High perceived stress is associated with unfavorable eating behavior in overweight and obese Finns of working age.
Stress-related eating may be a potential factor in the obesity epidemic. Rather little is known about how stress associates with eating behavior and food intake in overweight individuals in a free-living situation. Thus, the present study aims to investigate this question in psychologically distressed overweight and obese working-aged Finns. The study is a cross-sectional baseline analysis of a randomized controlled trial. Of the 339 study participants, those with all the needed data available (n = 297, 84% females) were included. The mean age was 48.9 y (SD = 7.6) and mean body mass index 31.3 kg/m(2) (SD = 3.0). Perceived stress and eating behavior were assessed by self-reported questionnaires Perceived Stress Scale (PSS), Intuitive Eating Scale, the Three-Factor Eating Questionnaire, Health and Taste Attitude Scales and ecSatter Inventory. Diet and alcohol consumption were assessed by 48-h dietary recall, Index of Diet Quality, and AUDIT-C. Individuals reporting most perceived stress (i.e. in the highest PSS tertile) had less intuitive eating, more uncontrolled eating, and more emotional eating compared to those reporting less perceived stress (p < 0.05). Moreover, individuals in the highest PSS tertile reported less cognitive restraint and less eating competence than those in the lowest tertile (p < 0.05). Intake of whole grain products was the lowest among those in the highest PSS tertile (p < 0.05). Otherwise the quality of diet and alcohol consumption did not differ among the PSS tertiles. In conclusion, high perceived stress was associated with the features of eating behavior that could in turn contribute to difficulties in weight management. Stress-related way of eating could thus form a potential risk factor for obesity. More research is needed to develop efficient methods for clinicians to assist in handling stress-related eating in the treatment of obese people.


Blackberry Fruit Classification in Underexposed Images Combining Deep Learning and Image Fusion Methods.
Berry production is increasing worldwide each year; however, high production leads to labor shortages and an increase in wasted fruit during harvest seasons. This problem opened new research opportunities in computer vision as one main challenge to address is the uncontrolled light conditions in greenhouses and open fields. The high light variations between zones can lead to underexposure of the regions of interest, making it difficult to classify between vegetation, ripe, and unripe blackberries due to their black color. Therefore, the aim of this work is to automate the process of classifying the ripeness stages of blackberries in normal and low-light conditions by exploring the use of image fusion methods to improve the quality of the input image before the inference process. The proposed algorithm adds information from three sources: visible, an improved version of the visible, and a sensor that captures images in the near-infrared spectra, obtaining a mean F1 score of 0.909±0.074 and 0.962±0.028 in underexposed images, without and with model fine-tuning, respectively, which in some cases is an increase of up to 12% in the classification rates. Furthermore, the analysis of the fusion metrics showed that the method could be used in outdoor images to enhance their quality; the weighted fusion helps to improve only underexposed vegetation, improving the contrast of objects in the image without significant changes in saturation and colorfulness.


The effect of electromagnetic radiation on the rat brain: an experimental study.
The aim of this study is to determine the structural changes of electromagnetic waves in the frontal cortex, brain stem and cerebellum. 24 Wistar Albino adult male rats were randomly divided into four groups: group I consisted of control rats, and groups II-IV comprised electromagnetically irradiated (EMR) with 900, 1800 and 2450 MHz. The heads of the rats were exposed to 900, 1800 and 2450 MHz microwaves irradiation for 1h per day for 2 months. While the histopathological changes in the frontal cortex and brain stem were normal in the control group, there were severe degenerative changes, shrunken cytoplasm and extensively dark pyknotic nuclei in the EMR groups. Biochemical analysis demonstrated that the Total Antioxidative Capacity level was significantly decreased in the EMR groups and also Total Oxidative Capacity and Oxidative Stress Index levels were significantly increased in the frontal cortex, brain stem and cerebellum. IL-1β level was significantly increased in the EMR groups in the brain stem. EMR causes to structural changes in the frontal cortex, brain stem and cerebellum and impair the oxidative stress and inflammatory cytokine system. This deterioration can cause to disease including loss of these areas function and cancer development.


Applying Standard Clinical Chemistry Assay Validation to Droplet Digital PCR Quantitative Liquid Biopsy Testing.
Droplet digital PCR (ddPCR) is an emerging technology for quantitative cell-free DNA oncology applications. However, assay performance criteria must be established in a standardized manner to harness this potential. We reasoned that standard protocols used in clinical chemistry assay validation should be able to fill this need. We validated KRAS, EGFR, and BRAF quantitative ddPCR assays based on the Clinical Laboratory Improvement Act regulations for laboratory-developed tests in clinical chemistry and the matching Clinical and Laboratory Standards Institute guidelines. This included evaluation of limit of the blank (LOB), limit of detection (LOD), limit of quantification (LOQ), intraassay and interassay imprecision, analytical range, dilution linearity, accuracy (including comparison with orthogonal platforms), reference range study, interference, and stability studies. For the ddPCR assays, the LOB was 4 mutant copies, LODs were 12 to 22 copies, and LOQs were 35 to 64 copies. The upper limit of the dynamic range was 30000 copies, and dilutions were linear down to the LOQs with good accuracy of spike recovery of Horizon reference material. Method comparisons with next-generation sequencing and an alternative ddPCR platform showed complete qualitative agreement and quantitative concordance, with slopes of 0.73 to 0.97 and R 2s of 0.83 to 0.99. No substantial interferences were discovered. Wild-type copy numbers in plasma ranged from 462 to 6169/mL in healthy individuals. Standard clinical chemistry assay validation protocols can be applied to quantitative ddPCR assays. This should facilitate comparison of the performance of different assays and allow establishment of minimal significant change thresholds in monitoring applications.


Protamine requirements in cardiac surgery: effect of changes in the heparin reference standard.
UFH (unfractionated heparin) and protamine are integral to cardiac surgery, and inappropriate dosing can predispose to coagulopathy and hemorrhage. The FDA (Food and Drug Administration) recently has instituted changes to UFH formulation and it is not known if this has influenced its susceptibility to neutralization by protamine. Hence, the authors sought to compare 2 commercial preparations of UFH (old and new) with regard to their neutralization by protamine in patients undergoing cardiopulmonary bypass (CPB). Prospective, observational, cohort study. Tertiary care university hospital and associated research laboratory Twenty adult patients undergoing elective cardiac surgery with CPB. Blood samples were drawn preinduction, prior to, and 5 and 30 minutes following protamine, and 0 and 2 hours after ICU admission. Protamine titration assays were conducted in vitro on samples drawn prior to and following protamine administration. Anti-IIa and anti-Xa activity were assayed in all samples. Anti-IIa and anti-Xa activity were detected ubiquitously at all time points following CPB, and there were no differences in susceptibility to protamine neutralization between the 2 groups. In vitro protamine titration studies revealed that anti-IIa was more resistant to protamine neutralization compared to anti-Xa activity. The 'old' and 'new' formulations of UFH evaluated in this study were similar in their susceptibility to protamine neutralization. Circulating UFH is detected as early as 5 minutes after protamine administration and anti-IIa is more resistant to protamine neutralization as compared to anti-Xa activity. Further studies are required to quantify the precise dose of protamine following CPB.


How to minimize formation and growth of tumours: potential benefits of decapod crustaceans for cancer research.
Tumours have only rarely been observed in the decapod crustaceans, a large animal group of more than 10,000 species that includes the commercially important and well investigated shrimp, lobsters, crayfish and crabs. Analysis of the literature and information from cancer and diseases data bases revealed a total of 15 incidences, some of them being questionable. Even in the long-lived species, which can reach life spans of almost 100 years, neoplasias are virtually unknown. The data published so far suggest that the strikingly different frequencies of carcinogenesis between decapods and other well investigated animal groups like mammals, fish, insects and molluscs is based on differences of the metabolic pathways for carcinogens, the immune systems, and the regulation of stem cells. Therefore, representatives of the Decapoda may serve as useful models to study how organisms can successfully prevent or control spontaneously and environmentally induced cell proliferation. A particularly promising candidate for in-depth investigation of these topics is the marbled crayfish, a rather new clonal lineage that is presently being introduced as a laboratory model in development and epigenetics.


Acid secretion and suppression.
Hydrochloric acid is involved in the causation of peptic ulcer, but the exact role has not been defined. Suppression of acid secretion is associated with ulcer healing. The acid secreting cell is the parietal cell, which possesses a proton pump in the secretory membrane; morphologic changes accompany and facilitate the active secretion of hydrochloric acid. Stimulation of acid secretion occurs by three major pathways, which utilize acetylcholine, histamine, and gastrin. The predominant effects of histamine are mediated by adenylate cyclase, whereas those of gastrin and acetylcholine involve cytosolic calcium. There is a complicated arrangement of receptors and pathways that culminate in the activation of the proton pump. The parietal cell is influenced by neurocrine, hormonal, and paracrine mechanisms. Peptides join the more familiar neurotransmitters in affecting the parietal cell. Somatostatin is present in the gut and acts to decrease acid secretion. The hormone gastrin is released, in a feedback fashion, when the antrum is alkalinized. Most stimuli of acid secretion are blocked by H2-antagonists. Inhibitory hormones are released when acid arrives in the intestine. Inhibition of acid secretion can be achieved by influencing the parietal cell at the level of histamine, gastrin, and muscarinic receptors. The proton pump itself can be blocked by drugs that inhibit the final phase of acid secretion.


Improved Accuracy of Component Positioning with Robotic-Assisted Unicompartmental Knee Arthroplasty: Data from a Prospective, Randomized Controlled Study.
Higher revision rates have been reported in patients who have undergone unicompartmental knee arthroplasty compared with patients who have undergone total knee arthroplasty, with poor component positioning identified as a factor in implant failure. A robotic-assisted surgical procedure has been proposed as a method of improving the accuracy of component implantation in arthroplasty. The aim of this prospective, randomized, single-blinded, controlled trial was to evaluate the accuracy of component positioning in unicompartmental knee arthroplasty comparing robotic-assisted and conventional implantation techniques. One hundred and thirty-nine patients were randomly assigned to treatment with either a robotic-assisted surgical procedure using the MAKO Robotic Interactive Orthopaedic Arm (RIO) system or a conventional surgical procedure using the Oxford Phase-3 unicompartmental knee replacement with traditional instrumentation. A postoperative computed tomographic scan was performed at three months to assess the accuracy of the axial, coronal, and sagittal component positioning. Data were available for 120 patients, sixty-two who had undergone robotic-assisted unicompartmental knee arthroplasty and fifty-eight who had undergone conventional unicompartmental knee arthroplasty. Intraobserver agreement was good for all measured component parameters. The accuracy of component positioning was improved with the use of the robotic-assisted surgical procedure, with lower root mean square errors and significantly lower median errors in all component parameters (p < 0.01). The proportion of patients with component implantation within 2° of the target position was significantly greater in the group who underwent robotic-assisted unicompartmental knee arthroplasty compared with the group who underwent conventional unicompartmental knee arthroscopy with regard to the femoral component sagittal position (57% compared with 26%, p = 0.0008), femoral component coronal position (70% compared with 28%, p = 0.0001), femoral component axial position (53% compared with 31%, p = 0.0163), tibial component sagittal position (80% compared with 22%, p = 0.0001), and tibial component axial position (48% compared with 19%, p = 0.0009). Robotic-assisted surgical procedures with the use of the MAKO RIO lead to improved accuracy of implant positioning compared with conventional unicompartmental knee arthroplasty surgical techniques. Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.


The Impact of Educational Attainment on Observed Race/Ethnic Disparities in Inflammatory Risk in the 2001-2008 National Health and Nutrition Examination Survey.
Inflammation has shown to be an independent predictor of cardiovascular disease (CVD) and growing evidence suggests Non-Hispanic Blacks (NHBs) and certain Hispanic subgroups have higher inflammation burden compared to Non-Hispanic Whites (NHWs). Socioeconomic status (SES) is a hypothesized pathway that may account for the higher inflammation burden for race/ethnic groups yet little is known about the biological processes by which SES "gets under the skin" to affect health and whether income and education have similar or distinct influences on elevated inflammation levels. The current study examines SES (income and education) associations with multiple levels of C-Reactive Protein (CRP), an important biomarker of inflammation, in a sample of 13,362 NHWs, 7696 NHBs and 4545 Mexican Americans (MAs) in the United States from the 2001 to 2008 National Health and Nutrition Examination Survey. After adjusting for age, sex, and statin use, NHBs and MAs had higher intermediate and high CRP levels compared to NHWs. Income lessened the magnitude of the association for both race/ethnic groups. The greater intermediate and high CRP burden for NHBs and MAs was strongly explained by educational attainment. MAs were more vulnerable to high CRP levels for the lowest (i.e., less than nine years) and post high school (i.e., associates degree) educational levels. After additional adjustment for smoking, heavy drinking, high waist circumference, high blood pressure, diabetes and statin use, the strength of the association between race/ethnicity and inflammation was reduced for NHBs with elevated intermediate (RR = 1.31; p ≤ 0.001) and high CRP levels (RR = 1.14; p ≤ 0.001) compared to NHWs but the effect attenuated for MAs for both intermediate (RR = 0.74; p ≤ 0.001) and high CRP levels (RR = 0.38; p ≤ 0.001). These findings suggest educational attainment is a powerful predictor of elevated CRP levels in race/ethnic populations and challenges studies to move beyond examining income as a better predictor in the SES-inflammation pathway.


Attentional demands of perception of passive self-motion in darkness.
The purpose of this study was to determine whether significant attentional resources are required to accurately monitor changes in bodily orientation, using vestibular information. This question was addressed firstly using a dual-task paradigm in which orientation perception tasks and a speeded auditory tone discrimination task were carried out either singly or in combination. For the active orientation perception task, subjects were seated in darkness on a motorised chair which could be rotated about an earth-vertical axis. Following passive angular displacements, subjects were required to return the chair to their perceived starting position, using a joy-stick which controlled chair motion. For the speeded auditory task, subjects pushed a hand-held button as fast as possible when a tone was presented over headphones. When the two tasks were combined, reaction times on the auditory task increased. Reaction time also increased when subjects were simply asked to fixate during rotation. A second experiment demonstrated that if attention was occupied by performance of a demanding mental arithmetic task during the passive rotation, accuracy of subsequently repositioning the chair to the origin declined, implying that change in orientation had been less accurately registered when performing the concurrent mental task. In combination, these findings indicate that a small but significant degree of attention or cognitive effort is necessary to monitor accurately the direction and amplitude of a brief angular rotation, and to suppress vestibulo-ocular reflex eye movement.


Survival, regeneration and functional recovery of motoneurons in adult rats by reimplantation of ventral root following spinal root avulsion.
We investigated the functional recovery of motoneurons after reimplanting an avulsed ventral root in a rat model of traction injury. The eighth cervical root (C8) was avulsed by controlled traction and immediately reimplanted to the spinal cord. Spinal nerves from neighbouring segments (C5, C6, C7 and T1) were ligated and cut. After 12 or 20 weeks, the survival, regeneration and functional recovery of spinal motoneurons were evaluated by Nissl staining, retrograde labelling of motoneurons, NOS histochemistry, histological examination of muscle and nerve-muscle junction, electromyography and behavioural observation. In the control animals, about 14% or 11% of spinal motoneurons survived 12 or 20 weeks postinjury, respectively. By contrast, in animals with ventral root reimplantation, 62% and 55% of motoneurons survived at 12 or 20 weeks postinjury, respectively. Retrograde labelling and histological examination indicated that about 90% of the surviving motoneurons in the C8 segment regenerated axons into the reimplanted ventral root. Staining the muscles with silver and cholinesterase revealed new motor endplates in the reinnervated muscle. Functionally significant electromyographic responses in flexor digitorum superficialis and flexor carpi radialis were observed in experimental animals; however, the average latency of the motor action potentials was greater than normal control. The grasping test showed functional recovery of finger flexors and median nerve. In conclusion, our results indicate that spinal motoneurons can regenerate axons through reimplanted roots and reinnervate muscles to recover partial function.


Realized gene flow within mixed stands of Quercus robur L. and Q. petraea (Matt.) L. revealed at the stage of naturally established seedling.
The estimates of contemporary gene flow assessed based on naturally established seedlings provide information much needed for understanding the abilities of forest tree populations to persist under global changes through migration and/or adaptation facilitated by gene exchange among populations. Here, we investigated pollen- and seed-mediated gene flow in two mixed-oak forest stands (consisting of Quercus robur L. and Q. petraea [Matt.] Liebl.). The gene flow parameters were estimated based on microsatellite multilocus genotypes of seedlings and adults and their spatial locations within the sample plots using models that attempt to reconstruct the genealogy of the seedling cohorts. Pollen and seed dispersal were modelled using the standard seedling neighbourhood model and a modification--the 2-component seedling neighbourhood model, with the later allowing separation of the dispersal process into local and long-distance components. The 2-component model fitted the data substantially better than the standard model and provided estimates of mean seed and pollen dispersal distances accounting for long-distance propagule dispersal. The mean distance of effective pollen dispersal was found to be 298 and 463 m, depending on the stand, while the mean distance of effective seed dispersal was only 8.8 and 15.6 m, which is consistent with wind pollination and primarily seed dispersal by gravity in Quercus. Some differences observed between the two stands could be attributed to the differences in the stand structure of the adult populations and the existing understory vegetation. Such a mixture of relatively limited seed dispersal with occasional long distance gene flow seems to be an efficient strategy for colonizing new habitats with subsequent local adaptation, while maintaining genetic diversity within populations.


Macula halo syndrome.
Niemann-Pick disease (NPD) is a hereditary lysosomal storage disorder in which mutations in the sphingomyelin phosphodiesterase gene leads to partial or complete deficiency of the sphingomyelinase enzyme. Niemann-Pick Type B is the intermediate form associated with hepatosplenomegaly, foam cells in the bone marrow, hyperlipidemia and diffuse pulmonary infiltrates, which is generally diagnosed in late adolescence. Central nervous system is not affected, and some cases may display macular halo. A 45-year-old female seen in ophthalmology clinic for the examination of the eyes. Extraocular motility was normal bilaterally, and the visual acuity was 20/25 for both eyes. Biomicroscopic examination revealed faint corneal haze bilaterally, Circular pale granular depositions were detected in the parafoveal retina on both eyes. Optical coherence tomography (OCT) revealed thin hyperreflective band corresponding to depositions located in the parafoveolar inner retina. Microperimeter showed slight depression in retinal sensitivity, which was more pronounced particularly on perifovea rather than parafovea. Challenge to identify the NPD subtype of this case is associated with phenotypic characteristics on a wider spectrum that overlap the currently described subtypes.


Deprivation of Sexual Reproduction during Garlic Domestication and Crop Evolution.
Garlic, originating in the mountains of Central Asia, has undergone domestication and subsequent widespread introduction to diverse regions. Human selection for adaptation to various climates has resulted in the development of numerous garlic varieties, each characterized by specific morphological and physiological traits. However, this process has led to a loss of fertility and seed production in garlic crops. In this study, we conducted morpho-physiological and transcriptome analyses, along with whole-genome resequencing of 41 garlic accessions from different regions, in order to assess the variations in reproductive traits among garlic populations. Our findings indicate that the evolution of garlic crops was associated with mutations in genes related to vernalization and the circadian clock. The decline in sexual reproduction is not solely attributed to a few mutations in specific genes, but is correlated with extensive alterations in the genetic regulation of the annual cycle, stress adaptations, and environmental requirements. The regulation of flowering ability, stress response, and metabolism occurs at both the genetic and transcriptional levels. We conclude that the migration and evolution of garlic crops involve substantial and diverse changes across the entire genome landscape. The construction of a garlic pan-genome, encompassing genetic diversity from various garlic populations, will provide further insights for research into and the improvement of garlic crops.


A Phase 1, Single-center, Double-blind, Placebo-controlled Study in Healthy Subjects to Assess the Safety, Tolerability, Clinical Effects, and Pharmacokinetics-Pharmacodynamics of Intravenous Cyclopropyl-methoxycarbonylmetomidate (ABP-700) after a Single Ascending Bolus Dose.
Cyclopropyl-methoxycarbonylmetomidate (ABP-700) is a new "soft" etomidate analog. The primary objectives of this first-in-human study were to describe the safety and efficacy of ABP-700 and to determine its maximum tolerated dose. Secondary objectives were to characterize the pharmacokinetics of ABP-700 and its primary metabolite (cyclopropyl-methoxycarbonyl acid), to assess the clinical effects of ABP-700, and to investigate the dose-response and pharmacokinetic/pharmacodynamic relationships. Sixty subjects were divided into 10 cohorts and received an increasing, single bolus of either ABP-700 or placebo. Safety was assessed by clinical laboratory evaluations, infusion-site reactions, continuous monitoring of vital signs, physical examination, adverse event monitoring, and adrenocorticotropic hormone stimulation testing. Clinical effects were assessed with modified observer's assessment of alertness/sedation and Bispectral Index monitoring. Pharmacokinetic parameters were calculated. Stopping criteria were met at 1.00 mg/kg dose. No serious adverse events were reported. Adverse events were dose-dependent and comprised involuntary muscle movement, tachycardia, and ventilatory effects. Adrenocorticotropic hormone stimulation evoked a physiologic cortisol response in all subjects, no different from placebo. Pharmacokinetics were dose-proportional. A three-compartment pharmacokinetic model described the data well. A rapid onset of anesthesia/sedation after bolus administration and also a rapid recovery were observed. A quantitative concentration-effect relationship was described for the modified observer's assessment of alertness/sedation and Bispectral Index. This first-in-human study of ABP-700 shows that ABP-700 was safe and well tolerated after single-bolus injections up to 1.00 mg/kg. Bolus doses of 0.25 and 0.35 mg/kg were found to provide the most beneficial clinical effect versus side-effect profile.


Antidepressants in black and white inpatients. Differential response to a controlled trial of chlorpromazine and imipramine.
Differential effects of chlorpromazine, imipramine hydrochloride, and a placebo were examined in 159 black and 555 white depressed patients in a multihospital collaborative study. In making these comparisons, the effects of age and social class were controlled. The major study findings were the differential effects of the active drugs for the black men and women. Chlorpromazine was the most efficacious treatment for black women, whereas imipramine was most efficacious for black men. These differences occurred on global ratings of improvement as well as on specific symptoms such as depression, anxiety, guilt-worthlessness, sleep disturbances, and social participation. Black patients also evidenced a higher improvement rate at one week, irrespective of treatment, than did the white patients.


The Shinyanga Patient: A Patient's Journey through HIV Treatment Cascade in Rural Tanzania.
The 2016-2017 Tanzania HIV Impact Survey (THIS) reported the accomplishments towards the 90-90-90 global HIV targets at 61-94-87, affirming the need to focus on the first 90 (i.e., getting 90% of people living with HIV (PLHIV) tested). We conducted a patient-pathway analysis to understand the gap observed, by assessing the alignment between where PLHIV seek healthcare and where HIV services are available in the Shinyanga region, Tanzania. We used existing and publicly available data from the National AIDS Control program, national surveys, registries, and relevant national reports. Region-wide, the majority (n = 458/722, 64%) of THIS respondents accessed their last HIV test at public sector facilities. There were 65.9%, 45.1%, and 74.1% who could also access antiretroviral therapy (ART), CD4 testing, and HIV viral load testing at the location of their last HIV test, respectively. In 2019, the viral suppression rate estimated among PLHIV on ART in the Shinyanga region was 91.5%. PLHIV access HIV testing mostly in public health facilities; our research shows that synergies can be achieved to improve access to services further down the cascade in this sector. Furthermore, effective engagement with the private sector (not-for-profit and for-profit) will help to achieve the last mile toward ending the HIV epidemic.


The combined repetitive oligopeptides of clostridium difficile toxin A counteract premature cleavage of the glucosyl-transferase domain by stabilizing protein conformation.
Toxin A (TcdA) and B (TcdB) from Clostridium difficile enter host cells by receptor-mediated endocytosis. A prerequisite for proper toxin action is the intracellular release of the glucosyltransferase domain by an inherent cysteine protease, which is allosterically activated by inositol hexaphosphate (IP6). We found that in in vitro assays, the C-terminally-truncated TcdA1-1065 was more efficient at IP6-induced cleavage compared with full-length TcdA. We hypothesized that the C-terminally-located combined repetitive oligopeptides (CROPs) interact with the N-terminal part of the toxin, thereby preventing autoproteolysis. Glutathione-S-transferase (GST) pull-down assays and microscale thermophoresis confirmed binding between the CROPs and the glucosyltransferase (TcdA1-542) or intermediate (TcdA1102-1847) domain of TcdA, respectively. This interaction between the N- and C-terminus was not found for TcdB. Functional assays revealed that TcdB was more susceptible to inactivation by extracellular IP6-induced cleavage. In vitro autoprocessing and inactivation of TcdA, however, significantly increased, either by acidification of the surrounding milieu or following exchange of its CROP domain by the homologous CROP domain of TcdB. Thus, TcdA CROPs contribute to the stabilization and protection of toxin conformation in addition to function as the main receptor binding domain.


NT-proBNP and troponin T levels differ after haemodialysis with a low versus high flux membrane.
Brain natriuretic peptide (BNP), N-terminal-proBNP (NT-proBNP), and high sensitive cardiac troponin T (TnT) are markers that are elevated in chronic kidney disease and correlate with increased risk of mortality. Data are conflicting on the effect of biomarker levels by hemodialysis (HD).Our aim was to clarify to what extent HD with low-flux (LF) versus high-flux (HF) membranes affects the plasma levels of BNP, NT-proBNP, and TnT. 31 HD patients were included in a crossover design, randomized to start dialysis with a LF-HD or HF-HD dialyzer. Each patient was his/her own control. The dialyses included in the study were the first treatments of two consecutive weeks with each mode of dialysis. Patients normally on hemodiafiltration (HDF) also performed a HDF the third week. Values after HD were corrected for extent of ultrafiltration. During LF-HD the biomarkers NT-proBNP and TnT increased (15 versus 6%, P ≤ .001) while there was a slight decrease in BNP (P<.05). During HF-HD the NT-proBNP, BNP and TnT levels decreased (P ≤ .01 for all). During HDF all three markers decreased (P<.01 for all). The rise in TnT during LF-HD correlated with dialysis vintage (months on HD, r = .407, P = .026), Kt/V-urea (r = .383, P = .037), HD time in hours/treatment (r = .447, P = .013) and inversely with residual urinary output (r = -.495, P = .005). The baseline levels of BNP and NT-proBNP correlated with blood pressure. Cardiac biomarkers increase slightly during LF-HD. A HF-HD eliminates the biomarkers and can mask increases caused by, e.g., myocardial infarction.


Cathepsin D associates with lysosomal membranous protein.
The membrane-association of early biosynthetic form of cathepsin D has been demonstrated in hepatoma cells, and this membrane-association is not mediated by mannose 6-phosphate residues, implying that a mannose 6-phosphate receptor-independent mechanism operates in the sorting of cathepsin D. In this paper, to demonstrate whether cathepsin D is associated with the lysosomal membranes, an in vitro binding experiment was carried out employing lysosomal cathepsin D or microsomal procathepsin D isolated from rat liver. Immunoblotting analysis revealed that an intermediate form of cathepsin D was associated with the lysosomal membranes; this lysosomal membrane-associated cathepsin D was released from the membranes by washing with Na2CO3 (pH 10.6) but not with solutions containing mannose 6-phosphate. This suggested that cathepsin D associates with the membranes by ionic-interaction, and that the membrane-associated cathepsin D resides as a peripheral membrane protein in the lysosomal membrane fraction. To confirm that the intermediate form of cathepsin D specifically interacts with the lysosomal integral membrane proteins, the lysosomal membrane fraction was treated with trypsin and the binding experiment was conducted. The result showed that the binding capacity of cathepsin D to the lysosomal membranes was apparently abolished and cathepsin D did not rebind to the membranes. These data suggest that the intermediate form of cathepsin D is preferentially recognized by the lysosomal membranous protein which complements the mannose 6-phosphate receptor-dependent intracellular sorting mechanism.


Disclosure of the differences of Mesorhizobium loti under the free-living and symbiotic conditions by comparative proteome analysis without bacteroid isolation.
Rhizobia are symbiotic nitrogen-fixing soil bacteria that show a symbiotic relationship with their host legume. Rhizobia have 2 different physiological conditions: a free-living condition in soil, and a symbiotic nitrogen-fixing condition in the nodule. The lifestyle of rhizobia remains largely unknown, although genome and transcriptome analyses have been carried out. To clarify the lifestyle of bacteria, proteome analysis is necessary because the protein profile directly reflects in vivo reactions of the organisms. In proteome analysis, high separation performance is required to analyze complex biological samples. Therefore, we used a liquid chromatography-tandem mass spectrometry system, equipped with a long monolithic silica capillary column, which is superior to conventional columns. In this study, we compared the protein profile of Mesorhizobium loti MAFF303099 under free-living condition to that of symbiotic conditions by using small amounts of crude extracts. We identified 1,533 and 847 proteins for M. loti under free-living and symbiotic conditions, respectively. Pathway analysis by Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that many of the enzymes involved in the central carbon metabolic pathway were commonly detected under both conditions. The proteins encoded in the symbiosis island, the transmissible chromosomal region that includes the genes that are highly upregulated under the symbiotic condition, were uniquely detected under the symbiotic condition. The features of the symbiotic condition that have been reported by transcriptome analysis were confirmed at the protein level by proteome analysis. In addition, the genes of the proteins involved in cell surface structure were repressed under the symbiotic nitrogen-fixing condition. Furthermore, farnesyl pyrophosphate (FPP) was found to be biosynthesized only in rhizobia under the symbiotic condition. The obtained protein profile appeared to reflect the difference in phenotypes under the free-living and symbiotic conditions. In addition, KEGG pathway analysis revealed that the cell surface structure of rhizobia was largely different under each condition, and surprisingly, rhizobia might provided FPP to the host as a source of secondary metabolism. M. loti changed its metabolism and cell surface structure in accordance with the surrounding conditions.


Congenital self-healing reticulohistiocytosis: report of a case.
A newborn male infant presented with a single crateriform nodule in the region of the right iliac fossa. No extracutaneous involvement was found and the lesion involuted spontaneously without scarring in one month. Histology showed histiocytelike cells of which 10% to 15% contained Birbeck granules. S100 protein could not be demonstrated. This case possibly represents a solitary variant of congenital self-healing reticulohistiocytosis.


Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies.
The human 80S ribosome is the cellular nucleoprotein nanomachine in charge of protein synthesis that is profoundly affected during cancer transformation by oncogenic proteins and provides cancerous proliferating cells with proteins and therefore biomass. Indeed, cancer is associated with an increase in ribosome biogenesis and mutations in several ribosomal proteins genes are found in ribosomopathies, which are congenital diseases that display an elevated risk of cancer. Ribosomes and their biogenesis therefore represent attractive anti-cancer targets and several strategies are being developed to identify efficient and specific drugs. Homoharringtonine (HHT) is the only direct ribosome inhibitor currently used in clinics for cancer treatments, although many classical chemotherapeutic drugs also appear to impact on protein synthesis. Here we review the role of the human ribosome as a medical target in cancer, and how functional and structural analysis combined with chemical synthesis of new inhibitors can synergize. The possible existence of oncoribosomes is also discussed. The emerging idea is that targeting the human ribosome could not only allow the interference with cancer cell addiction towards protein synthesis and possibly induce their death but may also be highly valuable to decrease the levels of oncogenic proteins that display a high turnover rate (MYC, MCL1). Cryo-electron microscopy (cryo-EM) is an advanced method that allows the visualization of human ribosome complexes with factors and bound inhibitors to improve our understanding of their functioning mechanisms mode. Cryo-EM structures could greatly assist the foundation phase of a novel drug-design strategy. One goal would be to identify new specific and active molecules targeting the ribosome in cancer such as derivatives of cycloheximide, a well-known ribosome inhibitor.


Arrhythmias in the gut.
In recent years, it has become possible to record, from a large number of extracellular electrodes, the electrical activities of smooth muscle organs. These recordings, after proper processing and analysis, may reveal origin and propagation of normal and abnormal electrical activities in these organs. Several publications have appeared in the past 5 years describing origin and propagation of slow waves in the stomach of experimental animals and in humans. Furthermore, publications are now starting to appear that describe pathophysiological patterns of propagation and these studies provide us with novel concepts regarding potential mechanisms of arrhythmias in the gut, crucial information if we are ever going to successfully treat patients suffering from such arrhythmias. In this issue of Neurogastroenterology & Motility, Angeli et al. have mapped the slow wave propagation in the porcine small intestine and discovered two types of reentry; functional reentry and circumferential reentry. Next to the descriptions of arrhythmias in the stomach, the fact that reentrant arrhythmias may also occur in the small intestine further extends this new emerging field of gastrointestinal (GI) arrhythmias. In this viewpoint, the relevance of these arrhythmias is further discussed and a few ideas for future research in this field, not necessarily constrained to the GI system, proposed.


Structural basis of recognition of monopartite and bipartite nuclear localization sequences by mammalian importin-alpha.
Importin-alpha is the nuclear import receptor that recognizes cargo proteins which contain classical monopartite and bipartite nuclear localization sequences (NLSs), and facilitates their transport into the nucleus. To determine the structural basis of the recognition of the two classes of NLSs by mammalian importin-alpha, we co-crystallized an N-terminally truncated mouse receptor protein with peptides corresponding to the monopartite NLS from the simian virus 40 (SV40) large T-antigen, and the bipartite NLS from nucleoplasmin. We show that the monopartite SV40 large T-antigen NLS binds to two binding sites on the receptor, similar to what was observed in yeast importin-alpha. The nucleoplasmin NLS-importin-alpha complex shows, for the first time, the mode of binding of bipartite NLSs to the receptor. The two basic clusters in the NLS occupy the two binding sites used by the monopartite NLS, while the sequence linking the two basic clusters is poorly ordered, consistent with its tolerance to mutations. The structures explain the structural basis for binding of diverse NLSs to the sole receptor protein.


Serum, red blood cell and whole blood magnesium in patients with uncomplicated acute myocardial infarction.
Serum, whole blood and red blood (intracellular) magnesium determinations were made in 52 patients, without other factors predisposing to hypomagnesemia, admitted to a coronary care unit. Acute uncomplicated myocardial infarction was documented in 31 and the serum cardiac enzymes as well as the electrocardiogram remained nondiagnostic in 21 patients. There was no significant difference in the serum magnesium level in the two groups. An increasing trend with time was noted in the serum (p less than 0.001) and whole blood magnesium (p less than 0.005) during the first 4 days postmyocardial infarction. The whole blood magnesium as well as the red blood (intracellular) magnesium was higher (p less than 0.01) in myocardial infarction patients. There was no significant difference in the hematocrit or other electrolytes during this time.


How Did Adolescents With Cancer Experience the COVID-19 Pandemic? A Report From Italian Pediatric Hematology Oncology Association Centers.
This study set out to evaluate the psychosocial effects of coronavirus disease 2019 (COVID-19) among adolescents with cancer, and whether these effects are significantly different among adolescents who were undergoing therapy or had completed it. The AIEOP Adolescents Working Group and the AIEOP Psychosocial Working Group adapted a questionnaire, which was completed by 214 adolescent cancer patients ( Mage =16.3 y, range: 15 to 19 y old) treated at 16 AIEOP centers in the North (38%), South (31%), and Center (31%) of Italy. The results highlighted that fear of the virus is equally distributed among adolescent cancer patients, with patients being particularly concerned about their parents and families. The adolescents reported that had no difficulty in following individual safety measures: they used personal protective equipment and they were attentive to their own health and adhering to the rules imposed by doctors and the wider community. There are very few, limited differences between adolescents undergoing treatment (active group) and those who have completed treatment (follow-up group). The reminder of their own therapy experience triggered by the use of personal protective equipment, and the more common refusal to follow some restrictions were the only 2 behaviors by which the follow-up group differed significantly from the adolescents in the active group. Adolescents with cancer seem to have coped well with the pandemic: although they were very afraid of the virus for themselves and their families, and had to limit their social contact, they did comply with the restrictions. Their experience of cancer probably also had a positive effect in cultivating adolescents who are more responsible and resilient in emergency situations such as the pandemic.


A cat with suspected laryngeal metastasis with mucosal irregularity resulting from apocrine/salivary gland adenocarcinoma in the head.
A 16-year-old castrated male mongrel cat presented with swelling under the left pinna and a 3 -month history of voice change. Laryngeal endoscopy revealed circumferential oedema around the arytenoid cartilages and hypersecretion of saliva. Histopathological examination of the mass around the left ear canal was considered the primary lesion that originated from cutaneous apocrine adenocarcinoma or parotid gland adenocarcinoma, and it metastasized to the larynx, lung and medial retropharyngeal lymph nodes. This report provides new insights into feline laryngeal diseases which could result in laryngeal metastasis with slight mucosal irregularity alone and without obvious radiographic abnormalities. Therefore, histopathological examination should be performed when a cat presents clinical signs such as stridor, dysphonia or voice change without any mass-forming laryngeal lesion.


Was the serine protease cathepsin G discovered by S. G. Hedin in 1903 in bovine spleen?
In the beginning of the 20th century, enzymes with proteolytic activity were classified as peptidases, Erepsin, and proteases. Among these, pepsin, trypsin, and autolytic enzymes were of the protease class. Spleen-derived proteases were poorly characterized until Sven Gustaf Hedin performed several digestion experiments with bovine spleen. He incubated minced bovine spleen under acidic or neutral conditions and characterized two active proteases; the results were published in 1903. The first protease was named α-protease and was active under neutral conditions. The second was named β-protease and was active under acidic conditions. We replicated Hedin's experiments according to his methods and found, by using activity-based probes to visualize proteases, that the historical α-protease is the present-day serine protease cathepsin G (CatG), which is known to be important in several immune processes, including antigen processing, chemotaxis, and activation of surface receptors. The β-protease, however, comprised different proteases including CatX, B, S, and D. We suggest that Hedin described CatG activity in bovine spleen over 100 years ago.


Epithelial interleukin-4 receptor expression promotes colon tumor growth.
Inflammatory mediators are of considerable interest as potential therapeutic targets in various cancers. Here we investigate whether interleukin (IL)-4 receptor alpha (IL4Ralpha), a component of the receptor complex for the T helper 2 cytokines IL4 and IL13, plays a role in colonic tumorigenesis. IL4Ralpha protein expression was seen in tumor cells of 28/48 human colon adenocarcinomas on a tissue microarray. In human and murine colon tumor cell lines analyzed in vitro, all of which expressed IL4Ralpha, treatment with exogenous ligand resulted in dose-dependent increases in proliferation. IL4 decreased apoptosis only in HCT116 cells. An orthotopic allograft model was used to determine in vivo effects of tumor cell-specific IL4Ra ablation. MC38 murine tumor cells with the IL4Ra gene knocked down showed reduced proliferation but no difference in apoptosis compared with controls after implantation in ceca of syngeneic mice. Mice null for IL4Ra and wild-type controls were treated with azoxymethane and dextran sulfate sodium to induce tumor formation. Mice with global deletion of IL4Ra had significantly fewer and smaller tumors. Reduced tumorigenicity correlated with decreased proliferation and increased apoptosis. Systemic blockade of IL4Ralpha-IL4 interactions with a chimeric soluble receptor protein gave similar results in the cecal implant model. Thus, IL4Ralpha, a component of the IL4R and IL13R, contributes to tumor formation in a mouse model of colitis-associated cancer. Proliferation appears to be directly mediated via IL4Ralpha on the epithelial tumor cells. Survival may be an indirect response mediated via other host cells. Our results support therapeutic targeting of IL4Ralpha in colon cancer.


Interferometric spherical surface testing with unknown phase shifts.
A general method is presented for spherical surface testing with unknown phase shifts based on a physical model of the interferometer cavity, which describes the phase shifts taking into account the rigid cavity motions and the radial imaging distortion of the interferometer. The captured interferograms are processed frame by frame with the regularized frequency-stabilizing method, so as to get the phase shifts between the frames. These phase shift data are subsequently fitted, and the initial estimations for the wavefront, direct current and interference contrast terms are calculated by the least-squares method. Specially, a simple way is proposed to find reasonable initial guess for numerical aperture (NA) of the test beam (when NA is unknown), so as to ensure the effectiveness of the above phase shift fitting procedure. Then, the wavefront result is further refined in an iterative way, by fitting the sequence of interferograms to the physical model of the interferometer cavity with the linear regression technique. Finally, the wavefront result related to the actual surface profile is retrieved after removing the aberrations due to the surface misalignment and the imaging distortion. Both simulations and experiments with the ZYGO interferometer have been carried out to validate the proposed method, with experimental accuracies better than 0.004λ RMS achieved. The proposed method provides a feasible way to spherical surface testing without the use of any phase-shifting devices, while retaining good accuracy and robust convergence performance.


Idiopathic subglottic stenosis: a review.
Idiopathic subglottic stenosis (iSGS) is a fibrotic disease of unclear etiology that produces obstruction of the central airway in the anatomic region under the glottis. The diagnosis of this entity is difficult, usually delayed and confounded with other common respiratory diseases. No apparent etiology is identified even after a comprehensive workup that includes a complete history, physical examination, pulmonary function testing, auto-antibodies, imaging studies, and endoscopic procedures. This approach, however, helps to exclude other conditions such as granulomatosis with polyangiitis (GPA). It is also helpful to characterize the lesion and outline management strategies. Therapeutic endoscopic procedures and surgery are the most common management modalities, but medical therapy can also play a significant role in preventing or delaying recurrence. In this review, we describe the morphology, pathophysiology, clinical presentation, evaluation, management, and prognosis of iSGS.


Improved neural network based scene-adaptive nonuniformity correction method for infrared focal plane arrays.
An improved scene-adaptive nonuniformity correction (NUC) algorithm for infrared focal plane arrays (IRFPAs) is proposed. This method simultaneously estimates the infrared detectors' parameters and eliminates the nonuniformity causing fixed pattern noise (FPN) by using a neural network (NN) approach. In the learning process of neuron parameter estimation, the traditional LMS algorithm is substituted with the newly presented variable step size (VSS) normalized least-mean square (NLMS) based adaptive filtering algorithm, which yields faster convergence, smaller misadjustment, and lower computational cost. In addition, a new NN structure is designed to estimate the desired target value, which promotes the calibration precision considerably. The proposed NUC method reaches high correction performance, which is validated by the experimental results quantitatively tested with a simulative testing sequence and a real infrared image sequence.


Even if I showed you where you looked, remembering where you just looked is hard.
People know surprisingly little about their own visual behavior, which can be problematic when learning or executing complex visual tasks such as search of medical images. We investigated whether providing observers with online information about their eye position during search would help them recall their own fixations immediately afterwards. Seventeen observers searched for various objects in "Where's Waldo" images for 3 s. On two-thirds of trials, observers made target present/absent responses. On the other third (critical trials), they were asked to click twelve locations in the scene where they thought they had just fixated. On half of the trials, a gaze-contingent window showed observers their current eye position as a 7.5° diameter "spotlight." The spotlight "illuminated" everything fixated, while the rest of the display was still visible but dimmer. Performance was quantified as the overlap of circles centered on the actual fixations and centered on the reported fixations. Replicating prior work, this overlap was quite low (26%), far from ceiling (66%) and quite close to chance performance (21%). Performance was only slightly better in the spotlight condition (28%, p = 0.03). Giving observers information about their fixation locations by dimming the periphery improved memory for those fixations modestly, at best.


Pharmacokinetics, biodistribution, and toxicity of folic acid-coated antiretroviral nanoformulations.
The drug delivery platform for folic acid (FA)-coated nanoformulated ritonavir (RTV)-boosted atazanavir (FA-nanoATV/r) using poloxamer 407 was developed to enhance cell and tissue targeting for a range of antiretroviral drugs. Such formulations would serve to extend the drug half-life while improving the pharmacokinetic profile and biodistribution to reservoirs of human immunodeficiency virus (HIV) infection. To this end, we now report enhanced pharmacokinetics and drug biodistribution with limited local and systemic toxicities of this novel nanoformulation. The use of FA as a targeting ligand for nanoATV/r resulted in plasma and tissue drug concentrations up to 200-fold higher compared to equimolar doses of native drug. In addition, ATV and RTV concentrations in plasma from mice on a folate-deficient diet were up to 23-fold higher for mice administered FA-nanoATV/r than for mice on a normal diet. Compared to earlier nanoATV/r formulations, FA-nanoATV/r resulted in enhanced and sustained plasma and tissue ATV concentrations. In a drug interaction study, ATV plasma and tissue concentrations were up to 5-fold higher in mice treated with FA-nanoATV/r than in mice treated with FA-nanoATV alone. As observed in mice, enhanced and sustained plasma concentrations of ATV were observed in monkeys. NanoATV/r was associated with transient local inflammation at the site of injection. There were no systemic adverse reactions associated with up to 10 weeks of chronic exposure of mice or monkeys to FA-nanoATV/r.


A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering.
Human tissue kallikrein (KLK) proteases are hormone-like signaling molecules with important functions in cancer pathophysiology. KLK-related peptidase 6 (KLK6), specifically, is highly up-regulated in several types of cancer, where its increased activity promotes cancer invasion and metastasis. This characteristic suggests KLK6 as an attractive target for therapeutic interventions. However, inhibitors that specifically target KLK6 have not yet been reported, possibly because KLK6 shares a high sequence homology and structural similarity with other serine proteases and resists inhibition by many polypeptide inhibitors. Here, we present an innovative combinatorial approach to engineering KLK6 inhibitors via flow cytometry-based screening of a yeast-displayed mutant library of the human amyloid precursor protein Kunitz protease inhibitor domain (APPI), an inhibitor of other serine proteases, such as anionic and cationic trypsins. On the basis of this screening, we generated APPIM17L,I18F,S19F,F34V (APPI-4M), an APPI variant with a KLK6 inhibition constant (Ki ) of 160 pm and a turnover time of 10 days. To the best of our knowledge, APPI-4M is the most potent KLK6 inhibitor reported to date, displaying 146-fold improved affinity and 13-fold improved proteolytic stability compared with WT APPI (APPIWT). We further demonstrate that APPI-4M acts as a functional inhibitor in a cell-based model of KLK6-dependent breast cancer invasion. Finally, the crystal structures of the APPIWT/KLK6 and APPI-4M/KLK6 complexes revealed the structural and mechanistic bases for the improved KLK6 binding and proteolytic resistance of APPI-4M. We anticipate that APPI-4M will have substantial translational potential as both imaging agent and therapeutic.


Development and Use a Novel combined in-vivo and in-vitro Assay for Anti-inflammatory and Immunosuppressive Agents.
Contact hypersensitivity (CHS) mouse model induced by 2, 4-dinitrofluorobenzene (DNFB) is thought to be a T helper 1 (Th1)-dominant response and used for investigating anti-inflammatory and immunosuppressive agents. However, it is hardly used for screening large-scale drugs because of the large number of animals and complex mechanisms involved in-vivo. In this study, we focused on whether T lymphocytes from CHS mouse model could maintain the state of immune response in-vitro and explored a suitable time for drugs screening. The results showed that CD4(+) T cells of CHS mice were higher compared with those in normal group. The expression of T-bet and GATA3 showed a Th1 shift and the levels of interleukin (IL)-2 and IL-4 also showed similar trend. Furthermore, IL-6 produced by T lymphocytes from CHS mice had a high level too. Then, we detected the effects of dexamethasone (DEX), cyclosporine A (CsA) and mycophenolate mofetil (MMF) on T lymphocytes in-vitro, and the data displayed that these immunosuppressive drugs could all inhibit the proliferation of T lymphocytes significantly. These findings suggested that T lymphocytes from CHS mice could mimic a similar immune response in-vitro, and it's also a suitable method for screening anti-inflammatory and immunosuppressive agents.


Human genetics. The genetics of Mexico recapitulates Native American substructure and affects biomedical traits.
Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation from this region remain largely uncharacterized. We studied genomic variation within Mexico from over 1000 individuals representing 20 indigenous and 11 mestizo populations. We found striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across the country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americans showed a significant association between subcontinental ancestry and lung function. Thus, accounting for fine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, in Mexican-descent populations, and likely in many other populations worldwide.


Synthesis of Porphyrin, Chlorin and Phthalocyanine Derivatives by Azide-Alkyne Click Chemistry.
The aim of this review is to provide a summary of the use of copper-catalyzed azide-alkyne cycloaddition (CuAAC) in the synthesis of porphyrin, chlorin and phthalocyanine derivatives for different types of therapeutic applications. The click reaction is a powerful and versatile tool for scientists working on the synthesis of various symmetrically and asymmetrically substituted tetrapyrrolic derivatives. For example, click chemistry is widely used for the elaboration of photosensitizer conjugates for photodynamic therapy applications. Other biological applications are also described.


Imaging H2O photofragments in the predissociation of the HCl-H2O hydrogen-bonded dimer.
The state-to-state vibrational predissociation (VP) dynamics of the hydrogen-bonded HCl-H(2)O dimer was studied following excitation of the dimer's HCl stretch by detecting the H(2)O fragment. Velocity map imaging (VMI) and resonance-enhanced multiphoton ionization (REMPI) were used to determine pair-correlated product energy distributions. Following vibrational excitation of the HCl stretch of the dimer, H(2)O fragments were detected by 2 + 1 REMPI via the C (1)B(1) (000) ← X (1)A(1) (000) transition. REMPI spectra clearly show H(2)O from dissociation produced in the ground vibrational state. The fragments' center-of-mass (c.m.) translational energy distributions were determined from images of selected rotational states of H(2)O and were converted to rotational state distributions of the HCl cofragment. The distributions were consistent with the previously measured dissociation energy of D(0) = 1334 ± 10 cm(-1) and show a clear preference for rotational levels in the HCl fragment that minimize translational energy release. The usefulness of 2 + 1 REMPI detection of water fragments is discussed.


Pore formation in lipid membrane II: Energy landscape under external stress.
Lipid membranes are extremely stable envelopes allowing cells to survive in various environments and to maintain desired internal composition. Membrane permeation through formation of transversal pores requires substantial external stress. Practically, pores are usually formed by application of lateral tension or transmembrane voltage. Using the same approach as was used for obtaining continuous trajectory of pore formation in the stress-less membrane in the previous article, we now consider the process of pore formation under the external stress. The waiting time to pore formation proved a non-monotonous function of the lateral tension, dropping from infinity at zero tension to a minimum at the tension of several millinewtons per meter. Transmembrane voltage, on the contrary, caused the waiting time to decrease monotonously. Analysis of pore formation trajectories for several lipid species with different spontaneous curvatures and elastic moduli under various external conditions provided instrumental insights into the mechanisms underlying some experimentally observed phenomena.


c-Abl mediates endothelial apoptosis induced by inhibition of integrins alphavbeta3 and alphavbeta5 and by disruption of actin.
Inhibition of integrins alphavbeta3 and alphavbeta5 in human brain microvascular endothelial cells (HBMECs) by the function-blocking peptide RGDfV induces loss of spreading on vitronectin, cell detachment, and apoptosis. We demonstrate that cell detachment is not required for apoptosis because plating on bovine serum albumin-blocked poly-L-lysine (allows attachment, but not integrin ligation and cell spreading) also induced apoptosis. Latrunculin B (LatB), which inhibits F-actin polymerization, induced transient loss of HBMEC spreading on vitronectin, but not their detachment, and induced apoptosis despite recovery of cell spreading. However, LatB did not cause apoptosis in 5 tumor cell lines. In HBMECs, both LatB and RGDfV induced transient Y412 and Y245 phosphorylation of endogenous c-Abl, a nonreceptor tyrosine kinase that reciprocally regulates F-actin. LatB also induced nuclear translocation of c-Abl in HBMECs. STI-571 (imatinib), a targeted therapy for BCR-ABL1(+) leukemias and inhibitor of c-Abl, platelet-derived growth factor receptor, and c-Kit, decreased endothelial apoptosis. LatB-induced HBMEC apoptosis, and its inhibition by STI-571 also occurred in a 3-dimensional collagen model, supporting physiologic relevance. Last, siRNA to c-Abl (but not nonspecific siRNA) also inhibited RGDfV- and LatB-induced apoptosis. Thus, endogenous c-Abl mediates endothelial apoptosis induced by inhibition of integrins alphavbeta3/alphavbeta5 or by LatB-induced disruption of F-actin.


Functional Equivalence of Retroviral MA Domains in Facilitating Psi RNA Binding Specificity by Gag.
Retroviruses specifically package full-length, dimeric genomic RNA (gRNA) even in the presence of a vast excess of cellular RNA. The "psi" (Ψ) element within the 5'-untranslated region (5'UTR) of gRNA is critical for packaging through interaction with the nucleocapsid (NC) domain of Gag. However, in vitro Gag binding affinity for Ψ versus non-Ψ RNAs is not significantly different. Previous salt-titration binding assays revealed that human immunodeficiency virus type 1 (HIV-1) Gag bound to Ψ RNA with high specificity and relatively few charge interactions, whereas binding to non-Ψ RNA was less specific and involved more electrostatic interactions. The NC domain was critical for specific Ψ binding, but surprisingly, a Gag mutant lacking the matrix (MA) domain was less effective at discriminating Ψ from non-Ψ RNA. We now find that Rous sarcoma virus (RSV) Gag also effectively discriminates RSV Ψ from non-Ψ RNA in a MA-dependent manner. Interestingly, Gag chimeras, wherein the HIV-1 and RSV MA domains were swapped, maintained high binding specificity to cognate Ψ RNAs. Using Ψ RNA mutant constructs, determinants responsible for promoting high Gag binding specificity were identified in both systems. Taken together, these studies reveal the functional equivalence of HIV-1 and RSV MA domains in facilitating Ψ RNA selectivity by Gag, as well as Ψ elements that promote this selectivity.


Evaluation of posterior ocular changes using enhanced depth imaging-optical coherence tomography in patients with obstructive sleep apnea syndrome.
Evaluation of the nerve fiber thicknesses of the macula, choroid, and retina using the apnea-hypopnea index in individuals with obstructive sleep apnea syndrome (OSAS) without systemic components. Prospective, controlled study. The central macular, choroidal, and retinal nerve fiber layer (RNFL) thicknesses were evaluated using enhanced depth imaging-spectral domain optical coherence tomography in individuals with OSAS. In people with severe OSAS who had received treatment, posterior ocular structures were examined over 3 months (4th and 12th weeks), and changes were evaluated. Only the right eyes of the participants were evaluated in the study. A total of 72 people were involved in the study, with 18 in the control group and 19 with mild, 16 with moderate, and 19 with severe OSAS. No significant difference was found among the groups in terms of demographic measures. No significant differences were found among the groups in terms of the measures of central macular, central subfoveal choroidal (CSCT), temporal choroidal, nasal choroidal, and RNFL thicknesses. In severe OSAS cases in which treatment was administered, although subjective clinical recovery was observed, statistically significant thinning was detected during the 3-month follow-up period in the CSCT, general RNFL, as well as in the inferior and superior nasal quadrants, and temporal superior quadrant (p=0.005, p=0.009, p=0.039, p=0.003, and p=0.02, respectively). In the group with severe OSAS, thinning in some posterior ocular tissues was observed. Although patients with severe OSAS may experience clinical recovery, we recommend that they would be followed up in terms of ocular ischemic injury.


Oral melanoacanthoma and oral melanotic macule: a report of 8 cases, review of the literature, and immunohistochemical analysis.
Oral melanoacanthoma (MA) is a rare, benign pigmented lesion, similar to cutaneous MA, characterized by hyperplasia of spinous keratinocytes and dendritic melanocytes. The pathogenesis of oral MA remains uncertain, although its clinical behavior is suggestive of a reactive origin. The most common intraoral sites are the buccal mucosa, lip, palate and gingiva. The average age of presentation is 28 years, mainly in blacks, with a strong female predilection. The oral melanotic macule (MM) is a small, well-circumscribed brown-to-black macule that occurs on the lips and mucous membranes. The etiology is not clear and it may represent a physiologic or reactive process. The average age of presentation is 43 years, with a female predilection. A biopsy is recommended to distinguish these lesions from each other and from other oral melanocytic lesions. We depict four cases each of oral MA and MM, affecting Caucasian and Latin American mestizo patients. The clinicopathological features of these cases reflect its ample spectrum, and to the best of our knowledge, it is the first example of oral MA affecting a Caucasian boy reported in the English literature. Therefore oral MA and MM should be considered in the differential diagnosis of pigmented lesions in the oral mucosa in these populations.


First demonstration of effective spatial training for near transfer to spatial performance and far transfer to a range of mathematics skills at 8 years.
There is evidence that spatial thinking is malleable, and that spatial and mathematical skills are associated (Mix et al. [2016] Journal of Experimental Psychology: General, 145, 1206; Mix et al. [2017] Journal of Cognition and Development, 18, 465; Uttal et al. [2013] Psychological Bulletin, 139, 352). However, few studies have investigated transfer of spatial training gains to mathematics outcomes in children, and no known studies have compared different modes of spatial instruction (explicit vs. implicit instruction). Based on a sample of 250 participants, this study compared the effectiveness of explicit and implicit spatial instruction in eliciting near transfer (to the specific spatial skills trained), intermediate transfer (to untrained spatial skills) and far transfer (to mathematics domains) at age 8. Spatial scaling and mental rotation skills were chosen as training targets as previous studies have found, and proposed explanations for, associations between these skills and mathematics in children of this age (Journal of Experimental Psychology: General, 145, 2016 and 1206). In this study, spatial training led to near, intermediate and far transfer of gains. Mental visualization and proportional reasoning were proposed to explain far transfer from mental rotation and spatial scaling skills respectively. For most outcomes, except for geometry, there was no difference in the effectiveness of implicit (practice with feedback) compared to explicit instruction (instructional videos). From a theoretical perspective, the study identified a specific causal effect of spatial skills on mathematics skills in children. Practically, the results also highlight the potential of instructional videos as a method of introducing spatial thinking into the classroom.


The self in conflict: actors and agency in the mediated sequential Simon task.
Executive control refers to the ability to withstand interference in order to achieve task goals. The effect of conflict adaptation describes that after experiencing interference, subsequent conflict effects are weaker. However, changes in the source of conflict have been found to disrupt conflict adaptation. Previous studies indicated that this specificity is determined by the degree to which one source causes episodic retrieval of a previous source. A virtual reality version of the Simon task was employed to investigate whether changes in a visual representation of the self would similarly affect conflict adaptation. Participants engaged in a mediated Simon task via 3D "avatar" models that either mirrored the participants' movements, or were presented statically. A retrieval cue was implemented as the identity of the avatar: switching it from a male to a female avatar was expected to disrupt the conflict adaptation effect (CAE). The results show that only in static conditions did the CAE depend on the avatar identity, while in dynamic conditions, changes did not cause disruption. We also explored the effect of conflict and adaptation on the degree of movement made with the task-irrelevant hand and replicated the reaction time pattern. The findings add to earlier studies of source-specific conflict adaptation by showing that a visual representation of the self in action can provide a cue that determines episodic retrieval. Furthermore, the novel paradigm is made openly available to the scientific community and is described in its significance for studies of social cognition, cognitive psychology, and human-computer interaction.


Cross-Linked Cholecyst-Derived Extracellular Matrix for Abdominal Wall Repair.
Abdominal wall repair frequently utilizes either nondegradable or biodegradable meshes, which are found to stimulate undesirable biological tissue responses or which possess suboptimal degradation rate. In this study, a biologic mesh prototype made from carbodiimide cross-linked cholecyst-derived extracellular matrix (EDCxCEM) was compared with small intestinal submucosa (Surgisis®), cross-linked bovine pericardium (Peri-Guard®), and polypropylene (Prolene®) meshes in an in vivo rabbit model. The macroscopic appearance and stereological parameters of the meshes were evaluated. Tailoring the degradation of the EDCxCEM mesh prevents untimely degradation, while allowing cellular infiltration and mesh remodeling to take place in a slower but predictable manner. The results suggest that the cross-linked biodegradable cholecyst-derived biologic mesh results in no seroma formation, low adhesion, and moderate stretching of the mesh. In contrast to Surgisis, Peri-Guard, and Prolene meshes, the EDCxCEM mesh showed a statistically significant increase in the volume fraction (Vv) of collagen (from 34% to 52.1%) in the central fibrous tissue region at both day 28 and 56. The statistically high length density (Lv), of blood vessels for the EDCxCEM mesh at 28 days was reflected also by the higher cellular activity (high Vv of fibroblast and moderate Vv of nuclei) indicating remodeling of this region in the vicinity of a slowly degrading EDCxCEM mesh. The lack of mesh area stretching/shrinkage in the EDCxCEM mesh showed that the remodeled tissue was adequate to prevent hernia formation. The stereo-histological assays suggest that the EDCxCEM delayed degradation profile supports host wound healing processes including collagen formation, cellular infiltration, and angiogenesis. The use of cross-linked CEM for abdominal wall repair is promising.


Social and emotional relevance in face processing: happy faces of future interaction partners enhance the late positive potential.
Human face perception is modulated by both emotional valence and social relevance, but their interaction has rarely been examined. Event-related brain potentials (ERP) to happy, neutral, and angry facial expressions with different degrees of social relevance were recorded. To implement a social anticipation task, relevance was manipulated by presenting faces of two specific actors as future interaction partners (socially relevant), whereas two other face actors remained non-relevant. In a further control task all stimuli were presented without specific relevance instructions (passive viewing). Face stimuli of four actors (2 women, from the KDEF) were randomly presented for 1s to 26 participants (16 female). Results showed an augmented N170, early posterior negativity (EPN), and late positive potential (LPP) for emotional in contrast to neutral facial expressions. Of particular interest, face processing varied as a function of experimental tasks. Whereas task effects were observed for P1 and EPN regardless of instructed relevance, LPP amplitudes were modulated by emotional facial expression and relevance manipulation. The LPP was specifically enhanced for happy facial expressions of the anticipated future interaction partners. This underscores that social relevance can impact face processing already at an early stage of visual processing. These findings are discussed within the framework of motivated attention and face processing theories.


Basic behavior of the finite helical axis in a simple tooth movement simulation.
A finite helical axis (FHA) analysis can provide precise three-dimensional information on orthodontic tooth movement compared to an analysis based on a rectangular coordinate system. The FHA has already been applied in an analysis of orthodontic tooth movement. Interestingly, the position of the FHA changes dramatically in different stages of treatment; however, no previous report has provided detailed information of its basic behavior for clinicians. The purpose of this study was to clarify the basic behavior of the FHA in simple tooth movement, which could promote a better understanding of the 3-D orientation of and rotation about the FHA during tooth movement. Parameters of the FHA were calculated from a simulation of canine retraction. As the tipping angle of the canine was increased from 5 degrees to 30 degrees , the orientation vector of the FHA approached the most affected axis of rotation (on a rectangular coordinate system) in a non-linear manner. The angle of rotation about the FHA also increased in a non-linear manner. This non-linear problem was solved analytically. The basic behavior of the orientation vector of the FHA and the non-linear characteristics of the FHA parameters clarified in this study should be important for the future analysis of actual tooth movement based on the FHA. However, we must be aware that the non-linearity of the FHA itself may affect the analysis of the mechanical properties of the periodontal tissue.


A meta-analysis of morphological interventions: effects on literacy achievement of children with literacy difficulties.
This study synthesizes 79 standardized mean-change differences between control and treatment groups from 17 independent studies, investigating the effect of morphological interventions on literacy outcomes for students with literacy difficulties. Average total sample size ranged from 15 to 261 from a wide range of grade levels. Overall, morphological instruction showed a significant improvement on literacy achievement (d = 0.33). Specifically, its effect was significant on several literacy outcomes such as phonological awareness (d = 0.49), morphological awareness (d = 0.40), vocabulary (d = 0.40), reading comprehension (d = 0.24), and spelling (d = 0.20). Morphological instruction was particularly effective for children with reading, learning, or speech and language disabilities, English language learners, and struggling readers, suggesting the possibility that morphological instruction can remediate phonological processing challenges. Other moderators were also explored to explain differences in morphological intervention effects. These findings suggest students with literacy difficulties would benefit from morphological instruction.


Perspectives of Transplant Professionals on the Values, Ethics, and Challenges of Living Kidney Donor Evaluation in Asia.
Deceased donor rates in Asia are among the lowest in the world. This has necessitated a reliance on living kidney donation, which has given rise to concerns about donor motivation and assessment in this region. We aimed to describe transplant professional perspectives on living kidney donor evaluation in Asia. Face-to-face, semistructured interviews were conducted with 53 transplant professionals (nephrologists [n = 21], surgeons/urologists [n = 17], coordinators [n = 7], social workers [n = 5], ethicists [n = 2], psychologist [n = 1]) from 20 centers in 10 countries. Transcripts were analyzed thematically to identify themes. The theme of traversing vulnerability overarched 4 themes. Vigilance against exploitation of the vulnerable meant mitigating the threat of commercial transplantation, combating disparities, and verifying volunteerism. Maintaining clarity of professional roles encompassed the perceived necessity of legal safeguards to determine legitimacy of relationships, ensuring informed consent, demarcating responsibilities, minimizing conflict of interest, meeting community expectations, and resolving ambivalence regarding donor risk. Societal plight driving caution about living kidney donor assessment was emphasized in the context of poverty and desperation, higher risk of disease, and lack of social security. Navigating sociocultural barriers acknowledged the centrality of the family, economic priorities, distrust in modern medicine, generational traditions, and emotional opacity limiting their ability to gauge donor motivation. Moral, professional, sociocultural and societal vulnerabilities contribute to the barriers and ethical quandaries in living kidney donation in Asia. Strategies are needed to address culturally based anxieties and disparities in living donation. Transplant professionals depend on strong legislation and policies to prevent exploitation of living donors.


Graphene metallization of high-stress silicon nitride resonators for electrical integration.
High stress stoichiometric silicon nitride resonators, whose quality factors exceed one million, have shown promise for applications in sensing, signal processing, and optomechanics. Yet, electrical integration of the insulating silicon nitride resonators has been challenging, as depositing even a thin layer of metal degrades the quality factor significantly. In this work, we show that graphene used as a conductive coating for Si3N4 membranes reduces the quality factor by less than 30% on average, which is minimal when compared to the effect of conventional metallization layers such as chromium or aluminum. The electrical integration of Si3N4-Graphene (SiNG) heterostructure resonators is demonstrated with electrical readout and electrostatic tuning of the frequency by up to 0.3% per volt. These studies demonstrate the feasibility of hybrid graphene/nitride mechanical resonators in which the electrical properties of graphene are combined with the superior mechanical performance of silicon nitride.


Dissociation between intracellular Ca2+ and modulation of [3H]noradrenaline release in chick sympathetic neurons.
1. We studied the relation between cyclic AMP, intracellular Ca2+ concentration and release of [3H]noradrenaline ([3H]NA) in sympathetic neurons cultured from chick embryos. 2. Forskolin (10 microM) and vasoactive intestinal polypeptide (VIP, 3 microM) increased cellular levels of cyclic AMP 8- and 3-fold, respectively, either in the absence or presence of electrical stimulation. Electrical stimulation (1 Hz for 10 s) alone had no effect on cyclic AMP levels. 3. Electrically evoked (1 Hz for 10 s) release of [3H]NA was facilitated by 10 microM-forskolin, 3 microM-VIP and by the non-hydrolysable cyclic AMP analogue, 8-bromoadenosine 3': 5'-cyclic monophosphate (8-Br-cyclic AMP). The inactive analogue of forskolin, dideoxyforskolin, had no effect on [3H]NA release. 4. The stimulation-evoked release of [3H]NA was completely inhibited by the neuronal blocking drugs guanethidine (1 microM) and bretylium (3 microM). 5. Whole-cell voltage-clamp studies showed that forskolin and VIP did not facilitate and guanethidine and bretylium did not block voltage-activated Ca2+ currents in the cell bodies of sympathetic neurons. 6. Fluorescence measurements using the Ca(2+)-sensitive dye Indo-1 revealed that forskolin and guanethidine had no effect on the electrically stimulated increase in intracellular Ca2+ concentration recorded from the cell bodies and the growth cones. 7. We conclude that release of [3H]NA can be enhanced or blocked without affecting the increase in intracellular Ca2+ concentration produced by electrical stimulation. Therefore, it is possible that pharmacological agents enhance or depress the release of [3H]NA by acting on steps of exocytosis that are down-stream from Ca2+ mobilization.


Relevance of amyloid precursor-like protein 2 C-terminal fragments in pancreatic cancer cells.
In some cellular systems, particularly neurons, amyloid precursor-like protein 2 (APLP2), and its highly homologous family member amyloid precursor protein (APP), have been linked to cellular growth. APLP2 and APP undergo regulated intramembrane proteolysis to produce C-terminal fragments. In this study, we found comprehensive expression of APLP2 C-terminal fragments in a panel of pancreatic cancer cell lines; however, APP C-terminal fragments were notably limited to the BxPC3 cell line. Extensive glycosaminoglycan modification on APLP2 was also found in the majority of pancreatic cancer cell lines. Glycosaminoglycan-modified and -unmodified APLP2, and particularly APLP2 C-terminal fragments, also demonstrated increased expression in oncogene-transformed pancreatic ductal cells. Additionally, elevated APLP2 levels were confirmed in human pancreatic cancer tissue. Downregulation of APLP2 and APP expression, alone or in combination, caused a decrease in the growth of a pancreatic cancer cell line with representatively low APP C-terminal fragment expression, the S2-013 cell line. Furthermore, we found that treatment with β-secretase inhibitors to block formation of APLP2 C-terminal fragments decreased the growth and viability of S2-013 cells, without affecting the survival of a non-transformed pancreatic ductal cell line. In conclusion, our studies demonstrate that abundant APLP2, but not APP, C-terminal fragment expression is conserved in pancreatic cancer cell lines; however, APP and APLP2 equally regulated the growth of S2-013 pancreatic cancer cells. Chiefly, our discoveries establish a role for APLP2 in the growth of pancreatic cancer cells and show that inhibitors preventing APLP2 cleavage reduce the viability of pancreatic cancer cells.


Aortic morphologic findings after thoracic endovascular aortic repair for type B aortic dissection.
Thoracic endovascular aortic repair (TEVAR) is used in the treatment of type B aortic dissections. Information related to aortic morphologic findings and the condition of the abdominal aorta after TEVAR is limited. To analyze aortic morphologic findings after TEVAR for type B aortic dissections. After a retrospective database review, the data for 30 patients who underwent TEVAR from January 1, 2007, through December 31, 2013, for type B aortic dissection were analyzed. Imaging software was used to calculate aortic diameters and volumes of the aorta on computed tomography (CT) or magnetic resonance imaging (MRI). Mean follow-up was 14.4 months. We performed TEVAR to cover proximal thoracic aorta tears in patients who underwent acute or chronic type B aortic dissections. Aortic morphologic findings of pre-TEVAR CT or MRI were compared with the most recent findings of post-TEVAR CT or MRI. Frequency of thoracic false lumen thrombosis (FLT) and false lumen patency (FLP) was determined and the effect on post-TEVAR aortic morphologic findings analyzed. Mean (SD) TEVAR increased true lumen diameter (19.50 [6.92] mm to 31.19 [5.36] mm, P < .001) and volume (77.92 [41.70] mL to 166.95 [69.69] mL, P < .001) and decreased false lumen diameter (29.77 [12.55] mm to 21.92 [12.05] mm, P = .001) on post-TEVAR CT or MRI when compared with pre-TEVAR scans. Seventy percent of patients experienced thoracic FLT; 30% had FLP. True lumen volume expansion and false lumen volume regression occurred in patients with FLT (82.07 [46.95] mm to 180.55 [77.99] mm, P < .001 and 161.84 [106.36] mm to 115.76 [140.77] mm, P = .002, respectively) and FLP (68.23 [21.43] mm to 128.22 [21.46] mm, P < .001 and 238.64 [174.00] mm to 198.93 [120.46] mm, P = .04, respectively). Patients with FLT had increased true lumen diameter (15.67 [6.43] mm to 26.13 [7.62] mm, P < .001) and volume (54.86 [30.52] mL to 88.08 [41.07] mL, P = .001) in the abdominal aorta after TEVAR, with no change in total abdominal aortic volume (161.94 [70.12] mL vs 160.36 [82.11] mL, P = .90). Total abdominal aortic volume significantly increased in patients with thoracic FLP (187.24 [89.88] mL to 221.41 [82.64] mL, P = .02). Favorable aortic remodeling of the thoracic aorta occurs after TEVAR for type B aortic dissections in patients with thoracic FLT and FLP. However, failure to achieve thrombosis of the thoracic false lumen negatively influences aortic morphologic findings of the contiguous abdominal aorta.


Review. Studying cumulative cultural evolution in the laboratory.
Cumulative cultural evolution is the term given to a particular kind of social learning, which allows for the accumulation of modifications over time, involving a ratchet-like effect where successful modifications are maintained until they can be improved upon. There has been great interest in the topic of cumulative cultural evolution from researchers from a wide variety of disciplines, but until recently there were no experimental studies of this phenomenon. Here, we describe our motivations for developing experimental methods for studying cumulative cultural evolution and review the results we have obtained using these techniques. The results that we describe have provided insights into understanding the outcomes of cultural processes at the population level. Our experiments show that cumulative cultural evolution can result in adaptive complexity in behaviour and can also produce convergence in behaviour. These findings lend support to ideas that some behaviours commonly attributed to natural selection and innate tendencies could in fact be shaped by cultural processes.


Biological relationships between mania and melancholia.
Although opposite mood and psychomotor disturbances usually occur in mania and melancholia, clinical features may also be shared in common or may be present at the same time in both phases of manic-depressive psychosis. In a parallel fashion, most pharmacological agents are selectively effective in one mood phase (tricyclics and monoamine oxidase inhibitors for depression, and neuroleptics for mania) and frequently precipitate or exacerbate the opposite phase. These agents, therefore, may be affecting biological substrates mediating the opposing phase of affective illness. With the exception of electroconvulsive therapy and lithium chemotherapy, few treatments are effective in both mania and melancholia. It is noteworthy, therefore, that carbamazepine may be useful in the acute and prophylactic treatment of mania and melancholia, including some lithium non-responders and patients vulnerable to tricyclic-induced "mood switches". The clinical and biological effects of carbamazepine will be discussed with special emphasis on its biochemical action and the possible mechanisms by which it might influence biological substrates mediating both phases of manic-depressive illness. In addition, the theoretical implications of the presence of both shared and opposing clinical, pharmacological, and biochemical characteristics of the illness will be discussed.


Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial.
We previously found that dual HER2 blockade with trastuzumab and lapatinib led to inhibition of tumour growth in patient-derived xenografts of HER2-amplified metastatic colorectal cancer. In this study, we aimed to assess the antitumour activity of trastuzumab and lapatinib in patients with HER2-positive colorectal cancer. HERACLES was a proof-of-concept, multicentre, open-label, phase 2 trial done at four Italian academic cancer centres. We enrolled adult patients with KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive metastatic colorectal cancer refractory to standard of care (including cetuximab or panitumumab), an Eastern Cooperative Oncology Group performance status of 0 or 1, and at least one measurable lesion. We defined HER2 positivity in tumour samples by use of immunohistochemistry and fluorescence in-situ hybridisation in accordance with our previously validated colorectal cancer-specific diagnostic criteria. Eligible patients received intravenous trastuzumab at 4 mg/kg loading dose followed by 2 mg/kg once per week, and oral lapatinib at 1000 mg per day until evidence of disease progression. The primary endpoint was the proportion of patients achieving an objective response (defined as complete response or partial response), which was assessed by independent central review in the intention-to-treat population. This trial is registered with EudraCT, number 2012-002128-33. Between Aug 27, 2012, and May 15, 2015, we screened 914 patients with KRAS exon 2 (codons 12 and 13) wild-type metastatic colorectal cancer and identified 48 (5%) patients with HER2-positive tumours, although two died before enrolment. Of these patients, 27 were eligible for the trial. All were evaluable for response. At the time of data cutoff on Oct 15, 2015, with a median follow-up of 94 weeks (IQR 51-127), eight (30%, 95% CI 14-50) of 27 patients had achieved an objective response, with one patient (4%, 95% CI -3 to 11) achieving a complete response, and seven (26%, 95% CI 9-43) achieving partial responses; 12 (44%, 95% CI 25-63) patients had stable disease. Six (22%) of 27 patients had grade 3 adverse events, which consisted of fatigue in four patients, skin rash in one patient, and increased bilirubin concentration in one patient. No grade 4 or 5 adverse events were reported. We detected no drug-related serious adverse events. The combination of trastuzumab and lapatinib is active and well tolerated in treatment-refractory patients with HER2-positive metastatic colorectal cancer. Associazione Italiana Ricerca Cancro (AIRC), Fondazione Oncologia Niguarda Onlus, and Roche.


Comparison of ginsenosides Rg1 and Rb1 for their effects on improving scopolamine-induced learning and memory impairment in mice.
Rg1 and Rb1 are two major active compounds of ginseng that facilitate learning and memory. The present study aimed to compare the nootropic effects of Rg1 and Rb1 in a scopolamine induced dementia mice model. After 6 and 12 mg/kg of Rg1 and Rb1 intraperitoneal administration to mice for 7 days, their effects were assessed using the step-down passive avoidance (SD) and the Morris water maze (MWM) tests, the acetylcholinesterase (AChE) activity, acetylcholine (ACh) content and serotonin (5-HT) level in the hippocampus were analysed after SD and MWM tests. The results showed that Rg1 and Rb1 ameliorated cognition-deficiency in mice with dementia. Rg1 showed stronger effects than Rb1 on escape acquisition in MWM. Both Rg1 and Rb1 increased ACh levels in the hippocampus, but Rg1 inhibited AChE activity while Rb1 had no effect on AChE activity. Both Rg1 and Rb1 inhibited the decrease of 5-HT induced by scopolamine, but Rb1 was more active than the same dose of Rg1. These results demonstrate that multiple administrations of Rg1 and Rb1 are effective in improving memory deficiency induced by scopolamine. Rg1 appears to be more potent than Rb1 in improving acquisition impairment, and the two ginsenosides may act through different mechanisms.


Transferable ionic parameters for first-principles Poisson-Boltzmann solvation calculations: Neutral solutes in aqueous monovalent salt solutions.
Implicit solvation calculations based on a Stern-layer corrected size-modified Poisson-Boltzmann (SMPB) model are an effective approach to capture electrolytic effects in first-principles electronic structure calculations. For a given salt solution, they require a range of ion-specific parameters, which describe the size of the dissolved ions as well as thickness and shape of the Stern layer. Out of this defined parameter space, we show that the Stern layer thickness expressed in terms of the solute's electron density and the resulting ionic cavity volume completely determine ion effects on the stability of neutral solutes. Using the efficient SMPB functionality of the full-potential density-functional theory package FHI-aims, we derive optimized such Stern layer parameters for neutral solutes in various aqueous monovalent electrolytes. The parametrization protocol relies on fitting to reference Setschenow coefficients that describe solvation free energy changes with ionic strength at low to medium concentrations. The availability of such data for NaCl solutions yields a highly predictive SMPB model that allows to recover the measured Setschenow coefficients with an accuracy that is comparable to prevalent quantitative regression models. Correspondingly derived SMPB parameters for other salts suffer from a much scarcer experimental data base but lead to Stern layer properties that follow a physically reasonable trend with ionic hydration numbers.


Evidence for distinct cognitive deficits after focal cerebellar lesions.
Anatomical evidence and lesion studies, as well as functional magnetic resonance imaging (fMRI) studies, indicate that the cerebellum contributes to higher cognitive functions. Cerebellar posterior lateral regions seem to be relevant for cognition, while vermal lesions seem to be associated with changes in affect. However, the results remain controversial. Deficits of patients are sometimes still attributed to motor impairment. We present data from a detailed neuropsychological examination of 21 patients with cerebellar lesions due to tumour or haematoma, and 21 controls matched for age, sex, and years of education. Patients showed deficits in executive function, and in attentional processes such as working memory and divided attention. Further analysis revealed that patients with right-sided lesions were in general more impaired than those with left-sided lesions. Those hypotheses that suggest that lesions of the right cerebellar hemisphere lead to verbal deficits, while those of the left lead to non-verbal deficits, have in part been confirmed. The generally greater impairment of those patients with a right-sided lesion has been interpreted as resulting from the connection of the right cerebellum to the left cerebral hemisphere, which is dominant for language functions and crucial for right hand movements. Motor impairment was correlated with less than half of the cognitive measures, with no stronger tendency for correlation with cognitive tests that require motor responses discernible. The results are discussed on the basis of an assumption that the cerebellum has a predicting and preparing function, indicating that cerebellar lesions lead to a "dysmetria of thought."