Observation of counterclockwise, clockwise and butterfly bistabilty in 1550 nm VCSOAs.
In this paper, we report counter-clockwise, clockwise, and, for the first time to our knowledge, butterfly bistability in 1550 nm Vertical Cavity Semiconductor Optical Amplifiers (VCSOA). Bistable operation is experimentally observed for bias currents ranging from 66-122% of threshold with switching powers as low as 2 microW. These switching powers are two orders of magnitude lower than any previous results in 1550 nm VCSOAs. These switching powers are consistent with previous reports on optical bistability in 850 nm VCSOAs and provide an important step towards the realization of small footprint, low power optical logic/switching elements in the 1550 nm wavelength band.


Determination of the mode reflection coefficient in air-core photonic bandgap fibers.
Using an eigenmode decomposition technique, we numerically determine the backreflection coefficient of the modes of air-core photonic bandgap fibers for flat terminations. This coefficient is found to be very small for the fundamental air-guided mode, of the order of 10(-5) to 10(-6), in contrast with the surface and bulk modes, which exhibit significantly higher reflections, by about three to four orders of magnitude. For the Crystal Fibre HC-1550-2 fiber, we find a reflection coefficient of 1.9x10(-6) for an air termination, and approximately 3.3% for a silica termination. We also find that the Fresnel approximation is ill suited for the determination of the modal reflection coefficient, and instead propose a more accurate new formula based on an averaged modal index.


Early combination therapy with hydroxychloroquine and azithromycin reduces mortality in 10,429 COVID-19 outpatients.
We evaluated the age-specific mortality of unselected adult outpatients infected with SARS-CoV-2 treated early in a dedicated COVID-19 day hospital and we assessed whether the use of hydroxychloroquine (HCQ) + azithromycin (AZ) was associated with improved survival in this cohort. A retrospective monocentric cohort study was conducted in the day hospital of our center from March to December 2020 in adults with PCR-proven infection who were treated as outpatients with a standardized protocol. The primary endpoint was 6-week mortality, and secondary endpoints were transfer to the intensive care unit and hospitalization rate. Among 10,429 patients (median age, 45 [IQR 32-57] years; 5597 [53.7%] women), 16 died (0.15%). The infection fatality rate was 0.06% among the 8315 patients treated with HCQ+AZ. No deaths occurred among the 8414 patients younger than 60 years. Older age and male sex were associated with a higher risk of death, ICU transfer, and hospitalization. Treatment with HCQ+AZ (0.17 [0.06-0.48]) was associated with a lower risk of death, independently of age, sex and epidemic period. Meta-analysis evidenced consistency with 4 previous outpatient studies (32,124 patients-Odds ratio 0.31 [0.20-0.47], I2 = 0%). Early ambulatory treatment of COVID-19 with HCQ+AZ as a standard of care is associated with very low mortality, and HCQ+AZ improve COVID-19 survival compared to other regimens.


Systemic delivery of microRNA-181b inhibits nuclear factor-κB activation, vascular inflammation, and atherosclerosis in apolipoprotein E-deficient mice.
Activated nuclear factor (NF)-κB signaling in the vascular endothelium promotes the initiation and progression of atherosclerosis. Targeting endothelial NF-κB may provide a novel strategy to limit chronic inflammation. To examine the role of microRNA-181b (miR-181b) in endothelial NF-κB signaling and effects on atherosclerosis. MiR-181b expression was reduced in the aortic intima and plasma in apolipoprotein E-deficient mice fed a high-fat diet. Correspondingly, circulating miR-181b in the plasma was markedly reduced in human subjects with coronary artery disease. Systemic delivery of miR-181b resulted in a 2.3-fold overexpression of miR-181b in the aortic intima of apolipoprotein E-deficient mice and suppressed NF-κB signaling revealed by bioluminescence imaging and reduced target gene expression in the aortic arch in apolipoprotein E-deficient/NF-κB-luciferase transgenic mice. MiR-181b significantly inhibited atherosclerotic lesion formation, proinflammatory gene expression and the influx of lesional macrophages and CD4+ T cells in the vessel wall. Mechanistically, miR-181b inhibited the expression of the target gene importin-α3, an effect that reduced NF-κB nuclear translocation specifically in the vascular endothelium of lesions, whereas surprisingly leukocyte NF-κB signaling was unaffected despite a 7-fold overexpression of miR-181b. Our findings uncover that NF-κB nuclear translocation in leukocytes does not involve importin-α3, but rather importin-α5, which miR-181b does not target, highlighting that inhibition of NF-κB signaling in the endothelium is sufficient to mediate miR-181b's protective effects. Systemic delivery of miR-181b inhibits the activation of NF-κB and atherosclerosis through cell-specific mechanisms in the vascular endothelium. These findings support the rationale that delivery of miR-181b may provide a novel therapeutic approach to treat chronic inflammatory diseases such as atherosclerosis.


An automated system for CE-MALDI and on-target digestion under a fluorocarbon lid applied on spermatophore proteins from Pieris napi.
A method for off-line CE-MALDI-TOF-MS and MS2, and on-target digestion under a fluorocarbon lid was developed and applied for the analysis of proteins in the spermatophore of the butterfly Pieris napi. Fractionation revealed many peptides otherwise not detected or resolved. Automated fractionation was performed with an in-lab developed robotic system, and automated on-target tryptic digestion under a fluorocarbon lid was demonstrated with the same system. Fractionation onto a pre-structured MALDI-concentration plate facilitated aligned deposition of trypsin and MALDI-matrix with the deposited sample, also under the fluorocarbon lid. Some indications of indigenous proteolysis of spermatophore proteins were seen, and searching MS2 spectra suggested three tentative sequence homologies to P. rapae. The study demonstrates the functionality of the lab-made robot. Detailed manufacturing instructions and code are provided. The feasibility of automated on-target digestion under a fluorocarbon lid, and the usefulness of a structured concentration plate in CE-MALDI fractionation was shown. Further, it constitutes a preliminary study of P. napi spermatophore proteins.


Correction to the Beer-Lambert-Bouguer law for optical absorption.
The Beer-Lambert-Bouguer absorption law, known as Beer's law for absorption in an optical medium, is precise only at power densities lower than a few kW. At higher power densities this law fails because it neglects the processes of stimulated emission and spontaneous emission. In previous models that considered those processes, an analytical expression for the absorption law could not be obtained. We show here that by utilizing the Lambert W-function, the two-level energy rate equation model is solved analytically, and this leads into a general absorption law that is exact because it accounts for absorption as well as stimulated and spontaneous emission. The general absorption law reduces to Beer's law at low power densities. A criterion for its application is given along with experimental examples.


Sub-optimal presentation of painful facial expressions enhances readiness for action and pain perception following electrocutaneous stimulation.
Observation of others' painful facial expressions has been shown to facilitate behavioral response tendencies and to increase pain perception in the observer. However, in previous studies, expressions were clearly visible to the observer and none of those studies investigated the effect of presence of peripheral stimulation on response tendencies. This study focuses on the effect of sub-optimal presentation of painful facial expressions in the presence and absence of an electrocutaneous stimulus. Twenty-two healthy individuals categorized arrow targets which were preceded by a sub-optimally presented facial expression (painful, happy, or neutral in different blocks). On half of the trials, aversive electrocutaneous stimulation was delivered to the wrist of the non-dominant hand between the presentation of facial expression and target (an arrow directing to right or left). Participants' task was to indicate direction of the arrow as soon as it appears on the screen by pressing the corresponding key on the keyboard and to rate their pain at the end of block. Analysis showed that responses were faster to targets preceded by aversive stimulation than to targets not preceded by stimulation, especially following painful expressions. Painfulness ratings were higher following painful expressions than following happy expressions. These findings suggest that sub-optimally presented painful expressions can enhance readiness to act to neutral, non-pain-related targets after aversive stimulation and can increase pain perception.


Neuroproteomics approaches to decipher neuronal regeneration and degeneration.
Given the complexity of brain and nerve tissues, systematic approaches are essential to understand normal physiological conditions and functional alterations in neurological diseases. Mass spectrometry-based proteomics is increasingly used in neurosciences to determine both basic and clinical differential protein expression, protein-protein interactions, and post-translational modifications. Proteomics approaches are especially useful to understand the mechanisms of nerve regeneration and degeneration because changes in axons following injury or in disease states often occur without the contribution of transcriptional events in the cell body. Indeed, the current understanding of axonal function in health and disease emphasizes the role of proteolysis, local axonal protein synthesis, and a broad range of post-translational modifications. Deciphering how axons regenerate and degenerate has thus become a postgenomics problem, which depends in part on proteomics approaches. This review focuses on recent proteomics approaches designed to uncover the mechanisms and molecules involved in neuronal regeneration and degeneration. It emerges that the principal degenerative mechanisms converge to oxidative stress, dysfunctions of axonal transport, mitochondria, chaperones, and the ubiquitin-proteasome systems. The mechanisms regulating nerve regeneration also impinge on axonal transport, cytoskeleton, and chaperones in addition to changes in signaling pathways. We also discuss the major challenges to proteomics work in the nervous system given the complex organization of the brain and nerve tissue at the anatomical, cellular, and subcellular levels.


Locus coeruleus noradrenergic innervation of the amygdala facilitates alerting-induced constriction of the rat tail artery.
The amygdala, innervated by the noradrenergic locus coeruleus, processes salient environmental events. α2-adrenoceptor-stimulating drugs (clonidine-like agents) suppress the behavioral and physiological components of the response to salient events. Activation of sympathetic outflow to the cutaneous vascular bed is part of the physiological response to salience-mediated activation of the amygdala. We have determined whether acute systemic and intra-amygdala administration of clonidine, and chronic immunotoxin-mediated destruction of the noradrenergic innervation of the amygdala, impairs salience-related vasoconstrictor episodes in the tail artery of conscious freely moving Sprague-Dawley rats. After acute intraperitoneal injection of clonidine (10, 50, and 100 μg/kg), there was a dose-related decrease in the reduction in tail blood flow elicited by alerting stimuli, an effect prevented by prior administration of the α2-adrenergic blocking drug idazoxan (1 mg/kg ip or 75 nmol bilateral intra-amygdala). A dose-related decrease in alerting-induced tail artery vasoconstriction was also observed after bilateral intra-amygdala injection of clonidine (5, 10, and 20 nmol in 200 nl), an effect substantially prevented by prior bilateral intra-amygdala injection of idazoxan. Intra-amygdala injection of idazoxan by itself did not alter tail artery vasoconstriction elicited by alerting stimuli. Intra-amygdala injection of saporin coupled to antibodies to dopamine-β-hydroxylase (immunotoxin) destroyed the noradrenergic innervation of the amygdala and the parent noradrenergic neurons in the locus coeruleus. The reduction in tail blood flow elicited by standardized alerting stimuli was substantially reduced in immunotoxin-treated rats. Thus, inhibiting the release of noradrenaline within the amygdala reduces activation of the sympathetic outflow to the vascular beds elicited by salient events.


Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR.
Adeno-associated virus (AAV) vectors are preeminent in emerging clinical gene therapies. Generalizing beyond the most tractable genetic diseases will require modulation of cell specificity and immune neutralization. Interactions of AAV with its cellular receptor, AAVR, are key to understanding cell-entry and trafficking with the rigor needed to engineer tissue-specific vectors. Cryo-electron tomography shows ordered binding of part of the flexible receptor to the viral surface, with distal domains in multiple conformations. Regions of the virus and receptor in close physical proximity can be identified by cross-linking/mass spectrometry. Cryo-electron microscopy with a two-domain receptor fragment reveals the interactions at 2.4 Å resolution. AAVR binds between AAV's spikes on a plateau that is conserved, except in one clade whose structure is AAVR-incompatible. AAVR's footprint overlaps the epitopes of several neutralizing antibodies, prompting a re-evaluation of neutralization mechanisms. The structure provides a roadmap for experimental probing and manipulation of viral-receptor interactions.


Targeting human telomerase reverse transcriptase with recombinant lentivector is highly effective to stimulate antitumor CD8 T-cell immunity in vivo.
The success of active immunotherapy is based on the vaccine's ability to overcome immune tolerance through recalibrating the immune system so that it is able to recognize tumor antigens as foreign rather than self. In this study, we used a lentiviral vector system to target human telomerase reverse transcriptase (lv-hTERT), a widely expressed tumor antigen. Immunization of HLA-A*0201 transgenic HHD mice with recombinant lv-hTERT vector induces potent and diversified cytotoxic T lymphocyte responses that recognize in vitro murine tumor cells, which overexpress telomerase. Compared with peptide-based vaccinations, the lv-hTERT vector triggers better and more sustained CD8(+) T-cell response against self/TERT epitope in vivo. The study found that the additional use of a heterologous boosted vaccination drastically improves self/TERT-specific CD8 responses in lv-hTERT primed mice. Both primary and long-lasting self/TERT-specific CD8(+) T-cell responses induced with Iv-hTERT vector required the presence of CD4 T cells in vivo. This lv-hTERT-based active immunotherapy efficiently inhibits the growth of telomerase expressing tumors (B16/HLA-A2.1 murine melanoma) in HHD mice. These data show that targeting hTERT with lentivector is highly effective in stimulating a broad range of CD8 T-cell immunity that can be exploited for cancer immunotherapy.


Marked susceptibility of South African Helicobacter pylori strains to ciprofloxacin and amoxicillin: clinical implications.
Helicobacter pylori-associated infection is common in South Africa, as in other developing countries. Antibiotic resistance is recognised as a major cause of treatment failure. We studied the susceptibility and resistance patterns of H. pylori to guide empiric treatment and prevent the emergence of resistance. Two hundred H. pylori strains obtained from gastric biopsies of patients presenting with gastric-related morbidities attending Livingstone Hospital, Port Elizabeth, were evaluated for their susceptibility to seven antibiotics - metronidazole, clarithromycin, tetracycline, amoxicillin, gentamicin, ciprofloxacin and erythromycin. H. pylori was isolated following standard microbiology procedures, and susceptibility determined using the Kirby-Bauer disc diffusion and agar dilution methods. Comparisons of antimicrobial resistance rates with sex of the patients were determined using the chi-square test; a p-value of <0.05 was considered significant. Marked susceptibility was observed for ciprofloxacin (100%) and amoxicillin (97.5%), and good activity for clarithromycin (80%) and gentamicin (72.5%). However, marked resistance (95.5%) was observed for metronidazole. The minimal inhibitory concentration (MIC) ranged from 0.0625 microg/ml to 8 microg/ml. The lowest MIC, with a range of 0.0625 - 1 microg/ml, was recorded for ciprofloxacin, while the highest (5 - 8 microg/ml) was noted for gentamicin. Multidrug resistance was commonly encountered - a finding of clinical significance that calls for continuous surveillance of antibiograms to guide empiric treatment. We advocate the inclusion of ciprofloxacin in the treatment regimen of H. pylori infection in our study environment.


Atrial fibrillation and mitral valve repair.
Atrial fibrillation (AF) is present in 30-40% of patients presenting for mitral valve surgery. In patients undergoing mitral valve repair, the presence of AF may be associated with increased mortality and morbidity and this is also the case in patients in whom AF persists postoperatively. Advances in understanding the pathogenesis of AF led to techniques that include both mitral valve repair and ablation of AF. The concomitant surgical treatment of AF during mitral surgery has become a commonly performed procedure, which was shown to be safe and which may improve the outcome for patients. AF after mitral valve replacement is an accepted indication for anticoagulation, but the data supporting anticoagulation in patients after mitral valverepair who convert to sinus rhythm are sparse. This article reviews the available data regarding outcomes of mitral repair and how they are influenced by AF and its therapy.


Prioritization of Molecular Targets for Antimalarial Drug Discovery.
There is a shift in antimalarial drug discovery from phenotypic screening toward target-based approaches, as more potential drug targets are being validated in Plasmodium species. Given the high attrition rate and high cost of drug discovery, it is important to select the targets most likely to deliver progressible drug candidates. In this paper, we describe the criteria that we consider important for selecting targets for antimalarial drug discovery. We describe the analysis of a number of drug targets in the Malaria Drug Accelerator (MalDA) pipeline, which has allowed us to prioritize targets that are ready to enter the drug discovery process. This selection process has also highlighted where additional data are required to inform target progression or deprioritization of other targets. Finally, we comment on how additional drug targets may be identified.


Moving Beyond "Health Education": Participatory Filmmaking for Cross-Cultural Health Communication.
In the process of developing short films with women in Australian Aboriginal (Yolŋu) communities in northeast Arnhem Land, questions arose about how the content and the process of production were defined and adjusted to suit both parties. This research examines how filmmakers take roles as health educators and how Yolŋu women as the "actors" define and direct the film. It explores ways that the filmmakers tried to ensure that Yolŋu identity was maintained in a biomedical agenda through the use of storytelling in language. An important dialogue develops regarding ownership and negotiation of health information and knowledge, addressing this intersection in a way that truly characterizes the spirit of community-based participatory research. Although the filmmaking processes were initially analyzed in the context of feminist and educational empowerment theories, we conclude that Latour's (2005) theory of actor networks leads to a more coherent way to explore participatory filmmaking as a health education tool. The analysis in this work provides a framework to integrate health communication, Indigenous women's issues, and filmmaking practices. In contrasting participatory filmmaking with health promotion and ethnographic film, the importance of negotiating the agenda is revealed.


Correlates and consequences of harsh discipline for young children.
To examine the incidence, predictors, and consequences of harsh discipline in a sample of low-birth-weight children at 1 and 3 years of age. Analysis of data from the Infant Health and Development Program, an 8-site randomized clinical trial of low-birth-weight infants. The sample for analysis consisted of 715 children who were 3 years of age. The independent measurements of primary interest were the mother's hitting and scolding of her child as disciplinary practice. Analyses were run separately for boys and girls. Bivariate and logistic analyses were used to examine the predictors of the mother's hitting and scolding behavior. Multivariate analysis of variance was used to examine the consequences of the mother's harsh discipline on a child's IQ measured at age 3 years. The mother's self-report of whether she used more than 1 physical punishment in the past week, as well as an observer's report from 2 home visits of whether the mother hit or scolded the child during the 2-hour home visit. In addition, the Stanford-Binet Intelligence Scale was used to examine the consequences of persistent harsh discipline on child well-being. Findings demonstrate child, maternal, and environmental factors that might aggravate a parent's use of corporal punishment. Boys received higher amounts of harsh discipline on all outcome measures. For boys, growing up in an impoverished home was predictive of the greater likelihood of receiving harsh punishment. Using IQ at age 3 years as the outcome measure, girls were found to be vulnerable to persistent harsh discipline and lack of maternal warmth. Maternal harsh discipline in a context of low maternal warmth was associated with IQ scores for girls that are 12 points lower than the IQ scores of girls who received low punishment and high warmth.


Development of, and initial validity evidence for, the referee self-efficacy scale: a multistudy report.
The purpose of this multistudy report was to develop, and then to provide initial validity evidence for measures derived from, the Referee Self-Efficacy Scale. Data were collected from referees (N = 1609) in the United States (n = 978) and Spain (n = 631). In Study 1 (n = 512), a single-group exploratory structural equation model provided evidence for four factors: game knowledge, decision making, pressure, and communication. In Study 2 (n = 1153), multiple-group confirmatory factor analytic models provided evidence for partial factorial invariance by country, level of competition, team gender, and sport refereed. In Study 3 (n = 456), potential sources of referee self-efficacy information combined to account for a moderate or large amount of variance in each dimension of referee self-efficacy with years of referee experience, highest level refereed, physical/mental preparation, and environmental comfort, each exerting at least two statistically significant direct effects.


Electronic transport in a graphene single layer: application in amino acid sensing.
We modeled a type of field-effect transistor device based on graphene for the recognition of amino acids with a potential application in the building of a protein sequencer. The theoretical model used was a combination of density functional theory (DFT) with the non-equilibrium Green's function (NEGF) in order to describe the coherent transport in molecular devices. First, we studied the physisorption of each amino acid on a graphene sheet and we reported the adsorption energy, the adsorption distances, the equilibrium configuration and the charge transfer of ten amino acids that can be considered as representative of all of the amino acids: histidine (His), alanine (Ala), aspartic acid (Asp), tyrosine (Tyr), arginine (Arg), glutamic acid (Glu), glycine (Gly), phenylalanine (Phe), proline (Pro) and lysine (Lys). As a result, significant differences were found in the density of states (DOS) after adsorption and there was a change in the semi-metallic character of the graphene due to the lysine and arginine interactions. Furthermore, we noticed changes in the electrical characteristics of the devices, as the amino acids adsorbed onto the surface of the graphene. The curves of current vs. bias voltage (I-Vb) display a distinct response for each amino acid, i.e. the I-Vb curves produce a characteristic footprint for each amino acid. We identified a possible rectification mechanism related to the voltage profile asymmetry, where the amino acids can control the transport characteristics in the device, i.e. Lys and Phe amino acids physisorbed on graphene act as a molecular diode, where electrons can easily flow in one direction and decrease in the other. This may be promising for the prospect of biosensors: graphene could be used as an amino acid detector.


The majority of 9,729 group A streptococcus strains causing disease secrete SpeB cysteine protease: pathogenesis implications.
Group A streptococcus (GAS), the causative agent of pharyngitis and necrotizing fasciitis, secretes the potent cysteine protease SpeB. Several lines of evidence suggest that SpeB is an important virulence factor. SpeB is expressed in human infections, protects mice from lethal challenge when used as a vaccine, and contributes significantly to tissue destruction and dissemination in animal models. However, recent descriptions of mutations in genes implicated in SpeB production have led to the idea that GAS may be under selective pressure to decrease secreted SpeB protease activity during infection. Thus, two divergent hypotheses have been proposed. One postulates that SpeB is a key contributor to pathogenesis; the other, that GAS is under selection to decrease SpeB during infection. In order to distinguish between these alternative hypotheses, we performed casein hydrolysis assays to measure the SpeB protease activity secreted by 6,775 GAS strains recovered from infected humans. The results demonstrated that 84.3% of the strains have a wild-type SpeB protease phenotype. The availability of whole-genome sequence data allowed us to determine the relative frequencies of mutations in genes implicated in SpeB production. The most abundantly mutated genes were direct transcription regulators. We also sequenced the genomes of 2,954 GAS isolates recovered from nonhuman primates with experimental necrotizing fasciitis. No mutations that would result in a SpeB-deficient phenotype were identified. Taken together, these data unambiguously demonstrate that the great majority of GAS strains recovered from infected humans secrete wild-type levels of SpeB protease activity. Our data confirm the important role of SpeB in GAS pathogenesis and help end a long-standing controversy.


Adapalene/Benzoyl Peroxide Gel 0.3%/2.5%: Effective Acne Therapy Regardless of Age or Gender.

BACKGROUND: Acne vulgaris affects a diverse group of people, and there is an increasingly wide variety of acne treatments. Because of the many options, clinicians have a better ability to individualize treatment; however, achieving optimal results relies on understanding how various agents perform in specific population segments. Fixed-combination adapalene plus benzoyl peroxide (A/BPO) is a first-line recommended acne therapy and is available in two adapalene concentrations (0.1% and 0.3%) combined with BPO 2.5%. This analysis investigated whether gender and age have an impact on either the efficacy or safety of topical A/BPO 0.3%.

METHODS: A post-hoc subanalysis was performed on data from a multicenter, randomized, double-blind, parallelgroup, 12-week study of A/BPO gel 0.3%/2.5% or vehicle gel in subjects ≥ 12 years old with moderate to severe acne vulgaris (Investigator global assessment [IGA] of 3 or 4). Efficacy measurements included achievement of an IGA of clear (0) or almost clear (1), and change in lesion counts from baseline to week 12. Safety measures included adverse events and cutaneous tolerability. The intent to treat (ITT) and safety populations were analyzed.

RESULTS: The A/BPO gel 0.3%/2.5% treatment group included 217 subjects. Among the subjects, 111 were 12-17 years old and 106 were ≥ 18 years old; 104 were male and 113 were female. A/BPO 0.3%/2.5% was safe, tolerable, and significantly superior to vehicle in success rates (IGA 0 or 1) and reduction of inflammatory/noninflammatory lesions (P≤0.05) across both age groups and genders.

CONCLUSIONS: A/BPO 0.3%/2.5% treatment achieved success and was equally effective and safe in younger vs older subjects and in males vs females. These results support the use of A/BPO 0.3%/2.5% in all subjects 12 and older.

Clinicaltrials.gov registry: (NCT01880320)

J Drugs Dermatol. 2017;16(6):582-589.
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Validation of high performance liquid chromatography-electrochemical detection methods with simultaneous extraction procedure for the determination of artesunate, dihydroartemisinin, amodiaquine and desethylamodiaquine in human plasma for application in clinical pharmacological studies of artesunate-amodiaquine drug combination.
With the expanded use of the combination of artesunate (AS) and amodiaquine (AQ) for the treatment of falciparum malaria and the abundance of products on the market, comes the need for rapid and reliable bioanalytical methods for the determination of the parent compounds and their metabolites. While the existing methods were developed for the determination of either AS or AQ in biological fluids, the current validated method allows simultaneous extraction and determination of AS and AQ in human plasma. Extraction is carried out on Supelclean LC-18 extraction cartridges where AS, its metabolite dihydroartemisinin (DHA) and the internal standard artemisinin (QHS) are separated from AQ, its metabolite desethylamodiaquine (DeAQ) and the internal standard, an isobutyl analogue of desethylamodiaquine (IB-DeAQ). AS, DHA and QHS are then analysed using Hypersil C4 column with acetonitrile-acetic acid (0.05M adjusted to pH 5.2 with 1.00M NaOH) (42:58, v/v) as mobile phase at flow rate 1.50ml/min. The analytes are detected with an electrochemical detector operating in the reductive mode. Chromatography of AQ, DeAQ and IB-DeAQ is carried out on an Inertsil C4 column with acetonitrile-KH(2)PO(4) (pH 4.0, 0.05M) (11:89, v/v) as mobile phase at flow rate 1.00ml/min. The analytes are detected by an electrochemical detector operating in the oxidative mode. The recoveries of AS, DHA, AQ and DeAQ vary between 79.1% and 104.0% over the concentration range of 50-1400ng/ml plasma. The accuracies of the determination of all the analytes are 96.8-103.9%, while the variation for within-day and day-to-day analysis are <15%. The lower limit of quantification for all the analytes is 20ng/ml and limit of detection is 8ng/ml. The method is sensitive, selective, accurate, reproducible and suited particularly for pharmacokinetic study of AS-AQ drug combination and can also be used to compare the bioavailability of different formulations, including a fixed-dose AS-AQ co-formulation.


Higher sweating rate and skin blood flow during the luteal phase of the menstrual cycle.
Evaporation by sweating is the most effective way to remove heat from the body. Sweat rates increase under both local and whole-body heat stress. Men and women differ in how they respond to heat, because sexual steroids alter resting body core temperature and the threshold for sweating and skin blood flow (SBF) during heating. The purpose of the present study was to compare local sweat rates and cutaneous vasodilatation during heat exposure in women with a regular menstrual cycle. The cutaneous vasodilatation was judged by measuring the SBF. Eight female and nine male subjects participated in this study, and their age range was 24-29 years. Female subjects were tested twice throughout one full menstrual cycle: once during the middle follicular phases and once during the luteal phase. Subjects remained in a temperature-regulated room at 41°C and 21% of relative humidity for 40 minutes. Sweat rate was recorded from the forehead, forearm, and thigh, and skin temperature and SBF were measured on the thigh and forehead. We found that the sweating rate and SBF were greater in the luteal phase compared to follicular phase (p<0.05). Since both SBF and sweating were controlled by the sympathetic nerve system, the sympathetic outflow was greater during whole body heat exposure in the luteal phase. In contrast, for men, there was no significant difference in sweating and SBF over the same calendar period (p>0.05). We propose the enhanced sympathetic activity in the luteal phase with a regular menstrual cycle.


Vital pulp therapy using calcium-enriched mixture: An evidence-based review.
Worldwide, casecontrol studies have revealed that the treatment outcomes of root canal therapy (RCT) are generally favorable; however, the overall epidemiological success rate of RCT in the general population is relatively low. On the other hand, vitality of dental pulp is a key factor in the long-term prognosis of permanent teeth; in recent years, vital pulp therapy (VPT) has received significant consideration as it has been revealed that the inflamed pulp has the potential to heal. In this review article, the current best evidence with regard to VPT using calcium-enriched mixture (CEM) cement in human permanent/primary teeth is discussed. A strategy based on a search using keywords for CEM cement as well as VPT was applied.


An expressive three-mode principal components model for gender recognition.
We present a three-mode expressive-feature model for recognizing gender (female, male) from point-light displays of walking people. Prototype female and male walkers are initially decomposed into a subspace of their three-mode components (posture, time, and gender). We then apply a weight factor to each point-light trajectory in the basis representation to enable adaptive, context-based gender estimations. The weight values are automatically learned from labeled training data. We present experiments using physical (actual) and perceived (from perceptual experiments) gender labels to train and test the system. Results with 40 walkers demonstrate greater than 90% recognition for both physically and perceptually labeled training examples. The approach has a greater flexibility over standard squared-error gender estimation to successfully adapt to different matching contexts.


Cooee bitumen. II. Stability of linear asphaltene nanoaggregates.
Asphaltene and smaller aromatic molecules tend to form linear nanoaggregates in bitumen. Over the years bitumen undergoes chemical aging and during this process, the size of the nanoaggregate increases. This increase is associated with an increase in viscosity and brittleness of the bitumen, eventually leading to road deterioration. This paper focuses on understanding the mechanisms behind nanoaggregate size and stability. We used molecular dynamics simulations to quantify the probability of having a nanoaggregate of a given size in the stationary regime. To model this complicated behavior, we chose first to consider the simple case where only asphaltene molecules are counted in a nanoaggregate. We used a master equation approach and a related statistical mechanics model. The linear asphaltene nanoaggregates behave as a rigid linear chain. The most complicated case where all aromatic molecules are counted in a nanoaggregate is then discussed. The linear aggregates where all aromatic molecules are counted seem to behave as a flexible linear chain.


Lipid-lowering therapy: who can benefit?
Cardiovascular disease (CVD) is the leading cause of death in the US. Despite the decline in CVD-associated mortality rates in recent years, coronary heart disease (CHD) still causes one in every six deaths in this country. Because most CHD risk factors are modifiable (eg, smoking, hypertension, obesity, onset of type 2 diabetes, and dyslipidemia), cardiovascular risk can be reduced by timely and appropriate interventions, such as smoking cessation, diet and lifestyle changes, and lipid-modifying therapy. Dyslipidemia, manifested by elevated low-density lipoprotein cholesterol (LDL-C), is central to the development and progression of atherosclerosis, which can be silent for decades before triggering a first major cardiovascular event. Consequently, dyslipidemia has become a primary target of intervention in strategies for the prevention of cardiovascular events. The guidelines of the Adult Treatment Panel (ATP) III, updated in 2004, recommend therapeutic lifestyle changes and the use of lipid-lowering medications, such as statins, to achieve specific LDL-C goals based on a person's global cardiovascular risk. For high-risk individuals, such as patients with CHD and diabetic patients without CHD, an LDL-C target of < 100 mg/dL is recommended, and statin therapy should be considered to help patients achieve this goal. If correctly dosed in appropriate patients, currently approved statins are generally safe and provide significant cardiovascular benefits in diverse populations, including women, the elderly, and patients with diabetes. A recent primary prevention trial also showed that statins benefit individuals traditionally not considered at high risk of CHD, such as those with no hyperlipidemia but elevated C-reactive protein. Additional evidence suggests that statins may halt or slow atherosclerotic disease progression. Recent evidence confirms the pivotal role of statins in primary and secondary prevention.


Hormone replacement therapy and stroke.
Stroke is the third most common cause of death in women and a major cause of disability. Stroke occurs in older age in women compared with men. High premenopausal estrogen concentrations in women are thought to be protective against stroke and cardiovascular disease. Estrogens are essential for normal reproductive function and they exert complex and diverse non reproductive actions on multiple tissues such as neuroprotective effects, vasodilatation, improved vascular reactivity, antithrombotic effects and lipid lowering effects. After menopause estrogen concentrations are depleted and in the past estrogen replacement therapy was considered as a potential protective agent against both cardiovascular disease and stroke. Although the use of hormone therapy was originally associated with a reduction in the risk of heart disease by about 50% in observational studies, the results regarding stroke have been less clear. In order to investigate the effect of hormone therapy on stroke risk, randomized controlled trials of cardio-and/or cerebrovascular-disease prevention in women with established heart disease have been designed. The Heart Estrogen-Progestin Replacement Study included stroke as secondary outcome. This study did not show any differences in myocardial infarction (MI) or coronary death (HR 0.99; 95%CI 0.80-1.22) and in stroke rate. In another study, the Women Estrogen Stroke Trial, 17 beta estradiol 1 mg/placebo was administered to women with previous ischemic stroke or transient ischaemic attack (TIA) having a mean age 71. No differences in stroke rate (RR 1.1; 95% CI 0.8-1.4) and in mortality rate (RR 1.2; 95% CI 0.8-1.8) were found, while a trend showing an increased rate of fatal strokes (RR 2.9; 95% CI 0.9-9.0) and for more severe non-fatal strokes (% patients with final National Institutes of Health Stroke Scale (NIHSS) 0-1: 19 % vs. 33%; p = 0.12) was observed. The Women's Health Initiative, a primary prevention study, where conjugated equine estrogen (CEE) plus medroxyprogesterone acetate/placebo was utilized, was stopped because of an excess in breast cancer and increased stroke rates (RR 1.4; 95% CI 1.1-1.8). Recently, a meta-analysis including 39,769 women participating in 28 trials has been published. Twelve studies were of secondary prevention and the overall stroke rate was 2%. In the hormone replacement therapy (HRT) arm there was a 29% increased rate of ischemic stroke (Number Needed to Harm, NNH:147). Furthermore, a 56% increased rate of death or dependency after stroke and a tendency of more fatal stroke were observed. Additionally, a higher stroke risk was reported in the first year of treatment. There seems to be no indication for hormone replacement therapy in the prevention of stroke in women. Further studies are needed to discover why estrogens have different effects on the heart and brain. Conventional risk-factors which could increase the risk of estrogen therapy need to be identified and as well as more restrictive inclusion and exclusion criteria such as coagulation parameters and intimal thickness should be adopted before new randomized trials are started.


The potentiation of myeloperoxidase activity by the glycosaminoglycan-dependent binding of myeloperoxidase to proteins of the extracellular matrix.
Myeloperoxidase (MPO) is an abundant hemoprotein expressed by neutrophil granulocytes that is recognized to play an important role in the development of vascular diseases. Upon degranulation from circulating neutrophil granulocytes, MPO binds to the surface of endothelial cells in an electrostatic-dependent manner and undergoes transcytotic migration to the underlying extracellular matrix (ECM). However, the mechanisms governing the binding of MPO to subendothelial ECM proteins, and whether this binding modulates its enzymatic functions are not well understood. We investigated MPO binding to ECM derived from aortic endothelial cells, aortic smooth muscle cells, and fibroblasts, and to purified ECM proteins, and the modulation of these associations by glycosaminoglycans. The oxidizing and chlorinating potential of MPO upon binding to ECM proteins was tested. MPO binds to the ECM proteins collagen IV and fibronectin, and this association is enhanced by the pre-incubation of these proteins with glycosaminoglycans. Correspondingly, an excess of glycosaminoglycans in solution during incubation inhibits the binding of MPO to collagen IV and fibronectin. These observations were confirmed with cell-derived ECM. The oxidizing and chlorinating potential of MPO was preserved upon binding to collagen IV and fibronectin; even the potentiation of MPO activity in the presence of collagen IV and fibronectin was observed. Collectively, the data reveal that MPO binds to ECM proteins on the basis of electrostatic interactions, and MPO chlorinating and oxidizing activity is potentiated upon association with these proteins. Our findings provide new insights into the molecular mechanisms underlying the interaction of MPO with ECM proteins.


Sotagliflozin for patients with type 2 diabetes: A systematic review and meta-analysis.
To assess the efficacy and safety of sotagliflozin in patients with type 2 diabetes. We searched Medline, Embase, the Cochrane Library, and grey literature sources up to August 2021 for randomized controlled trials (RCTs) that compared sotagliflozin with placebo or other antidiabetic agents in patients with type 2 diabetes. Our primary outcome was change in HbA1c from baseline. We additionally assessed three secondary efficacy and 15 safety outcomes. We synthesized data using weighted mean differences (WMDs) and odds ratios (ORs), along with 95% confidence intervals (CIs). We included 11 RCTs comprising 16 411 subjects in the meta-analysis. Compared with placebo, sotagliflozin reduced HbA1c (WMD -0.42%, 95% CI -0.56 to -0.29), body weight (WMD -1.33 kg, 95% CI -1.57 to -1.09), and systolic blood pressure (WMD -2.44 mmHg, 95% CI -2.81 to -2.07). No difference was evident against other active comparators. Sotagliflozin reduced myocardial infarction (OR 0.72, 95% CI 0.54 to 0.97) and heart failure (OR 0.68, 95% CI 0.58 to 0.79) compared with placebo, and had a neutral effect on all-cause mortality, cardiovascular mortality, and stroke. Treatment with sotagliflozin was safe regarding the incidence of serious adverse events, hypoglycaemia, and diabetic ketoacidosis. Nevertheless, it was associated with an increased incidence of diarrhoea, genital infections, and volume depletion events. Sotagliflozin reduces blood glucose, body weight, and systolic blood pressure, and demonstrates a beneficial effect on heart failure and myocardial infarction. Its overall safety profile is comparable with other sodium-glucose co-transporter-2 inhibitors.


Highly efficient 1 GHz repetition-frequency femtosecond Yb3+:KY(WO4)2 laser.
We present a highly efficient, diode-pumped, femtosecond Yb3+:KY(WO4)2 (Yb:KYW) laser operating at a 1.024 GHz repetition rate. The output was centered at a wavelength of 1042 nm and had a bandwidth of 3.8 nm, leading to transform-limited pulses with durations of 278 fs determined by fringe-resolved autocorrelation measurements. The optical-to-optical conversion efficiency and slope efficiency were 61% and 69%, respectively, and the relative intensity noise was <0.1%.


Differential erbB signaling in astrocytes from the cerebral cortex and the hypothalamus of the human brain.
Studies in rodents have shown that astroglial erbB tyrosine kinase receptors are key regulatory elements in neuron-glia communication. Although both astrocytes and deregulation of erbB functions have been implicated in the pathogenesis of many common human brain disorders, erbB signaling in native human brain astrocytes has never been explored. Taking advantage of our ability to perform primary cultures from the cortex and the hypothalamus of human fetuses, we conducted a thorough analysis of erbB signaling in human astrocytes. We showed that human cortical astrocytes express erbB1, erbB2, and erbB3, whereas human hypothalamic astrocytes express erbB1, erbB2, and erbB4 receptors. Ligand-dependent activation of different erbB receptor heterodimeric complexes in these two populations of astrocytes translated into different morphological and proliferative responses. Although morphological plasticity was more pronounced in hypothalamic astrocytes than in cortical astrocytes, the former showed a lower mitogenic potential. Decreasing erbB4 expression via siRNA-mediated gene knockdown revealed that erbB4 constitutively restrains basal proliferative activity in hypothalamic astrocytes. We further show that treatment of human astrocytes with a protein kinase C activator results in rapid tyrosine phosphorylation of erbB receptors that involves cleavage of endogenous membrane bound erbB ligands by metalloproteinases. Together, these results indicate that erbB signaling in primary human brain astrocytes is functional, region-specific, and can be activated in a paracrine and/or autocrine manner. In addition, by revealing that some aspects of astroglial erbB signaling are different between human and rodents, our results provide a molecular framework to explore the potential involvement of astroglial erbB signaling deregulation in human brain disorders.


Glial cell line-derived neurotrophic factor-secreting genetically modified human bone marrow-derived mesenchymal stem cells promote recovery in a rat model of Parkinson's disease.
Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive degeneration of nigrostriatal dopaminergic (DA) neurons. The therapeutic potential of glial cell line-derived neurotrophic factor (GDNF), the most potent neurotrophic factor for DA neurons, has been demonstrated in many experimental models of PD. However, chronic delivery of GDNF to DA neurons in the brain remains an unmet challenge. Here, we report the effects of GDNF-releasing Notch-induced human bone marrow-derived mesenchymal stem cells (MSC) grafted into striatum of the 6-hydroxydopamine (6-OHDA) progressively lesioned rat model of PD. Human MSC, obtained from bone marrow aspirates of young, healthy adult volunteers, were transiently transfected with the intracellular domain of the Notch1 gene (NICD) to generate SB623 cells. SB623 cells expressing GDNF and/or humanized Renilla green fluorescent protein (hrGFP) following lentiviral transduction or nontransduced cells were stereotaxically placed into rat striatum 1 week after a unilateral partial 6-OHDA striatal lesion. At 4 weeks, rats that had received GDNF-transduced SB623 cells had significantly decreased amphetamine-induced rotation compared with control rats, although this effect was not observed in rats that received GFP-transduced or nontransduced SB623 cells. At 5 weeks, rejuvenated tyrosine hydroxylase-immunoreactive (TH-IR) fibers that appeared to be host DA axons were observed in and around grafts. This effect was more prominent in rats that received GDNF-secreting cells and was not observed in controls. These observations suggest that human bone-marrow derived MSC, genetically modified to secrete GDNF, hold potential as an allogeneic or autologous stem cell therapy for PD.


Multicellular tumor invasion and plasticity in biomimetic materials.
Cancer cell invasion through the extracellular matrix is associated with metastatic spread and therapeutic resistance. In carcinomas, the detachment and dissemination of individual cells has been associated with an epithelial-mesenchymal transition, but tumors can also invade using collective, multicellular phenotypes. This malignant tumor progression is also associated with alignment and stiffening of the surrounding extracellular matrix. Historically, tumor invasion has been investigated using 2D monolayer culture, small animal models or patient histology. These assays have been complemented by the use of natural biomaterials such as reconstituted basement membrane and collagen I. More recently, engineered materials with well-defined physical, chemical and biomolecular properties have enabled more controlled microenvironments. In this review, we highlight recent developments in multicellular tumor invasion based on microfabricated structures or hydrogels. We emphasize the role of interfacial geometries, biomaterial stiffness, matrix remodeling, and co-culture models. Finally, we discuss future directions for the field, particularly integration with precision measurements of biomaterial properties and single cell heterogeneity, standardization and scale-up of these platforms, as well as integration with patient-derived samples.


Mutational analysis of Hsp90 function: interactions with a steroid receptor and a protein kinase.
Hsp90 is a protein chaperone whose functions are focused on a specific set of target proteins. The nature of Hsp90's interactions with these proteins is poorly understood. To provide tools for examining these interactions, we have isolated eight broadly distributed temperature-sensitive (ts) point mutations in the Hsp90 gene (HSP82) of Saccharomyces cerevisiae. The mutants fall into two distinct classes. One has a classic ts phenotype, with nearly wild-type activity at 25 degrees C and a precipitous loss of function at 34 degrees C. The remaining seven mutants, in contrast, cause a general reduction in Hsp90 function and are ts because they do not provide the high level of function required for growth at high temperatures. The effects of these mutants on two target proteins, a transcription factor (glucocorticoid receptor) and a tyrosine kinase (pp60v-src), provided several insights on Hsp90 function. First, Hsp90 is not only required to help the glucocorticoid receptor achieve a hormone-activable state, it is continuously required to maintain that state. Second, Hsp90's function in the maturation of pp60v-src involves separable roles in protein accumulation and kinase activation. Thus, Hsp90 is an integral component of both the steroid receptor and kinase signaling pathways. Finally, all eight point mutants affect the activation of both the glucocorticoid receptor and pp60v-src, indicating that Hsp90 promotes the activity of these very different target proteins through common mechanisms.


[Evaluation of gefitinib plus radiotherapy in non-small-cell lung cancer patients with brain metastases].
To evaluate the efficacies of gefitinib plus radiotherapy in the treatment of brain metastases in non-small-cell lung carcinoma (NSCLC) patients. A retrospective analysis was conducted for 161 NSCLC patients with brain metastases treated in Xinqiao Hospital from January 2001 to January 2010. And 38 patients aged 38 - 77 years old received the combined regimen of gefitinib plus radiotherapy. It consisted of synchronically practicing general or stereotactic brain radiotherapy and an oral intake of gefitinib (250 mg, QD for at least 8 consecutive weeks). The efficacies and toxicity were evaluated at Week 12 after the initial treatment. A total of 123 patients aged 37 - 76 years old undergoing whole brain or stereotactic radiotherapy were used as control. χ(2) test between two groups was carried out to evaluate the objective response rate (ORR), disease control rate (DCR), brain metastasis related symptoms and III-IV degree of toxicity. Non-parametric rank tests were performed to compare the U.S. Eastern Cooperative Oncology Group (ECOG) performance status score between two groups. In the combination therapy group, the levels of ORR and DCR were significantly higher than those in the conventional treatment group (31.6%, 78.9% vs 15.4%, 60.2%). The differences were statistically significant (χ(2) = 4.859, P = 0.027 and χ(2) = 4.479, P = 0.034); significant difference existed in brain metastasis-related symptoms between two groups (χ(2) = 4.612, P = 0.037); the ECOG scores were evaluated in the combination therapy group. And they were as follows: 0 - 1 (n = 18), 2 (n = 11), 3 - 4 (n = 9) at pre-treatment vs 0 - 1 (n = 27), 2 (n = 6), 3 - 4 (n = 5) at post-treatment. The ECOG score significantly improved after treatment (Z = -2.012, P = 0.044). Regarding the III-IV degree of toxicity, the combination therapy group had 4 patients with acne-like rash and it was significantly higher than that in the conventional therapy group (n = 0) (P = 0.003). But no difference existed in the occurrence of fatigue, nausea, vomiting, diarrhea and myelosuppression. The combined regimen of gefitinib plus radiotherapy can improve the therapeutic efficacies of brain metastases and enhance the quality-of-life in NSCLC patients, side effects are tolerable.


Dispersion of polarization coupling, localized and collective plasmon modes in a metallic photonic crystal mapped by Mueller Matrix Ellipsometry.
We report a spectroscopic Mueller matrix experimental study of a plasmonic photonic crystal consisting of gold hemispheroidal particles (lateral radius 54 nm, height 25 nm) arranged on a square lattice (lattice constant 210 nm) and supported by a glass substrate. Strong polarization coupling is observed for ultraviolet wavelengths and around the surface plasmon resonance for which the off-block-diagonal Mueller matrix elements show pronounced anisotropies. Due to the Rayleigh anomalies, the block-diagonal Mueller matrix elements produce a direct image of the Brillouin Zone (BZ) boundaries of the lattice and resonances are observed at the M-point in the first and at the X-point in the second BZ. These elements show also the dispersion of the localized surface plasmon resonance.


Transposon display for active DNA transposons in rice.
Transposon display (TD) is a powerful technique to identify the integration site of transposons in gene tagging as a functional genomic tool for elucidating gene function. Although active endogenous DNA transposons have been used extensively for gene tagging in maize, only two active endogenous DNA transposons in rice have been identified, the 0.43-kb element mPing of the MITE family and the 0.6-kb nDart element of the hAT family. The nDart transposition was shown to be induced by crossing with a line containing its autonomous element aDart and stabilized by segregating aDart under natural growth conditions, while mPing-related elements were shown to transpose in cultured cells, plants regenerated from an anther culture, and gamma-ray-irradiated plants. No somaclonal variation should occur in nDart-promoted gene tagging because no tissue culture was involved in nDart activation. As an initial step to develop an effective tagging system using nDart in rice, we tried to visualize GC-rich nDart-related elements comprising 18 nDart-related sequences of 0.6-kb and 63 nDart-related elements longer than 2 kb in Nipponbare by TD. Comparing the observed bands in TD with the anticipated virtual bands of the nDart-related elements based upon the available rice genome sequence, we have improved our TD protocol by optimizing the PCR amplification conditions and are able to visualize approximately 87% of the anticipated bands produced from the nDart-related elements. To compare the visualization efficiency of these nDart-related elements with that of 50 mPing elements and a unique Ping sequence in Nipponbare, we also tried to visualize the mPing-related elements; all mPing-related elements are easily visualized. Based on these results, we discuss the parameters affecting the visualization efficiencies of these rice DNA transposons. We also discuss the utilization of nDart elements in gene tagging for functional genomics in rice.


Biohorizons: An eConference to assess human biology in large, first-year classes.
We detail the design, implementation and evaluation of an eConference entitled "Biohorizons", using a presage-process-product model to describe the development of an eLearning community. Biohorizons was a summative learning and assessment task aiming to introduce large classes of first-year Human Biology students to the practices of professional scientists. It was implemented in semester 1 for students enrolled in Pharmacy and Human Movement Studies degree programs, and in semester 2, for Science students. Pairs of students selected a topic of interest in Human Biology, registered into on-line clusters, then developed and wrote a short scientific paper and accompanying PowerPoint presentation. They then individually participated in an online Discussion. All three tasks were assessed using standards-referenced assessment rubrics. Learning was supported by eTutors, working in asynchronous mode. Biohorizons was evaluated by analyzing student achievement data, surveys and focus group interviews. Most students were able to achieve high academic standards (global mean scores for semester 1, 85-96%; semester 2, 81-90%). Student evaluations support: 1) the successful integration of eLearning into large classes of Human Biology, 2) the engagement of first-year students through collaborative learning, and 3) the fostering of learning through challenging assessment relevant to the core practices of professional scientists.


Isolation of Bartonella washoensis from a dog with mitral valve endocarditis.
We report the first documented case of Bartonella washoensis bacteremia in a dog with mitral valve endocarditis. B. washoensis was isolated in 1995 from a human patient with cardiac disease. The main reservoir species appears to be ground squirrels (Spermophilus beecheyi) in the western United States. Based on echocardiographic findings, a diagnosis of infective vegetative valvular mitral endocarditis was made in a spayed 12-year-old female Doberman pinscher. A year prior to presentation, the referring veterinarian had detected a heart murmur, which led to progressive dyspnea and a diagnosis of congestive heart failure the week before examination. One month after initial presentation, symptoms worsened. An emergency therapy for congestive heart failure was unsuccessfully implemented, and necropsy evaluation of the dog was not permitted. Indirect immunofluorescence tests showed that the dog was strongly seropositive (titer of 1:4,096) for several Bartonella antigens (B. vinsonii subsp. berkhoffii, B. clarridgeiae, and B. henselae), highly suggestive of Bartonella endocarditis. Standard aerobic and aerobic-anaerobic cultures were negative. However, a specific blood culture for Bartonella isolation grew a fastidious, gram-negative organism 7 days after being plated. Phenotypic and genotypic characterizations of the isolate, including partial sequencing of the citrate synthase (gltA), groEL, and 16S rRNA genes, indicated that this organism was identical to B. washoensis. The dog was seronegative for all tick-borne pathogens tested (Anaplasma phagocytophilum, Ehrlichia canis, and Rickettsia rickettsii), but the sample was highly positive for B. washoensis (titer of 1:8,192) and, according to indirect immunofluorescent-antibody assay, weakly positive for phase II Coxiella burnetii infection.


Changes in absorptive and peptide hydrolase activities in rat small intestine after administration of 5-fluorouracil.
1. Glucose absorption, water absorption and dipeptide hydrolase activities have been determined in isolated rat small intestine at 1, 3, 5 and 21 days after a single intraperitoneal injection of 5-fluorouracil. 2. Absorption rates and enzyme activities were elevated 1 day after treatment, but were reduced to 40% of control values at 3 and 5 days. Changes were seen regardless of whether absorption was expressed per unit length or per unit dry weight of intestine. 3. There were highly significant positive correlations between glucose or water absorption rates and peptidase activities, especially in proximal jejunum. The most significant correlation was observed between water absorption rate and jejunal L-Leu-Gly hydrolase activity. 4. Malabsorption may account for some of the gastrointestinal side effects associated with treatment with 5-fluorouracil. Enzyme measurements may be useful as an index of intestinal function.


ERK1/2 blockade prevents epithelial-mesenchymal transition in lung cancer cells and promotes their sensitivity to EGFR inhibition.
Overcoming cellular mechanisms of de novo and acquired resistance to drug therapy remains a central challenge in the clinical management of many cancers, including non-small cell lung cancer (NSCLC). Although much work has linked the epithelial-mesenchymal transition (EMT) in cancer cells to the emergence of drug resistance, it is less clear where tractable routes may exist to reverse or inhibit EMT as a strategy for drug sensitization. Here, we demonstrate that extracellular signal-regulated kinase (ERK) 1/2 (mitogen-activated protein kinase 3/1, MAPK3/1) signaling plays a key role in directing the mesenchymal character of NSCLC cells and that blocking ERK signaling is sufficient to heighten therapeutic responses to EGF receptor (EGFR) inhibitors. MEK1/2 (MAPKK1/2) inhibition promoted an epithelial phenotype in NSCLC cells, preventing induction of EMT by exogenous TGF-β. Moreover, in cells exhibiting de novo or acquired resistance to the EGFR inhibitor gefitinib, MEK inhibition enhanced the sensitivity to gefitinib and slowed cell migration. These effects only occurred, however, if MEK was inhibited for a period sufficient to trigger changes in EMT marker expression. Consistent with these findings, changes in EMT phenotypes and markers were also induced by the expression of mutant KRAS in a MEK-dependent manner. Our results suggest that prolonged exposure to MEK or ERK inhibitors may not only restrain EMT but also overcome naïve or acquired resistance of NSCLC to EGFR-targeted therapy in the clinic.


Elements controlling follicular expression of the s36 chorion gene during Drosophila oogenesis.
An 84-bp proximal regulatory protein (PRR) of the Drosophila melanogaster s36 chorion gene is sufficient for directing proper temporal and spatial expression of a reporter gene in three domains of the follicle: anterior, posterior, and main body. Here we show that the fidelity of PRR-directed s36 expression is dependent on the proper dorsal-ventral differentiation of the follicular epithelium, which requires the Drosophila epidermal growth factor receptor homolog. Transgenic analysis of site-directed mutants of the PRR suggests that s36 expression is regulated by the concerted action of multiple positive activators. Several cis-acting transcriptional elements have been identified: some appear to function in a quantitative manner, while others either are essential or appear to regulate expression in particular spatial domains. The approximate locations of these regulatory elements have been defined; some map within sequences that are strongly conserved in widely divergent dipteran species. In fact, the PRR analog of the medfly Ceratitis capitata Ccs36 gene directs expression in a manner similar to the D. melanogaster s36 PRR. We propose a model for transcriptional regulation of s36 based on the prechoriogenic polarization of the follicular epithelium that surrounds the developing egg chamber.


Assessing differential attrition in clinical trials: self-monitoring of oral anticoagulation and type II diabetes.
Analyzing drop out rates and when they occur may give important information about the patient characteristics and trial characteristics that affect the overall uptake of an intervention. We searched Medline and the Cochrane library from the beginning of the databases to May 2006 for published systematic reviews that compared the effects of self-monitoring (self-testing) or self-management (self-testing and self-dosage) of oral anticoagulation or self-monitored blood glucose in type 2 diabetics who were not using insulin. We assessed all study withdrawals pre-randomization and post randomization and sought information on the reasons for discontinuation of all participants.To measure the differential between groups in attrition we used the relative attrition (RA), which is equivalent to relative risk but uses attrition as the outcome (i.e. attrition in intervention group/attrition in control group). We determined the percentage drop outs for control and intervention groups and used DerSimonian and Laird random effects models to estimate a pooled relative attrition. L'abbe type plots created in R (version 2.0.2) were used to represent the difference in the relative attrition among the trials with 95% confidence areas and weights derived from the random effects model. With self-monitoring of blood glucose in type 2 diabetes, attrition ranged from 2.3% to 50.0% in the intervention groups and 0% to 40.4% in the control groups. There was no significant difference between the intervention and control, with an overall RA of 1.18 [95% CI, 0.70-2.01]. With self-monitoring of oral anticoagulation attrition ranged from 0% to 43.2% in the intervention groups and 0% to 21.4% in the control group. The RA was significantly greater in the intervention group, combined RA, 6.05 [95% CI, 2.53-14.49]. This paper demonstrates the use of relative attrition as a new tool in systematic review methodology which has the potential to identify patient, intervention and trial characteristics which influences attrition in trials.


Optimal screening of children with acute malnutrition requires a change in current WHO guidelines as MUAC and WHZ identify different patient groups.
Timely treatment of acute malnutrition in children <5 years of age could prevent >500,000 deaths annually. Screening at community level is essential to identify children with malnutrition. Current WHO guidelines for community screening for malnutrition recommend a Mid Upper Arm Circumference (MUAC) of <115 mm to identify severe acute malnutrition (SAM). However, it is currently unclear how MUAC relates to the other indicator used to define acute malnutrition: weight-for-height Z-score (WHZ). Secondary data from >11,000 Cambodian children, obtained by different surveys between 2010 and 2012, was used to calculate sensitivity and ROC curves for MUAC and WHZ. The secondary analysis showed that using the current WHO cut-off of 115 mm for screening for severe acute malnutrition over 90% of children with a weight-for-height z-score (WHZ) <-3 would have been missed. Reversely, WHZ<-3 missed 80% of the children with a MUAC<115 mm. The current WHO cut-off for screening for SAM should be changed upwards from the current 115 mm. In the Cambodian data-set, a cut-off of 133 mm would allow inclusion of >65% of children with a WHZ<-3. Importantly, MUAC and WHZ identified different sub-groups of children with acute malnutrition, therefore these 2 indicators should be regarded as independent from each other. We suggest a 2-step model with MUAC used a screening at community level, followed by MUAC and WHZ measured at a primary health care unit, with both indicators used independently to diagnose severe acute malnutrition. Current guidelines should be changed to reflect this, with treatment initiated when either MUAC <115 mm or WHZ<-3.


Advances in swine biomedical model genomics.
This review is a short update on the diversity of swine biomedical models and the importance of genomics in their continued development. The swine has been used as a major mammalian model for human studies because of the similarity in size and physiology, and in organ development and disease progression. The pig model allows for deliberately timed studies, imaging of internal vessels and organs using standard human technologies, and collection of repeated peripheral samples and, at kill, detailed mucosal tissues. The ability to use pigs from the same litter, or cloned or transgenic pigs, facilitates comparative analyses and genetic mapping. The availability of numerous well defined cell lines, representing a broad range of tissues, further facilitates testing of gene expression, drug susceptibility, etc. Thus the pig is an excellent biomedical model for humans. For genomic applications it is an asset that the pig genome has high sequence and chromosome structure homology with humans. With the swine genome sequence now well advanced there are improving genetic and proteomic tools for these comparative analyses. The review will discuss some of the genomic approaches used to probe these models. The review will highlight genomic studies of melanoma and of infectious disease resistance, discussing issues to consider in designing such studies. It will end with a short discussion of the potential for genomic approaches to develop new alternatives for control of the most economically important disease of pigs, porcine reproductive and respiratory syndrome (PRRS), and the potential for applying knowledge gained with this virus for human viral infectious disease studies.


Comparison of a User-Centered Design, Self-Management App to Existing mHealth Apps for Persons Living With HIV.
There is preliminary evidence that mobile health (mHealth) apps are feasible, attractive, and an effective platform for the creation of self-management tools for persons living with HIV (PLWH). As a foundation for the current study, we conducted formative research using focus groups, participatory design sessions, and usability evaluation methods to inform the development of a health management app for PLWH. The formative research resulted in identification of the following functional requirements of a mHealth app for self-management: (1) communication between providers and peers, (2) medication reminders, (3) medication log, (4) lab reports, (5) pharmacy information, (6) nutrition and fitness, (7) resources (eg, social services, substance use, video testimonials), (8) settings, and (9) search function. The purpose of this study was to conduct an ecological review of the existing apps for PLWH and to compare the functionality of existing apps with the app specifications identified in our formative work. We searched two mobile app stores (Google Play and iTunes) and found a total of 5606 apps. We reviewed the apps, narrowed our search terms, and found a total of 112 apps. Of these, we excluded 97 (86.6%) apps that were either not in English (10/112, 8.9%), not HIV focused (32/112, 28.9%), or focused only on HIV prevention (2/112, 7.8%); targeted health care providers (26/112, 23.2%); provided information only on conference schedules and events (7/112, 6.3%), fundraisers (7/112, 6.3%), specific clinics (7/112, 6.3%), international or narrow local resources (3/112, 2.7%); or were identified in the first search but were no longer on the market at the next review (4/112, 3.6%). The 15 apps meeting inclusion criteria were then evaluated for inclusion of the nine functionalities identified in our earlier work. Of the 15 apps that we included in our final review, none had all of the functionalities that were identified in our formative work. The apps that we identified included the following functionalities: communication with providers and/or peers (4/15, 27%), medication reminders (6/15, 40%), medication logs (7/15, 47%), lab reports (5/15, 33%), pharmacy information (4/15, 27%), resources (7/15, 47%), settings (11/15, 73%), and search function (6/15, 40%). No apps included nutrition or fitness information. Currently, there are only a small number of apps that have been designed for PLWH to manage their health. Of the apps that are currently available, none have all of the desired functionalities identified by PLWH and experts in our formative research. Findings from this work elucidate the need to develop and evaluate mobile apps that meet PLWH's desired functional specifications.


Changes in mumps virus gene sequence associated with variability in neurovirulent phenotype.
Mumps virus is highly neurotropic and, prior to widespread vaccination programs, was the major cause of viral meningitis in the United States. Nonetheless, the genetic basis of mumps virus neurotropism and neurovirulence was until recently not understood, largely due to the lack of an animal model. Here, nonneurovirulent (Jeryl Lynn vaccine) and highly neurovirulent (88-1961 wild type) mumps virus strains were passaged in human neural cells or in chicken fibroblast cells with the goal of neuroadapting or neuroattenuating the viruses, respectively. When tested in our rat neurovirulence assay against the respective parental strains, a Jeryl Lynn virus variant with an enhanced propensity for replication (neurotropism) and damage (neurovirulence) in the brain and an 88-1961 wild-type virus variant with decreased neurotropic and neurovirulent properties were recovered. To determine the molecular basis for the observed differences in neurovirulence and neuroattenuation, the complete genomes of the parental strains and their variants were fully sequenced. A comparison at the nucleotide level associated three amino acid changes with enhanced neurovirulence of the neuroadapted vaccine strain: one each in the nucleoprotein, matrix protein, and polymerase and three amino acid changes with reduced neurovirulence of the neuroattenuated wild-type strain: one each in the fusion protein, hemagglutinin-neuraminidase protein, and polymerase. The potential role of these amino acid changes in neurotropism, neurovirulence, and neuroattenuation is discussed.


Reactive oxygen species regulate hypoxia-inducible factor 1alpha differentially in cancer and ischemia.
In exercise, as well as cancer and ischemia, hypoxia-inducible factor 1 (HIF1) transcriptionally activates hundreds of genes vital for cell homeostasis and angiogenesis. While potentially beneficial in ischemia, upregulation of the HIF1 transcription factor has been linked to inflammation, poor prognosis in many cancers, and decreased susceptibility of tumors to radiotherapy and chemotherapy. Considering HIF1's function, HIF1alpha protein and its hydroxylation cofactors look increasingly attractive as therapeutic targets. Independently, antioxidants have shown promise in lowering the risk of some cancers and improving neurological and cardiac function following ischemia. The mechanism of how different antioxidants and reactive oxygen species influence HIF1alpha expression has drawn interest and intense debate. Here we present an experimentally based computational model of HIF1alpha protein degradation that represents how reactive oxygen species and antioxidants likely affect the HIF1 pathway differentially in cancer and ischemia. We use the model to demonstrate effects on HIF1alpha expression from combined doses of five potential therapeutically targeted compounds (iron, ascorbate, hydrogen peroxide, 2-oxoglutarate, and succinate) influenced by cellular oxidation-reduction and involved in HIF1alpha hydroxylation. Results justify the hypothesis that reactive oxygen species work by two opposite ways on the HIF1 system. We also show how tumor cells and cells under ischemic conditions would differentially respond to reactive oxygen species via changes to HIF1alpha expression over the course of hours to days, dependent on extracellular hydrogen peroxide levels and largely independent of initial intracellular levels, during hypoxia.


1H-MRS in autism spectrum disorders: a systematic meta-analysis.
We conducted a systematic review and meta-analysis of proton magnetic resonance spectroscopy (1H-MRS) studies comparing autism spectrum disorder (ASD) patients with healthy controls, with the aim of profiling ASD-associated changes in the metabolites N-acetyl-aspartate (NAA) and Creatine (Cr). Meta-regression models of NAA and Cr levels were employed, using data from 20 eligible studies (N = 852), to investigate age-dependent differences in both global brain and region-specific metabolite levels, while controlling for measurement method (Cr-ratio versus absolute concentrations). Decreased NAA concentrations that were specific to children were found for whole-brain grey and white matter. In addition, a significant decrease in NAA was evident across age categories in the parietal cortex, the cerebellum, and the anterior cingulate cortex. Higher levels of Cr were observed for ASD adults than children in global grey matter, with specific increases for adults in the temporal lobe and decreased Cr in the occipital lobe in children. No differences were found for either NAA or Cr in the frontal lobes. These data provide some evidence that ASD is characterized by age-dependent fluctuations in metabolite levels across the whole brain and at the level of specific regions thought to underlie ASD-associated behavioural and affective deficits. Differences in Cr as a function of age and brain region suggests caution in the interpretation of Cr-based ratio measures of metabolites. Despite efforts to control for sources of heterogeneity, considerable variability in metabolite levels was observed in frontal and temporal regions, warranting further investigation.


The plume also rises: trajectories of pheromone plumes issuing from point sources in an orchard canopy at night.
The trajectories of pheromone plumes in canopied habitats, such as orchards, have been little studied. We documented the capture of male navel orangeworm moths, Amyelois transitella, in female-baited traps positioned at 5 levels, from ground level to the canopy top, at approximately 6 m above ground, in almond orchards. Males were captured in similar proportions at all levels, suggesting that they do not favor a particular height during ranging flight. A 3-D sonic anemometer was used to establish patterns of wind flow and temperature at 6 heights from 2.08 to 6.65 m in an almond orchard with a 5 m high canopy, every 3 h over 72 h. The horizontal velocity of wind flow was highest above the canopy, where its directionality also was the most consistent. During the time of A. transitella mating (0300-0600), there was a net vertical displacement upward. Vertical buoyancy combined with only minor reductions in the distance that plumes will travel in the lower compared to the upper canopy suggest that the optimal height for release of pheromone from high-release rate sources, such as aerosol dispensers ("puffers"), that are deployed at low densities (e.g., 3 per ha.) would be at mid or low in the canopy, thereby facilitating dispersion of disruptant throughout the canopy. Optimal placement of aerosol dispensers will vary with the behavioral ecology of the target pest; however, our results suggest that current protocols, which generally propose dispenser placement in the upper third of the canopy, should be reevaluated.


Erythroleukemia induction by replication-competent type C viruses cloned from the anemia- and polycythemia-inducing isolates of Friend leukemia virus.
In this study, the biological properties of the replication-competent viruses, F-MuLVA, present in the anemia-inducing isolate of Friend leukemia virus complex (FV-A); and F-MuLVP, present in the polycythemia-inducing isolate of Friend leukemia virus complex (FV-P) have been examined. BALB/c mice infected as newborns with clonal isolates of F-MuLVA or F-MuLVP become anemic and show splenic enlargement characterized by an increased proportion of cells that resemble immature nucleated erythroid cells. In addition, the spleens of these F-MuLVA- or F-MuLVP-infected mice contain a markedly increased proportion of both erythropoietin-dependent erythroid progenitor cells and spectrin-containing erythroid cells. These results suggest that Friend murine leukemia virus (F-MuLV) by itself can induce an erythroleukemic transformation in newborn BALB/c mice similar to that induced by the anemia-inducing spleen focus-forming virus (SFFVA) in newborn or adult mice. Kinetic studies indicated that the alterations in hemopoietic cell populations induced by F-MuLVA or F-MuLVP in newborn BALB/c mice occurred more slowly than the rapid changes observed after infection with FV-A. In addition, adult BALB/c mice were fully susceptible to the erythroleukemic transformation induced by either SFFVA or SFFVP, whereas only newborn mice were susceptible to F-MuLV. Taken together, these results suggest that, although the replication-defective Friend spleen focus-forming viruses appear to be the major determinant of erythroleukemia induction in adults, the replication-competent helper F-MuLV also have erythroleukemic potential when assayed in newborn animals.


Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy - a multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study).
At time of diagnosis, less than 10% of patients with pancreatic adenocarcinomas (PDAC) are considered to be immediately operable (i.e. resectable). Considering their poor overall survival (OS), only tumours without vascular invasion (NCCN 2017) should be considered for resection, i.e. those for which resection with disease-free margins (R0) is theoretically possible in absence of presurgery treatment. With regard to high R1 rates and undetectable locoregional and/or metastatic spreading prior to surgery explain (at least in part) the observed 1-year relapse and mortality rates of 50 and 25%, respectively. Today, upfront surgery followed by adjuvant chemotherapy is the reference treatment in Europe. The main limitation of the adjuvant approach is the low rate of completion of the full therapeutic sequence. Indeed, only 47 to 60% patients received any adjuvant therapy after resection compared to more than 75% for neoadjuvant therapy. No previous prospective study has compared this approach to a neoadjuvant FOLFIRINOX or FOLFOX chemotherapy for resectable PDAC. PANACHE01-PRODIGE48 is a prospective multicentre controlled randomized non comparative Phase II trial, evaluating the safety and efficacy of two regimens of neo-adjuvant chemotherapy (4 cycles of mFOLFIRINOX or FOLFOX) relative to the current reference treatment (surgery and then adjuvant chemotherapy) in patients with resectable PDAC. The main co-primary endpoints are OS rate at 12 months and the rate of patients undergoing the full therapeutic sequence. The "ideal" cancer treatment for resectable PDAC would have the following characteristics: administration to the highest possible proportion of patients, ability to identify fast-progressing patients (i.e. poor candidates for surgery), a low rate of R1 resections (through optimisation of local disease control), and an acceptable toxicity profile. The neoadjuvant approach may meet all these criteria. With respect to published data on the efficacy of FOLFOX and mFOLFIRINOX, these two regimens are potential candidates for neoadjuvant use in the aim to optimising oncological outcomes in resectable PDAC. ClinicalTrials.gov , NCT02959879 . Trial registration date: November 9, 2016.


Chromaffin Cells of the Adrenal Medulla: Physiology, Pharmacology, and Disease.
Chromaffin cells (CCs) of the adrenal gland and the sympathetic nervous system produce the catecholamines (epinephrine and norepinephrine; EPI and NE) needed to coordinate the bodily "fight-or-flight" response to fear, stress, exercise, or conflict. EPI and NE release from CCs is regulated both neurogenically by splanchnic nerve fibers and nonneurogenically by hormones (histamine, corticosteroids, angiotensin, and others) and paracrine messengers [EPI, NE, adenosine triphosphate, opioids, γ-aminobutyric acid (GABA), etc.]. The "stimulus-secretion" coupling of CCs is a Ca2+ -dependent process regulated by Ca2+ entry through voltage-gated Ca2+ channels, Ca2+ pumps, and exchangers and intracellular organelles (RE and mitochondria) and diffusible buffers that provide both Ca2+ -homeostasis and Ca2+ -signaling that ultimately trigger exocytosis. CCs also express Na+ and K+ channels and ionotropic (nAChR and GABAA ) and metabotropic receptors (mACh, PACAP, β-AR, 5-HT, histamine, angiotensin, and others) that make CCs excitable and responsive to autocrine and paracrine stimuli. To maintain high rates of E/NE secretion during stressful conditions, CCs possess a large number of secretory chromaffin granules (CGs) and members of the soluble NSF-attachment receptor complex protein family that allow docking, fusion, and exocytosis of CGs at the cell membrane, and their recycling. This article attempts to provide an updated account of well-established features of the molecular processes regulating CC function, and a survey of the as-yet-unsolved but important questions relating to CC function and dysfunction that have been the subject of intense research over the past 15 years. Examples of CCs as a model system to understand the molecular mechanisms associated with neurodegenerative diseases are also provided. Published 2019. Compr Physiol 9:1443-1502, 2019.


Radiology curriculum for medical students: clinicians' perspectives.
This study was conducted to establish clinicians' perspectives of a set of radiology curriculum topics for medical student teaching, which were held to be important by radiologists. A questionnaire was sent to clinicians in all specialties. Forty-six clinicians (51.1%) out of 90 returned the questionnaires. All curriculum topics were scored above an average of 4 (agree). The five highest ranking curriculum topics in order of importance were: developing a system for viewing chest radiographs (5.59), developing a system for viewing abdominal radiographs (5.56), developing a system for viewing bone and joint radiographs (5.33), distinguishing normal structures from abnormal in chest and abdominal radiographs (5.33) and identifying gross bone or joint abnormalities in skeletal radiographs (5.22). Correlative analysis between speciality groups showed surgical and medical specialities were significantly different in their responses of two learning outcomes: basic knowledge about the contrast media benefits and risks (P= 0.01) and ability to select the most appropriate and the most cost-effective methods of radiological investigations for clinical situations (P= 0.03). Acute specialities were not significantly different from the other two groups for these two learning outcomes. There was no statistically significant difference for other learning outcomes between the three speciality groups.


Impact of surface defects on the surface charge of gibbsite nanoparticles.
We use high resolution Atomic Force Microscopy to study the surface charge of the basal plane of gibbsite nanoparticles, with a lateral resolution of approximately 5 nm, in ambient electrolyte of variable pH and salt content. Our measurements reveal surface charge variations on the basal planes that correlate with the presence of topographic defects such as atomic steps. This surface charge heterogeneity, which increases with increasing pH, suggests that for a pH between 6 and 9 the defect sites display a stronger chemical activity than adjacent, apparently atomically smooth regions of the basal plane. Smooth regions display a slight positive surface charge of ≈0.05e per nm2 that hardly varies within this pH range. In contrast, near the topographic defects we observe a much lower charge. Considering the size of the interaction area under the probing tip, this implies that at the defect sites the charge density must be negative, ≈-0.1e per nm2. These measurements demonstrate that surface defects have a large influence on the average surface charge of the gibbsite basal plane. These findings will contribute to understand why surface defects play an important role in various applications, such as fuel cells, chemical synthesis, self-assembly, catalysis and surface treatments.


A Systematic Review of Adherence Strategies for Adult Populations in Speech-Language Pathology Treatment.
Speech-language pathologists (SLPs) often advise adult patients to complete at-home programs in order to improve outcomes. Despite this widespread practice, relatively little is known about treatment adherence. The purposes of this systematic review were to identify adherence strategies and adherence tracking methods used by adult populations that are commonly treated by SLPs (i.e., dysphagia, aphasia, traumatic brain injury, dysphonia, dysarthria), and to identify the efficacy of these strategies. The systematic review was conducted in accordance with A Measurement Tool to Assess Systematic Reviews guidelines. A comprehensive literature search was performed in three databases (CINAHL, PubMed, and Web of Science). Of the 679 articles found, 18 were selected for analysis. Two thirds of the included articles received the second highest rating on the 5-point JAMA Quality Rating Scheme. Interventions designed to alter treatment adherence included (most to least frequent) computer programs, portable devices/phone apps, alarm reminders, instructional DVDs, check-ins from a clinician/volunteer, and wearable device. Adherence reporting methods included (most to least frequent) self-report diaries, computer program/app-aided collection, wearable device, and clinician/volunteer observation. Of the articles that reported practice frequency, 58% found that adherence strategies improved practice frequency as compared to control. Of the articles that reported treatment outcomes, 66% found that adherence strategies were associated with improved treatment outcomes as compared to control. The paucity of publications reviewed suggests that treatment adherence is considerably understudied in speech-language pathology. A clearer understanding of how to improve the design of adherence strategies could yield highly valuable clinical outcomes. https://doi.org/10.23641/asha.19393793.


XML-based clinical data standardisation in the National Health Service Scotland.
The objective of this paper is to clarify the role that socio-economic factors played in shaping the development of XML-based clinical data standards in the National Health Service in Scotland from 2000 to 2004. The paper discusses the NHS Scotland approach to clinical data standardisation, emphasising the actors involved, their choices during the standard development process and the factors that have shaped these choices. The case suggests that the NHS Scotland approach to clinical data standardisation is shaped by strong political pressures for fast development of an integrated electronic patient care system, economic pressures for high efficiency and cost reductions, and organisational requirements for strong clinical support. Such economic, political and organisational pressures explain the informal approach to standard development, the emphasis on fast system development and strong clinical involvement. At the same time, market factors explain the low commitment of the IT vendors, which might have otherwise put significant pressure on NHS Scotland to pursue a more formalised standardisation approach within an internationally recognised standard-setting body.


Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers.
Skeletal muscle is composed of heterogeneous myofibers with distinctive rates of contraction, metabolic properties, and susceptibility to fatigue. We show that class II histone deacetylase (HDAC) proteins, which function as transcriptional repressors of the myocyte enhancer factor 2 (MEF2) transcription factor, fail to accumulate in the soleus, a slow muscle, compared with fast muscles (e.g., white vastus lateralis). Accordingly, pharmacological blockade of proteasome function specifically increases expression of class II HDAC proteins in the soleus in vivo. Using gain- and loss-of-function approaches in mice, we discovered that class II HDAC proteins suppress the formation of slow twitch, oxidative myofibers through the repression of MEF2 activity. Conversely, expression of a hyperactive form of MEF2 in skeletal muscle of transgenic mice promotes the formation of slow fibers and enhances running endurance, enabling mice to run almost twice the distance of WT littermates. Thus, the selective degradation of class II HDACs in slow skeletal muscle provides a mechanism for enhancing physical performance and resistance to fatigue by augmenting the transcriptional activity of MEF2. These findings provide what we believe are new insights into the molecular basis of skeletal muscle function and have important implications for possible therapeutic interventions into muscular diseases.


Research on cancer diagnosis in Malaysia: current status.
Cancer is a major morbidity and mortality concern in Malaysia. Based on National Cancer Registry data, the Malaysian population is estimated to bear a cancer burden of about 40,000 new cases per year, and a cumulative lifetime risk of about 1:4. Cancer research in Malaysia has to consider needs relevant to our population, and resources constraints. Hence, funding bodies prioritise cancers of high prevalence, unique to our community and posing specific clinical problems. Cancer diagnosis is crucial to cancer management. While cancer diagnosis research largely aims at improvements in diagnostic information towards more appropriate therapy, it also impacts upon policy development and other areas of cancer management. The scope of cancer diagnosis upon which this paper is based, and their possible impact on other R&D areas, has been broadly categorized into: (1) identification of aetiological agents and their linkages to the development of precancer and cancer (impact on policy development, cancer prevention and treatment), (2) cancer biology and pathogenesis (impact on cancer prevention, treatment strategies and product development), (3) improvements in accuracy, sensitivity and specificity in cancer detection, monitoring and classification (impact on technology development) and (4) prognostic and predictive parameters (impact on treatment strategies). This paper is based on data collected by the Working Group on Cancer Diagnosis Research for the First National Conference on Cancer Research Coordination in April 2004. Data was collated from the databases of Institutions/Universities where the authors are employed, the Ministry of Science, Technology and Innovation (MOSTI) and targeted survey feedback from key cancer researchers. Under the 7th Malaysia Plan, 76 cancer projects were funded through the Intensified Research in Priority Areas (IRPA) scheme of MOSTI, amounting to almost RM15 million of grant money. 47(61.8%) of these projects were substantially in cancer diagnosis, accounting for 65.6% (RM 9.7 million) of cancer project funds. The 8th Malaysia Plan saw a change in research strategy. The IRPA agency fielded several top-down projects which encouraged a multicentre and multidisciplinary approach. This resulted in larger funding per project i.e. RM32 million for 49 projects. There was also a surge of interest in drug development and natural products. Because of this shift in direction, cancer diagnosis projects constituted only 51% of IRPA-funded cancer projects. Nonetheless funding for cancer diagnosis research has exceeded that of the 7th Malaysia Plan, being RM12.5 million by March 2004. The majority of such research is carried out at the Universities, engaging a large number of young scientists and postgraduate students (51 MSc and 21 PhD). A lot of research findings presented at scientific meetings have not yet been published and there is a glaring shortage of patents and commercialization of research findings (such as creation of test kits). Because diagnosis is very much a part of clinical practice, many researchers felt satisfied and confident that their work will be translated into practice and will significantly improve diagnostic services in Malaysia. National guidelines and consensus development on at least three malignancies i.e. breast cancer, oral cancer and lymphoma, have substantial basis in local R&D work. Problems encountered in research included (1) insufficient funding to realize research objectives, (2) lack of local expertise (most research assistants are inexperienced BSc graduates with no or minimal research experience), (3) inadequate technical support from vendors during equipment failure, (4) inexperienced Institutional development units to assist in product development, (5) lack of venture capital for commercialization of findings, and (6) inadequate incentives to undertake research. Researchers pointed out that plans to promote research should include the establishment of (1) regional and national cancer tissue banks, (2) a National Cancer Research Institute, (3) a dedicated cancer research fund, (4) a registry of cancer researchers, (5) national research coordinators, (6) improved coverage by the National Cancer Registry, (7) more international collaboration, (8) a better career structure for researchers, (9) improved Institutional support for product realization, and (10) better recognition for cancer researchers.