access to expertise or with no access to expertise. Intermediate results show that referral networks give sarcoma patients access to sarcoma expertise despite the remoteness of some of them. Regional expert centers mostly receive requests from within their area while national referral centers receive requests from the whole country. Delays in the access to expertise may be reduced by making outside practitioners more sensitive to the issues of rare cancers. The perception and involvement of outside practitioners in this device will be assessed using a qualitative survey. All the results are discussed and will contribute to design guidelines to improve early access to expertise and reduce inequalities. Results of the IGéAS research program may contribute to the assessment of referral sarcoma networks and provide some useful lessons to improve cancer care management.


Pulmonary vein mass with extension to the left atrium diagnosed by echocardiography.
We report a case of a man aged 65 years presenting with chronic cough, haemoptysis and intermittent atrial tachyarrhythmias on ECG. On 2D transthoracic echocardiography, an incidental left atrial mass was seen, initially thought to be a thrombus predisposed by intermittent atrial fibrillation. Transoesophageal echocardiography confirmed that this left atrial mass originated from a fixed, non-homogenous, right superior pulmonary vein mass with an extracardiac extension. Because of this finding, a thorough search for a primary focus lead to the discovery of a contiguous posterior mediastinal mass, which was a round cell neoplasm on histology. Management was deemed palliative. Although rare, left-sided cardiac masses should prompt the physician to search for a malignancy in the lung in high-risk patients, as haematogenous spread via the pulmonary vein is a potential mechanism for spread.


Microfluidic flow-flash: method for investigating protein dynamics.
We report a new method, microfluidic flow-flash, for measuring protein reaction kinetics. The method couples a microscope imaging detection system with a microfluidic flow cell to reduce data acquisition times and sample consumption. This combination allows for the simultaneous collection of spectral and temporal information. The microfluidic flow cell design utilizes three-dimensional sheath flow to reduce sample dispersion and minimize sample consumption. The ability to alter the flow rates in the microfluidic flow cells allows a variety of time scales to be studied with submillisecond time resolution. The imaging detection system can be coupled with several spectroscopic probes including fluorescence and UV/visible absorbance spectroscopy. Here, we utilize the microfluidic flow-flash method to probe the kinetics of CO recombination or O2 binding to myoglobin after the laser-induced photolysis of CO from myoglobin by UV/visible absorbance spectral imaging.


The Role of Polyphenoloxidase, Peroxidase, and β-Glucosidase in Phenolics Accumulation in Olea europaea L. Fruits under Different Water Regimes.
Olive fruits and oils contain an array of compounds that contribute to their sensory and nutritional properties. Phenolic compounds in virgin oil and olive-derived products have been proven to be highly beneficial for human health, eliciting increasing attention from the food industry and consumers. Although phenolic compounds in olive fruit and oil have been extensively investigated, allowing the identification of the main classes of metabolites and their accumulation patterns, knowledge of the molecular and biochemical mechanisms regulating phenolic metabolism remains scarce. We focused on the role of polyphenoloxidase (PPO), peroxidase (PRX) and β-glucosidase (β-GLU) gene families and their enzyme activities in the accumulation of phenolic compounds during olive fruit development (35-146 days after full bloom), under either full irrigation (FI) or rain-fed (RF) conditions. The irrigation regime affected yield, maturation index, mesocarp oil content, fruit size, and pulp-to-pit ratio. Accumulation of fruit phenolics was higher in RF drupes than in FI ones. Members of each gene family were developmentally regulated, affected by water regime, and their transcript levels were correlated with the respective enzyme activities. During the early phase of drupe growth (35-43 days after full bloom), phenolic composition appeared to be linked to β-GLU and PRX activities, probably through their effects on oleuropein catabolism. Interestingly, a higher β-GLU activity was measured in immature RF drupes, as well as a higher content of the oleuropein derivate 3,4-DHPEA-EDA and verbascoside. Activity of PPO enzymes was slightly affected by the water status of trees during ripening (from 120 days after full bloom), but was not correlated with phenolics content. Overall, the main changes in phenolics content appeared soon after the supply of irrigation water and remained thereafter almost unchanged until maturity, despite fruit growth and the progressive decrease in pre-dawn leaf water potential. We suggest that enzymes involved in phenolic catabolism in the olive fruit have a differential sensitivity to soil water availability depending on fruit developmental stage.


Enantioseparation of extended metal atom chain complexes: unique compounds of extraordinarily high specific rotation.
Extended metal atom chains (EMACs) contain a linear metal chain wrapped by various ligands. Most complexes are of the form M(3)(dpa)(4)X(2), where M = metal, dpa = 2,2'-dipyridylamide, and X = various anions. The ligands form helical coils about the metal chain, which results in chiral EMAC complexes. The EMACs containing the metals Co and Cu were partially separated in polar organic mode using a vancomycin-based chiral stationary phase. Under similar conditions, two EMACs with Ni metal and varying anions could be baseline separated. The polar organic mode was used because of the instability of the compounds in aqueous mobile phases. Also, these conditions are more conducive to preparative separations. Polarimetric measurements on the resolved enantiomers of Ni(3)(dpa)(4)Cl(2) indicate that they have extraordinarily high specific rotations (on the order of 5000 deg cc/g dm).


How many human immunodeficiency virus type 1-infected target cells can a cytotoxic T-lymphocyte kill?
The antiviral role of CD8+ cytotoxic T lymphocytes (CTLs) in human immunodeficiency virus type 1 (HIV-1) infection is poorly understood. Specifically, the degree to which CTLs reduce viral replication by killing HIV-1-infected cells in vivo is not known. Here we employ mathematical models of the infection process and CTL action to estimate the rate that CTLs can kill HIV-1-infected cells from in vitro and in vivo data. Our estimates, which are surprisingly consistent considering the disparities between the two experimental systems, demonstrate that on average CTLs can kill from 0.7 to 3 infected target cells per day, with the variability in this figure due to epitope specificity or other factors. These results are compatible with the observed decline in viremia after primary infection being primarily a consequence of CTL activity and have interesting implications for vaccine design.