Convergent evolution: floral guides, stingless bee nest entrances, and insectivorous pitchers.
Several recent hypotheses, including sensory drive and sensory exploitation, suggest that receiver biases may drive selection of biological signals in the context of sexual selection. Here we suggest that a similar mechanism may have led to convergence of patterns in flowers, stingless bee nest entrances, and pitchers of insectivorous plants. A survey of these non-related visual stimuli shows that they share features such as stripes, dark centre, and peripheral dots. Next, we experimentally show that in stingless bees the close-up approach to a flower is guided by dark centre preference. Moreover, in the approach towards their nest entrance, they have a spontaneous preference for entrance patterns containing a dark centre and disrupted ornamentation. Together with existing empirical evidence on the honeybee's and other insects' orientation to flowers, this suggests that the signal receivers of the natural patterns we examined, mainly Hymenoptera, have spontaneous preferences for radiating stripes, dark centres, and peripheral dots. These receiver biases may have evolved in other behavioural contexts in the ancestors of Hymenoptera, but our findings suggest that they have triggered the convergent evolution of visual stimuli in floral guides, stingless bee nest entrances, and insectivorous pitchers.


[Pulmonary atresia with intact interventricular septum. Study of 28 cases].
The present report is based on the study of 28 cases of pulmonary atresia with intact ventricular septum, all of them necropsically and/or angiographically verified. A microscopic study of the wall of both ventricles was performed in the 20 necropsy cases. The size of the right ventricular cavity, a fact of great surgical significance, did not correlate with the electrocardiogram and varied from diminute to very large. In two cases necropsically proved there was as associated atresia of the infundibular, in one of them existing additionally an Ebstein malformation of the tricuspid valve, which could be angiocardiographically diagnosed. The surgical mortality, in our hands, is 64.3%. All survivors have a small right ventricle.


Intake of fruit, berries, and vegetables and risk of type 2 diabetes in Finnish men: the Kuopio Ischaemic Heart Disease Risk Factor Study.
Although higher intakes of fruit, berries, and vegetables (FBV) have been associated with reduced risk of type 2 diabetes (T2D) in some observational studies, the evidence is limited and inconclusive. We assessed the relation of FBV intake and T2D incidence in Finnish men. We studied 2332 men from the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study who were aged 42-60 y and free of T2D or impaired fasting glucose at baseline in 1984-1989. Food intake was assessed with 4-d food recording. T2D was assessed by using self-administered questionnaires, a fasting blood glucose measurement, a 2-h oral-glucose-tolerance test, and record linkage to a reimbursement register on diabetes medication expenses. In the Cox proportional hazards model, HRs for T2D were computed for the highest compared with lowest quartiles of FBV intake adjusted for age, examination year, body mass index, waist-to-hip ratio, smoking, education, physical activity, family history of diabetes, and energy and alcohol intakes. During the mean follow-up time of 19.3 y, 432 new cases of T2D occurred. For the total FBV intake (with the exclusion of potatoes and fruit and berry juices), the extreme-quartile multivariable-adjusted HR for T2D was 0.76 (95% CI: 0.57, 1.02; P-trend = 0.15). In the analysis for FBV components, berries had a corresponding HR of 0.65 (95% CI: 0.49, 0.88; P-trend = 0.003), whereas no significant associations were shown for fruit, fruit and berry juices, and vegetables. Fruit and vegetables, particularly berries, may reduce risk of T2D in men.


Identification of HPV oncogene and host cell differentiation associated cellular heterogeneity in cervical cancer via single-cell transcriptomic analysis.
Human Papillomaviruses (HPVs) are associated with around 5%-10% of human cancer, notably nearly 99% of cervical cancer. The mechanisms HPV interacts with stratified epithelium (differentiated layers) during the viral life cycle, and oncogenesis remain unclear. In this study, we used single-cell transcriptome analysis to study viral gene and host cell differentiation-associated heterogeneity of HPV-positive cervical cancer tissue. We examined the HPV16 genes-E1, E6, and E7, and found they expressed differently across nine epithelial clusters. We found that three epithelial clusters had the highest proportion of HPV-positive cells (33.6%, 37.5%, and 32.4%, respectively), while two exhibited the lowest proportions (7.21% and 5.63%, respectively). Notably, the cluster with the most HPV-positive cells deviated significantly from normal epithelial layer markers, exhibiting functional heterogeneity and altered epithelial structuring, indicating that significant molecular heterogeneity existed in cancer tissues and that these cells exhibited unique/different gene signatures compared with normal epithelial cells. These HPV-positive cells, compared to HPV-negative, showed different gene expressions related to the extracellular matrix, cell adhesion, proliferation, and apoptosis. Further, the viral oncogenes E6 and E7 appeared to modify epithelial function via distinct pathways, thus contributing to cervical cancer progression. We investigated the HPV and host transcripts from a novel viewpoint focusing on layer heterogeneity. Our results indicated varied HPV expression across epithelial clusters and epithelial heterogeneity associated with viral oncogenes, contributing biological insights to this critical field of study.


Peptidoglycan biosynthesis-associated enzymatic kinetic characteristics and β-lactam antibiotic inhibitory effects of different Streptococcus pneumoniae penicillin-binding proteins.
Penicillin-binding proteins (PBPs) include transpeptidases, carboxypeptidases, and endopeptidases for biosynthesis of peptidoglycans in the cell wall to maintain bacterial morphology and survival in the environment. Streptococcus pneumoniae expresses six PBPs, but their enzymatic kinetic characteristics and inhibitory effects on different β-lactam antibiotics remain poorly understood. In this study, all the six recombinant PBPs of S. pneumoniae displayed transpeptidase activity with different substrate affinities (Km = 1.56-9.11 mM) in a concentration-dependent manner, and rPBP3 showed a greater catalytic efficiency (Kcat = 2.38 s-1) than the other rPBPs (Kcat = 3.20-7.49 × 10-2 s-1). However, only rPBP3 was identified as a carboxypeptidase (Km = 8.57 mM and Kcat = 2.57 s-1). None of the rPBPs exhibited endopeptidase activity. Penicillin and cefotaxime inhibited the transpeptidase and carboxypeptidase activity of all the rPBPs but imipenem did not inhibited the enzymatic activities of rPBP3. Except for the lack of binding of imipenem to rPBP3, penicillin, cefotaxime, and imipenem bound to all the other rPBPs (KD = 3.71-9.35 × 10-4 M). Sublethal concentrations of penicillin, cefotaxime, and imipenem induced a decrease of pneumococcal pbps-mRNA levels (p < 0.05). These results indicated that all six PBPs of S. pneumoniae are transpeptidases, while only PBP3 is a carboxypeptidase. Imipenem has no inhibitory effect on pneumococcal PBP3. The pneumococcal genes for encoding endopeptidases remain to be determined.


Emergence of multiple-antibiotic-resistant Streptococcus pneumoniae in Hong Kong.
Two hundred four strains of Streptococcus pneumoniae isolated in Hong Kong from January 1993 to May 1995 were analyzed for their antibiotic susceptibilities and epidemiological patterns. The ages of the patients from whom the strains were isolated from 1 month to 93 years (median, 53 years); the male-to-female ratio was 2.8, with a predominance of males in the pediatric group. Fifty-nine (28.9%) strains showed reduced penicillin susceptibility, including 40 (19.6%) with frank penicillin resistance (MIC > 1 microgram/ml). Tetracycline resistance alone was found in 28.4% of strains. Isolates with reduced penicillin susceptibility were more common in children than adults (40 versus 23.9%, P = 0.02), and penicillin resistance rates were significantly higher in hospitalized patients than in outpatients (39.5 versus 12.5%; p < 0.001). Penicillin resistance was significantly associated with resistance to ceftriaxone, erythromycin, and tetracycline (P < 0.01) but not with ofloxacin or vancomycin (P = 0.5). Among eight different patterns of resistance to three or more antibiotics, the commonest one (14.2%) was multiple resistance to penicillin, chloramphenicol, ceftriaxone, erythromycin, and tetracycline. Emergence of multiple-antibiotic-resistant S. pneumoniae reflects changes in the pneumococcus itself and the general indiscriminate use of antibiotics in treatment of respiratory infections in Hong Kong.


Crystal structure of eta-crystallin: adaptation of a class 1 aldehyde dehydrogenase for a new role in the eye lens.
Eta-crystallin is a retinal dehydrogenase that has acquired a role as a structural protein in the eye lens of elephant shrews, members of an ancient order of mammals. While it retains some activity toward retinal, which is oxidized to retinoic acid, the protein has acquired a number of specific sequence changes that have presumably been selected to enhance the lens role. The crystal structure of eta-crystallin, in common with class 1 and 2 ALDHs, is a dimer of dimers. It has a better-defined NAD binding site than those of related mammalian ALDH1 enzymes with the cofactor bound in the "hydride transfer" position in all four monomers with small differences about the dimer dyads. Although the active site is well conserved, the substrate-binding site is larger in eta-crystallin, and there are some mutations to the substrate access tunnel that might affect binding or release of substrate and product. It is possible that eta-crystallin has lost flexibility to improve its role in the lens. Enhanced binding of cofactor could enable it to act as a UV/blue light filter in the lens, improving visual acuity. The structure not only gives a view of a "natural mutant" of ALDH1 illustrating the adaptive conflict that can arise in multifunctional proteins, but also provides a well-ordered NAD binding site structure for this class of enzymes with important roles in development and health.


The Psychological Inflexibility in Pain Scale (PIPS)--statistical properties and model fit of an instrument to assess change processes in pain related disability.
Recent developments within CBT have emphasized acceptance rather than control of pain and distress in treatments aimed at improving functioning and life quality, but there is still a lack of reliable and valid instruments to assess relevant processes in such interventions. The Psychological Inflexibility in Pain Scale (PIPS) was developed to assess target variables in exposure and acceptance oriented treatments. A preliminary validation study resulted in a two-factor solution with subscales for avoidance and cognitive fusion related to pain, showing satisfactory psychometric properties. This study sought to evaluate the instrument with 611 participants with whiplash associated disorders. Exploratory and confirmatory factor analyses supported a two-factor solution with 12 items which showed an acceptable model fit, adequate internal consistencies, and strong relations with criteria variables (e.g. disability and life satisfaction). The construct validity of the instrument was supported by high correlations with subscales from the Chronic Pain Acceptance Questionnaire (CPAQ) and the Tampa Scale of Kinesiophobia (TSK). Notably, hierarchical regression analyses illustrated that PIPS explained more variance than TSK in pain, disability, life satisfaction and depression. Furthermore, PIPS was found to mediate the relationship between e.g. pain and disability, suggesting the usefulness of PIPS as a process measure in treatments of people with chronic pain. Thus, it is argued that this 12-item version of PIPS may be used to explore the importance of psychological in/flexibility in chronic pain and to analyse processes of change in exposure based interventions, as well as for clinicians in tailoring interventions for patients with chronic debilitating pain.


[Functional characteristics of electroreceptors (small pitted organs) of the dwarf catfish].
The response characteristics of the small pit organs in the catfish Ictalurus nebulosus to electrical stimuli of various polarities, intensities and durations were investigated using the recording of electrical activity from single nerve fibres of the lateral nerve. The fibres showed background activity either rhythmical (35-45 imp/s) or modulated by fish swimming movements. The current density thresholds were in a range of 10 minus 10 -10 minus 11 /mm-2. Electrical stimulation evoked a phasic-tonic response in the electroreceptor fibres. The latencies varied from 10 to 50 ms for on-responses and from 10 to 200 ms for off-responses. Certain units responded with excitation to strong cathodal stimulation, and with excitatory response to anodal stimulus of weak or moderate intensity. The properties of small pit organs and other electroreceptors are compared.


In vitro and in vivo evaluation of a pH-, microbiota- and time-based oral delivery platform for colonic release.
Several formulation strategies have been proposed for oral colon delivery, particularly for the therapy of inflammatory bowel disease (IBD). However, targeting the large intestine remains a challenging goal. The aim of this study was to develop and evaluate a novel type of drug delivery system, which is based on multiple drug release triggers for reliable performance. The system consists of: (i) a drug core, (ii) an inner swellable low-viscosity hydroxypropyl methylcellulose (HPMC) layer, and (iii) an outer film coating based on a Eudragit® S:high-methoxyl (HM) pectin (7:3 w/w) blend, optionally containing chitosan. Convex immediate release tablets (2 or 4 mm in diameter) containing paracetamol or 5-aminosalicylic acid (5-ASA) were coated in a fluid bed. The double-coated tablets exhibited pulsatile release profiles when changing the release medium from 0.1 N HCl to phosphate buffer pH 7.4. Also, drug release was faster in simulated colonic fluid (SCF) in the presence of fecal bacteria from IBD patients compared to control culture medium from tablets with outer Eudragit® S: HM pectin: chitosan coatings. The latter systems showed promising results in the control of the progression of colitis and alteration of the microbiota in a preliminary rat study.


Chemoreceptor dependence of very low frequency rhythms in advanced chronic heart failure.
Factors responsible for very low frequency oscillations (VLF; cycle > 30 s) in the cardiovascular system remain obscure. We tested the hypothesis that increased peripheral chemosensitivity is important in the pathogenesis of VLF oscillations in patients with chronic heart failure (CHF). Fourteen male patients with stable, moderate to severe CHF (age 60 +/- 1.1 yr, ejection fraction 23 +/- 11%) and reproducible VLF oscillations in heart rate underwent a protocol consisting of three consecutive 20-min phases during which they breathed air, hyperoxia (O2 via mask, 60% O2 concn), and air again. Autoregressive spectral analysis of R-R intervals, blood pressure, and respiration was used to quantify total oscillatory power (TP), VLF, low (0.04-0.15 Hz)- and high (0.15-0.40Hz)-frequency power, and the coherence between these signals. Peripheral chemosensitivity was studied by assessing the ventilatory response to hypoxia using transient inhalations of pure N2. Discrete VLF rhythms were seen in R-R intervals in all 14 patients, in blood pressure in 7 of 14, and in respiration in 8 of 14 patients. A significant coherence (> 0.5) between heart rate and systolic blood pressure within the VLF band with mean phase value of -140 degrees, suggesting an antibaroreflex relationship, was seen in six subjects. Transient hyperoxia abolished the VLF oscillations in most subjects (12 of 14 in R-R intervals) and decreased R-R variability power within the VLF band. This response significantly correlated with peripheral chemoreceptor sensitivity (r = 0.77, P = 0.014). This study suggests that in CHF, enhanced peripheral chemoreceptor activity may facilitate slow oscillations in the cardiorespiratory signals.


Closing-in behavior in mild cognitive impairment: an executive deficit.
This study explored Closing-in behavior (CIB), the tendency in figure copying to draw very close to or on top of the model, in mild cognitive impairment (MCI). The files of 154 people diagnosed with MCI were reviewed and CIB was identified in 21% of cases. Two approaches were used to explore CIB. First, we capitalized on the diverse cognitive profiles within MCI, subdividing the overall sample into people with and without memory deficits. The frequency of CIB was significantly higher in multidomain non-amnestic MCI than in multidomain amnestic MCI, suggesting that CIB is not associated with specific memory impairment. Second, we assessed the cognitive correlates of CIB, by selecting patients with MCI who completed a battery of executive, visuo-constructional and memory tasks. Sub-groups of patients with and without CIB showed a similar overall severity of cognitive decline and comparable performance in visuo-constructional and memory tasks, but those with CIB were slightly but significantly more impaired on executive function tasks. The study provides evidence against memory-based accounts of CIB, and supports recent suggestions that executive impairments are the dominant cognitive correlate of this clinical sign.


The "incompleat" physicians: community physicians' lack of knowledge of medical socioeconomics and politics.
The suspicion that physicians in this community know little about current events in American medical socioeconomics and politics led to a survey of the local medical society membership. The results showed a discouraging lack of knowledge about information that is readily available to physicians. We concluded that current methods for educating physicians in these subjects are largely ineffective. Live, as opposed to printed, presentations at local, state, and specialty medical society meetings may be more effective in educating, and thereby involving, physicians in the critical political and economic issues presently facing them.


Measurement of tissue scattering properties using multi-diameter single fiber reflectance spectroscopy: in silico sensitivity analysis.
Multiple diameter single fiber reflectance (MDSFR) measurements of turbid media can be used to determine the reduced scattering coefficient (μ'(s)) and a parameter that characterizes the phase function (γ). The MDSFR method utilizes a semi-empirical model that expresses the collected single fiber reflectance intensity as a function of fiber diameter (d(fiber)), μ'(s), and γ. This study investigated the sensitivity of the MDSFR estimates of μ'(s) and γ to the choice of fiber diameters and spectral information incorporated into the fitting procedure. The fit algorithm was tested using Monte Carlo simulations of single fiber reflectance intensities that investigated biologically relevant ranges of scattering properties (μ'(s) ∈ [0.4 - 4]mm(-1)) and phase functions (γ ∈ [1.4 - 1.9]) and for multiple fiber diameters (d(fiber) ∈ [0.2 - 1.5] mm). MDSFR analysis yielded accurate estimates of μ'(s) and γ over the wide range of scattering combinations; parameter accuracy was shown to be sensitive to the range of fiber diameters included in the analysis, but not to the number of intermediate fibers. Moreover, accurate parameter estimates were obtained without a priori knowledge about the spectral shape of γ. Observations were used to develop heuristic guidelines for the design of clinically applicable MDSFR probes.


Hsa_circ_0136666 stimulates gastric cancer progression and tumor immune escape by regulating the miR-375/PRKDC Axis and PD-L1 phosphorylation.
Targeted drugs are not quite effective for prolonging the survival of patients with gastric cancer due to off-target effects as well as tumor immune escape mechanisms. Circular RNAs widely exist in tumor regions as biomarkers and can be developed as effective drug targets. Western blot, QRT-PCR, fluorescence in situ hybridization, and flow cytometry were used to investigate the function of hsa_circ_0136666 in promoting the proliferation of gastric cancer cells. Tissue immunofluorescence, enzyme-linked immunosorbent assay (ELISA), as well as flow cytometric analysis, was conducted to explore the process of tumor immune evasion in tumor-bearing mice. The differences of circRNA expression in clinical samples were analyzed through tissue microarray FISH. The effect of siRNA on improving the efficacy of anti-PDL1 drugs and suppressing the immune microenvironment was evaluated by the coadministration model. We demonstrated that hsa_circ_0136666 was widely and highly expressed in gastric cancer tissues and cells. Functionally, hsa_circ_0136666 promoted gastric cancer tumor proliferation and tumor microenvironment formation, leading to tumorigenesis immune escape, and this effect was dependent on CD8 + T cells. Mechanistically, we confirmed that hsa_circ_0136666 competitively upregulated PRKDC expression by sponging miR-375-3p, regulating immune checkpoint proteins, prompting phosphorylation of PD-L1 to preventing its degradation, driving PD-L1 aggregation and suppressing immune function, thereby impairing cancer immune responses. In terms of application, we found that LNP-siRNA effectively improved anti-PDL1 drug efficacy and inhibited immune escape. Our results reveal an oncogenic role played by hsa_circ_0136666 in gastric cancer, driving PD-L1 phosphorylation via the miR-375/PRKDC signaling axis, prompting immune escape. This work proposes a completely new pathogenic mechanism of gastric cancer, uncovers a novel role for hsa_circ_0136666 as an immune target, and provides a rationale for enhancing the efficacy of anti-PD-L1 therapy for gastric cancer.


[Features of pathological changes of fibro-cartilaginous tissue knee in patients with Baker cyst.]
Using magnetic resonance imaging (MRI) to evaluate the characteristics of pathological changes of fibro-cartilage of the knee in patients with Baker cyst, to assess the compliance of degrees of damage stages of osteoarthritis on a scale of Kellgren–Lawrence (K–L), and compare the results with the data of other researchers. This study included patients (38–82 years) with a cyst Baker accidentally detected during ultrasound veins of the lower extremities. The subjects underwent a single knee MRI. MRI was made in three dimensions using 3D gradient-echo protocol. Independent radiologist evaluated the presence and severity of chondral defect osteophytosis, damage to the menisci and ligaments, intraosseous edema and subchondral cysts. The osteoarthritis stage of the knee were identified by X-ray performed in a standing position in the standard two projections, with K–L scale. In this study, the results of a survey of 20 people, whose average age was 57.2 years. According to the radiological scale of K–L two patients were assigned to the stage 0 degree, 5 people to stage 1, 2, 4 each, and 3 – to stage 3. Synovitis of various severity was detected in 85% of the studies. Nineteen visualized the patellar cartilage damage, the condyles of the femur and tibia are most commonly affects the joint area. Among the most commonly injured ligament anterior cruciate ligament was determined – 9 (45%) patients in the same amount of detected intramedullary edema condyles femur and tibia. Eighteen subjects had at least one anomaly meniscus detectable by MRI, while in 11 (55%) persons were deviations, at least two or more regions of the knee examined. Our results suggest that not all visualized on MRI degenerative damage to intra fibro-cartilaginous tissue correlate positively with the stages of osteoarthritis of the knee, identified by standard radiographs and may not significantly affect the onset and progression of synovial cyst of the popliteal region.


Posterior Canal Fibrosis: A Case Series.
To establish a case series where loss of magnetic resonance fluid signal intensity in the posterior semicircular canal (SCC) corresponded with a functional deficit on clinical and video head impulse testing, and most likely a result of canal fibrosis or obstruction. Three patients with an magnetic resonance imaging (MRI) showing loss of T2-weighted signal intensity in their posterior SCC corresponding to a vestibular weakness in that canal. All patients underwent a comprehensive neuro-otologic examination. Vestibulo-ocular reflex was evaluated using clinical head impulse testing (cHIT) and quantified with video head impulse testing. MRI for all patients was obtained using clinical protocols for gadolinium-enhanced MRI of the internal auditory canal on 1.5 or 3 T scanners, which all included high-resolution, heavily T2-weighted imaging of the membranous labyrinth. Correlation of MRI findings with vestibular weakness in the corresponding posterior SCC. Subject 1 showed abnormal vHIT in the left lateral and left posterior SCCs. MRI showed loss of T2 signal intensity of the entire left posterior SCC as well as in the posterior limb of the superior SCC. Subject 2 showed isolated loss of function (cHIT) and low gain with catch-up saccade (vHIT) of the left posterior SCC. MRI showed loss of T2 signal intensity of the superior portion of the left posterior SCC, as well as in the posterior limb of the superior SCC. Subject 3 showed catch-up saccades of the left posterior SCC on cHIT and vHIT and loss of T2 signal intensity of the entire left posterior SCC and partial loss of bilateral lateral SCC on MRI. In this case series, loss of posterior SCC function correlated with vestibular function testing and high-resolution, T2-weighted MRI findings, perhaps related to fibrosis of the posterior SCC.


The pursuit of being in the life and thought of Jean-Paul Sartre.
This paper has examined the relationship between the life and the thought of Jean-Paul Sartre. The central themes of Sartre's personal existence are shown to revolve around a struggle for self-definition and self-formation, rooted in the empathic failures of significant others during his formative years. It is argued that Sartre's experience of this struggle is mirrored and symbolized by the dialectic of being and nothingness which constitutes the central preoccupation of his philosophy.


Optical properties of size selected neutral Ag clusters: electronic shell structures and the surface plasmon resonance.
We present optical absorption spectra from the ultraviolet to the visible for size selected neutral Agn clusters (n = 5-120) embedded in solid Ne. We compare the spectra to time-dependent density functional calculations (TDDFT) that address the influence of the Ne matrix. With increasing size, several highly correlated electron excitations gradually develop into a single surface plasmon. Its energy is situated between 3.9 and 4.1 eV and varies with size according to the spherical electronic shell model. The plasmon energy is highest for clusters with atom numbers fully filling states with the lowest radial quantum number (e.g. 1s, 1p, 1d,...). TDDFT calculations for clusters with several candidate geometrical structures embedded in Ne show excellent agreement with the experimental data, demonstrating that the absorption bands depend only weakly on the exact structure of the cluster.


Tactile and visual distractors induce change blindness for tactile stimuli presented on the fingertips.
Recent studies of change detection have revealed that people are surprisingly poor at detecting changes between two consecutively-presented scenes, when they are separated by a distractor that masks the transients typically associated with change. This failure, known as 'change blindness', has been reported within vision, audition, and touch. In the three experiments reported here, we investigated people's ability to detect the change between two patterns of tactile stimuli presented to their fingertips. The two to-be-compared patterns were presented either consecutively, separated by an empty interval or else by a tactile, visual, or auditory mask. Participants' performance was impaired when an empty interval was inserted between the two consecutively-presented patterns as compared with the consecutive stimulus presentation. Participants' performance was further impaired not only when a tactile mask was introduced between the two to-be-compared displays, but also when a visual mask was used instead. Interestingly, however, the addition of an auditory mask to an empty interval did not have any effect on participants' performance. These results are discussed in relation to the multisensory/amodal nature of spatial attention.


Response of Gallium Nitride Chemiresistors to Carbon Monoxide is Due to Oxygen Contamination.
We report on the influence of oxygen impurities on the gas sensing properties of gallium nitride (GaN) chemiresistors. As shown by XRD, elemental analysis, and TEM characterization, surface oxidation of GaN-for example, upon contact to ambient air atmosphere-creates an oxidative amorphous layer which provides the sites for the sensing toward CO. Treating this powder under dry ammonia at 800 °C converts the oxide layer in nitride, and consequently the sensing performance toward CO is dramatically reduced for ammonia treated GaN gas sensors. Hence the response of GaN sensors to CO is caused by oxygen in the form of amorphous surface oxide or oxynitride.


A 14-year study of heparin-induced thrombocytopenia.
To determine the sites of thromboses (venous versus arterial circulation) that complicate the clinical course of immunemediated heparin-induced thrombocytopenia, and to determine the 30-day risk for thrombosis in patients who are initially recognized with isolated heparin-induced thrombocytopenia. We analyzed objectively documented thrombotic events that complicated the clinical course of 127 patients with serologically confirmed heparin-induced thrombocytopenia identified in one medical community over a 14-year period. We classified heparin-induced thrombocytopenia patients into two groups: patients recognized with heparin-induced thrombocytopenia only after a new thrombosis had occurred, and patients initially recognized with isolated heparin-induced thrombocytopenia. We determined the subsequent 30-day risk for thrombosis for the cohort of patients initially recognized with isolated thrombocytopenia. Heparin-induced thrombocytopenia was associated with the development of new venous thrombotic events and arterial thrombotic events in 78 and 18 patients, respectively (ratio venous/arterial thrombosis = 4:1). Pulmonary embolism was the most common life-threatening thrombotic event, occurring in 25% of all patients. Approximately half of all heparin-induced thrombocytopenia patients were recognized only after they had a complicating thrombotic event. Of the remaining 62-patient cohort initially recognized with isolated thrombocytopenia, the subsequent 30-day risk of thrombosis was 52.8%. The risk of thrombosis did not differ whether the heparin had been discontinued alone or whether warfarin had been substituted for the heparin. Venous thrombosis complicates heparin-induced thrombocytopenia more frequently than does arterial thrombosis. The high risk of thrombosis in patients initially recognized with isolated thrombocytopenia suggests that conventional management approaches require reappraisal.


Role of complex carbohydrates and neurulation.
Extracellular and cell-coat complex carbohydrates play a major role in critical cellular functions, e.g., cell recognition and cell-to-cell adherence, which are involved in neurulation. To date, available evidence suggests that neurulation is a combination of intercellular and extracellular biochemical and morphological events which are under the direction of the genome. To define the carbohydrate components that are essential to neurulation, normal C-57 and abnormal splotch (Sp/Sp) mouse embryos were studied using fluorescein-labeled lectins and computer-aided microspectrophotometric analysis of hyaluronate lyase and chondroitin ABC lyase-sensitive Alcian blue staining. Preliminary results of these studies indicate that the neuroepithelium of the splotch Sp/Sp mutant, a genetic model of a primary neural tube defect, is characterized by alterations in the type and amount of glycoconjugates and in the concentration of individual glycosaminoglycans. This review of mammalian neurulation discusses the importance of complex carbohydrates on the cell surface of the neuroepithelium of the closing neural fold.


Small effect of water on upper-mantle rheology based on silicon self-diffusion coefficients.
Water has been thought to affect the dynamical processes in the Earth's interior to a great extent. In particular, experimental deformation results suggest that even only a few tens of parts per million of water by weight enhances the creep rates in olivine by orders of magnitude. However, those deformation studies have limitations, such as considering only a limited range of water concentrations and very high stresses, which might affect the results. Rock deformation can also be understood as an effect of silicon self-diffusion, because the creep rates of minerals at temperatures as high as those in the Earth's interior are limited by self-diffusion of the slowest species. Here we experimentally determine the silicon self-diffusion coefficient DSi in forsterite at 8 GPa and 1,600 K to 1,800 K as a function of water content CH2O from less than 1 to about 800 parts per million of water by weight, yielding the relationship, DSi ≈ (CH2O)(1/3). This exponent is strikingly lower than that obtained by deformation experiments (1.2; ref. 7). The high nominal creep rates in the deformation studies under wet conditions may be caused by excess grain boundary water. We conclude that the effect of water on upper-mantle rheology is very small. Hence, the smooth motion of the Earth's tectonic plates cannot be caused by mineral hydration in the asthenosphere. Also, water cannot cause the viscosity minimum zone in the upper mantle. And finally, the dominant mechanism responsible for hotspot immobility cannot be water content differences between their source and surrounding regions.


Illegitimacy moderates the effects of power on approach.
A wealth of research has found that power leads to behavioral approach and action. Four experiments demonstrate that this link between power and approach is broken when the power relationship is illegitimate. When power was primed to be legitimate or when power positions were assigned legitimately, the powerful demonstrated more approach than the powerless. However, when power was experienced as illegitimate, the powerless displayed as much approach as, or even more approach than, the powerful. This moderating effect of legitimacy occurred regardless of whether power and legitimacy were manipulated through experiential primes, semantic primes, or role manipulations. It held true for behavioral approach (Experiment 1) and two effects associated with it: the propensity to negotiate (Experiment 2) and risk preferences (Experiments 3 and 4). These findings demonstrate that how power is conceptualized, acquired, and wielded determines its psychological consequences and add insight into not only when but also why power leads to approach.


Estimating the heritability of reporting stressful life events captured by common genetic variants.
Although usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies. Method We examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings. A significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This 'heritability' was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10-8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R 2 = 0.08 in SLEs (p = 0.03). These results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality.


[Gerontologic aspects of postmenopausal measurement of bone density and prevention of osteoporosis].
I. Among 454 postmenopausal women to undergo bone mineral density (BMD) examination 7 out of 10 were aged 50 to 70 years. 1. 50 of patients older than 70 years had BMD examination because of being clinically suspicious of osteoporosis. 2. In this group of age 4 out of 10 women had BMD results of the lumbar spine below 0,8 gcm2. 3. Half of all women aged up to 50 years had a positive family history of osteoporosis. 4. Patients older than 60 years often underestimated their own risk of osteoporosis. 5. 50 of women up to the age of 50 and only one sixth of women older than 70 said they had very good to good knowledge of osteoporosis. 6. Resentments against estrogen substitution are rapidly growing with every decade of age. 7. Only one third of the women selected by BMD-indication were ready to accept longterm estrogen substitution to prevent osteoporosis. II. 4 out of 10 women had entered menopause maximally 8 years ago.1. Out of this group 6 of 10 patients were substituted with estrogen. 2. When menstruation had sisted more than 15 years ago the BMD examination indication, clinically suspicious of osteoporosis, rose immensely and made up for 50 of patients. 3. One third to one half of patients who had reached menopause more than 22 years ago showed pathological BMD results, which means they were at risk of fractures. 4. In this group only 1 in 10 women had a positive history of osteoporosis. III. Obese postmenopausal women (more than 25 of overweight according to Broca) had pathologic BMD results only half as often as postmenopausal women with normal weight. Summing it up these facts may be the basis of special counselling on the prevention of osteoporosis by estrogen substitution.


Nuclear activity of ROXY1, a glutaredoxin interacting with TGA factors, is required for petal development in Arabidopsis thaliana.
Glutaredoxins (GRXs) have thus far been associated mainly with redox-regulated processes participating in stress responses. However, ROXY1, encoding a GRX, has recently been shown to regulate petal primorida initiation and further petal morphogenesis in Arabidopsis thaliana. ROXY1 belongs to a land plant-specific class of GRXs that has a CC-type active site motif, which deviates from ubiquitously occurring CPYC and CGFS GRXs. Expression studies of yellow fluorescent protein-ROXY1 fusion genes driven by the cauliflower mosaic virus 35S promoter reveal a nucleocytoplasmic distribution of ROXY1. We demonstrate that nuclear localization of ROXY1 is indispensable and thus crucial for its activity in flower development. Yeast two-hybrid screens identified TGA transcription factors as interacting proteins, which was confirmed by bimolecular fluorescence complementation experiments showing their nuclear interaction in planta. Overlapping expression patterns of ROXY1 and TGA genes during flower development demonstrate that ROXY1/TGA protein interactions can occur in vivo and support their biological relevance in petal development. Deletion analysis of ROXY1 demonstrates the importance of the C terminus for its functionality and for mediating ROXY1/TGA protein interactions. Phenotypic analysis of the roxy1-2 pan double mutant and an engineered chimeric repressor mutant from PERIANTHIA (PAN), a floral TGA gene, supports a dual role of ROXY1 in petal development. Together, our results show that the ROXY1 protein functions in the nucleus, likely by modifying PAN posttranslationally and thereby regulating its activity in petal primordia initiation. Additionally, ROXY1 affects later petal morphogenesis, probably by modulating other TGA factors that might act redundantly during differentiation of second whorl organs.


Remembering as an observer: how is autobiographical memory retrieval vantage perspective linked to depression?
It has long been noted that the emotional impact of an autobiographical memory is associated with the vantage perspective from which it is recalled (Freud, 1950). Memories recalled from a first-person "field" perspective are phenomenologically rich, while third-person "observer" perspective memories contain more descriptive but less affective detail (Nigro & Neisser, 1983). Although there is some evidence that depressed individuals retrieve more observer memories than non-depressed individuals (e.g., Kuyken & Howell, 2006), little is known of the cognitive mechanisms associated with observer memories in depression. At pre- and post-treatment, 123 patients with a history of recurrent depression completed self-report measures and the autobiographical memory task (AMT). Participants also indicated the vantage perspective of the memories recalled on the AMT. Observer memories were less vivid, older, and more frequently rehearsed. The tendency to retrieve observer perspective memories was associated with greater negative self-evaluation, lower dispositional mindfulness, and greater use of avoidance. Furthermore, participants who recalled more field perspective memories at pre-treatment had lower levels of post-treatment depression, controlling for pre-treatment levels of depression and trait rumination. We apply contemporary accounts from social and cognitive psychology, and propose potential mechanisms that link the tendency to retrieve observer perspective memories to depression.


Deregulation of Cdt1 induces chromosomal damage without rereplication and leads to chromosomal instability.
The activity of human Cdt1 is negatively regulated by multiple mechanisms. This suggests that Cdt1 deregulation may have a deleterious effect. Indeed, it has been suggested that overexpression of Cdt1 can induce rereplication in cancer cells and that rereplication activates Ataxia-telangiectasia-mutated (ATM) kinase and/or ATM- and Rad3-related (ATR) kinase-dependent checkpoint pathways. In this report, we highlight a new and interesting aspect of Cdt1 deregulation: data from several different systems all strongly indicate that unregulated Cdt1 overexpression at pathophysiological levels can induce chromosomal damage other than rereplication in non-transformed cells. The most important finding in these studies is that deregulated Cdt1 induces chromosomal damage and activation of the ATM-Chk2 DNA damage checkpoint pathway even in quiescent cells. These Cdt1 activities are negatively regulated by cyclin A/Cdks, probably through modification by phosphorylation. Furthermore, we found that deregulated Cdt1 induces chromosomal instability in normal human cells. Since Cdt1 is overexpressed in cancer cells, this would be a new molecular mechanism leading to carcinogenesis.


A meal with mixed soy/whey proteins is as efficient as a whey meal in counteracting the age-related muscle anabolic resistance only if the protein content and leucine levels are increased.
With aging, skeletal muscle becomes resistant to the anabolic effect of dietary proteins and sarcopenia develops. Animal proteins, which are rich in leucine, are recommended for the elderly, but it is not known whether their replacement by plant proteins would maintain the health and physical independence of this population. Aged rats were fed with animal proteins (casein and whey proteins) with different leucine contents and compared to rats fed with diets in which whey was substituted with soy proteins and by increasing the total protein content or not. Our results clearly showed that the meal with mixed soy/whey proteins allowed the anabolic response of skeletal muscle during aging only if the protein content was increased by 25%. Indeed, if the protein content of the soy/whey diet was decreased to a similar protein content such as a whey diet, i.e. 13%, the anabolic effect decreased. The same observation was recorded if the whey proteins were totally substituted with soy proteins.


Use of RFID technology to characterize feeder visitations and contact network of hummingbirds in urban habitats.
Despite the popular use of hummingbird feeders, there are limited studies evaluating the effects of congregation, sharing food resources and increased contact when hummingbirds visit feeders in urban landscapes. To evaluate behavioral interactions occurring at feeders, we tagged 230 individuals of two species, Anna's and Allen's Hummingbirds, with passive integrated transponder tags and recorded their visits with RFID transceivers at feeders. For detecting the presence of tagged birds, we developed an RFID equipped feeding station using a commercially available antenna and RFID transceiver. Data recorded included the number of feeder visits, time spent at the feeder, simultaneous feeder visitation by different individuals, and identifying which feeders were most commonly visited by tagged birds. For the study period (September 2016 to March 2018), 118,017 detections were recorded at seven feeding stations located at three California sites. The rate of tagged birds returning to RFID equipped feeders at least once was 61.3% (141/230 birds). Females stayed at feeders longer than males per visit. We identified primary, secondary and tertiary feeders at Sites 2 and 3, according to the frequency of visitation to them, with a mean percentage of 86.9% (SD±19.13) visits to a primary feeder for each tagged hummingbird. During spring and summer, hummingbirds visited feeders most often in morning and evening hours. Feeder visits by males overlapped in time with other males more frequently than other females. The analysis of the contact network at the feeders did not distinguish any significant differences between age or sex. Although most hummingbirds visited the feeders during the daytime, our system recorded night feeder visitations (n = 7 hummingbirds) at one site. This efficient use of RFID technology to characterize feeder visitations and contact networks of hummingbirds in urban habitats could be used in the future to elucidate behaviors, population dynamics and community structure of hummingbirds visiting feeders.


[Total gastrectomy versus partial gastrectomy of adenocarcinoma of the antrum. A French prospective controlled study].
In a prospective multicentric trial we compared the post-operative mortality and the 5-year survival of elective total gastrectomy (TG) versus subtotal gastrectomy (SG) for adenocarcinoma of the antrum operated on with intent of cure. Two hundred and one patients were included in the study: thirty two were excluded after pathological examination (linitis plastica, superficial cancer, lymphoma). One hundred and sixty nine patients remained for analysis with 93 TG and 76 SG. Elective TG did not increase post-operative mortality (1.3%) in comparison with SG (3.2%). There was no difference in the 5-year survival rate (48%). Analysis of survival showed no difference in the two techniques when related to nodal involvement and serosal extension. It is concluded that both operations TG and SG can be performed safely in patients with adenocarcinoma of the antrum; however TG did not increase the survival rate.


A model for educational simulation of infant cardiovascular physiology.
Full-body patient simulators provide the technology and the environment necessary for excellent clinical education while eliminating risk to the patient. The extension of simulator-based training into management of basic and critical situations in complex patient populations is natural. We describe the derivation of an infant cardiovascular model through the redefinition of a complete set of parameters for an existing adult model. Specifically, we document a stepwise parameter estimation process, explicit simplifying assumptions, and sources for these parameters. The simulated vital signs are within the target hemodynamic variables, and the simulated systemic arterial pressure wave form and left ventricular pressure volume loop are realistic. The system reacts appropriately to blood loss, and incorporation of aortic stenosis is straightforward. This infant cardiovascular model can form the basis for screen-based educational simulations. The model is also an essential step in attaining a full-body, model-driven infant simulator.


Energetics of the ruthenium-halide bond in olefin metathesis (pre)catalysts.
A DFT analysis of the strength of the Ru-halide bond in a series of typical olefin metathesis (pre)catalysts is presented. The calculated Ru-halide bond energies span the rather broad window of 25-43 kcal mol(-1). This indicates that in many systems dissociation of the Ru-halide bond is possible and is actually competitive with dissociation of the labile ligand generating the 14e active species. Consequently, formation of cationic Ru species in solution should be considered as a possible event.


The associations of cardiorespiratory fitness, adiposity and sports participation with arterial stiffness in youth with chronic diseases or physical disabilities.
Background The evidence on the associations of cardiorespiratory fitness, body adiposity and sports participation with arterial stiffness in children and adolescents with chronic diseases or physical disabilities is limited. Methods Altogether 140 children and adolescents with chronic diseases or physical disabilities participated in this cross-sectional study. Cardiorespiratory fitness was assessed using maximal exercise test with respiratory gas analyses either using shuttle run, shuttle ride, or cycle ergometer test. Cardiorespiratory fitness was defined as peak oxygen uptake by body weight or fat-free mass. Body adiposity was assessed using waist circumference, body mass index standard deviation score and body fat percentage. Sports participation was assessed by a questionnaire. Aortic pulse wave velocity and augmentation index were assessed by a non-invasive oscillometric tonometry device. Results Peak oxygen uptake/body weight (standardised regression coefficient β -0.222, 95% confidence interval (CI) -0.386 to -0.059, P = 0.002) and peak oxygen uptake/fat-free mass (β -0.173, 95% CI -0.329 to -0.017, P = 0.030) were inversely and waist circumference directly (β 0.245, 95% CI 0.093 to 0.414, P = 0.002) associated with aortic pulse wave velocity. However, the associations of the measures of cardiorespiratory fitness with aortic pulse wave velocity were attenuated after further adjustment for waist circumference. A higher waist circumference (β -0.215, 95% CI -0.381 to -0.049, P = 0.012) and a higher body mass index standard deviation score (β 0.218, 95% CI -0.382 to -0.054, P = 0.010) were related to lower augmentation index. Conclusions Poor cardiorespiratory fitness and higher waist circumference were associated with increased arterial stiffness in children and adolescents with chronic diseases and physical disabilities. The association between cardiorespiratory fitness and arterial stiffness was partly explained by waist circumference.


Acetylenic Coupling: A Powerful Tool in Molecular Construction.
Acetylenic coupling is currently experiencing some of the most intensive study of its long history. Rigid and sterically undemanding di- and oligoacetylene moieties, which are frequently encountered in natural products, are finding increasing application as key structural elements in synthetic receptors for molecular recognition. Interesting electronic and optical properties of extensively pi-conjugated systems have spurred research into new linear oligoalkynes and acetylenic carbon allotropes. The synthetic challenges associated with these efforts have in turn spawned new methods. While classical Glaser conditions are still frequently used for homocoupling, the demand for increasingly selective heterocoupling conditions has provided the focus of research over the past decades. These efforts have undoubtedly been hampered by a relatively poor mechanistic understanding of these processes. More recently, palladium-catalyzed coupling methods have led to improvements in both the selectivity and reliability of acetylenic homo- and heterocouplings and paved the way for their application to ever more complicated systems. The variety of acetylenic coupling protocols, the current mechanistic understanding, and their application in natural product and targeted synthesis are discussed comprehensively for the first time in this review, with an emphasis on the most recently developed methods, and their application to the synthesis of complex macromolecular structures.


Interventional endoscopic ultrasound.
Endoscopic ultrasonography (EUS), since its development in the 1980s, has undergone a great deal of technological advancement in imaging, scopes with larger channels and accessories. This has given the endosonographer an immense reach in terms of accessing difficult areas with fewer complications. Currently, it is possible not only to obtain tissue for histological diagnosis but also to perform therapeutic procedures that hitherto would have needed surgery with its attendant morbidity. EUS has evolved over the years and EUS-guided fine needle aspiration for histological diagnosis has become standard practice. A wide array of interventional procedures are performed under EUS guidance including, celiac plexus neurolysis, drainage of pancreatic and pelvic fluid collections, drainage of obstructive biliary/pancreatic ducts, and implantation of fiducial markers/radioactive seeds into gastrointestinal tumors. Also, various experimental procedures are underway evaluating the role of EUS in radiofrequency ablation, vascular therapy, and natural orifice transluminal endoscopic surgery. In this review, we examine the various EUS-guided interventions currently undertaken and explore the potential of other emerging experimental techniques.


Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients.
Three-hundred and twenty-four patients were enrolled in an open-label, multicenter, international study in which pre- and post-liver transplantation (LT) patients with recurrent chronic hepatitis B (CHB) and evidence of lamivudine-resistant HBV were treated with adefovir dipivoxil 10 mg once daily. In the pre- and post-LT cohorts, 128 and 196 patients were treated for a median duration of 18.7 and 56.1 weeks, respectively. In patients who received 48 weeks of treatment, 81% of the pre-LT and 34% of the post-LT cohort achieved undetectable serum hepatitis B virus (HBV) DNA (Roche Amplicor Monitor polymerase chain reaction [PCR] assay lower limit of quantification [LLQ] < 400 copies/mL) with a median change in serum HBV DNA from baseline of -4.1 log(10) and -4.3 log(10) copies/mL, respectively. Serum alanine aminotransferase (ALT), albumin, bilirubin, and prothrombin time normalized in 76%, 81%, 50%, and 83% of pre-LT patients and 49%, 76%, 75%, and 20% of post-LT patients. The Child-Pugh-Turcotte (CPT) score improved in over 90% of patients in both cohorts. Genotypic analysis of 122 HBV baseline samples revealed that 98% of these patients had lamivudine-resistant mutant HBV. No adefovir resistance mutations were identified in patients after 48 weeks of therapy. One-year survival was 84% for pre-LT and 93% for post-LT patients (Kaplan-Meier analysis). Treatment-related adverse effects associated with adefovir dipivoxil in this setting were primarily mild to moderate in severity. In conclusion, 48 weeks of adefovir dipivoxil resulted in significant improvements in virologic, biochemical, and clinical parameters in CHB patients pre- and post-LT with lamivudine-resistant HBV.


Pathogenesis of emphysema: from the bench to the bedside.
Chronic obstructive pulmonary disease (COPD) is characterized physiologically by expiratory flow limitation and pathologically by alveolar destruction and enlargement and small and large airway inflammation and remodeling. An imbalance between protease and antiprotease activity in the lung is proposed as the major mechanism resulting in emphysema. The imbalance is mostly due to an increase in the numbers of alveolar macrophages and neutrophils. Emphysema can also develop from increased alveolar wall cell death and/or failure in alveolar wall maintenance. Chronic inflammation and increased oxidative stress contribute to increased destruction and/or impaired lung maintenance and repair. Genetic factors may play an important role in disease susceptibility because only a minority of smokers develops emphysema. Recent literature implicates surfactant instability, malnutrition, and alveolar cell apoptosis as possible etiologies. Identification of cellular and molecular mechanisms of COPD pathogenesis is an area of active, ongoing research that may help to determine therapeutic targets for emphysema.


Polyomavirus simian virus 40 infection associated with nephropathy in a lung-transplant recipient.
Between 1955 and 1963, millions of individuals worldwide received vaccines contaminated with polyomavirus simian virus (SV)40. Recent data suggest that some individuals may develop renal dysfunction related to SV40 infection, including individuals too young to have received contaminated vaccines. Three years after bilateral lung transplantation, a 32-year-old man with cystic fibrosis developed nephrotic syndrome and progressed to end-stage renal failure over 1.5 years. He was shown to have nephropathy caused by SV40. The diagnosis was documented by detecting and confirming sequences of SV40 (but not BK or JC virus) in his kidney biopsy and urine by polymerase chain reaction, Southern blot, and DNA sequencing. Positive immunohistochemistry for SV40 was found in his kidney, and neutralizing antibodies for SV40 were detected in his serum, before and after the onset of renal dysfunction. A source for the virus was not determined. His household contacts did not have serologic or molecular evidence of SV40 infection. No serum or tissue samples were available from his 27-year-old donor. This report shows that SV40 is circulating in the community and can cause nephropathy in transplant patients.


Two-Dimensional Flexible High Diffusive Spin Circuits.
Owing to their unprecedented electronic properties, graphene and two-dimensional (2D) crystals have brought fresh opportunities for advances in planar spintronic devices. Graphene is an ideal medium for spin transport while being an exceptionally resilient material for flexible nanoelectronics. However, these extraordinary traits have never been combined to create flexible graphene spin circuits. Realizing such circuits could lead to bendable strain-spin sensors, as well as a unique platform to explore pure spin current based operations and low-power 2D flexible nanoelectronics. Here, we demonstrate graphene spin circuits on flexible substrates for the first time. Despite the rough topography of the flexible substrates, these circuits prepared with chemical vapor deposited monolayer graphene reveal an efficient room temperature spin transport with distinctively large spin diffusion coefficients ∼0.2 m2 s-1. Compared to earlier graphene devices on Si/SiO2 substrates, such values are up to 20 times larger, leading to one order higher spin signals and an enhanced spin diffusion length ∼10 μm in graphene-based nonlocal spin valves fabricated using industry standard systems. This high performance arising out of a characteristic substrate terrain shows promise of a scalable and flexible platform towards flexible 2D spintronics. Our innovation is a key step for the exploration of strain-dependent 2D spin phenomena and paves the way for flexible graphene spin memory-logic units and planar spin sensors.


Mechanisms of global diversification in the brown booby (Sula leucogaster) revealed by uniting statistical phylogeographic and multilocus phylogenetic methods.
Recent theoretical and empirical research suggests that statistical models based on coalescent theory can improve both phylogeographic and phylogenetic inference. An approach that involves elements of both statistical phylogeography (e.g. Isolation with Migration analyses) and multilocus phylogenetic inference (e.g. *beast) may be particularly useful when applied to populations with relatively old divergence times. Here, we use such an approach in the globally distributed brown booby (Sula leucogaster). We sampled 215 individuals from all major breeding areas and genotyped them at eight microsatellite and three nuclear intron loci. We found that brown booby populations were highly differentiated and that colonies can be grouped into four major genetic populations (Caribbean Sea, Central Atlantic Ocean, Indo-Central Pacific and Eastern Pacific). These populations apparently diverged in the absence of gene flow and, with one exception, currently exchange few to no migrants. The Eastern Pacific population diverged from all other populations approximately one million years ago [90% highest posterior density: 330,000-2,000,000 years ago] and exhibits a distinct male plumage, relative to other populations. However, recent gene flow from the Indo-Central Pacific into the Eastern Pacific appears to have occurred, suggesting that approximately one million years of genetic isolation and divergence in male plumage colour are not sufficient to prevent interbreeding. Gene flow following secondary contact of the Indo-Central Pacific and Eastern Pacific populations was not detected in previous mitochondrial DNA (mtDNA) studies, and the contrast between the mtDNA results and our current results highlights the advantage of a multilocus phylogeographic approach.


Predictors for quality of life in older adults: network analysis on cognitive and neuropsychiatric symptoms.
Quality of life (QoL) of older adults has become a pivotal concern of the public and health system. Previous studies found that both cognitive decline and neuropsychiatric symptoms (NPS) can affect QoL in older adults. However, it remains unclear how these symptoms are related to each other and impact on QoL. Our aim is to investigate the complex network relationship between cognitive and NPS symptoms in older adults, and to further explore their association with QoL. A cross-sectional study was conducted in a sample of 389 older individuals with complaints of memory decline. The instruments included the Neuropsychiatric Inventory, the Mini Mental State Examination, and the 36-item Short Form Health Survey. Data was analyzed using network analysis and mediation analysis. We found that attention and agitation were the variables with the highest centrality in cognitive and NPS symptoms, respectively. In an exploratory mediation analysis, agitation was significantly associated with poor attention (β = -0.214, P < 0.001) and reduced QoL (β = -0.137, P = 0.005). The indirect effect of agitation on the QoL through attention was significant (95% confidence interval (CI) [-0.119, -0.035]). Furthermore, attention served as a mediator between agitation and QoL, accounting for 35.09% of the total effect. By elucidating the NPS-cognition-QoL relationship, the current study provides insights for developing rehabilitation programs among older adults to ensure their QoL.


The skin is a significant but overlooked anatomical reservoir for vector-borne African trypanosomes.
The role of mammalian skin in harbouring and transmitting arthropod-borne protozoan parasites has been overlooked for decades as these pathogens have been regarded primarily as blood-dwelling organisms. Intriguingly, infections with low or undetected blood parasites are common, particularly in the case of Human African Trypanosomiasis caused by Trypanosoma brucei gambiense. We hypothesise, therefore, the skin represents an anatomic reservoir of infection. Here we definitively show that substantial quantities of trypanosomes exist within the skin following experimental infection, which can be transmitted to the tsetse vector, even in the absence of detectable parasitaemia. Importantly, we demonstrate the presence of extravascular parasites in human skin biopsies from undiagnosed individuals. The identification of this novel reservoir requires a re-evaluation of current diagnostic methods and control policies. More broadly, our results indicate that transmission is a key evolutionary force driving parasite extravasation that could further result in tissue invasion-dependent pathology.


Adenine nucleotide and lysine transport in Chlamydia psittaci.
Isolated reticulate bodies of Chlamydia psittaci were found to transport ATP and ADP by an ATP-ADP exchange mechanism. ATP uptake activity was not detected in elementary bodies. The apparent Km of transport for both ATP and ADP was approximately 5 microM, and the calculated Vmax for both was about 1 nmol of nucleotide transported per min per mg of protein. ADP competitively inhibited ATP transport with a Ki of 4.5 microM. Other nucleotides tested had no effect on the uptake of ATP. A magnesium-dependent, oligomycin-sensitive ATPase (ATP phosphohydrolase, EC 126.96.36.199) was associated with reticulate bodies, and most of the transported ATP was hydrolyzed to ADP, which was exchanged for additional, extracellular nucleotide. Some ADP was hydrolyzed to AMP, which exited the cells slowly. Lysine was transported against the electrochemical gradient by reticulate bodies in the presence of ATP. Oligomycin and carbonyl cyanide p-trifluoromethoxyphenylhydrazone inhibited ATP-dependent lysine transport. Lysine exited reticulate bodies when the reticulate bodies were incubated in the presence of ADP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone, or a reduced concentration of ATP. The results support the concept that chlamydiae are energy parasites which are capable of drawing upon the adenine nucleotides of their hosts, hydrolyzing ATP, and establishing an energized membrane.


Impact of local rivers on coastal acidification.
Coastal ecosystems are highly dynamic areas for carbon cycling and are likely to be negatively impacted by increasing ocean acidification. This research focused on dissolved inorganic carbon (DIC) and total alkalinity (TA) in the Mississippi Sound to understand the influence of local rivers on coastal acidification. This area receives large fluxes of freshwater from local rivers, in addition to episodic inputs from the Mississippi River through a human-built diversion, the Bonnet Carré Spillway. Sites in the Sound were sampled monthly from August 2018 to November 2019 and weekly from June to August 2019 in response to an extended spillway opening. Prior to the 2019 spillway opening, the contribution of the local, lower alkalinity rivers to the Sound may have left the study area more susceptible to coastal acidification during winter months, with aragonite saturation states (Ωar) < 2. After the spillway opened, despite a large increase in TA throughout the Sound, aragonite saturation states remained low, likely due to hypoxia and increased CO2 concentrations in subsurface waters. Increased Mississippi River input could represent a new normal in the Sound's hydrography during spring and summer months. The spillway has been utilized more frequently over the last two decades due to increasing precipitation in the Mississippi River watershed, which is primarily associated with climate change. Future increases in freshwater discharge and the associated declines in salinity, dissolved oxygen, and Ωar in the Sound will likely be detrimental to oyster stocks and the resilience of similar ecosystems to coastal acidification.


Carpal bone anatomy measured by computer analysis of three-dimensional reconstructions of computed tomography images.
Using quantitative analysis of three-dimensional reconstructions of computed tomography scan data, a normative database of carpal bone morphology was built. Thirty-five wrists were imaged in a computed tomography scanner. Each slice was processed to determine the bone edges and assembled as a three-dimensional model by stacking. Quantitative measurements of volume, surface area, maximum length, and intercarpal distances were then assessed. A reliable three-dimensional carpal height ratio was calculated by dividing the carpal height (minimum distance between the fourth metacarpal and the radius) by the capitate maximum length. For volume, maximum length, and surface area, the order for the eight carpal bones with respect to size (in descending order) were: capitate, hamate, scaphoid, trapezium, lunate, trapezoid, triquetrum, and pisiform. Male wrists were significantly larger than female wrists. There were no significant differences in the relative dimensions between left and right wrists, or between left and right wrists of matched pairs. This technology offers automated analysis of three-dimensional geometric carpal information and the opportunity to obtain a body of information about normal and abnormal morphology as well as spatial relationships between carpal bones.


Effects of cyclic loading and toothbrush abrasion on cervical lesion formation.
This study sought to determine the effect of cyclic loading and toothbrush abrasion (with and without abrasive slurries) on cervical lesion formation. The roots of extracted human third molars were embedded in acrylic resin, leaving 2 mm of root structure and crowns exposed. Teeth were divided into 6 groups (n = 10) with the following treatments: no treatment (control), cyclic load in distilled water, brushing with distilled water, cyclic load followed by brushing with distilled water, brushing with toothpaste slurry, and cyclic load followed by brushing with toothpaste slurry. Cyclic loading and toothbrushing machines subjected the teeth to 1.6 million cyclic loads and 30,000 brushing strokes, the equivalent of 4 years of function and brushing for an average patient. The teeth were scanned with a 3-dimensional optical profilometer to determine the volumetric loss of tooth structure. Load cycling had no significant effect on cervical tooth loss. Brushing with toothpaste resulted in significantly greater cervical tooth loss than brushing with water, which in turn was significantly greater than no treatment at all.


Advocacy resource: engaging the media and promoting your cancer program in Africa.
To address the need for a significant increase in cancer advocacy programs in Africa, the University of Florida (UF), the Prostate Net, and the African Organization for Research and Training in Cancer (AORTIC) co-hosted the first biennial International Workshop on Cancer Advocacy for African Countries (CAAC) on November 29, 2011, one-day prior to AORTIC's 8th International Cancer Conference in Cairo, Egypt. Over 70 African cancer advocates representing about 12 African countries participated in this workshop.The primary goal of the one-day workshop was to inform, educate and empower African cancer advocates to increase the promotion of their cancer programs. The first half of the workshop consisted of five formal PowerPoint presentations focused on the following topics: (a) Understanding Your Community and Assessing your Community Health Assets and Needs; (b) Developing a successful advocacy model for your cancer program; (c) Developing a Relationship with your Elected Officials to Advocate Cancer-related Policies; (d) Engaging the Media and promoting your cancer program; and (e) Developing advocacy plans for sustainability. In this article we summarize the informational content given in the PowerPoint presentation entitled "Engaging the Media and promoting your cancer program". The content given in this article is useful as a how-to guide for both the beginner and the experienced cancer advocate who wants to establish/promote a cancer awareness program.


Self-selected walking speed was consistent when recorded while using a cane.
To assess whether loss of consistency or systematic measurement error is introduced by allowing older individuals to use a cane during measurement of self-selected walking speed (SSWS). Observational study of women aged 65+ (Women's Health and Aging Study I, n=1,002). Of individuals who use a cane in daily life, 201 (50.76%) did not use an aid during testing. The Coefficient of Variation was low in individuals who reported cane use in daily life but did not use one in testing (10.72%), and did not vary substantially if a cane was used (12.04%). The Intra-Class Correlation Coefficient was high: 0.958 for those who reported cane use in daily life but did not use one during testing and 0.962 for those who used a cane. In both groups, Bland-Altman plots revealed a small systematic difference between the first and second trials. There was no evidence of effect modification of the association between SSWS and mobility disability by cane use during testing. This observational study found neither evidence of poorer consistency nor increased measurement bias in SSWS recorded while using a cane compared to using no assistive device.


Expression and activity of key hepatic gluconeogenesis enzymes in response to increasing intravenous infusions of glucose in dairy cows.
The present study aimed at investigating whether increasing concentrations of glucose supply have a depressive effect on the mRNA abundance and activity of key gluconeogenic enzymes in dairy cows. Twelve Holstein-Friesian dairy cows in mid-lactation were intravenously infused with saline (SI; n = 6) or a 40% glucose solution (GI; n = 6). For GI cows, the infusion dose increased by 1.25%/d relative to the initial NE(l) requirement until a maximum dose equating to surplus 30% NE(l) was reached on d 24. Cows receiving SI received an equivalent volume of 0.9% saline solution. Blood samples were taken every 2 d, and liver biopsies were collected every 8 d. A treatment x quadratic dose interaction (P < 0.01) was observed for the concentration of plasma glucose and serum insulin. The interactions were due to positive quadratic responses of the concentrations of glucose and insulin for GI cows, whereas the concentrations of glucose and insulin did not change over time for SI cows. The concentration of beta-hydroxybutyric acid (BHBA) and serum urea nitrogen (BUN) responded in a treatment x quadratic dose manner, such that greater decreases (P < 0.01) in BHBA and BUN concentrations were observed for cows receiving GI than SI as the dosage increased. Serum NEFA concentration tended to follow a similar pattern as serum BHBA and BUN; however, the interaction was not significant (P = 0.07). The mRNA abundance of gluconeogenesis enzymes followed a linear treatment x dose interaction (P < 0.05) for only pyruvate carboxylase (PC), which was paralleled by a trend for a linear treatment x dose interaction (P = 0.13) for PC enzyme activity. The least PC expression and activity were observed at the largest glucose dosage. The activity, but not mRNA abundance, of fructose 1,6-bisphosphatase (FBPase) showed treatment x quadratic dose interactions (P < 0.05) with decreasing activity at increasing glucose dose. Activities and expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase were not affected (P > 0.25) by treatment. In conclusion, hepatic gluconeogenic enzymes are only moderately affected by slowly increasing glucose supply, including a translational or posttranslational downregulation of FBPase activity and a decrease in the mRNA abundance of PC with possible consequences for PC enzyme activity.


Economic evidence in decision-making process in laboratory medicine.
Laboratory data play a pivotal role in the clinical decision-making process. Major transformations have occurred in laboratory medicine in recent decades. To face the economic pressures, hospital laboratories are forced to enhance efficiency. Decisions on policy and practice take place at many levels. However, decision-making often does not follow Evidence Based Laboratory Medicine principles. Also, the literature shows limited influence of economic evaluations on health care decisions and diagnostic processes. Several barriers to the use of economic evaluation in decision-making process have been identified, and guidelines tend to focus on issues of effectiveness and have not explicitly considered broader issues, particularly cost. As an example, we analyzed recommendations on the use of brain natriuretic peptide (BNP) or N-terminal fragment of the prohormone BNP (NT-proBNP) in patients with chronic heart failure. All guidelines recommend the use of BNP if available. Nevertheless, none included economic data explicitly, even if economic information exists in the literature. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group, propose using a balance sheet approach, one way of helping decision makers to explicitly consider resource use along with other outcomes when making recommendations. Key aspects of GRADE, such as the explicit presentation of information and the quality evaluation of the economic data can help overcome barriers in the use of economic evaluations in the decision-making in process. This approach can help to give health decision makers, clinical guideline panels and patients, a better appreciation of the overall health benefits, harms and costs of laboratory tests.


Interactions between opposite-sex dizygotic fetuses and the assumptions of Weinberg difference method epidemiology.
The Weinberg difference method in twin epidemiology may be subject to a major error related to a fundamental assumption that seems not to have been previously questioned. Results presented here indicate that the mortality of like-sex dizygotics (DZs) resembles that of monozygotics (MZs) much more than that of unlike-sex DZs, who are not representative of any other group. Unlike-sex twins enjoy a relative protection from fetal and neonatal mortality and probably from at least one effect of the transient perinatal hypoxia common for second twins. Unlike-sex twins develop, and maintain into adulthood, an intermediate gender phenotype with respect to integration of craniofacial growth.


Prediction of motor recovery using initial impairment and fMRI 48 h poststroke.
There is substantial interpatient variation in recovery from upper limb impairment after stroke in patients with severe initial impairment. Defining recovery as a change in the upper limb Fugl-Meyer score (ΔFM), we predicted ΔFM with its conditional expectation (i.e., posterior mean) given upper limb Fugl-Meyer initial impairment (FM(ii)) and a putative functional magnetic resonance imaging (fMRI) recovery measure. Patients with first time, ischemic stroke were imaged at 2.5 ± 2.2 days poststroke with 1.5-T fMRI during a hand closure task alternating with rest (fundamental frequency = 0.025 Hz, scan duration = 172 s). Confirming a previous finding, we observed that the prediction of ΔFM by FM(ii) alone is good in patients with nonsevere initial hemiparesis but is not good in patients with severe initial hemiparesis (96% and 16% of the total sum of squares of ΔFM explained, respectively). In patients with severe initial hemiparesis, prediction of ΔFM by the combination of FM(ii) and the putative fMRI recovery measure nonsignificantly increased predictive explanation from 16% to 47% of the total sum of squares of ΔFM explained. The implications of this preliminary negative result are discussed.


Loss of enterocyte mass is accompanied by diminished turnover of enterocytes after myeloablative therapy in haematopoietic stem-cell transplant recipients.
Intestinal mucosal barrier injury (MBI), resulting from myeloablative conditioning for haematopoietic stem-cell transplantation (HSCT), is an important cause of morbidity. Despite its frequency, recognition presents a challenge, while the aetiology needs still to be unravelled. The relationship between enterocyte mass and enterocyte loss was explored by examining citrulline serum levels and by assessing circulating intestinal fatty acid-binding protein (I-FABP) and ileal bile acid-binding protein (I-BABP), proteins released by dying mature enterocytes. Thirty-four adult patients with haematological malignancy received allogeneic HSCT (HSCT day 0) 12 days after being given idarubicin, cyclophosphamide and total body irradiation as myeloablative conditioning, a regimen known to induce oral and intestinal MBI. Serum levels of citrulline, I-FABP and I-BABP were measured on HSCT days -12, -6, 0, +7, +14 and +21. Myeloablative conditioning resulted in a significant decrease in serum citrulline with the nadir on HSCT day +7; thereafter, levels rose gradually. Simultaneously, a significant decrease in I-FABP and I-BABP levels occurred from the day of transplant until day +14. Simultaneous reduction and subsequent increase of citrulline and I-FABP and I-BABP levels following cytotoxic treatment show that enterocyte mass corresponds to lower rate of dying enterocytes, indicating reduced turnover of enterocytes. Assessment of enterocyte turnover and mass offers opportunities for evaluation of new MBI therapies.


Accuracy of physician and nurse predictions for 28-day prognosis in ICU: a single center prospective study.
The proportion of correctly predicted prognoses and factors associated with prediction accuracy are unknown. The objective of this study was to explore the accuracy of physician and nurse predictions of 28-day mortality in the ICU. This was a prospective observational single-center study. All medical staff in the ICU have access to patient data, can communicate with patients or clients, and can independently predict the prognosis of patients within 24 h of patient admission. The only question of the questionnaire survey was: What is the patient's outcome on day 28 (alive or death)? There were 2155 questionnaires completed by 18 physicians and 1916 submitted by 15 nurses. In the 312 patients included, the 28-day mortality rates were predicted by physicians and nurses. The overall proportion of correct prognosis prediction was 90.1% for physicians and 64.4% for nurses (P = 0.000). There was no significant difference in the overall correct proportion and average correct proportion among physicians with different seniority levels. The overall correct proportion and average correct proportion increased among nurses with seniority. Physicians in the ICU can moderately predict 28-day mortality in critically ill patients. Nurses with a seniority of less than 10 years in ICU cannot accurately predict 28-day mortality in critically ill patients. However, the accuracy of nurses' prediction of patients' 28-day prognosis increased with their seniority in the ICU.


Red Beetroot Fermentation with Different Microbial Consortia to Develop Foods with Improved Aromatic Features.
The European culinary culture relies on a wide range of fermented products of plant origin, produced mostly through spontaneous fermentation. Unfortunately, this kind of fermentations is difficult to standardize. Therefore, the use of commercial starter cultures is becoming common to achieve more stable, reproducible, and predictable results. Among plant-based fermentation processes, that of the red beet (Beta vulgaris L. var. conditiva) is scarcely described in the scientific literature. In this work, we compared different types of fermentation methods of beetroot and evaluated the processes' micro-biological, physico-chemical, structural, and volatilome features. A multi-variate analysis was used to match the production of specific VOCs to each starter and to define the correlations between the process variables and volatilome. Overall, the results showed a successful lactic acid fermentation. The analysis of the volatilome clearly discriminated the metabolic profiles of the different fermentations. Among them, the sample fermented with the mixture was the one with the most complex and diversified volatilome. Furthermore, samples did not appear softened after fermentation. Although this work had its weaknesses, such as the limited number of samples and variety, it may pave the way for the standardization of artisanal fermentation procedures of red beetroot in order to improve the quality and safety of the derived food products.


Parental origin of the two additional haploid sets of chromosomes in an embryo with tetraploidy.
We report on the molecular investigations performed on an embryo with tetraploidy, karyotype 92,XXXY. The embryo was spontaneously aborted after eight weeks of gestation. Molecular analyses were performed in order to determine the parental origin and mode of formation of the two additional haploid sets of chromosomes. Microsatellite markers mapping to pericentromeric chromosome regions were used. Our results show a maternal origin of one additional set of chromosomes most likely due to the incorporation of the polar body of meiosis I and a paternal origin of the second additional set of chromosomes most likely due to dispermy. The karyotype 92,XXXY is rather unusual, indeed the vast majority of cases with tetraploidy have the karyotypes 92,XXXX or 92,XXYY. To the best of our knowledge this is the first case with 92,XXXY for which molecular investigations have been performed.


A Qualitative Study of Parental Knowledge and Perceptions of Human Papillomavirus and Cervical Cancer Prevention in Rural Central Java, Indonesia: Understanding Community Readiness for Prevention Interventions.
Background: Cervical cancer (CC) is a leading cause of cancer deaths among Indonesian women. Pilot prevention programs, including human papillomavirus (HPV) vaccination for young adolescent girls, and cervical screening for women, have been implemented. However, many communities are yet to receive these interventions, nor targeted education regarding CC prevention. This study explored community readiness and acceptance of HPV vaccination and CC screening, as well as knowledge and perceptions of HPV and CC, to determine facilitators and barriers to upscaling CC prevention in rural Central Java. Methods: Qualitative data collection in October 2015 consisted of four focus group discussions with married women and men, and 22 semi-structured interviews with married women. All 57 participants, 39 women and 15 men, lived in Purworejo Regency in rural Central Java. Results: Most participants had no knowledge of HPV or the causal link between HPV and CC. However, most participants were supportive of vaccinating their children against HPV. Most participants had heard of cervical cancer, although understandings of symptoms and causes were very poor. Less than half of the women interviewed had undergone CC screening. Multiple barriers to screening were reported, including: a dislike of pelvic exams; embarrassment at being screened by a male doctor; anxiety over the cost; fearing a positive result; and being asymptomatic and thus not perceiving the need for screening. Conclusions: Extensive community education about HPV and CC, targeting women and men, adolescents, health workers and teachers, is crucial to support the introduction of the HPV Demonstration Program and the upscaling of CC screening. Low incomes among rural families underline the need for the HPV vaccine to be provided free within the National Immunization Program, and for CC screening to be free at primary health clinics.


Apoptosis of human melanoma cells induced by inhibition of B-RAFV600E involves preferential splicing of bimS.
Bim is known to be critical in killing of melanoma cells by inhibition of the RAF/MEK/ERK pathway. However, the potential role of the most potent apoptosis-inducing isoform of Bim, Bim(S), remains largely unappreciated. Here, we show that inhibition of the mutant B-RAF(V600E) triggers preferential splicing to produce Bim(S), which is particularly important in induction of apoptosis in B-RAF(V600E) melanoma cells. Although the specific B-RAF(V600E) inhibitor PLX4720 upregulates all three major isoforms of Bim, Bim(EL), Bim(L), and Bim(S), at the protein and mRNA levels in B-RAF(V600E) melanoma cells, the increase in the ratios of Bim(S) mRNA to Bim(EL) and Bim(L) mRNA indicates that it favours Bim(S) splicing. Consistently, enforced expression of B-RAF(V600E) in wild-type B-RAF melanoma cells and melanocytes inhibits Bim(S) expression. The splicing factor SRp55 appears necessary for the increase in Bim(S) splicing, as SRp55 is upregulated, and its inhibition by small interfering RNA blocks induction of Bim(S) and apoptosis induced by PLX4720. The PLX4720-induced, SRp55-mediated increase in Bim(S) splicing is also mirrored in freshly isolated B-RAF(V600E) melanoma cells. These results identify a key mechanism for induction of apoptosis by PLX4720, and are instructive for sensitizing melanoma cells to B-RAF(V600E) inhibitors.


Reversible extralimbic paraneoplastic encephalopathies with large abnormalities on magnetic resonance images.
To describe reversible extralimbic paraneoplastic encephalopathies with large, lobar lesions on magnetic resonance imaging (MRI). Case series. Autoimmune Neurology Clinic, Mayo Clinic, Rochester, Minnesota. Three patients had large confluent areas of signal abnormality on T2-weighted MRI, including frontal in 2 and frontal and occipital in 1. Patient 1, a woman aged 63 years, experienced hemiparesis with hemianopia 3 years after a diagnosis of adenocarcinoma of the breast. Nine years later, rapidly progressive dementia developed. Patient 2, a woman aged 79 years, presented with monoparesis and epilepsia partialis continua, 1 year after a diagnosis of adenocarcinoma of the breast. Patient 3, a man aged 65 years, had paraneoplastic sensory neuronopathy, limbic encephalitis, antineuronal nuclear autoantibody type 1 (ANNA-1), and squamous cell carcinoma of the lung. He was stable for 3 years after treatment. Subacute onset of aphasia, delirium, worsening seizures, and rising ANNA-1 titers led to a diagnosis of recurrent limited carcinoma. Brain MRI abnormalities in all patients improved dramatically after immunotherapy. Two patients had sustained clinical remission. Recognition of paraneoplastic extralimbic lobar encephalopathies is important because these disorders and their underlying cancers are treatable.


Pharmacokinetics, Mass Balance, Tissue Distribution and Metabolism of [14C]101BHG-D01, a Novel Muscarinic Receptor Antagonist, in Rats.
101BHG-D01, a novel long-acting and selective muscarinic receptor antagonist for the treatment of chronic obstructive pulmonary disease (COPD), is undergoing Phase Ib clinical trial in patients and has shown its potential efficacy. Its preparation method and medical use thereof have been patented in the United States (Patent No.US9751875B2). In this study, the pharmacokinetics, mass balance, tissue distribution and metabolism of radioactive 101BHG-D01 were investigated in rats after an intravenous dose of 1 mg/kg [14C]101BHG-D01 (100 μCi/kg). Radioactivity in rat plasma, urine, feces, and tissues was measured by liquid scintillation counting (LSC), and metabolite profiling and identification were conducted by UHPLC-β-RAM and UHPLC-Q-Exactive Plus MS. The total radioactivity of the study drug in rat plasma rapidly declined with an average terminal elimination half-life of 0.35 h. The radioactivity in most tissues reached the maximum concentration at 0.25 h post-- dosing. The radioactivity is mainly concentrated in the kidney and pancreas. The drug-related substances tended to be distributed into the blood cells in the circulation. At 168 h post dosing, the mean recovery of the total radioactivity in urine and feces was 78.82%. Fecal excretion was the major excretion route, accounting for approximately 61% of the radioactive dose. The study drug was metabolized extensively, and a total of 17 metabolites were identified in rat plasma, urine, and feces. The major metabolic pathways involved oxidation, oxidation and dehydrogenation, and O-dephenylation. In conclusion, the study results are useful for better understanding the pharmacokinetic profiles of 101BHG-D01 and provide a robust foundation for subsequent clinical studies.


Sensory Deprivation Triggers Synaptic and Intrinsic Plasticity in the Hippocampus.
Hippocampus, a temporal lobe structure involved in learning and memory, receives information from all sensory modalities. Despite extensive research on the role of sensory experience in cortical map plasticity, little is known about whether and how sensory experience regulates functioning of the hippocampal circuits. Here, we show that 9 ± 2 days of whisker deprivation during early mouse development depresses activity of CA3 pyramidal neurons by several principal mechanisms: decrease in release probability, increase in the fraction of silent synapses, and reduction in intrinsic excitability. As a result of deprivation-induced presynaptic inhibition, CA3-CA1 synaptic facilitation was augmented at high frequencies, shifting filtering properties of synapses. The changes in the AMPA-mediated synaptic transmission were accompanied by an increase in NR2B-containing NMDA receptors and a reduction in the AMPA/NMDA ratio. The observed reconfiguration of the CA3-CA1 connections may represent a homeostatic adaptation to augmentation in synaptic activity during the initial deprivation phase. In adult mice, tactile disuse diminished intrinsic excitability without altering synaptic facilitation. We suggest that sensory experience regulates computations performed by the hippocampus by tuning its synaptic and intrinsic characteristics.


Isotope effects and the nature of stereo- and regioselectivity in hydroaminations of vinylarenes catalyzed by palladium(ii)-diphosphine complexes.
[reaction: see text] The hydroamination of styrene with aniline catalyzed by phosphine-ligated palladium triflates exhibits a substantial (13)C isotope effect at the benzylic carbon. This supports rate-determining nucleophilic attack of amine on a eta(3)-phenethyl palladium complex. Deuterium exchange observations and predicted isotope effects based on DFT calculations support this mechanism. Selectivity in these reactions is determined by the facility of palladium displacement after reversible hydropalladation of the alkene.


Intraocular Inflammation Associated with New Therapies for Cutaneous Melanoma - Case Series and Review.
Background. In advanced cutaneous melanoma, new systemic therapies include immunotherapy by checkpoint inhibition and targeted inhibition of the mitogen-activated protein kinase pathway; these are becoming increasingly well established. We describe the clinical presentation of uveitis in three patients with concomitant systemic melanoma treatment. History and Signs. Three patients with metastatic melanoma receiving systemic therapy (ipilimumab, vemurafenib) presented at our institution with a short history of ocular symptoms. Clinical findings included anterior uveitis, intermediate uveitis, disc swelling, inflammatory choroidal lesions and retinal vasculitis. Therapy and Outcome. All three patients responded well to local and/or systemic steroid treatment. In one case, the systemic anti-cancer drug was discontinued after the onset of uveitis. Conclusions. Ocular inflammation may occur in the setting of systemic melanoma therapy. Presentations of uveitis include Vogt-Koyanagi-Harada-like syndromes. Ocular inflammation can usually be controlled by topical and sometimes systemic corticosteroid therapy. However, treatment guidelines are not established and management of these patients demands close cooperation with the oncologist.


The evolutionary implications of knox-I gene duplications in conifers: correlated evidence from phylogeny, gene mapping, and analysis of functional divergence.
Class I knox genes code for transcription factors that play an essential role in plant growth and development as central regulators of meristem cell identity. Based on the analysis of new cDNA sequences from various tissues and genomic DNA sequences, we identified a highly diversified group of class I knox genes in conifers. Phylogenetic analyses of complete amino acid sequences from various seed plants indicated that all conifer sequences formed a monophyletic group. Within conifers, four subgroups here named genes KN1 to KN4 were well delineated, each regrouping pine and spruce sequences. KN4 was sister group to KN3, which was sister group to KN1 and KN2. Genetic mapping on the genomes of two divergent Picea species indicated that KN1 and KN2 are located close to each other on the same linkage group, whereas KN3 and KN4 mapped on different linkage groups, correlating the more ancient divergence of these two genes. The proportion of synonymous and nonsynonymous substitutions suggested intense purifying selection for the four genes. However, rates of substitution per year indicated an evolution in two steps: faster rates were noted after gene duplications, followed subsequently by lower rates. Positive directional selection was detected for most of the internal branches harboring an accelerated rate of evolution. In addition, many sites with highly significant amino acid rate shift were identified between these branches. However, the tightly linked KN1 and KN2 did not diverge as much from each other. The implications of the correlation between phylogenetic, structural, and functional information are discussed in relation to the diversification of the knox-I gene family in conifers.