Existence of hydration forces in the interaction between apoferritin molecules adsorbed on silica surfaces.
The atomic force microscope, together with the colloid probe technique, has become a very useful instrument to measure interaction forces between two surfaces. Its potential has been exploited in this work to study the interaction between protein (apoferritin) layers adsorbed on silica surfaces and to analyze the effect of the medium conditions (pH, salt concentration, salt type) on such interactions. It has been observed that the interaction at low salt concentrations is dominated by electrical double layer (at large distances) and steric forces (at short distances), the latter being due to compression of the protein layers. The DLVO theory fits these experimental data quite well. However, a non-DLVO repulsive interaction, prior to contact of the protein layers, is observed at high salt concentration above the isoelectric point of the protein. This behavior could be explained if the presence of hydration forces in the system is assumed. The inclusion of a hydration term in the DLVO theory (extended DLVO theory) gives rise to a better agreement between the theoretical fits and the experimental results. These results seem to suggest that the hydration forces play a very important role in the stability of the proteins in the physiological media.


Spatial selection of features within perceived and remembered objects.
Our representation of the visual world can be modulated by spatially specific attentional biases that depend flexibly on task goals. We compared searching for task-relevant features in perceived versus remembered objects. When searching perceptual input, selected task-relevant and suppressed task-irrelevant features elicited contrasting spatiotopic ERP effects, despite them being perceptually identical. This was also true when participants searched a memory array, suggesting that memory had retained the spatial organization of the original perceptual input and that this representation could be modulated in a spatially specific fashion. However, task-relevant selection and task-irrelevant suppression effects were of the opposite polarity when searching remembered compared to perceived objects. We suggest that this surprising result stems from the nature of feature- and object-based representations when stored in visual short-term memory. When stored, features are integrated into objects, meaning that the spatially specific selection mechanisms must operate upon objects rather than specific feature-level representations.


Sub-THz specific relaxation times of hydrogen bond oscillations in E.coli thioredoxin. Molecular dynamics and statistical analysis.
Hydrogen bonds (H-bonds) in biological macromolecules are important for the molecular structure and functions. Since interactions via hydrogen bonds are weaker than covalent bonds, it can be expected that atomic movements involving H-bonds have low frequency vibrational modes. Sub-Terahertz (sub-THz) vibrational spectroscopy that combines measurements with molecular dynamics (MD) computational prediction has been demonstrated as a promising approach for biological molecule characterization. Multiple resonance absorption lines have been reported. The knowledge of relaxation times of atomic oscillations is critical for the successful application of THz spectroscopy for hydrogen bond characterization. The purpose of this work is to use atomic oscillations in the 0.35-0.7 THz range, found from molecular dynamic (MD) simulations of E.coli thioredoxin (2TRX), to study relaxation dynamics of two intra-molecular H-bonds, OH-N and OH-C. Two different complimentary techniques are used in this study, one is the analysis of the statistical distribution of relaxation time and dissipation factor values relevant to low frequency oscillations, and the second is the analysis of the autocorrelation function of low frequency quasi-periodic movements. By studying hydrogen bond atomic displacements, it was found that the atoms are involved in a number of collective oscillations, which are characterized by different relaxation time scales ranging from 2-3 ps to more than 150 ps. The existence of long lasting relaxation processes opens the possibility to directly observe and study H-bond vibrational modes in sub-THz absorption spectra of bio-molecules if measured with an appropriate spectral resolution. The results of measurements using a recently developed frequency domain spectroscopic sensor with a spectral resolution of 1 GHz confirm the MD analysis.


Partner effects on a woman's intention to conceive: 'not with this partner'.
Current definitions of pregnancy intention that are useful at aggregate levels are weak at the individual level. This is especially true in social contexts where childbearing and pregnancy often occur within casual or transient relationships. Extensive data on lifetime partnerships and sexual behaviors, including pregnancies and births, from 250 low-income women who had experienced a total of 839 pregnancies are used to explore correlates of intention to conceive, as well as the extent to which women attribute their intentions to a current partnership. Some 57% of reported pregnancies were unintended. Overall, 21% of the women had not wished to conceive at least one of their pregnancies with the partner who impregnated them; that proportion rose to 33% among women who had had only unintended pregnancies. Even among women who had had no unintended pregnancies, 18% had had at least one conception that they had not wanted with their partner at the time of conception. Women were less likely to say they had not wanted to conceive with a particular partner if they were living with that partner than if they were not. The likelihood of not having wanted a pregnancy with a given partner rose with the lifetime number of serious partners. Pregnancies that were not wanted with a particular partner were more than twice as likely to end in abortion as were those that were (33% vs. 14%). Among these women, the desire to avoid childbearing relates more to the couple involved in the conception than to abstract notions of completed family size. It would therefore be useful to include items pertaining to partner relationships in future studies of pregnancy intention.


A New Way in Deciding NOAEL Based on the Findings from GLP-Toxicity Test.
The FDA guidance focuses on the use of the NOAEL to establish the maximum recommended starting dose. The majority of NOAEL has been described inaccurately or incompletely in final reports for 90-days repeated dose toxicity test based on GLP (good laboratory practice) regulation. This is the most serious one of reasons for why most pharmaceutical companies targeting global markets have disregarded the final report produced from GLP facilities in Korea. The problems in deciding NOAEL reflected in the final reports are mainly due to the followings; 1) Inaccurate description or use of NOEL, NOAEL and LOAEL, 2) Insufficient and inappropriate interpretations in findings from toxicity test. This paper is intended to provide the insight into distinguishing NOAEL from NOEL and LOAEL, and into classifying findings from toxicity test. Here, the three step method is newly suggested by applying the weight-based classification to the NOEL, NOAEL and LOAEL based on the findings.


Autoimmune cytopenia does not predict poor prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma.
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is characterized by an acquired immune defect that can cause autoimmune complications, including anemia and thrombocytopenia. We conducted an observational study of the epidemiology, clinical presentation and significance of autoimmune complications of CLL/SLL in 132 patients from a large population (>45,000 veterans), in which at least 90% of patients with CLL/SLL have been previously identified. Over a period of 12.5 years, 12 patients (9.1%) had autoimmune complications; of these, 6 (4.5%) had autoimmune hemolytic anemia (AIHA), 5 (3.8%) had immune thrombocytopenia (ITP), and 1 (0.8%) had pure red blood cell aplasia (PRBA). All 6 cases of AIHA had a positive direct immunoglobulin test for IgG and C3d. In 6 patients, CLL/SLL was an incidental finding at the time of presentation with autoimmune cytopenia. Nine out of 10 patients responded to immunosuppressive therapy, which was complicated by serious infection in 7 cases, one of which was fatal. The major cause of mortality in patients with autoimmune complications of CLL/SLL was secondary malignancy. Survival of patients with immune cytopenia was not significantly different from CLL/SLL patients without immune cytopenia. Among patients with anemia or thrombocytopenia, mortality was significantly higher in those with bone marrow failure compared to an autoimmune etiology. We show that in a non-referred population with a high incidence of CLL/SLL, autoimmune cytopenia can occur early in the natural history of the disease. These data suggest that the Rai and Binet classifications for CLL need to be modified for patients with autoimmune cytopenia. .


In the eye of the beholder: individual differences in perceived social isolation predict regional brain activation to social stimuli.
Prior research has shown that perceived social isolation (loneliness) motivates people to attend to and connect with others but to do so in a self-protective and paradoxically self-defeating fashion. Although recent research has shed light on the neural correlates of social perception, cooperation, empathy, rejection, and love, little is known about how individual differences in loneliness relate to neural responses to social and emotional stimuli. Using functional magnetic resonance imaging, we show that there are at least two neural mechanisms differentiating social perception in lonely and nonlonely young adults. For pleasant depictions, lonely individuals appear to be less rewarded by social stimuli, as evidenced by weaker activation of the ventral striatum to pictures of people than of objects, whereas nonlonely individuals showed stronger activation of the ventral striatum to pictures of people than of objects. For unpleasant depictions, lonely individuals were characterized by greater activation of the visual cortex to pictures of people than of objects, suggesting that their attention is drawn more to the distress of others, whereas nonlonely individuals showed greater activation of the right and left temporo-parietal junction to pictures of people than of objects, consistent with the notion that they are more likely to reflect spontaneously on the perspective of distressed others.


Neuropathology of propionic acidemia: a report of two patients with basal ganglia lesions.
Propionic acidemia is a rare genetic disorder of amino acid metabolism caused by deficient activity of propionyl coenzyme A carboxylase. Neuropathologic changes previously reported in infants have been white-matter vacuolization or spongiosis. In children who survive beyond infancy, abnormalities have been found primarily in the basal ganglia. We report neuropathologic findings in two patients with propionic acidemia diagnosed in infancy who survived 35 months and 9 years, respectively. Examination of the brain of the 35-month-old boy showed vascular and parenchymal mineralization, focal pallor and spongy change, and foci of acute neuronal injury. These changes were similar to those previously described. The 9-year-old girl was in good metabolic control when she died, and presented a neuropathologic picture not previously described. She was found at autopsy to have acute hemorrhagic lesions in the caudate, putamen, and globus pallidus bilaterally and in the left ventral thalamus. There was focal neuronal loss, but no acute hypoxic/ischemic neuronal injury. Vascular proliferation and swollen endothelial cells were seen in the basal ganglia, thalamus, and substantia nigra, but not in other regions of the brain. Electron microscopy showed swelling of endothelial cells with viable adjacent brain parenchyma. The endothelial changes suggest a breakdown of the blood-brain barrier.


The cycad genotoxin MAM modulates brain cellular pathways involved in neurodegenerative disease and cancer in a DNA damage-linked manner.
Methylazoxymethanol (MAM), the genotoxic metabolite of the cycad azoxyglucoside cycasin, induces genetic alterations in bacteria, yeast, plants, insects and mammalian cells, but adult nerve cells are thought to be unaffected. We show that the brains of adult C57BL6 wild-type mice treated with a single systemic dose of MAM acetate display DNA damage (O⁶-methyldeoxyguanosine lesions, O⁶-mG) that remains constant up to 7 days post-treatment. By contrast, MAM-treated mice lacking a functional gene encoding the DNA repair enzyme O⁶-mG DNA methyltransferase (MGMT) showed elevated O⁶-mG DNA damage starting at 48 hours post-treatment. The DNA damage was linked to changes in the expression of genes in cell-signaling pathways associated with cancer, human neurodegenerative disease, and neurodevelopmental disorders. These data are consistent with the established developmental neurotoxic and carcinogenic properties of MAM in rodents. They also support the hypothesis that early-life exposure to MAM-glucoside (cycasin) has an etiological association with a declining, prototypical neurodegenerative disease seen in Guam, Japan, and New Guinea populations that formerly used the neurotoxic cycad plant for food or medicine, or both. These findings suggest environmental genotoxins, specifically MAM, target common pathways involved in neurodegeneration and cancer, the outcome depending on whether the cell can divide (cancer) or not (neurodegeneration). Exposure to MAM-related environmental genotoxins may have relevance to the etiology of related tauopathies, notably, Alzheimer's disease.


Geniohyoid muscle activity in normal men during wakefulness and sleep.
Reduction in the activity of upper airway "dilator" muscles during sleep may allow the pharyngeal airway to collapse in some individuals. However, quantitative studies concerning the effect of sleep on specific upper airway muscles that may influence pharyngeal patency are sparse and inconclusive. We studied seven normal men (mean age 27, range 22-37 yr) during a single nocturnal sleep study and recorded sleep staging parameters, ventilation, and geniohyoid muscle electromyogram (EMGgh) during nasal breathing throughout the night. Anatomic landmarks for placement of intramuscular geniohyoid recording electrodes were determined from a cadaver study. These landmarks were used in percutaneous placement of wire electrodes, and raw and moving-time-averaged EMGgh activities were recorded. Sleep stage was determined using standard criteria. Stable periods of wakefulness and non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep were selected for analysis. The EMGgh exhibited phasic inspiratory activity during wakefulness and sleep in all subjects. In six of seven subjects, mean and peak inspiratory EMGgh activities were significant (P less than 0.05) reduced during stages 2 and 3/4 NREM sleep and REM sleep compared with wakefulness. This reduction of EMGgh activity was shown to result from a sleep-related decline in the level of tonic muscle activity. Phasic inspiratory EMGgh activity during all stages of sleep was not significantly different from that during wakefulness. Of interest, tonic, phasic, and peak EMGgh activities were not significantly reduced during REM sleep compared with any other sleep stage in any subject. In addition, the slope of onset of phasic EMGgh activity was not different during stage 2 NREM and REM sleep compared with wakefulness in these subjects.(ABSTRACT TRUNCATED AT 250 WORDS)


Association of Adverse Pregnancy Outcomes With Glyburide vs Insulin in Women With Gestational Diabetes.
Glyburide is thought to be safe for use during pregnancy for treatment of gestational diabetes mellitus (GDM). However, there are limited data on the effectiveness of glyburide when compared with insulin as used in a real-world setting. To estimate the risk of adverse maternal and neonatal outcomes in women with GDM treated with glyburide compared with insulin. Retrospective cohort study of a population-based cohort from a nationwide US employer-based insurance claims database from January 1, 2000, to December 31, 2011. We identified women with GDM and their newborns. We excluded those with type 1 or 2 diabetes and those younger than 15 years or older than 45 years. Treatment with glyburide or insulin during pregnancy within 150 days before delivery. We used binomial regression to estimate risk ratios (RRs) and risk differences with 95% confidence intervals for the association of glyburide with diagnosis codes for obstetric trauma, cesarean delivery, birth injury, preterm birth, hypoglycemia, respiratory distress, jaundice, large for gestational age, and hospitalization in the neonatal intensive care unit. Inverse probability of treatment weights were used to adjust for maternal characteristics that differed between the treatment groups. Among 110,879 women with GDM, 9173 women (8.3%) were treated with glyburide (n = 4982) or insulin (n = 4191). After adjusting for differences at baseline, newborns of women treated with glyburide were at increased risk for neonatal intensive care unit admission (RR = 1.41; 95% CI, 1.23-1.62), respiratory distress (RR = 1.63; 95% CI, 1.23-2.15), hypoglycemia (RR = 1.40; 95% CI, 1.00-1.95), birth injury (RR = 1.35; 95% CI, 1.00-1.82), and large for gestational age (RR = 1.43; 95% CI, 1.16-1.76) compared with those treated with insulin; they were not at increased risk for obstetric trauma (RR = 0.92; 95% CI, 0.71-1.20), preterm birth (RR = 1.06; 95% CI, 0.93-1.21), or jaundice (RR = 0.96; 95% CI, 0.48-1.91). The risk of cesarean delivery was 3% lower in the glyburide group (adjusted RR = 0.97; 95% CI, 0.93-1.00). The risk difference associated with glyburide was 2.97% (95% CI, 1.82-4.12) for neonatal intensive care unit admission, 1.41% (95% CI, 0.61-2.20) for large for gestational age, and 1.11% (95% CI, 0.50-1.72) for respiratory distress. Newborns from privately insured mothers treated with glyburide were more likely to experience adverse outcomes than those from mothers treated with insulin. Given the widespread use of glyburide, further investigation of these differences in pregnancy outcomes is a public health priority.


Identification of five phytosterols from Aloe vera gel as anti-diabetic compounds.
The genus Aloe in the family Liliaceae is a group of plants including Aloe vera (Aloe barbadensis MILLER) and Aloe arborescens (Aloe arborescens MILLER var. natalensis BERGER) that are empirically known to have various medical efficacies. In the present study, we evaluated the anti-hyperglycemic effect of Aloe vera gel and isolated a number of compounds from the gel. On the basis of spectroscopic data, these compounds were identified as lophenol, 24-methyl-lophenol, 24-ethyl-lophenol, cycloartanol, and 24-methylene-cycloartanol. These five phytosterols were evaluated for their anti-hyperglycemic effects in type 2 diabetic BKS.Cg-m(+/+)Lepr(db/J) (db/db) mice. In comparison with the hemoglobin A1c (HbA1c) levels of vehicle-treated mice, statistically significant decreases of 15 to 18% in HbA1c levels were observed in mice treated with 1 mug of the five phytosterols. Considering the ability to reduce blood glucose in vivo, there were no differences between the five phytosterols. Administration of beta-sitosterol did not reduce the blood glucose levels in db/db mice. After administration of the five phytosterols for 28 d, fasting blood glucose levels decreased to approximately 64%, 28%, 47%, 51%, and 55% of control levels, respectively. Severe diabetic mice treated with phytosterols derived from Aloe vera gel did not suffer weight reduction due to glucose loss in the urine. These findings suggest that Aloe vera gel and phytosterols derived from Aloe vera gel have a long-term blood glucose level control effect and would be useful for the treatment of type 2 diabetes mellitus.


Dynamic Light Scattering: A New Noninvasive Technology for Neonatal Heart Rate Monitoring.
Heart rate (HR) detection in premature infants using electrocardiography (ECG) is challenging due to a low signal amplitude and the fragility of the premature skin. Recently, the dynamic light scattering (DLS) technique has been miniaturized, allowing noninvasive HR measurements with a single sensor. The aim was to determine the accuracy of DLS for HR measurement in infants, compared to ECG-derived HR. Stable infants with a gestational age of ≥26 weeks, monitored with ECG, were eligible for inclusion. HR was measured with the DLS sensor at 5 different sites for 15 min each. We recorded every 10th second of the DLS-derived HR and the DLS signal-to-noise ratio (SNR), and the ECG-derived HR was extracted for analysis. Patients were randomly divided into 2 groups. In the first group, the optimal SNR cut-off value was determined and then applied to the second group to assess agreement. HR measurements from 31 infants were analyzed. ECG-DLS paired data points were collected at the forehead, an upper extremity, the thorax, a lower extremity, and the abdomen. When applying the international accuracy standard for HR detection, DLS accuracy in the first group (n = 15) was optimal at the forehead (SNR cut-off 1.66). Application of this cut-off to the second group (n = 16) showed good agreement between DLS-derived HR and ECG-derived HR (bias -0.73 bpm; 95% limits of agreement -15.46 and 14.00 bpm) at the forehead with approximately 80% (i.e., 1,066/1,310) of all data pairs remaining. The investigated DLS sensor was sensitive to movement, overall providing less accurate HR measurements than ECG and pulse oximetry. In this study population, specific measurement sites provided excellent signal quality and good agreement with ECG-derived HR.


The effect of a regional hepatopancreaticobiliary surgical program on clinical volume, quality of cancer care, and outcomes in the Veterans Affairs system.
Malignant neoplasms of the hepatopancreaticobiliary (HPB) system constitute a significant public health problem worldwide. Treatment coordination for these tumors is challenging and can result in substandard care. Referral centers for HPB disease have been used as a strategy to improve postoperative outcomes, but their effect on accomplishing regionalization of care and improving quality of cancer care is not well known. To evaluate the effect of implementing a multidisciplinary HPB surgical program (HPB-SP) on regionalization of care, the quality of cancer care, and surgical outcomes within an integrated health care system. We designed a retrospective cohort study in a tertiary referral Veterans Affairs (VA) medical center within an 8-state designated VA health care region from November 23, 2005, through December 31, 2013. We compared patients with HPB tumors undergoing evaluation by the surgical oncology service before and after implementation of the HPB-SP on November 1, 2008. Implementation of the HPB-SP to improve access to specialized, multidisciplinary cancer care for veterans across the region. Clinical and surgical volume, proportion of patients undergoing a comprehensive multidisciplinary evaluation, and postoperative adverse events included as a composite outcome defined by occurrence of postoperative mortality, severe complications, and/or reoperation. We identified 516 patients referred to the surgical oncology service. Establishment of the HPB-SP resulted in significant increases in regional referrals (17.3% vs 44.4%; P < .001), median monthly clinic visits (5 vs 20; P < .001), and median number of HPB surgical procedures (3 vs 9; P = .003) per quarter. Multidisciplinary assessment increased from 52.6% to 70.0% (P < .001). When we compared patients with hepatocellular carcinoma before (n = 55) and after (n = 131) implementation, more patients received any treatment (35 [63.6%] vs 109 [83.2%]; P = .004) with increased use of liver resection (0 vs 20 [15.3%]; P = .002), percutaneous ablation (0 vs 15 [11.5%]; P = .009), and oncosurgical strategies (0 vs 16 [12.2%]; P = .007) after implementation. Among patients with colorectal liver metastases (29 before vs 76 after implementation), a significant shift occurred from use of ablations (5 [17.2%] vs 3 [3.9]%; P = .02) to resections (6 [20.7%] vs 40 [52.6%]; P = .003), and use of perioperative chemotherapy increased (5 of 11 [45.5%] vs 33 of 43 [76.7%]; P = .01). The HPB-SP was associated with lower odds of postoperative adverse events, even after adjusting for important covariates (odds ratio, 0.29 [95% CI, 0.12-0.68]; P = .005), and a high rate of margin-negative liver (94.6%) and pancreatic (90.0%) resections. The development of an HPB-SP led to regionalization of care and improved quality of cancer care and surgical outcomes. Establishment of regional programs within the VA system can help improve the quality of care for patients presenting with complex cancers requiring subspecialized care.


Constraints representing a meta-stable régime facilitate exploration during practice and transfer of learning in a complex multi-articular task.
Previous investigations have shown that inducing meta-stability in behavior can be achieved by overlapping affordances through constraint manipulation, allowing cooperative and competitive tendencies to functionally coexist. The purpose of this paper was to test a number of conditions applying these design principles on performance during skills practice and transfer. Of additional interest, was whether the existing skill level interacted with the environmental properties of the experimental tasks (varying indoor climbing routes). Two skill groups practised on three routes per session over four separate sessions. At the end of the final session, climbers undertook a transfer test. Routes, matched for difficulty, were manipulated in terms of hand-hold design. Route-1 and Route-2 were designed with holds with a single graspable edge, aligned entirely parallel or perpendicular to the ground plane respectively. Route-3 had at each hold, two graspable edges (one parallel and one perpendicular to the ground plane). Behavioral exploration at the hip and hands were largest under the metastable condition (Route-3). Skill level also interacted with route properties during practice and influenced transfer. Data suggest meta-stability induces exploratory behaviors. Less skilled individuals explore both hand and hip levels, whereas, more experienced climbers explore at the hip level.


Drug penetration enhancement techniques in ablative fractional laser assisted cutaneous delivery of indocyanine green.
Topical drug delivery can be increased by pretreatment of the skin with ablative fractional laser (AFXL). Several physical penetration enhancement techniques have been investigated to further improve AFXL-assisted drug delivery. This study investigated the influence of three of these techniques, namely massage, acoustic pressure wave treatment, and pressure vacuum alterations (PVP) on the distribution of the fluorescent drug indocyanine green (ICG) at different depths in the skin after topical application on AFXL pretreated skin. In ex vivo human skin, test regions were pretreated with AFXL (10,600 nm, channel depth 300 μm, channel width 120 μm, density 15%). Subsequently, ICG was applied, followed by massage, acoustic pressure wave treatment or PVP. ICG fluorescence intensity (FI) was assessed after 1, 3, and 24 hours at several depths using fluorescence photography. FI was higher when using enhancement techniques compared to control (AFXL-only) up to 3 hours application time (P < 0.05). After 3 hours, mean surface FI was highest after acoustic pressure wave treatment (61.5 arbitrary units; AU), followed by massage (57.5AU) and PVP (46.9AU), respectively (for comparison: AFXL-only 31.6AU, no pretreatment 14.9AU). Comparable or higher FI was achieved already after 1 hour with enhancement techniques compared to 3-24 hours application time without. After 24 hours, no significant differences between enhancement techniques and AFXL-only were observed (P = 0.31). Penetration enhancement techniques, especially acoustic pressure wave treatment and massage, result in improved drug accumulation in AFXL-pretreated skin and reduce the application time needed. Lasers Surg. Med. © 2019 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.


In situ gene expression profiling of the thermoacidophilic alga Cyanidioschyzon in relation to visible and ultraviolet irradiance.
Ultraviolet and high-intensity visible radiation generate reactive intermediates that damage phototrophic microorganisms. In Yellowstone National Park, the thermoacidophilic alga Cyanidioschyzon exhibits an annual seasonal biomass fluctuation referred to as 'mat decline', where algal viability decreases as ultraviolet and visible irradiances increase during summer. We examined the role irradiance might play in mat decline using irradiance filters that uncouple ultraviolet and visible effects along with custom microarrays to study gene expression in situ. Of the 6507 genes, 88% showed no response to ultraviolet or visible, implying that at the biomolecular level, these algae inhabit a chemostat-like environment and is consistent with the near constant aqueous chemistry measured. The remaining genes exhibited expression changes linked to ultraviolet exposure, to increased visible radiation, or to the apparent combined effects of ultraviolet and visible. Expression of DNA repetitive elements was synchronized, being repressed by visible but also influenced by ultraviolet. At highest irradiance levels, these algae reduced transcription of genes encoding functions involved with DNA replication, photosynthesis and cell cycle progression but exhibited an uptick in activities related to repairing DNA damage. This corroborates known physiological responses to ultraviolet and visible radiation, and leads us to provisionally conclude that mat decline is linked to photoinhibition.


Effects of 1-week and 6-week exposure to GSM/DCS radiofrequency radiation on micronucleus formation in B6C3F1 mice.
The aim of this study was to examine the possible induction of micronuclei in erythrocytes of the peripheral blood and bone marrow and in keratinocytes and spleen lymphocytes of mice exposed to radiofrequency (RF) radiation for 2 h per day over periods of 1 and 6 weeks, respectively. The applied signal simulated the exposure from GSM900 and DCS1800 handsets, including the low-frequency amplitude-modulation components as they occur during speaking (GSM Basic), listening (DTX) and moving within the environment (handovers, power control). The carrier frequency was set to the center of the system's uplink band, i.e., 902 MHz for GSM and 1747 MHz for DCS. Uniform whole-body exposure was achieved by restraining the mice in tubes at fixed positions in the exposure setup. Mice were exposed to slot-averaged whole-body SARs of 33.2, 11.0, 3.7 and 0 mW/g during the 1-week study and 24.9, 8.3, 2.8 and 0 mW/g during the 6-week study. Exposure levels for the 1- and 6-week studies were determined in a pretest to confirm that no thermal effect was present that could influence the genotoxic end points. During both experiments and for both frequencies, no clinical abnormalities were detected in the animals. Cells of the bone marrow from the femur (1-week study), erythrocytes of the peripheral blood (6-week study), keratinocytes from the tail root, and lymphocytes from the spleen (both studies) were isolated on slides and stained for micronucleus analysis. Two thousand cells per animal were scored in erythrocyte and keratinocyte samples. In spleen lymphocytes, 1000 binucleated lymphocytes were scored for each animal. The RF-field exposure had no influence on the formation of red blood cells. After 1 week of exposure, the ratio of polychromatic to normochromatic erythrocytes was unchanged in the treated groups compared to the sham-exposed groups. Furthermore, the RF-field exposure of mice did not induce an increase in the number of micronuclei in erythrocytes of the bone marrow or peripheral blood, in keratinocytes, or in spleen lymphocytes compared to the sham-treated control.


Vocal Attack Time of Different Pitch Levels and Vowels in Mandarin.
The purpose of this study was to investigate how vocal attack time (VAT) varies when young adults articulate the three vertex vowels in Mandarin Chinese at five linguistically unconstrained pitch levels. Sound pressure and electroglottographic signals were recorded simultaneously from 53 male and 53 female subjects saying sustained /A/, /i/, and /u/ at five equally spaced pitch heights, each being higher than the preceding one. Then analyses of means, variance, and correlation were performed to explore the relationships of VAT/pitch levels and VAT/vowels. Findings were As mean STs (semitone) increase linearly from levels 1 to 5, mean VATs decrease nonlinearly in a big group of subjects but increase nonlinearly in a small group of them. Based on the body-cover model of F0 control, data here lead to the guess that different people incline to use different strategies in increasing pitch height. When males, females, and males plus females are considered as a whole, average STs and VATs tend to be positively correlated among the three vertex vowels.


Hypersusceptibility of neutrophil granulocytes towards lethal action of free fatty acids contained in enzyme-modified atherogenic low density lipoprotein.
The bulk of LDL entrapped in the arterial intima is modified by hydrolytic enzymes, leading to extensive cleavage of cholesterylesters and liberation of fatty acids. The latter induce apoptosis in endothelial cells but are far less cytotoxic towards macrophages. We have compared the cytotoxic effects of enzymatically modified LDL (E-LDL) on macrophages and polymorphonuclear granulocytes (PMN). E-LDL displayed toxicity towards PMN at far lower concentrations than towards monocyte-derived macrophages. Native or oxidized LDL had no effect. Free fatty acids contained in E-LDL were the cause of the observed toxicity, which could be mimicked by linoleic acid, oleic acid and arachidonic acid. E-LDL provoked Ca(2+) influx and activated PMN, as witnessed by the generation of superoxide anions and peroxidase secretion. Inhibition of either oxidative burst or calcium influx did not diminish the cytotoxicity of E-LDL. Similar to free linoleic acid, E-LDL lysed red blood cells and rapidly rendered cells permeable to propidium iodide. Possibly through their capacity to directly perturb cell membranes, free fatty acids contained in E-LDL exert potent cytotoxic effects on PMN. This may be one reason why PMN are not abundantly present in atherosclerotic lesions, and why PMN-depletion suppresses atherogenesis.


Tension-free vaginal tape and autologous rectus fascia pubovaginal sling for the treatment of urinary stress incontinence: a medium-term follow-up.
To compare two different procedures, tension-free vaginal tape (TVT) and autologous rectus fascia sling, according to their medium-term subjective and objective outcomes and satisfaction rates in the treatment of urinary stress incontinence in women. One hundred women with type II urinary stress incontinence were randomized to be treated with either TVT or autologous rectus fascia sling. They were evaluated by means of a cough-induced stress test, 1-hour pad test, Incontinence Impact Questionnaire (IIQ), and urodynamic study. They were reevaluated postoperatively every 6 months, and the collected data of more than 1 year's follow-up were compared with preoperative assessments. All patients completed the full 6-month postoperative assessment. However, of the 100 patients, only 61 (25 in the TVT and 36 in the sling group) were followed for more than 1 year. Mean follow-up time was 38.5 and 40 months in the TVT and sling group, respectively. Objective cure was achieved in 22 (88%) of the TVT group and in 30 (83%) of the sling group (p = 0.78) using a cough-induced stress test, and in 76 and 75% of the women in the TVT versus sling group (p = 0.83), respectively, using a 1-hour pad test. Postoperative mean IIQ scores were 44.3 (range 35.5-61.5) and 48.5 (range 38.5-69.7) in the TVT versus sling group (p = 0.46). Five (20%) and 11 (30%) of the TVT and sling group, respectively, reported some changes in the voiding pattern or posture at more than 1 year's follow-up. There is no significant difference between the TVT and autologous rectus fascia sling procedures in the treatment of urinary stress incontinence at medium-term follow-up. There were changes in the voiding pattern for patients in both groups at more than 1 year postoperatively, which were not evident at early follow-up.


Colloidal PbS quantum dot solar cells with high fill factor.
We fabricate PbS colloidal quantum dot (QD)-based solar cells using a fullerene derivative as the electron-transporting layer (ETL). A thiol treatment and oxidation process are used to modify the morphology and electronic structure of the QD films, resulting in devices that exhibit a fill factor (FF) as high as 62%. We also show that, for QDs with a band gap of less than 1 eV, an open-circuit voltage (VOC) of 0.47 V can be achieved. The power conversion efficiency reaches 1.3% under 1 sun AM1.5 test conditions and 2.4% under monochromatic infrared (lambda=1310 nm) illumination. A consistent mechanism for device operation is developed through a circuit model and experimental measurements, shedding light on new approaches for optimization of solar cell performance by modifying the interface between the QDs and the neighboring charge transport layers.


A Novel Picture Guide to Improve Spiritual Care and Reduce Anxiety in Mechanically Ventilated Adults in the Intensive Care Unit.
Hospital chaplains provide spiritual care that helps patients facing serious illness cope with their symptoms and prognosis, yet because mechanically ventilated patients cannot speak, spiritual care of these patients has been limited. To determine the feasibility and measure the effects of chaplain-led picture-guided spiritual care for mechanically ventilated adults in the intensive care unit (ICU). We conducted a quasi-experimental study at a tertiary care hospital between March 2014 and July 2015. Fifty mechanically ventilated adults in medical or surgical ICUs without delirium or dementia received spiritual care by a hospital chaplain using an illustrated communication card to assess their spiritual affiliations, emotions, and needs and were followed until hospital discharge. Feasibility was assessed as the proportion of participants able to identify spiritual affiliations, emotions, and needs using the card. Among the first 25 participants, we performed semistructured interviews with 8 ICU survivors to identify how spiritual care helped them. For the subsequent 25 participants, we measured anxiety (on 100-mm visual analog scales [VAS]) immediately before and after the first chaplain visit, and we performed semistructured interviews with 18 ICU survivors with added measurements of pain and stress (on ±100-mm VAS). The mean (SD) age was 59 (±16) years, median mechanical ventilation days was 19.5 (interquartile range, 7-29 d), and 15 (30%) died in-hospital. Using the card, 50 (100%) identified a spiritual affiliation, 47 (94%) identified one or more emotions, 45 (90%) rated their spiritual pain, and 36 (72%) selected a chaplain intervention. Anxiety after the first visit decreased 31% (mean score change, -20; 95% confidence interval, -33 to -7). Among 28 ICU survivors, 26 (93%) remembered the intervention and underwent semistructured interviews, of whom 81% felt more capable of dealing with their hospitalization and 0% felt worse. The 18 ICU survivors who underwent additional VAS testing during semistructured follow-up interviews reported a 49-point reduction in stress (95% confidence interval, -72 to -24) and no significant change in physical pain that they attributed to picture-guided spiritual care. Chaplain-led picture-guided spiritual care is feasible among mechanically ventilated adults and shows potential for reducing anxiety during and stress after an ICU admission.


Dynamic Neuromuscular Control of the Lower Limbs in Response to Unexpected Single-Planar versus Multi-Planar Support Perturbations in Young, Active Adults.
An anterior cruciate ligament (ACL) injury involves a multi-planar injury mechanism. Nevertheless, unexpected multi-planar perturbations have not been used to screen athletes in the context of ACL injury prevention yet could reveal those more at risk. The objective of this study was to compare neuromuscular responses to multi-planar (MPP) and single-planar perturbations (SPP) during a stepping-down task. These results might serve as a basis for future implementation of external perturbations in ACL injury screening programs. Thirteen young adults performed a single leg stepping-down task in eight conditions (four MPP and four SPP with a specified amplitude and velocity). The amplitudes of vastus lateralis (VL), vastus medialis (VM), hamstrings lateralis (HL), hamstrings medialis (HM) EMG activity, medio-lateral and anterior-posterior centre of mass (COM) displacements, the peak knee flexion and abduction angles were compared between conditions using an one-way ANOVA. Number of stepping responses were monitored during all conditions. Significantly greater muscle activity levels were found in response to the more challenging MPP and SPP compared to the less challenging conditions (p < 0.05). No differences in neuromuscular activity were found between the MPP conditions and their equivalents in the SPP. Eighteen stepping responses were monitored in the SPP versus nine in the MPP indicating that the overall neuromuscular control was even more challenged during the SPP which was supported by greater COM displacements in the SPP. The more intense MPP and SPP evoked different neuromuscular responses resulting in greater muscle activity levels compared to small perturbations. Based on the results of COM displacements and based on the amount of stepping responses, dynamic neuromuscular control of the knee joint appeared less challenged during the MPP. Therefore, future work should investigate extensively if other neuromuscular differences (i.e. co-activation patterns and kinetics) exist between MPP and SPP. In addition, future work should examine the influence on the neuromuscular control of the magnitude of the perturbations and the magnitude of stepping height and stepping distance.


Solid state NMR studies of photoluminescent cadmium chalcogenide nanoparticles.
Solid state (113)Cd, (77)Se, (13)C and (31)P NMR have been used to study a number of Cd chalcogenide nanoparticles synthesized in tri-n-octyl-phosphine (TOP) with different compositions and architectures. The pure CdSe and CdTe nanoparticles show a dramatic, size-sensitive broadening of the (113)Cd NMR line, which can be explained in terms of a chemical shift distribution arising from multiple Cd environments. From (13)C NMR, it has been discovered that TOP, or its derivatives such as TOPO (trioctylphosphine oxide), is rapidly moving about the surface of the nanoparticles, indicating that it is relatively weakly bound as compared to other materials used as surface ligands, such as hexadecylamine. (31)P NMR of the nanoparticles shows at least five species arising from coordination of the ligands to different surface sites. (113)Cd NMR of CdSeTe alloy and layered nanoparticles has provided crucial information which, in conjunction with results from other techniques (especially optical characterization), has made it possible to develop a detailed picture of the composition and structure of these materials: (i) a true CdSeTe homogeneous alloy nanoparticle, (ii) a nanoparticle segregated into an alloy core region rich in Te, with a CdSeTe (close to 1 : 1 Se : Te) alloy shell and (iii) a CdSe/CdTe/CdSe layered nanoparticle in which the CdTe layer contains a small amount of Se and which forms a Quantum Dot Quantum Well (QDQW) system. The results demonstrate that solid state NMR is a vital tool in the arsenal of characterisation techniques available for nanomaterials.


Modifying effects of prepubertal exposure to potassium perchlorate and tetrabromobisphenol A on susceptibility to N-bis(2-hydroxypropyl)nitrosamine- and 7,12-dimethylbenz(a)anthracene-induced carcinogenesis in rats.
Early life exposure to certain kinds of chemicals is of concern because of a possible increase in cancer risk, but relevant data are limited. In the present experiment, modifying effects of prepubertal administration of potassium perchlorate (KClO(4)) and tetrabromobisphenol A (TBBPA) on susceptibility to multi-organ carcinogenesis were evaluated. F344 dam rats were administered 0% (control), 0.01%, 0.1% or 1% TBBPA in diet or 0.01% KClO(4) in drinking water after parturition. Their weaned offspring in each group were treated for 2 weeks in the same manner. From 6 weeks of age, all offspring were treated with N-bis(2-hydroxypropyl)nitrosamine in drinking water for 4 weeks. In addition the females at 7 weeks of age were gavaged once with 7,12-dimethylbenz(a)anthracene. At weeks 39 and 47 of age, the males and females, respectively, were euthanized and the liver, kidney, lung, esophagus, thyroid, urinary bladder, testis, epididymis, ovary and mammary gland were histopathologically examined. The incidences of thyroid follicular adenomas in 1% TBBPA females (p<0.05) and of transitional cell papillomas in the urinary bladder of 0.01%, 0.1% and 1% TBBPA females were increased (p<0.05) as compared to the controls. These results indicate that prepubertal exposure to TBBPA raises susceptibility to thyroid and urinary bladder tumorigenesis in rats. Although causes of the effect on thyroid carcinogenesis might be direct and/or indirect hormonal actions, further studies are needed for confirmation.


High Phosphate Induces and Klotho Attenuates Kidney Epithelial Senescence and Fibrosis.
Cellular senescence is an irreversible cell growth arrest and is associated with aging and age-related diseases. High plasma phosphate (Pi) and deficiency of Klotho contribute to aging and kidney fibrosis, a pathological feature in the aging kidney and chronic kidney disease. This study examined the interactive role of Pi and Klotho in kidney senescence and fibrosis. Homozygous Klotho hypomorphic mice had high plasma Pi, undetectable Klotho in plasma and kidney, high senescence with massive collagen accumulation in kidney tubules, and fibrin deposits in peritubular capillaries. To examine the Pi effect on kidney senescence, a high (2%) Pi diet was given to wild-type mice. One week of high dietary Pi mildly increased plasma Pi, and upregulated kidney p16/p21 expression, but did not significantly decrease Klotho. Two weeks of high Pi intake led to increase in plasminogen activator inhibitor (PAI)-1, and decrease in kidney Klotho, but still without detectable increase in kidney fibrosis. More prolonged dietary Pi for 12 weeks exacerbated kidney senescence and fibrosis; more so in heterozygous Klotho hypomorphic mice compared to wild-type mice, and in mice with chronic kidney disease (CKD) on high Pi diet compared to CKD mice fed a normal Pi diet. In cultured kidney tubular cells, high Pi directly induced cellular senescence, injury and epithelial-mesenchymal transition, and enhanced H2O2-induced cellular senescence and injury, which were abrogated by Klotho. Fucoidan, a bioactive molecule with multiple biologic functions including senescence inhibition, blunted Pi-induced cellular senescence, oxidation, injury, epithelial-mesenchymal transition, and senescence-associated secretary phenotype. In conclusion, high Pi activates senescence through distinct but interconnected mechanisms: upregulating p16/p21 (early), and elevating plasminogen activator inhibitor-1 and downregulating Klotho (late). Klotho may be a promising agent to attenuate senescence and ameliorate age-associated, and Pi-induced kidney degeneration such as kidney fibrosis.


IgG4-mediated sclerosing fibroinflammatory disease presenting as inflammatory breast malignancy.
IgG4-mediated sclerosing fibroinflammatory disease is a rare systemic disease which has the ability to form masses in multiple organs and may mimic malignancy. In this case we describe a 53-year-old female who presented with clinical and imaging findings in her right breast consistent with inflammatory breast carcinoma and associated right axillary nodal mass. She underwent CT which also uncovered a left thyroid mass and suggested both masses were possibly malignancies. She proceeded to ultrasound-guided core biopsy of each, which showed an appearance characteristic of IgG4-mediated sclerosing fibroinflammatory disease. The patient was treated with steroids with good outcome. This is the first described case of this condition presenting in this way to our knowledge and this diagnosis should be considered in patients with similar presentations.


Infection and pathology in Queensland grouper, Epinephelus lanceolatus, (Bloch), caused by exposure to Streptococcus agalactiae via different routes.
Since 2007, 96 wild Queensland groupers, Epinephelus lanceolatus, (Bloch), have been found dead in NE Australia. In some cases, Streptococcus agalactiae (Group B Streptococcus, GBS) was isolated. At present, a GBS isolate from a wild grouper case was employed in experimental challenge trials in hatchery-reared Queensland grouper by different routes of exposure. Injection resulted in rapid development of clinical signs including bilateral exophthalmia, hyperaemic skin or fins and abnormal swimming. Death occurred in, and GBS was re-isolated from, 98% fish injected and was detected by PCR in brain, head kidney and spleen from all fish, regardless of challenge dose. Challenge by immersion resulted in lower morbidity with a clear dose response. Whilst infection was established via oral challenge by admixture with feed, no mortality occurred. Histology showed pathology consistent with GBS infection in organs examined from all injected fish, from fish challenged with medium and high doses by immersion, and from high-dose oral challenge. These experimental challenges demonstrated that GBS isolated from wild Queensland grouper reproduced disease in experimentally challenged fish and resulted in pathology that was consistent with that seen in wild Queensland grouper infected with S. agalactiae.


Host-plant-induced larval decision-making in a habitat/host-plant generalist butterfly.
Phenotypic plasticity can be a passive response to fluctuating environmental conditions or an active and presumably adaptive (evolved) response selected for in different environments. Here we ask if the larval decision to enter diapause when reared on a host plant associated with a colder habitat is an active or a passive response to host-plant quality or suitability. We compare plasticity in larval propensity to enter diapause of the habitat generalist butterfly Leptidea sinapis and the meadow specialist Leptidea reali in a range of temperatures and long day length on a forest plant, Lathyrus linifolius, and a meadow-associated plant, Lathyrus pratensis. The warmer meadow habitat promotes direct development whereas the colder forest habitat is conducive to diapause. Larvae of L. sinapis had a higher propensity to enter diapause when reared on the forest plant L. linifolius across all temperatures. Conversely, the propensity of L. reali to enter diapause was consistently lower and did not differ between host plants. Larval growth rates were similar between and within butterfly species and between host plants. Hence, we conclude that larval pathway decision-making in L. sinapis is an active response mediated by information from their host plants.


Tumor-associated macrophages derived from cancer stem cells.
Macrophages are the most abundant immune cells in the microenvironment of solid tumors. The present study displayed histological and immunohistochemical analyses of a malignant tumor model developed from cancer stem cells (CSCs) converted from human induced pluripotent stem cells (hiPSCs) in a cancer microenvironment prepared from the conditioned medium (CM) of a pancreatic cancer cell line. We focused on the localization and the origin of tumor-associated macrophages (TAMs), To the best of our knowledge this may be the first study to suggest the potential differentiation of CSCs to TAMs. hiPSCs were converted into CSCs in the presence of CM from PK8 cells. CSCs were then transplanted in vivo and formed primary tumors. Primary cultures for these tumors were serially transplanted again to obtain secondary tumors. Secondary tumors exhibited histopathological features of malignancy. Cells derived from tumors maintained the expression of endogenous stemness markers and pancreatic CSCs markers. Simultaneously, high immunoreactivity to anti-mouse CD68, anti-human CD68, CD206 and CD11b antibodies were detected revealing that the tumor tissue derived from CSCs was enriched for macrophages which can originate from both human and mouse cells. The model of CSCs highlighted the possibility of CSCs to differentiate into TAMs.


Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice.
Relapsing C. difficile disease in humans is linked to a pathological imbalance within the intestinal microbiota, termed dysbiosis, which remains poorly understood. We show that mice infected with epidemic C. difficile (genotype 027/BI) develop highly contagious, chronic intestinal disease and persistent dysbiosis characterized by a distinct, simplified microbiota containing opportunistic pathogens and altered metabolite production. Chronic C. difficile 027/BI infection was refractory to vancomycin treatment leading to relapsing disease. In contrast, treatment of C. difficile 027/BI infected mice with feces from healthy mice rapidly restored a diverse, healthy microbiota and resolved C. difficile disease and contagiousness. We used this model to identify a simple mixture of six phylogenetically diverse intestinal bacteria, including novel species, which can re-establish a health-associated microbiota and clear C. difficile 027/BI infection from mice. Thus, targeting a dysbiotic microbiota with a defined mixture of phylogenetically diverse bacteria can trigger major shifts in the microbial community structure that displaces C. difficile and, as a result, resolves disease and contagiousness. Further, we demonstrate a rational approach to harness the therapeutic potential of health-associated microbial communities to treat C. difficile disease and potentially other forms of intestinal dysbiosis.


Under pressure, out of control, or home alone? Reviewing research and policy debates on the occupational health and safety effects of outsourcing and home-based work.
The practice of outsourcing or subcontracting of work has grown rapidly in most countries over the past two decades. Outsourcing, de-institutionalization, and a range of other practices have also resulted in a growth of home-based work. Home-based workers, even when not part of a subcontracting process, operate in an isolated situation remote from their employer and other workers. Do such work arrangements expose workers to greater risk of injury, illness, or assault? The authors reviewed international studies of the occupational health and safety (OHS) effects of subcontracting and home-based work undertaken over the past 20 years. Of the 25 studies analyzed, 92 percent found poorer OHS outcomes. The studies were examined for clues about the reasons for these negative outcomes. The authors also identified similarities and differences between subcontracting and home-based work. Despite the evidence of poor OHS outcomes, research into outsourcing has stalled in recent years. With notable exceptions, governments have taken little account of findings on these work arrangements in their laws and policies, in part because neoliberal ideas dominate national and global policy agendas. The authors examine policy challenges and regulatory responses and make suggestions for future research and policy interventions.


Reforming private drug coverage in Canada: inefficient drug benefit design and the barriers to change in unionized settings.
Prescription drugs are the highest single cost component for employees' benefits packages in Canada. While industry literature considers cost-containment for prescription drug costs to be a priority for insurers and employers, the implementation of cost-containment measures for private drug plans in Canada remains more of a myth than a reality. Through 18 semi-structured phone interviews conducted with experts from private sector companies, unions, insurers and plan advisors, this study explores the reasons behind this incapacity to implement cost-containment measures by examining how private sector employers negotiate drug benefit design in unionized settings. Respondents were asked questions on how employee benefits are negotiated; the relationships between the players who influence drug benefit design; the role of these players' strategies in influencing plan design; the broad system that underpins drug benefit design; and the potential for a universal pharmacare program in Canada. The study shows that there is consensus about the need to educate employees and employers, more collaboration and data-sharing between these two sets of players, and for external intervention from government to help transform established norms in terms of private drug plan design.


Coarse-grained molecular dynamics simulations of phase transitions in mixed lipid systems containing LPA, DOPA, and DOPE lipids.
The mechanisms that mediate biomembrane shape transformations are of considerable interest in cell biology. Recent in vitro experiments show that the chemical transformation of minor membrane lipids can induce dramatic shape changes in biomembranes. Specifically, it was observed that the addition of DOPA to DOPE has no effect on the stability of the bilayer structure of the membrane. In contrast, the addition of LPA to DOPE stabilizes the bilayer phase of DOPE, increasing the temperature of a phase transition from the bilayer to the inverted hexagonal phase. This result suggests that the chemical conversion of DOPA to LPA is sufficient for triggering a dramatic change in the shape of biomembranes. The LPA/DOPA/DOPE mixture of lipids provides a simple model system for understanding the molecular events driving the shape change. In this work, we used coarse-grained molecular dynamics simulations to study the phase transitions of this lipid mixture. We show that despite the simplicity of the coarse-grained model, it reproduces the experimentally observed phase changes of: 1), pure LPA and DOPA with respect to changes in the concentration of cations; and 2), LPA/DOPE and DOPA/DOPE mixtures with respect to temperature. The good agreement between the model and experiments suggests that the computationally inexpensive coarse-grained approach can be used to infer macroscopic membrane properties. Furthermore, analysis of the shape of the lipid molecules demonstrates that the phase behavior of single-lipid systems is consistent with molecular packing theory. However, the phase stability of mixed lipid systems exhibits significant deviations from this theory, which suggests that the elastic energy of the lipids, neglected in the packing theory, plays an important role.


Enabling more dying people to remain at home.
When it comes to dying there is no place like home. Since earliest times most cultures have accepted that dying people should remain at home. But this was never possible for all. Some were destined to die in accidents, on battlefields, by execution, and from catastrophic illness, maybe many miles away. Nevertheless, with few exceptions people could expect to die in their own beds and in the bosom of their families. In Europe from the Middle Ages until a century ago there was a simplicity about dying. Aware that the end was approaching, people would take to their sickbeds and preside over the ritual. The family, including children, friends, and neighbours would congregate. The ceremony was public and doctors often complained about overcrowding. Death was not regarded as a frightening event and was accepted as an inevitable and integral part of life. Dramatic changes in attitudes to death have taken place since the mid-nineteenth century. The natural acceptance of a biological reality has been lost and people are now unable to come to terms with their own mortality. One consequence is that death has become institutionalised. This paper seeks to answer five questions. These refer to where people die, where they would choose to die, where they spend their last year of life, the reasons for admission for terminal care, and whether more dying people could remain at home. Discussion is restricted to adults in the United Kingdom. References are mostly from the past decade.


Long-term trends in Anopheles gambiae insecticide resistance in Côte d'Ivoire.
Malaria control is heavily dependent on the use of insecticides that target adult mosquito vectors via insecticide treated nets (ITNs) or indoor residual spraying (IRS). Four classes of insecticide are approved for IRS but only pyrethroids are available for ITNs. The rapid rise in insecticide resistance in African malaria vectors has raised alarms about the sustainability of existing malaria control activities. This problem might be particularly acute in Côte d'Ivoire where resistance to all four insecticide classes has recently been recorded. Here we investigate temporal trends in insecticide resistance across the ecological zones of Côte d'Ivoire to determine whether apparent pan-African patterns of increasing resistance are detectable and consistent across insecticides and areas. We combined data on insecticide resistance from a literature review, and bioassays conducted on field-caught Anopheles gambiae mosquitoes for the four WHO-approved insecticide classes for ITN/IRS. The data were then mapped using Geographical Information Systems (GIS) and the IR mapper tool to provide spatial and temporal distribution data on insecticide resistance in An. gambiae sensu lato from Côte d'Ivoire between 1993 and 2014. Bioassay mortality decreased over time for all insecticide classes, though with significant spatiotemporal variation, such that stronger declines were observed in the southern ecological zone for DDT and pyrethroids than in the central zone, but with an apparently opposite effect for the carbamate and organophosphate. Variation in relative abundance of the molecular forms, coupled with dramatic increase in kdr 1014F frequency in M forms (An. coluzzii) seems likely to be a contributory factor to these patterns. Although records of resistance across insecticide classes have become more common, the number of classes tested in studies has also increased, precluding a conclusion that multiple resistance has also increased. Our analyses attempted synthesis of 22 years of bioassay data from Côte d'Ivoire, and despite a number of caveats and potentially confounding variables, suggest significant but spatially-variable temporal trends in insecticide resistance. In the light of such spatio-temporal dynamics, regular, systematic and spatially-expanded monitoring is warranted to provide accurate information on insecticide resistance for control programme management.


The influence of procedure volumes and standardization of care on quality and efficiency in total joint replacement surgery.
The relationship between surgeon and hospital procedure volumes and clinical outcomes in total joint arthroplasty has long fueled a debate over regionalization of care. At the same time, numerous policy initiatives are focusing on improving quality by incentivizing surgeons to adhere to evidence-based processes of care. The purpose of this study was to evaluate the independent contributions of surgeon procedure volume, hospital procedure volume, and standardization of care on short-term postoperative outcomes and resource utilization in lower-extremity total joint arthroplasty. An analysis of 182,146 consecutive patients who underwent primary total joint arthroplasty was performed with use of data entered into the Perspective database by 3421 physicians from 312 hospitals over a two-year period. Adherence to evidence-based processes of care was defined by administration of appropriate perioperative antibiotic prophylaxis, beta-blockade, and venous thromboembolism prophylaxis. Patient outcomes included mortality, length of hospital stay, discharge disposition, surgical complications, readmissions, and reoperations within the first thirty days after discharge. Hierarchical models were used to estimate the effects of hospital and surgeon procedure volume and process standardization on individual and combined surgical outcomes and length of stay. After adjustment in multivariate models, higher surgeon volume was associated with lower risk of complications, lower rates of readmission and reoperation, shorter length of hospital stay, and higher likelihood of being discharged home. Higher hospital volume was associated with lower risk of mortality, lower risk of readmission, and higher likelihood of being discharged home. The impact of process standardization was substantial; maximizing adherence to evidence-based processes of care resulted in improved clinical outcomes and shorter length of hospital stay, independent of hospital or surgeon procedure volume. Although surgeon and hospital procedure volumes are unquestionably correlated with patient outcomes in total joint arthroplasty, process standardization is also strongly associated with improved quality and efficiency of care. The exact relationship between individual processes of care and patient outcomes has not been established; however, our findings suggest that process standardization could help providers optimize quality and efficiency in total joint arthroplasty, independent of hospital or surgeon volume.


The effect of a natural, standardized bilberry extract (Mirtoselect®) in dry eye: a randomized, double blinded, placebo-controlled trial.
Dry eye, a chronic disease of lachrymal fluid and corneo-conjunctival epithelium, could significantly impact visual function, affects quality of life and work productivity. Beside several conventional treatments, nutritional supplements based on bilberry extract have been identified as effective contributors to eye health. Here, we aim at investigating the bioavailability of a standardized bilberry extract, its ability to alleviate dry eye symptoms and its antioxidant potential. Either bilberry dried standardized extract derived from Vaccinium myrtillus L. fresh frozen fruits (Mirtoselect®) or a highly purified anthocyanin-rich extract, devoid of the non anthocyanin component and supported on maltodextrins, were each orally administrated to 5 male rats. Blood samples were collected at 5, 10, 15, 20, 30, 45, 60, 90, 120 minutes after treatment, processed and analyzed by UV spectrophotometric method. In a parallel analysis, 22 otherwise healthy subjects suffering from dry eye symptoms were enrolled randomly assigned to receive the more bioavailable bilberry extract or placebo. Ophthalmological and clinical examinations including Schirmer's test, pupil constriction, diacron-reactive oxygen metabolites (d-ROMs) test and biological antioxidant potential (BAP) test were performed at inclusion and after the 4-week study period. The area under the curve of plasmatic levels of anthocyanosides in rats resulted 202.34±24.23 µg·min/ml for Mirtoselect® and 130.93±4.93 µg·min/ml for the highly purified anthocyanin-rich bilberry extract, notwithstanding the fact that the highly purified anthocyanin-rich extract group received an anthocyanins dosage much higher than the Mirtoselect® group (354 mg/Kg in anthocyanosides vs. 136 mg/Kg in anthocyanosides). 21 subjects, 11 subjects in the bilberry extract (Mirtoselect®) group and 10 subjects in the placebo group completed the clinical study. Schirmer's test values indicating the volume of tear secretion were significantly improved in the bilberry extract group (p=0.019), whereas no significant changes were observed in the placebo group. A subset analysis revealed that Mirtoselect® could be more effective in subjects with higher tendency of dry eye. In terms of antioxidant potential, the bilberry extract produced significant improvement of BAP (p=0.003) and an increase of modified BAP/d-ROMs ratio, an indicator of overall balance between antioxidant potential and oxidative stress. Our results suggested that natural, standardized bilberry extract (Mirtoselect®) is a natural more bioavailable delivery form anthocyanins, suggesting a strong matrix effect exerted by the non-anthocyanin component. Furthermore, it can improve tear secretion and plasmatic antioxidant potential in subjects suffering from DED symptoms.


Podometry: a critical evaluation of its use in Hansen's disease.
The aim of this paper is to evaluate the effectiveness of podometry to measure the pressure developed over the feet and the value of these findings to help in the prevention of the plantar neuropathic ulcer in patients bearing Hansen's disease. We evaluated 13 patients with impaired plantar pain and touch sensations and 17 normal patients. All the patients were submitted to static evaluation using the podometer. The system employed was the "Midcapteur" commercial podometer composed of a platform for acquisition of analogic data capable of registering the segmental pressures applied to the feet. These data are read by a 386 IBM/PC compatible computer that registers the graphic patterns obtained from the pressures developed and also calculates the modes of pressure distribution in the four quadrants of the foot. These data obtained by means of static podometry were compared to the clinical evaluation of pain and touch sensation of the feet in hansenian patients. The results demonstrate that podometery is an efficient method for evaluating the pressure in impaired feet in Hansen's disease and is a progression of neuropathic ulcer; it is sensitive in the identification of the spots of increased pressure in anesthetic and anomalous areas, asymmetries and in correlating the presence of ulcers with increased pressure.


Metastatic hepatocellular carcinoma of the heart. A case report.
A metastatic tumour growing in the heart more than 2 years after total removal of the primary hepatic growth is a rare event. Jaundice as a result of bile production by the metastasis is most unusual. The primary tumour did not recur in the regenerated liver. Features which may prove useful in making a clinical diagnosis are briefly considered. Death resulted from a thrombo-embolus from the right atrium lodging in the opening of the tricuspid valve.


Indices of immune function used by ecologists are mostly unaffected by repeated freeze-thaw cycles and methodological deviations.
Over the past couple of decades, measuring immunological parameters has become widespread in studies of ecology and evolution. A combination of different immunological indices is useful for quantifying different parts of the immune system and comprehensively assessing immune function. Running multiple immune assays usually requires samples to be repeatedly thawed and re-frozen. There is some evidence that repeated freezing and thawing can affect assay results, but this has never been comprehensively studied in some common ecological immunology assays. We tested the effect of multiple (1, 2, 3, 4, 5, 10) freeze-thaw cycles on the results of four commonly used immunological assays: haemolysis-haemagglutination titres, haptoglobin concentration, bacterial killing capacity and total immunoglobulins (IgY). We tested five different bird species from four different bird orders (Passeriformes, Columbiformes, Charadriiformes and Galliformes), and we included both captive and free-living individuals. In addition, we tested for haptoglobin concentrations and the haemolysis-haemagglutination assay if re-analysing samples 1 year apart led to different results. For the haemolysis-haemagglutination assay we also tested two different sources of rabbit blood, and we compared untreated microtitre plates with plates that were "blocked" to prevent nonspecific interactions between the plate and assay reagents. Repeated freezing and thawing of plasma had no effect on lysis titres, haptoglobin concentrations, bacterial killing capacity, or total immunoglobulin levels. Agglutination titres were unaffected by up to five cycles but were lower after ten freeze-thaw cycles. For the haemolysis-haemagglutination assay and haptoglobin concentrations, re-analysing samples 1 year apart yielded highly correlated data. For the haemolysis-haemagglutination assay, the source of rabbit blood did not influence the results, and the untreated vs. blocked plates differed slightly overall, but at the individual level assay results were highly correlated. Using different rabbit blood sources or different types of microtitre plates yielded highly correlated data. Our data suggest that repeated freeze-thaw cycles do not impair assay results to the point of influencing ecological or evolutionary conclusions. Plasma samples can be safely stored in one tube and thawed repeatedly for different assays. Nevertheless, we recommend consistent treatment of samples in terms of freeze-thaw cycles or other laboratory treatments to minimize the potential for introducing a systematic bias.


A systems approach to teach core topics across graduate medical education programmes.
Core curricula including Ethics, Medico-legal issues, Socioeconomics, and Quality Improvement (QI) are relevant and significant for graduate medical education programmes, regardless of specialty. A lack of faculty expertise in these content areas is a frequently cited concern among specialty programmes in graduate medical education. We report the results of an institutional systems-approach to assist this challenge. Our institution has 86 post-graduate residency and fellowship training programmes serving 1068 learners. Directors of these programmes expressed the need for a centralised approach to teach learners about insurance systems and the basics of QI. Two subject matter experts in the fields of insurance systems and 1 expert in QI conducted 2 institution-wide didactics on each of the content areas, attended by 192 and 225 learners respectively. Significant improvement in learner knowledge was noted for all 3 knowledge-based questions for both content areas (P <0.0001). Learner self-assessment of knowledge of insurance systems increased from a pre-session mean of 2.86 to a post-session mean of 3.80 (P <0.0001) and from 3.29 to a post-session mean of 4.17 (P <0.0001) for the QI didactics. Systems-wide didactic sessions for learners of different residencies has several advantages including the efficient use of content experts, prevention of resource burnout, and cost effectiveness. This strategy may also assist programmes directors in meeting external accreditation requirements.


Involving service users in trials: developing a standard operating procedure.
Many funding bodies require researchers to actively involve service users in research to improve relevance, accountability and quality. Current guidance to researchers mainly discusses general principles. Formal guidance about how to involve service users operationally in the conduct of trials is lacking. We aimed to develop a standard operating procedure (SOP) to support researchers to involve service users in trials and rigorous studies. Researchers with experience of involving service users and service users who were contributing to trials collaborated with the West Wales Organisation for Rigorous Trials in Health, a registered clinical trials unit, to develop the SOP. Drafts were prepared in a Task and Finish Group, reviewed by all co-authors and amendments made. We articulated core principles, which defined equality of service users with all other research team members and collaborative processes underpinning the SOP, plus guidance on how to achieve these. We developed a framework for involving service users in research that defined minimum levels of collaboration plus additional consultation and decision-making opportunities. We recommended service users be involved throughout the life of a trial, including planning and development, data collection, analysis and dissemination, and listed tasks for collaboration. We listed people responsible for involving service users in studies and promoting an inclusive culture. We advocate actively involving service users as early as possible in the research process, with a minimum of two on all formal trial groups and committees. We propose that researchers protect at least 1% of their total research budget as a minimum resource to involve service users and allow enough time to facilitate active involvement. This SOP provides guidance to researchers to involve service users successfully in developing and conducting clinical trials and creating a culture of actively involving service users in research at all stages. The UK Clinical Research Collaboration should encourage clinical trials units actively to involve service users and research funders should provide sufficient funds and time for this in research grants.


Alterations in the porcine colon microbiota induced by the gastrointestinal nematode Trichuris suis.
Helminth parasites ensure their survival by regulating host immunity through mechanisms that dampen inflammation. These properties have recently been exploited therapeutically to treat human diseases. The biocomplexity of the intestinal lumen suggests that interactions between the parasite and the intestinal microbiota would also influence inflammation. In this study, we characterized the microbiota in the porcine proximal colon in response to Trichuris suis (whipworm) infection using 16S rRNA gene-based and whole-genome shotgun (WGS) sequencing. A 21-day T. suis infection in four pigs induced a significant change in the composition of the proximal colon microbiota compared to that of three parasite-naive pigs. Among the 15 phyla identified, the abundances of Proteobacteria and Deferribacteres were changed in infected pigs. The abundances of approximately 13% of genera were significantly altered by infection. Changes in relative abundances of Succinivibrio and Mucispirillum, for example, may relate to alterations in carbohydrate metabolism and niche disruptions in mucosal interfaces induced by parasitic infection, respectively. Of note, infection by T. suis led to a significant shift in the metabolic potential of the proximal colon microbiota, where 26% of all metabolic pathways identified were affected. Besides carbohydrate metabolism, lysine biosynthesis was repressed as well. A metabolomic analysis of volatile organic compounds (VOCs) in the luminal contents showed a relative absence in infected pigs of cofactors for carbohydrate and lysine biosynthesis, as well as an accumulation of oleic acid, suggesting altered fatty acid absorption contributing to local inflammation. Our findings should facilitate development of strategies for parasitic control in pigs and humans.


The epigenetic bottleneck of neurodegenerative and psychiatric diseases.
The orchestrated expression of genes is essential for the development and survival of every organism. In addition to the role of transcription factors, the availability of genes for transcription is controlled by a series of proteins that regulate epigenetic chromatin remodeling. The two most studied epigenetic phenomena are DNA methylation and histone-tail modifications. Although a large body of literature implicates the deregulation of histone acetylation and DNA methylation with the pathogenesis of cancer, recently epigenetic mechanisms have also gained much attention in the neuroscientific community. In fact, a new field of research is rapidly emerging and there is now accumulating evidence that the molecular machinery that regulates histone acetylation and DNA methylation is intimately involved in synaptic plasticity and is essential for learning and memory. Importantly, dysfunction of epigenetic gene expression in the brain might be involved in neurodegenerative and psychiatric diseases. In particular, it was found that inhibition of histone deacetylases attenuates synaptic and neuronal loss in animal models for various neurodegenerative diseases and improves cognitive function. In this article, we will summarize recent data in the novel field of neuroepigenetics and discuss the question why epigenetic strategies are suitable therapeutic approaches for the treatment of brain diseases.


Catalytic Converters for Water Treatment.
Fresh water demand is driven by human consumption, agricultural irrigation, and industrial usage and continues to increase along with the global population. Improved methods to inexpensively and sustainably clean water unfit for human consumption are desired, particularly at remote or rural locations. Heterogeneous catalysts offer the opportunity to directly convert toxic molecules in water to nontoxic products. Heterogeneous catalytic reaction processes may bring to mind large-scale industrial production of chemicals, but they can also be used at the small scale, like catalytic converters used in cars to break down gaseous pollutants from fuel combustion. Catalytic processes may be a competitive alternative to conventional water treatment technologies. They have much faster kinetics and are less operationally sensitive than current bioremediation-based methods. Unlike other conventional water treatment technologies (i.e., ion exchange, reverse osmosis, activated carbon filtration), they do not transfer contaminants into separate, more concentrated waste streams. In this Account, we review our efforts on the development of heterogeneous catalysts as advanced reduction technologies to treat toxic water contaminants such as chlorinated organics and nitrates. Fundamental understanding of the underlying chemistry of catalytic materials can inform the design of superior catalytic materials. We discuss the impact of the catalytic structure (i.e., the arrangement of metal atoms on the catalyst surface) on the catalyst activity and selectivity for these aqueous reactions. To explore these aspects, we used model metal-on-metal nanoparticle catalysts along with state-of-the-art in situ spectroscopic techniques and density functional theory calculations to deduce the catalyst surface structure and how it affects the reaction pathways and hence the activity and selectivity. We also discuss recent developments in photocatalysis and electrocatalysis for the treatment of nitrates, touching on fundamentals and surface reaction mechanisms. Finally, we note that despite over 20 years of growing research into heterogeneous catalytic systems for water contaminants, only a few pilot-scale studies have been conducted, with no large-scale implementation to date. We conceive of modular, on- or off-grid catalytic units that treat drinking water at the household tap, at a community well, or for larger-scale reuse of agricultural runoff. We discuss how these may be enhanced by combination with photocatalytic or electrocatalytic processes and how these reductive catalytic modules (catalytic converters for water) can be coupled with other modules for the removal of potential water contaminants.


The world bacterial biogeography and biodiversity through databases: a case study of NCBI Nucleotide Database and GBIF Database.
Databases are an essential tool and resource within the field of bioinformatics. The primary aim of this study was to generate an overview of global bacterial biodiversity and biogeography using available data from the two largest public online databases, NCBI Nucleotide and GBIF. The secondary aim was to highlight the contribution each geographic area has to each database. The basis for data analysis of this study was the metadata provided by both databases, mainly, the taxonomy and the geographical area origin of isolation of the microorganism (record). These were directly obtained from GBIF through the online interface, while E-utilities and Python were used in combination with a programmatic web service access to obtain data from the NCBI Nucleotide Database. Results indicate that the American continent, and more specifically the USA, is the top contributor, while Africa and Antarctica are less well represented. This highlights the imbalance of exploration within these areas rather than any reduction in biodiversity. This study describes a novel approach to generating global scale patterns of bacterial biodiversity and biogeography and indicates that the Proteobacteria are the most abundant and widely distributed phylum within both databases.


Mood changes in bulimia nervosa.
Daily measurement of mood, and the occurrence of specific eating behaviours, were assessed concurrently over an eight-week period in a sample of 50 patients meeting diagnostic criteria for bulimia nervosa. Results of observer-rated scales of mood showed a significant reduction of scores, whereas self-assessment of mood showed no change over the study period. Negative mood states, although not severe, were more marked when the specific behavioural symptoms of binge-eating, vomiting, or purging occurred, and they increased as abnormal eating behaviours accumulated. It is suggested that the accompanying dysphoric mood states of bulimia nervosa are likely to be a secondary manifestation related to the presence of abnormal eating symptoms, and that they do no constitute a primary depressive illness.


Ginsenoside compound K induces apoptosis in nasopharyngeal carcinoma cells via activation of apoptosis-inducing factor.
Nasopharyngeal carcinoma (NPC) has a high incidence rate in Southern China. Although there are conventional therapies, the side effects and toxicities are not always tolerable for patients. Recently, the tumoricidal effect of ginsenosides on different cancer cells has been studied. This study aims to investigate the anti-cancer effect of ginsenosides on NPC cells and their underlying mechanism. The cytotoxicity of ginsenosides on NPC cell line HK-1 was measured by MTT assay. Apoptosis was detected by propidium iodide staining followed by flow cytometry. A xenograft tumor model was established by injecting nude mice with HK-1 cells. The activation of caspases and apoptosis-inducing factor (AIF) were evaluated by Western blot analysis. Nuclear translocation of AIF was also studied by immunofluorescence staining. Mitochondrial membrane potential was measured by JC-1 dye using flow cytometry. Four ginsenosides, 20 (S)-Rh2, compound K (CK), panaxadiol (PD) and protopanaxadiol (PPD), induced apoptotic cell death in HK-1 cells in a concentration-dependent manner. CK inhibited HK-1 xenograft tumor growth most extensively and depleted mitochondrial membrane potential depolarization and induced translocation of AIF from cytoplasm to nucleus in HK-1 cells. In addition, depletion of AIF by siRNA abolished CK-induced HK-1 cell death. Ginsenoside CK-induced apoptosis of HK-1 cells was mediated by the mitochondrial pathway and could significantly inhibit tumor growth in vivo.


Cation-Activated Avidity for Rapid Reconfiguration of DNA Nanodevices.
The ability to design and control DNA nanodevices with programmed conformational changes has established a foundation for molecular-scale robotics with applications in nanomanufacturing, drug delivery, and controlling enzymatic reactions. The most commonly used approach for actuating these devices, DNA binding and strand displacement, allows devices to respond to molecules in solution, but this approach is limited to response times of minutes or greater. Recent advances have enabled electrical and magnetic control of DNA structures with sub-second response times, but these methods utilize external components with additional fabrication requirements. Here, we present a simple and broadly applicable actuation method based on the avidity of many weak base-pairing interactions that respond to changes in local ionic conditions to drive large-scale conformational transitions in devices on sub-second time scales. To demonstrate such ion-mediated actuation, we modified a DNA origami hinge with short, weakly complementary single-stranded DNA overhangs, whose hybridization is sensitive to cation concentrations in solution. We triggered conformational changes with several different types of ions including mono-, di-, and trivalent ions and also illustrated the ability to engineer the actuation response with design parameters such as number and length of DNA overhangs and hinge torsional stiffness. We developed a statistical mechanical model that agrees with experimental data, enabling effective interpretation and future design of ion-induced actuation. Single-molecule Förster resonance energy-transfer measurements revealed that closing and opening transitions occur on the millisecond time scale, and these transitions can be repeated with time resolution on the scale of one second. Our results advance capabilities for rapid control of DNA nanodevices, expand the range of triggering mechanisms, and demonstrate DNA nanomachines with tunable analog responses to the local environment.


Retrospective Quantitative Genetic Analysis and Genomic Prediction of Global Wheat Yields.
Breeding for grain yield (GY) in bread wheat at the International Maize and Wheat Improvement Center (CIMMYT) involves three-stage testing at Obregon, Mexico in different selection environments (SEs). To understand the efficiency of selection in the SEs, we performed a large retrospective quantitative genetics study using CIMMYT's yield trials evaluated in the SEs (2013-2014 to 2017-2018), the South Asia Bread Wheat Genomic Prediction Yield Trials (SABWGPYTs) evaluated in India, Pakistan, and Bangladesh (2014-2015 to 2017-2018), and the Elite Spring Wheat Yield Trials (ESWYTs) evaluated in several sites globally (2003-2004 to 2016-2017). First, we compared the narrow-sense heritabilities in the Obregon SEs and target sites and observed that the mean heritability in the SEs was 44.2 and 92.3% higher than the mean heritabilities in the SABWGPYT and ESWYT sites, respectively. Second, we observed significant genetic correlations between a SE in Obregon and all the five SABWGPYT sites and 65.1% of the ESWYT sites. Third, we observed high ratios of response to indirect selection in the SEs of Obregon with a mean of 0.80 ± 0.21 and 2.6 ± 5.4 in the SABWGPYT and ESWYT sites, respectively. Furthermore, our results also indicated that for all the SABWGPYT sites and 82% of the ESWYT sites, a response greater than 0.5 can be achieved by indirect selection for GY in Obregon. We also performed genomic prediction for GY in the target sites using the performance of the same lines in the SEs of Obregon and observed moderate mean prediction accuracies of 0.24 ± 0.08 and 0.28 ± 0.08 in the SABWGPYT and ESWYT sites, respectively using the genotype x environment (GxE) model. However, we observed similar accuracies using the baseline model with environment and line effects and no advantage of modeling GxE interactions. Overall, this study provides important insights into the suitability of the Obregon SEs in breeding for GY, while the variable genomic predictabilities of GY and the high year-to-year GY fluctuations reported, highlight the importance of multi-environment testing across time and space to stave off GxE induced uncertainties in varietal yields.


Nicotinic and muscarinic interactions and choice accuracy in the radial-arm maze.
Muscarinic acetylcholine (ACh) systems have long been known to be necessary for accurate performance in cognitive tests. Nicotinic ACh systems have been shown to be involved as well. However, there is only a limited amount of information concerning the interactions of these two branches of the ACh transmitter system. The current study was conducted to investigate the improvement in choice accuracy caused by muscarinic and nicotinic agonists and how it is affected by antagonists of these systems. Adult female Sprague-Dawley strain rats (N = 11) were trained on a working memory task in an 8-arm radial maze. Acute injections of the muscarinic and nicotinic agonists, pilocarpine (PILO, 1.0 mg/kg) and nicotine (NIC, 0.2 mg/kg), were made alone or in combination with the muscarinic and nicotinic antagonists, scopolamine (SCOP, 0.1 mg/kg) and mecamylamine (MEC, 10 mg/kg). NIC administration caused a significant improvement in choice accuracy compared with saline (p less than 0.01) and PILO caused a marginally significant improvement in choice accuracy (p less than 0.06). The combination of these nicotinic and muscarinic agonists did not cause an additive improvement. However, the improvement caused by either agonist was reversed by both nicotinic or muscarinic antagonists. This reversal was more complete for NIC than PILO despite the fact that NIC caused a greater improvement than PILO. These results suggest that muscarinic and nicotinic components of the ACh system, which are both important for cognitive function, interact in important ways. These interactions may be critical to consider when devising treatments for cognitive dysfunction associated with cholinergic hypofunction such as with Alzheimer's disease.


Optimizing adherence to preexposure and postexposure prophylaxis: the need for an integrated biobehavioral approach.
Preexposure prophylaxis (PrEP) and postexposure prophylaxis (PEP) has been shown to be effective in preventing transmission of human immunodeficiency virus (HIV). A dose-response relationship between adherence and HIV transmission is illustrated in the current PrEP literature, and adherence interventions for PrEP may be useful, although currently few effective programs have been developed and tested. There is a paucity of randomized controlled trials testing PEP adherence interventions, and further research is needed. We conclude by proposing the importance of tailoring adherence counseling to address psychosocial factors and mental health stressors that may negatively affect adherence.


Compositional development of Bifidobacterium and Lactobacillus microbiota is linked with crying and fussing in early infancy.
Our aim was to establish whether there is an interconnection between the compositional development of the gut microbiota and the amount of fussing and crying in early infancy. Behavioral patterns of 89 infants during the 7(th) and 12(th) week of life were recorded in parental diaries. Total distress was defined as the sum of daily amounts of crying and fussing. Infants' gut microbiota profiles were investigated by several molecular assays during the first six months of life. The median (range) duration of total distress among the infants was 106 (0-478) minutes a day during the 7(th) and 58 (0-448) minutes a day during the 12(th) week. The proportion of Bifidobacterium counts to total bacterial counts was inversely associated with the amount of crying and fussing during the first 3 months of life (p = 0.03), although the number of Bifidobacterium breve was positively associated with total distress (p = 0.02). The frequency of Lactobacillus spp. at the age of 3 weeks was inversely associated with total infant distress during the 7(th) week of life (p = 0.02). Bifidobacterium and Lactobacillus appear to protect against crying and fussing. Identification of specific strains with optimal protective properties would benefit at-risk infants.


Bioproduction of a Therapeutic Vaccine Against Human Papillomavirus in Tomato Hairy Root Cultures.
Human papillomavirus (HPV) tumor disease is a critical public health problem worldwide, especially in the developing countries. The recognized pathogenic function of E5, E6, and E7 oncoproteins offers the opportunity to devise therapeutic vaccines based on engineered recombinant proteins. The potential of plants to manufacture engineered compounds for pharmaceutical purposes, from small to complex protein molecules, allows the expression of HPV antigens and, possibly, the regulation of immune functions to develop very specific therapies as a reinforcement to available nonspecific therapies and preventive vaccination also in developed countries. Among plant-based expression formats, hairy root cultures are a robust platform combining the benefits of eukaryotic plant-based bioreactors, with those typical of cell cultures. In this work, to devise an experimental therapeutic vaccine against HPV, hairy root cultures were used to express a harmless form of the HPV type 16 E7 protein (E7*) fused to SAPKQ, a noncytotoxic form of the saporin protein from Saponaria officinalis, that we had shown to improve E7-specific cell-mediated responses as a fusion E7*-SAPKQ DNA vaccine. Hairy root clones expressing the E7*-SAPKQ candidate vaccine were obtained upon infection of leaf explants of Solanum lycopersicum using a recombinant plant expression vector. Yield was approximately 35.5 μg/g of fresh weight. Mouse immunization with vaccine-containing crude extracts was performed together with immunological and biological tests to investigate immune responses and anticancer activity, respectively. Animals were primed with either E7*-SAPKQ DNA-based vaccine or E7*-SAPKQ root extract-based vaccine and boosted with the same (homologous schedule) or with the other vaccine preparation (heterologous schedule) in the context of TC-1 experimental mouse model of HPV-associated tumor. All the formulations exhibited an immunological response associated to anticancer activity. In particular, DNA as prime and hairy root extract as boost demonstrated the highest efficacy. This work, based on the development of low-cost technologies, highlights the suitability of hairy root cultures as possible biofactories of therapeutic HPV vaccines and underlines the importance of the synergic combination of treatment modalities for future developments in this field.