The root meristem is shaped by brassinosteroid control of cell geometry.
Growth extent and direction determine cell and whole-organ architecture. How they are spatio-temporally modulated to control size and shape is not well known. Here we tackled this question by studying the effect of brassinosteroid (BR) signalling on the structure of the root meristem. Quantification of the three-dimensional geometry of thousands of individual meristematic cells across different tissue types showed that the modulation of BR signalling yields distinct changes in growth rate and anisotropy, which affects the time that cells spend in the meristem and has a strong impact on the final root form. By contrast, the hormone effect on cell volume was minor, establishing cell volume as invariant to the effect of BR. Thus, BR has the highest effect on cell shape and growth anisotropy, regulating the overall longitudinal and radial growth of the meristem, while maintaining a coherent distribution of cell sizes. Moving from single-cell quantification to the whole organ, we developed a computational model of radial growth. The simulation demonstrates how differential BR-regulated growth between the inner and outer tissues shapes the meristem and thus explains the non-intuitive outcomes of tissue-specific perturbation of BR signalling. The combined experimental data and simulation suggest that the inner and outer tissues have distinct but coordinated roles in growth regulation.


Metrics and similarity measures for hidden Markov models.
Hidden Markov models were introduced in the beginning of the 1970's as a tool in speech recognition. During the last decade they have been found useful in addressing problems in computational biology such as characterising sequence families, gene finding, structure prediction and phylogenetic analysis. In this paper we propose several measures between hidden Markov models. We give an efficient algorithm that computes the measures for left-right models, e.g. profile hidden Markov models, and briefly discuss how to extend the algorithm to other types of models. We present an experiment using the measures to compare hidden Markov models for three classes of signal peptides.


Antiplatelet drugs in cardiological practice: established strategies and new developments.
A common pathophysiological course in vascular diseases is an overwhelming activation and aggregation of blood platelets, which results in atherothrombosis. By causing the last decisive step of cerebral, coronary, or peripheral arterial ischemia thrombotic complications of atherosclerotic disease represent a major player in death cause statistics of most western countries. The development of novel therapies against platelet-dependent thrombosis and the concurrent improvement of existing therapeutic strategies thus is a paramount focus of pharmaceutical research. Currently, efficiency, dosing and indications of established antiplatelet substances are being re-evaluated, whilst new, so far unrecognized molecular targets for inhibition of platelet activity come up front. This not only allows for interesting new therapeutical options, but also widens our insight into the role platelets play in atherosclerosis in general. This article summarizes the relevant pathophysiology of platelet activation, presents current concepts in antiplatelet drug therapy, and highlights the role of platelets in vascular diseases apart from atherothrombosis.


Aging increases distraction by auditory oddballs in visual, but not auditory tasks.
Aging is typically considered to bring a reduction of the ability to resist distraction by task-irrelevant stimuli. Yet recent work suggests that this conclusion must be qualified and that the effect of aging is mitigated by whether irrelevant and target stimuli emanate from the same modalities or from distinct ones. Some studies suggest that aging is especially sensitive to distraction within-modality while others suggest it is greater across modalities. Here we report the first study to measure the effect of aging on deviance distraction in cross-modal (auditory-visual) and uni-modal (auditory-auditory) oddball tasks. Young and older adults were asked to judge the parity of target digits (auditory or visual in distinct blocks of trials), each preceded by a task-irrelevant sound (the same tone on most trials-the standard sound-or, on rare and unpredictable trials, a burst of white noise-the deviant sound). Deviant sounds yielded distraction (longer response times relative to standard sounds) in both tasks and age groups. However, an age-related increase in distraction was observed in the cross-modal task and not in the uni-modal task. We argue that aging might affect processes involved in the switching of attention across modalities and speculate that this may due to the slowing of this type of attentional shift or a reduction in cognitive control required to re-orient attention toward the target's modality.


Impact of longitudinal cardiac rotation on mitral and tricuspid atrioventricular annular diastolic motion.
It is unknown whether longitudinal rotation (LR), often seen in cardiac resynchronization therapy candidates, may affect mitral annular early diastolic (E') velocities and tricuspid annular motion. We assessed whether (1) LR affects the amplitude and timing of septal and lateral mitral annular E' velocities and tricuspid annular systolic and E' velocities and (2) if systolic strain heterogeneity seen in cardiac resynchronization therapy patients with LR extends into diastole. Ninety-nine cardiac resynchronization therapy candidates with suitable baseline echocardiograms were identified. Early diastolic (E') and systolic myocardial velocities of the tricuspid annulus and E' velocities of the septal and lateral part of the mitral annulus were analyzed from tissue Doppler images. Longitudinal rotation and basal systolic and diastolic strain rates were analyzed by speckle-tracking. LR correlated with lateral mitral annular E' (r= 0.45, P<0.001), tricuspid annular E' (r=-0.3, P=0.003), and with a difference between septal and lateral mitral annular E' velocities (r= -0.49, P<0.001) but not with septal mitral annular E' velocity. LR also correlated with tricuspid annular systolic velocity (r= 0.60, P<0.001). After categorizing the patients according to the quartiles of their LR, we showed that with decreasing quartile number, heterogeneity of systolic (P=0.003) but not diastolic (P>0.1) strain rates increased. LR direction and magnitude correlates with the amplitude of, and relative differences between, diastolic velocities of tricuspid, lateral mitral, and septal mitral annulus, which are a cornerstone of diastolic function assessment. LR is associated with systolic but not with diastolic regional heterogeneity.


Supracondylar Humerus Fractures: When Lateral Entry Pins Are Not Enough.
Percutaneous pin configuration for the management of pediatric supracondylar humerus fractures has been studied extensively both in the biomechanics laboratory and in the clinical setting. Medial entry pins (ie, crossed pinning) increase supracondylar humerus fracture construct stability under certain loading conditions. However, there are noted drawbacks of medial entry pinning, specifically the risk of iatrogenic ulnar nerve injury. In most circumstances, the additional biomechanical stability of crossed pinning is unlikely to be clinically necessary for maintenance of fracture alignment, but there are scenarios in which medial entry pins should be strongly considered. It is important to review the biomechanics of various pin configurations in the setting of pediatric supracondylar humerus fractures, discuss the indications for medial entry pinning (crossed pinning), and discuss a safe technique for applying medial entry pins when indicated.


Regulation of Gi by the CB1 cannabinoid receptor C-terminal juxtamembrane region: structural requirements determined by peptide analysis.
A CB1 cannabinoid receptor peptide fragment from the C-terminal juxtamembrane region autonomously inhibits adenylyl cyclase activity in a neuroblastoma membrane preparation. The cannabinoid receptor antagonist, SR141716A, failed to block the response. The peptide was able to evoke the response in membranes from Chinese hamster ovary (CHO) cells that do not express the CB1 receptor. These studies are consistent with a direct activation of Gi by the peptide. To test the importance of a BXBXXB sequence, Lys403 was acetylated, resulting in a peptide having similar affinity but reduced efficacy. N-Terminal truncation of Arg401 resulted in a 6-fold loss of affinity, which was not further reduced by sequential truncation of up to the first seven amino acids, four of which are charged. N-Terminal-truncated peptides exhibited maximal activity, suggesting that Gi activation can be conferred by the remaining amino acids. Truncation of the C-terminal Glu417 or substitution of Glu417 by a Leu or of Arg401 by a Norleucine reduced activity at 100 microM. The C-terminal juxtamembrane peptide was constrained to a loop peptide by placement of Cys residues at both terminals and disulfide coupling. This modification reduced the affinity 3-fold but yielded near-maximal efficacy. Blocking the Cys termini resulted in a loss of efficacy. Circular dichroism spectropolarimetry revealed that all C-terminal juxtamembrane peptide analogues exist in a random coil conformation in an aqueous environment. A hydrophobic environment (trifluoroethanol) failed to induce alpha-helix formation in the C-terminal juxtamembrane peptide but did so in less active peptides. The anionic detergent sodium dodecyl sulfate induced alpha-helix formation in all analogues except the loop peptide, where it induces a left-handed PII conformation. It is concluded that alpha-helix formation is not required for Gi activation.


Food safety knowledge, attitudes, and practices of food handlers at kitchen premises in the Port 'X' area, North Jakarta, Indonesia 2018.
Improper food handling can be a major cause of food contamination. To prevent food contamination, the food handler should have good knowledge, display a positive attitude, and practice proper food handling practices. This study aimed to evaluate the food safety and personal hygiene knowledge, attitudes, and practices of food handlers at kitchen premises in the Port 'X' area in North Jakarta, Indonesia. This study uses a cross-sectional design. The research was conducted in April 2018 and May 2018. Data were collected from 72 food handlers from kitchens located in the Port 'X' area in North Jakarta. Data collection was performed through interviews and observations, using questionnaires and checklists as research instruments. The results show a significant correlation between the level of knowledge about food safety and the attitude of food handlers (p=0.01), and attitude scores were significantly higher among food handlers who reported attending a previous food safety training course (p=0.002) with (r=0.302) it means a weak uphill (positive) linear relationship attitude scores and training that food handlers attended. This study found a significant relationship between the knowledge and attitude of food handlers, but there was no significant relationship between knowledge or attitude and food handling practices. Thus, it is recommended that training activities for food handlers be held regularly, as the food safety knowledge obtained from training or courses can translate into the improvement of attitudes and food handling practices.


Heat Illness Requiring Emergency Care for People Experiencing Homelessness: A Case Study Series.
Extreme heat and hot weather has a negative impact on human health and society. Global warming has resulted in an increase in the frequency and duration of heatwaves. Heat-related illnesses are a significant negative consequence of high temperatures and can be life-threatening medical emergencies. The severity of the symptoms can depend on the pre-existing medical conditions and vary from mild headaches to severe cases that can lead to coma and death. The risk of heat-related illness may be higher for people experiencing homelessness due to a lack of access to cool places and water, and the complex interactions between mental illness, medications and substance use disorder. This paper presents two cases of people experiencing homelessness who were admitted to the emergency department of a hospital in Sydney, Australia during a heatwave in November 2020. Both cases were adult males with known risk factors for heat-related illness including hypertension and schizophrenia (Case One) and hepatitis C, cirrhosis, and alcohol use disorder (Case Two). These cases show that severe weather can not only be detrimental to homeless people's health but can also cause a significant economic toll, evident by the $70,184 AUD expenditure on the care for these two cases. This case report highlights the requirement to determine the risk of heat-related illness to people experiencing homelessness and need to protect this vulnerable population from weather-related illness and death.


GABA A/Bz receptor subtypes as targets for selective drugs.
The gamma-aminobutyric acid type A (GABA(A)) receptors are the major inhibitory neuronal receptors in the mammalian brain. Their activation by GABA opens the intrinsic ion channel, enabling chloride flux into the cell with subsequent hyperpolarization. Several GABA(A) receptor subunit isoforms have been cloned, the major isoform containing alpha, beta, and gamma subunits, and a regional heterogeneity associated with distinct physiological effects has been suggested. As a variety of allosteric ligands can modulate GABA-gated conductance changes through binding to distinct sites, the development of subtype-selective ligands may lead to the selective treatment of GABA system-associated pathology. In particular, the best characterized binding site is the benzodiazepine site (BzR), localized at the alpha/gamma subunit interface, in which the alpha subunit is the main determinant of BzR ligand action selectivity. The alpha1-containing BzR have been proposed to be responsible for the sedative action; the alpha2 and/or the alpha3 subtypes have been suggested to mediate the anxiolytic activity and the myorelaxation effects, and the alpha5 subtype has been associated with cognition processes. The discovery of alpha-selective subtype ligands may help in the specific treatment of anxiety, sleep disorders, convulsions and memory deficits with fewer side effects. Selectivity may be achieved by two approaches: selective affinity or selective efficacy. Selective affinity needs a compound to bind with a higher affinity to one receptor subtype compared with another, whereas subtype-selective efficacy relies on a compound binding to all subtypes, but having different efficacies at various subtypes. The status of BzR ligands, subdivided on the basis of their main chemical structural features, is reviewed in relation to structure-activity relationships which determine their affinity or efficacy selectivity for a certain BzR subtype.


Renal disease in an antiretroviral-naïve HIV-infected outpatient population in Western Kenya.
Several commonly used antiretrovirals (ARVs) require dose adjustments to prevent toxicities in the presence of renal insufficiency. Because no prospective studies of the prevalence or risk factors for kidney disease in stable outpatient human immunodeficiency virus (HIV)-infected indigenous African populations have been published to date, it is not known if already scarce resources should be allocated to detect renal dysfunction, in those without risk factors for kidney disease, prior to initiation of increasingly available antiretrovirals in developing countries. A cross-sectional study to determine the prevalence of and risk factors for renal disease in a cohort of medically stable, HIV-infected, antiretroviral-naïve adults, without diabetes or hypertension, presenting to an HIV clinic in western Kenya. Of 373 patients with complete data, renal insufficiency (CrCl <60 ml/min) was identified in 43 (11.5%) [18 (4.8%) had a CrCl <50 ml/min]. Despite high correlation coefficients between the three renal function estimating equations used, when compared to creatinine clearance as calculated by Cockcroft-Gault, lower rates of moderate to severe renal insufficiency were identified by the Modification of Diet in Renal Disease equations. Proteinuria, defined as a urine dipstick protein of equal to or greater than 1+, was detected in only 23 subjects (6.2%). Renal insufficiency is not uncommon, even in stable patients without diabetes or hypertension. Conversely, proteinuria was unexpectedly infrequent in this population. Utilizing resources to assess renal function prior to initiation of antiretrovirals in order to identify those likely to benefit from dosage adjustment is justified.


Computational fluid dynamics modeling of the paddle dissolution apparatus: agitation rate, mixing patterns, and fluid velocities.
The purpose of this research was to further investigate the hydrodynamics of the United States Pharmacopeia (USP) paddle dissolution apparatus using a previously generated computational fluid dynamics (CFD) model. The influence of paddle rotational speed on the hydrodynamics in the dissolution vessel was simulated. The maximum velocity magnitude for axial and tangential velocities at different locations in the vessel was found to increase linearly with the paddle rotational speed. Path-lines of fluid mixing, which were examined from a central region at the base of the vessel, did not reveal a region of poor mixing between the upper cylindrical and lower hemispherical volumes, as previously speculated. Considerable differences in the resulting flow patterns were observed for paddle rotational speeds between 25 and 150 rpm. The approximate time required to achieve complete mixing varied between 2 to 5 seconds at 150 rpm and 40 to 60 seconds at 25 rpm, although complete mixing was achievable for each speed examined. An analysis of CFD-generated velocities above the top surface of a cylindrical compact positioned at the base of the vessel, below the center of the rotating paddle, revealed that the fluid in this region was undergoing solid body rotation. An examination of the velocity boundary layers adjacent to the curved surface of the compact revealed large peaks in the shear rates for a region within ~3 mm from the base of the compact, consistent with a "grooving" effect, which had been previously seen on the surface of compacts following dissolution, associated with a higher dissolution rate in this region.


Prevalence and Prognostic Significance of Apparent Treatment Resistant Hypertension in Chronic Kidney Disease: Report From the Chronic Renal Insufficiency Cohort Study.
The association between apparent treatment resistant hypertension (ATRH) and clinical outcomes is not well studied in chronic kidney disease. We analyzed data on 3367 hypertensive participants in the Chronic Renal Insufficiency Cohort (CRIC) to determine prevalence, associations, and clinical outcomes of ATRH in nondialysis chronic kidney disease patients. ATRH was defined as blood pressure ≥140/90 mm Hg on ≥3 antihypertensives, or use of ≥4 antihypertensives with blood pressure at goal at baseline visit. Prevalence of ATRH was 40.4%. Older age, male sex, black race, diabetes mellitus, and higher body mass index were independently associated with higher odds of having ATRH. Participants with ATRH had a higher risk of clinical events than participants without ATRH-composite of myocardial infarction, stroke, peripheral arterial disease, congestive heart failure (CHF), and all-cause mortality (hazard ratio [95% confidence interval], 1.38 [1.22-1.56]); renal events (1.28 [1.11-1.46]); CHF (1.66 [1.38-2.00]); and all-cause mortality (1.24 [1.06-1.45]). The subset of participants with ATRH and blood pressure at goal on ≥4 medications also had higher risk for composite of myocardial infarction, stroke, peripheral arterial disease, CHF, and all-cause mortality (hazard ratio [95% confidence interval], (1.30 [1.12-1.51]) and CHF (1.59 [1.28-1.99]) than those without ATRH. ATRH was associated with significantly higher risk for CHF and renal events only among those with estimated glomerular filtration rate ≥30 mL/min per 1.73 m(2). Our findings show that ATRH is common and associated with high risk of adverse outcomes in a cohort of patients with chronic kidney disease. This underscores the need for early identification and management of patients with ATRH and chronic kidney disease.


Djurleite (Cu1.94S) and Low Chalcocite (Cu2S): New Crystal Structure Studies.
Additional x-ray structure studies on low chalcocite generally confirm the previously reported structure but show that either disorder is present or the true space group is not P2(1)/c but Pc, four of the 96 copper atoms in the monoclinic unit cell taking on twofold (linear) coordination. The crystal structure of djurleite has been solved in space group P2(1)/n, the monoclinic cell having parameters a = 26.897, b = 15.745, and c = 13.565 angstroms; beta = 90.13 degrees ; and a content of 248 copper and 128 sulfur atoms. Of the 62 different copper atoms in the structure, 52 are in threefold, triangular coordination with sulfur, nine in tetrahedral, and one in linear coordination.


Advanced Cancer in Young Adults (YAs): Living in a Liminal Space.
Young adults (YAs), defined as individuals between the ages of 18 and 39 years, experience unique challenges when diagnosed with advanced cancer. Using the social constructivist grounded theory approach, we aimed to develop a theoretical understanding of how YAs live day to day with their diagnosis. A sample of 25 YAs (aged 22-39 years) with advanced cancer from across Canada participated in semi-structured interviews. Findings illustrate that the YAs described day-to-day life as an oscillating experience swinging between two opposing disease outcomes: (1) hoping for a cure and (2) facing the possibility of premature death. Oscillating between these potential outcomes was characterized as living in a liminal space wherein participants were unsure how to live from one day to the next. The participants oscillated at various rates, with different factors influencing the rate of oscillation, including inconsistent and poor messaging from their oncologists or treatment team, progression or regression of their cancer, and changes in their physical functioning and mental health. These findings provide a theoretical framework for designing interventions to help YAs adapt to their circumstance.


A comprehensive review of the effects of rTMS on motor cortical excitability and inhibition.
Repetitive transcranial magnetic stimulation (rTMS) procedures are being widely applied in therapeutic and investigative studies. Numerous studies have investigated the effects of rTMS on cortical excitability and inhibition, yielding somewhat contradictory results. The purpose of this study was to comprehensively review this literature to guide the selection of methodology in therapeutic studies. We conducted a comprehensive review of all identified studies that investigated effects of low and/or high frequency rTMS on motor cortical excitability or inhibition. Low frequency rTMS appears to produce a transient reduction in cortical excitability as assessed by motor evoked potential (MEP) size and produces no substantial effect on cortical inhibition. High frequency rTMS appears to produce a persistent increase in MEP size and a reduction in cortical inhibition measured with paired pulse methods although few studies have investigated frequencies greater than 5Hz. A number of novel stimulation paradigms have significant potential for altering cortical excitability but require further investigation. Although commonly applied forms of rTMS have effects on cortical excitability, more substantial effects may be obtained through the use of novel stimulation paradigms or innovative approaches to the stimulation of areas connected to a potential target site. Further research is required, however, before these paradigms can be more widely adopted.


Systematics and Distributions of Upper Bathyal Species in Bathyancistrolepis, a Deep-Sea Whelk Genus Endemic to the Northwest Pacific (Gastropoda: Buccinidae).
The deep-sea buccinid snail genus Bathyancistrolepis is redefined based on the reconstruction of a molecular phylogeny and morphological examination of shell and radular characters. This genus is distinguished from other genera of the subfamily Parancistrolepidinae with a combination of shell traits, including (1) a low spire, (2) sharp, carinate spiral cords or keels and (3) a long, curved siphonal canal, but not with a difference in radular morphology as suggested by previous authors. Three allopatric or parapatric species are recognized in the upper bathyal (447-2057 m) waters around Japan and Taiwan: B. tokoyodaensis from off Hokkaido to Sagami Bay in the Northwest Pacific, B. trochoidea off Kumano-nada to Miyazaki in the Northwest Pacific and along Nansei Islands in the East China Sea, and B. taiwanensis sp. nov. in the South China Sea. These species bear large paucispiral protoconchs that are indicative of benthic early development without a pelagic larval period, and hence low dispersal capability. Seafloor topography seems to have acted as a barrier for their dispersal; the range of B. tokoyodaensis supports the previous finding that Izu Peninsula delimits westward distribution of bathyal gastropod species of boreal origins.


The impact of angler groundbait on benthic invertebrates and sediment respiration in a shallow eutrophic reservoir.
In an experiment to determine the impact of angler baits, cereal or maggots were added to areas of sediment in a eutrophic reservoir at realistic rates, over a 12-week period. The densities of benthic invertebrate taxa were estimated before treatment, immediately after treatment, and, finally, after a 4-month recovery period. All taxa except the tubificid Limnodrilus hoffmeisteri were reduced in density by cereal baiting, the most sensitive being naidid worms and cladocerans. Recovery of the benthic community was not apparent after 4 months, although cyclopoid copepods were significantly more abundant in treated areas. Baiting with maggots had a qualitatively similar effect. Laboratory experiments to determine the rate of oxygen consumption by sediments treated with cereal bait suggest that demand for oxygen can be increased 100-fold by a single application of bait. It is suggested that this demand for oxygen could result in local deoxygenation under warm, calm conditions, and that this is the probable mechanism of the impact of cereal bait on benthic invertebrates.


Effects of cyanobacteria producing microcystins on seed germination and seedling growth of several agricultural plants.
The effects of cyanobacteria aqueous extracts containing Microcystin-LR (MC-LR) on the seed germination and growth of Pisum sativum, Lens esculenta, Zea mays and Triticum durum were investigated. Experiments were carried out on a range of doses of the extract (equivalent to 0, 1.6, 2.9, 5.8, 8.7 and 11.6 mu g MC-LR/mL). The results confirm that these plants were sensitive to cell-free extracts of a toxic Microcystis and that germination inhibition was dose dependent. One-way analysis of variance (ANOVA) showed that P. sativum is the most sensitive tested species with a 97% germination rate reduction and L. esculenta was the most resistant. At the 8th day, the exposure to the microcystins (MC) resulted in a significant decrease of plant epicotyls length, roots length and a net inhibition of lateral root formation. It is concluded that MC could affect also terrestrial plants seedling germination and growth. Therefore, the use of water for irrigation contaminated by MC could exert negative biochemical effects on seed and plant metabolism which might influence the agricultural crops.


Clinical Consensus Statement: Balloon Dilation of the Eustachian Tube.
To develop a clinical consensus statement on the use of balloon dilation of the eustachian tube (BDET). An expert panel of otolaryngologists was assembled with nominated representatives of general otolaryngology and relevant subspecialty societies. The target population was adults 18 years or older who are candidates for BDET because of obstructive eustachian tube dysfunction (OETD) in 1 or both ears for 3 months or longer that significantly affects quality of life or functional health status. A modified Delphi method was used to distill expert opinion into clinical statements that met a standardized definition of consensus. After 3 iterative Delphi method surveys, 28 statements met the predefined criteria for consensus, while 28 statements did not. The clinical statements were grouped into 3 categories for the purposes of presentation and discussion: (1) patient criteria, (2) perioperative considerations, and (3) outcomes. This panel reached consensus on several statements that clarify diagnosis and perioperative management of OETD. Lack of consensus on other statements likely reflects knowledge gaps regarding the role of BDET in managing OETD. Expert panel consensus may provide helpful information for the otolaryngologist considering the use of BDET for the management of patients with OETD.


Human atrial ion channel and transporter subunit gene-expression remodeling associated with valvular heart disease and atrial fibrillation.
Valvular heart disease (VHD), which often leads to atrial fibrillation (AF), and AF both cause ion-channel remodeling. We evaluated the ion-channel gene expression profile of VHD patients, in permanent AF (AF-VHD) or in sinus rhythm (SR-VHD), in comparison with patients without AF or VHD, respectively. We used microarrays containing probes for human ion-channel and Ca2+-regulator genes to quantify mRNA expression in atrial tissues from 7 SR-VHD patients and 11 AF-VHD patients relative to 11 control patients in SR without structural heart disease (SR-CAD). From the data set, we selected for detailed analysis 59 transcripts expressed in the human heart. SR-VHD patients differentially expressed 24/59 ion-channel and Ca2+-regulator transcripts. There was significant overlap between VHD groups, with 66% of genes altered in SR-VHD patients being similarly modified in AF-VHD. Statistical differences between the AF- and SR-VHD groups identified the specific molecular portrait of AF, which involved 12 genes that were further confirmed by real-time reverse transcription-polymerase chain reaction. For example, phospholamban, the beta-subunit MinK (KCNE1) and MIRP2 (KCNE3), and the 2-pore potassium channel TWIK-1 were upregulated in AF-VHD compared with SR-VHD, whereas the T-type calcium-channel Cav3.1 and the transient-outward potassium channel Kv4.3 were downregulated. Two-way hierarchical clustering separated SR-VHD from AF-VHD patients. AF-related changes in L-type Ca2+-current and inward-rectifier current were confirmed at protein and functional levels. Finally, for 13 selected genes, SR restoration reversed ion-channel remodeling. VHD extensively remodels cardiac ion-channel and transporter expression, and AF alters ion-channel expression in VHD patients.


Role of the transcriptional corepressor Bcor in embryonic stem cell differentiation and early embryonic development.
Bcor (BCL6 corepressor) is a widely expressed gene that is mutated in patients with X-linked Oculofaciocardiodental (OFCD) syndrome. BCOR regulates gene expression in association with a complex of proteins capable of epigenetic modification of chromatin. These include Polycomb group (PcG) proteins, Skp-Cullin-F-box (SCF) ubiquitin ligase components and a Jumonji C (Jmjc) domain containing histone demethylase. To model OFCD in mice and dissect the role of Bcor in development we have characterized two loss of function Bcor alleles. We find that Bcor loss of function results in a strong parent-of-origin effect, most likely indicating a requirement for Bcor in extraembryonic development. Using Bcor loss of function embryonic stem (ES) cells and in vitro differentiation assays, we demonstrate that Bcor plays a role in the regulation of gene expression very early in the differentiation of ES cells into ectoderm, mesoderm and downstream hematopoietic lineages. Normal expression of affected genes (Oct3/4, Nanog, Fgf5, Bmp4, Brachyury and Flk1) is restored upon re-expression of Bcor. Consistent with these ES cell results, chimeric animals generated with the same loss of function Bcor alleles show a low contribution to B and T cells and erythrocytes and have kinked and shortened tails, consistent with reduced Brachyury expression. Together these results suggest that Bcor plays a role in differentiation of multiple tissue lineages during early embryonic development.


Redox-active triazatruxene-based conjugated microporous polymers for high-performance supercapacitors.
Conjugated polymers (CPs) have been intensively explored for various optoelectronic applications in the last few decades. Nevertheless, CP based electrochemical energy storage devices such as supercapacitors remain largely unexplored. This is mainly owing to the low specific capacitance, poor structural/electrochemical stability, and low energy density of most existing CPs. In this contribution, a novel set of redox-active conjugated microporous polymers, TAT-CMP-1 and TAT-CMP-2, based on nitrogen-rich and highly conductive triazatruxene building blocks, were successfully designed and synthesized to explore their potential application as efficient and stable electrode materials for supercapacitors. Despite a moderate surface area of 88 m2 g-1 for TAT-CMP-1 and 106 m2 g-1 for TAT-CMP-2, exceptional specific capacitances of 141 F g-1 and 183 F g-1 were achieved at a current density of 1 A g-1. The resulting polymers exhibited unusually high areal specific capacitance (>160 μF cm-2), which is attributed to the pseudocapacitance resulting from redox-active structures with high nitrogen content. More importantly, the TAT-CMP-2 electrode exhibits excellent cycling stability: only 5% capacitance fading is observed after 10 000 cycles at a high current density of 10 A g-1, enabling the possible use of these materials as electrodes in electrochemical devices.


Association of central pontin myelinolysis and extra-pontin myelinolysis in diabetic patient.
Central pontin myelinolysis and extra-pontin myelinolysis (CPM/EPM) implies the clinical picture after rapid recovery of hyponatremia or hyponatremia alone. SPM/EPM picture can occur without hyponatremia. Findings such as dysarthria, dysphagia, tetraparesia/plegy accompanies the clinical table. Our case was also diabetic, but there were no electrolyte imbalance in admission. The presence of diarrhea in medical history of the patient might indicate a short-term undetected electrolyte imbalance. In our diabetic case that has borderline metabolic status and lack of any detected electrolyte imbalance, we decided to present SPM/EPM table together with literature information.


Variability and heritability of mouse brain structure: Microscopic MRI atlases and connectomes for diverse strains.
Genome-wide association studies have demonstrated significant links between human brain structure and common DNA variants. Similar studies with rodents have been challenging because of smaller brain volumes. Using high field MRI (9.4 T) and compressed sensing, we have achieved microscopic resolution and sufficiently high throughput for rodent population studies. We generated whole brain structural MRI and diffusion connectomes for four diverse isogenic lines of mice (C57BL/6J, DBA/2J, CAST/EiJ, and BTBR) at spatial resolution 20,000 times higher than human connectomes. We measured narrow sense heritability (h2) I.e. the fraction of variance explained by strains in a simple ANOVA model for volumes and scalar diffusion metrics, and estimates of residual technical error for 166 regions in each hemisphere and connectivity between the regions. Volumes of discrete brain regions had the highest mean heritability (0.71 ± 0.23 SD, n = 332), followed by fractional anisotropy (0.54 ± 0.26), radial diffusivity (0.34 ± 0.022), and axial diffusivity (0.28 ± 0.19). Connection profiles were statistically different in 280 of 322 nodes across all four strains. Nearly 150 of the connection profiles were statistically different between the C57BL/6J, DBA/2J, and CAST/EiJ lines. Microscopic whole brain MRI/DTI has allowed us to identify significant heritable phenotypes in brain volume, scalar DTI metrics, and quantitative connectomes.


Computerized screening for cognitive impairment in patients with COPD.
COPD is associated with cognitive impairment. These impairments should be diagnosed, but due to time- and budget-reasons, they are often not investigated. The aim of this study is to examine the viability of a brief computerized cognitive test battery, Central Nervous System Vital Signs (CNSVS), in COPD patients. Patients with COPD referred to tertiary pulmonary rehabilitation were included. Cognitive functioning of patients was assessed with CNSVS before pulmonary rehabilitation and compared with age-corrected CNSVS norms. CNSVS is a 30 minute computerized test battery that includes tests of verbal and visual memory, psychomotor speed, processing speed, cognitive flexibility, complex attention, executive functioning, and reaction time. CNSVS was fully completed by 205 (93.2%, 105 females, 100 males) of the total group of patients (n=220, 116 females, 104 males). Z-tests showed that COPD patients performed significantly worse than the norms on all CNSVS cognitive domains. Slightly more than half of the patients (51.8%) had impaired functioning on 1 or more cognitive domains. Patients without computer experience performed significantly worse on CNSVS than patients using the computer frequently. The completion rate of CNSVS was high and cognitive dysfunctions measured with this screening were similar to the results found in prior research, including paper and pen cognitive tests. These results support the viability of this brief computerized cognitive screening in COPD patients, that may lead to better care for these patients. Cognitive performance of patients with little computer experience should be interpreted carefully. Future research on this issue is needed.


Evolutionary drivers of group foraging: A new framework for investigating variance in food intake and reproduction.
A proposed fundamental driver of group living is more reliable, predictable foraging and reproduction, i.e., reduced variance in food intake and reproductive output. However, existing theories on variance reduction in group foraging are simplistic, refer to variance at the level of individuals and groups without linking the two, and do not spell out crucial underlying assumptions. We provide a new, widely applicable framework for identifying when variance reduction conveys fitness benefits of group foraging in a wide range of organisms. We discuss critical limitations of established theories, the Central Limit Theorem and Risk-Sensitive Foraging Theory applied to group foraging, and incorporate them into our framework while addressing the confusion over the levels of variance and identifying previously unaddressed assumptions. Through a field study on colonial spiders, Cyrtophora citricola, we demonstrate the importance of evaluating the level of food sharing as a critical first step, previously overlooked in the literature. We conclude that variance reduction provides selective advantages only under narrow conditions and does not provide a universal benefit to group foraging as previously proposed. Our framework provides an important tool for identifying evolutionary drivers of group foraging and understanding the role of fitness variance in the evolution of group living.


Genetic and pharmacological inhibition of TTK impairs pancreatic cancer cell line growth by inducing lethal chromosomal instability.
Pancreatic ductal adenocarcinoma, which accounts for the majority of pancreatic cancers, is a lethal disease with few therapeutic options. Genomic profiling of pancreatic ductal adenocarcinoma has identified a complex and heterogeneous landscape. Understanding the molecular characteristics of pancreatic ductal adenocarcinoma will facilitate the identification of potential therapeutic strategies. We analyzed the gene expression profiles of primary tumors from patients compared to normal pancreas and identified high co-overexpression of core components of the spindle assembly checkpoint, including the protein kinase TTK (also known as MPS-1). We found overexpression of TTK protein in a subset of pancreatic ductal adenocarcinoma primary tumors and cell lines. siRNA-mediated depletion or catalytic inhibition of TTK resulted in an aberrant cell cycle profile, multi- and micro-nucleation, induction of apoptosis, and decreased cell proliferation and transformed growth. Selective catalytic inhibition of TTK caused override of the spindle assembly checkpoint-induced cell cycle arrest. Interestingly, we identified ubiquitin specific peptidase 16 (Usp16), an ubiquitin hydrolase, as a phosphorylation substrate of TTK. Usp16 regulates chromosomal condensation and G2/M progression by deubiquitinating histone H2A and polo-like kinase 1. Phosphomimetic mutants of Usp16 show enhanced proteosomal degradation and may prolong the G2/M transition allowing for correction of replication errors. Taken together, our results suggest a critical role for TTK in preventing aneuploidy-induced cell death in pancreatic cancer.


Advances in the catalytic, asymmetric synthesis of beta-lactams.
In this Account, we illustrate our contribution to the catalytic, asymmetric synthesis of beta-lactams through a flexible [2 + 2] cycloaddition strategy. We also explore the scope of our methodology and comment on future directions.


Five minutes' field study on each Indian hockey player in a coaching camp.
Peak expiratory flow rate (PEFR) was measured using portable Wright's peak flow meter on 21 male hockey players of Indian national hockey team probables attending a zonal coaching camp. The mean PEFR was observed to be 580.95 +/- 43.34 1/minute. The PEFR in hockey players were higher than those recorded in inter-university 'kabaddi', basketball players and football goalkeepers. All the group of players had shown higher mean PEFR than those of age matched healthy Indian males.


HDL, Atherosclerosis, and Emerging Therapies.
This review aims to provide an overview on the properties of high-density lipoproteins (HDLs) and their cardioprotective effects. Emergent HDL therapies will be presented in the context of the current understanding of HDL function, metabolism, and protective antiatherosclerotic properties. The epidemiological association between levels of HDL-C or its major apolipoprotein (apoA-I) is strong, graded, and coherent across populations. HDL particles mediate cellular cholesterol efflux, have antioxidant properties, and modulate vascular inflammation and vasomotor function and thrombosis. A link of causality has been cast into doubt with Mendelian randomization data suggesting that genes causing HDL-C deficiency are not associated with increased cardiovascular risk, nor are genes associated with increased HDL-C, with a protective effect. Despite encouraging data from small studies, drugs that increase HDL-C levels have not shown an effect on major cardiovascular end-points in large-scale clinical trials. It is likely that the cholesterol mass within HDL particles is a poor biomarker of therapeutic efficacy. In the present review, we will focus on novel therapeutic avenues and potential biomarkers of HDL function. A better understanding of HDL antiatherogenic functions including reverse cholesterol transport, vascular protective and antioxidation effects will allow novel insight on novel, emergent therapies for cardiovascular prevention.


Significant genetic differentiation between Poland and Germany follows present-day political borders, as revealed by Y-chromosome analysis.
To test for human population substructure and to investigate human population history we have analysed Y-chromosome diversity using seven microsatellites (Y-STRs) and ten binary markers (Y-SNPs) in samples from eight regionally distributed populations from Poland (n = 913) and 11 from Germany (n = 1,215). Based on data from both Y-chromosome marker systems, which we found to be highly correlated (r = 0.96), and using spatial analysis of the molecular variance (SAMOVA), we revealed statistically significant support for two groups of populations: (1) all Polish populations and (2) all German populations. By means of analysis of the molecular variance (AMOVA) we observed a large and statistically significant proportion of 14% (for Y-SNPs) and 15% (for Y-STRs) of the respective total genetic variation being explained between both countries. The same population differentiation was detected using Monmonier's algorithm, with a resulting genetic border between Poland and Germany that closely resembles the course of the political border between both countries. The observed genetic differentiation was mainly, but not exclusively, due to the frequency distribution of two Y-SNP haplogroups and their associated Y-STR haplotypes: R1a1*, most frequent in Poland, and R1*(xR1a1), most frequent in Germany. We suggest here that the pronounced population differentiation between the two geographically neighbouring countries, Poland and Germany, is the consequence of very recent events in human population history, namely the forced human resettlement of many millions of Germans and Poles during and, especially, shortly after World War II. In addition, our findings have consequences for the forensic application of Y-chromosome markers, strongly supporting the implementation of population substructure into forensic Y chromosome databases, and also for genetic association studies.


APLP1 and Rab5A interact with the II-III loop of the voltage-gated Ca-channel Ca(v)2.3 and modulate its internalization differently.
Voltage gated calcium channels (VGCCs) regulate cellular activity in response to membrane depolarization by altering calcium homeostasis. Because calcium is the most versatile second messenger, regulation of the amount of VGCCs at the plasma membrane is highly critical for several essential cellular processes. Among the different types of VGCCs, the Ca(v)2.3 calcium channel and its regulation mechanisms are least understood due to Ca(v)2.3's resistance to most pharmacological agents. In order to study regulation and surface expression of Ca(v)2.3, a yeast two hybrid (Y2H) screen with the II-III loop of human Ca(v)2.3 as bait, was performed. APLP1, a member of the APP gene family and Rab5A, an endocytotic catalyst were identified as putative interaction partners. The interaction were confirmed by immunoprecipitation. To study the functional importance of the interaction, patch-clamp recordings in Ca(v)2.3 stably transfected HEK-293 cells (2C6) and surface biotin endocytosis assays were performed. We are able to show that the II-III loop of the Ca(v)2.3 calcium channel binds APLP1 and that this binding promotes internalization of the channel. In addition, Rab5A also binds to the same loop of the channel and exerts an inhibitory effect on APLP1 mediated channel internalization. This study identifies a regulation mechanism of Ca(v)2.3's surface expression, which implicates APLP1 as a regulator of calcium homeostasis. Thus APLP1 may play a crucial role in neuropathological mechanisms, which involve modulation of surface expression of voltage-gated Ca(2+) channels.


Classification of tastants: A deep learning based approach.
Predicting the taste of molecules is of critical importance in the food and beverages, flavor, and pharmaceutical industries for the design and screening of new tastants. In this work, we have built deep learning models to classify sweet, bitter, and umami molecules- the three basic tastes whose sensation is mediated by G protein-coupled receptors. An extensive dataset containing 1466 bitter, 1764 sweet, and 238 umami tastants was curated from existing literature. We analyzed the chemical characteristics of the molecules, with special focus on the presence of different functional groups. A deep neural network model based on molecular descriptors and a graph neural network model were trained for taste prediction. The class imbalance due to fewer umami molecules was tackled using special sampling techniques. Both models show comparable performance during evaluation, but the graph-based model can learn task-specific representations from the molecular structure without requiring handcrafted features. We further explain the deep neural network predictions using Shapley additive explanations. Finally, we demonstrated the applicability of the models by screening bitter, sweet, and umami molecules from a large food database. This study develops an in-silico approach to classify molecules based on their taste by leveraging the recent progress in deep learning, which can serve as a powerful tool for tastant design.


Barriers to colorectal cancer screening among women in rural central Pennsylvania: primary care physicians' perspective.
Colorectal cancer (CRC) is the third leading cause of death among women in the USA. Rural populations have lower rates of CRC screening than their urban counterparts, and rural women have lower screening rates compared with rural men. The purpose of this qualitative study was to identify (1) beliefs of primary care physicians (PCPs) about CRC screening in rural communities, (2) factors that may cause gender disparities in CRC screening in rural areas, and (3) solutions to overcome those barriers. Semi-structured interviews were conducted with 17 PCPs practicing in rural central Pennsylvania. PCPs were asked about their CRC screening practices for women, availability of CRC screening services, reminder systems for CRC screening, and barriers to screening specific to their rural communities and to gender. Thematic analysis was used to identify major themes. All 17 PCPs endorsed the importance of CRC screening, but believed that there are barriers to CRC screening specific to women and to rural location. All PCPs identified colonoscopy as their screening method of choice, and generally reported that access to colonoscopy services in their rural areas was not a significant barrier. Barriers to CRC screening for women in rural communities were related to (1) PCPs' CRC screening practices, (2) gender-specific barriers to CRC screening, (3) patient-related barriers, (4) community-related barriers, and (5) physician practice-related barriers. Physicians overwhelmingly identified patient education as necessary for improving CRC screening in their rural communities, but believed that education would have to come from a source outside the rural primary care office due to lack of resources, personnel, and time. Overall, the PCPs in this study were motivated to identify ways to improve their ability to engage more eligible patients in CRC screening. These findings suggest several interventions to potentially improve CRC screening for women in rural areas, including encouraging use of other effective CRC screening modalities (eg fecal occult blood testing) when colonoscopy is not possible, systems-based reminders that leverage electronic resources and are not visit-dependent, and public health education campaigns aimed specifically at women in rural communities.


Relationship Between Sleep and Symptoms of Tear Dysfunction in Singapore Malays and Indians.
The purpose of this study was to investigate the association between sleep (duration and quality) and symptoms of dry eye in Singapore Malay and Indian adults. This was a prospective cross-sectional study. A total of 3303 subjects aged 40 years and above from two large population-based cohorts, the Singapore Malay Eye Study-2 (n = 1191, 2011-2013) and the Singapore Indian Eye Study-2 (n = 2112, 2013-2015), were included. The presence of symptoms of dry eye was defined as having at least one of six symptoms often or all the time. Sleep questionnaires included the Epworth Sleepiness Scale, Berlin Questionnaire, STOP-bang questionnaire, and Insomnia Severity Index. Poor sleep quality was defined as meeting the respective questionnaire thresholds. General health questionnaires (including sleep duration) and standardized ocular and systemic tests were also used. Of 3303 participants, 6.4% had excessive sleepiness, 20.5% had high risk for sleep apnea, 2.7% had clinical insomnia, and 7.8% had <5 hours of sleep. These sleep factors were associated with symptoms of dry eye. After adjusting for relevant demographic, medical, and social factors, the following were associated with higher odds of symptoms of dry eye: excessive sleepiness (Epworth Sleepiness Scale: odds ratio [OR] = 1.77 [1.15-2.71]), high risk of sleep apnea (Berlin Questionnaire: OR = 1.55 [1.17-2.07], STOP-Bang Questionnaire: OR = 2.66 [1.53-4.61]), clinical insomnia (Insomnia Severity Index: OR = 3.68 [2.17-6.26]) and <5 hours of sleep (OR = 1.73 [1.17-2.57], reference sleep duration 5-9 hours). Sleep apnea, insomnia, and sleep duration were each shown to be independently associated with symptoms of dry eye. Short sleep duration and poor quality are both significantly and independently associated with symptoms of dry eye.


Testosterone is positively associated with risk taking in the Iowa Gambling Task.
The association between testosterone and economic risk is not well-understood and is understudied. The present study aimed to further characterize what if any relationship testosterone has with risky economic decisions. To do so, 154 participants (78 men) completed the Iowa Gambling Task (IGT) (Bechara et al., 1994) and also provided saliva samples, which were assayed for endogenous testosterone levels using radioimmunoassay. High-levels of endogenous testosterone were associated with choosing less frequently from advantageous IGT decks of cards, indicating greater risk taking. The data showed that the effects of testosterone on IGT performance were similar for men and women. High-testosterone women and high-testosterone men made riskier choices than their low-testosterone counterparts of the same sex, and this effect was pronounced in women. Thus, high levels of testosterone are associated with willingness to incur greater risk in both sexes.


Detection and characterization of two co-infection variant strains of avian orthoreovirus (ARV) in young layer chickens using next-generation sequencing (NGS).
Using next-generation sequencing (NGS) for full genomic characterization studies of the newly emerging avian orthoreovirus (ARV) field strains isolated in Pennsylvania poultry, we identified two co-infection ARV variant strains from one ARV isolate obtained from ARV-affected young layer chickens. The de novo assembly of the ARV reads generated 19 contigs of two different ARV variant strains according to 10 genome segments of each ARV strain. The two variants had the same M2 segment. The complete genomes of each of the two variant strains were 23,493 bp in length, and 10 dsRNA segments ranged from 1192 bp (S4) to 3958 bp (L1), encoding 12 viral proteins. Sequence comparison of nucleotide (nt) and amino acid (aa) sequences of all 10 genome segments revealed 58.1-100% and 51.4-100% aa identity between the two variant strains, and 54.3-89.4% and 49.5-98.1% aa identity between the two variants and classic vaccine strains. Phylogenetic analysis revealed a moderate to significant nt sequence divergence between the two variant and ARV reference strains. These findings have demonstrated the first naturally occurring co-infection of two ARV variants in commercial young layer chickens, providing scientific evidence that multiple ARV strains can be simultaneously present in one host species of chickens.


Osteoporosis: primary prevention in the community.
The incidence of osteoporosis is increasing worldwide. It has great impact on the life of the elderly population. The most significant medical consequence of osteoporosis is fragility fracture which without proper treatment will cause severe medical and psychosocial complications. The overall cost in managing osteoporosis and its related fractures is escalating. Using bone densitometry to measure bone mineral density is useful in the diagnosis of osteoporosis but it is costly and not feasible in the community. Drugs such as estrogen replacement, raloxifene and calcitonin are effective in prevention and treatment of osteoporosis but they are also expensive. Identifying modifiable risk factors such as smoking, lack of exercise, low dietary calcium and vitamin D intake and healthy life style remain strategy in the primary prevention of osteoporosis in the community.


Spatial and Temporal Integration Abnormalities in X-Linked Retinoschisis.
To evaluate spatial and temporal integration across the visual field in individuals with juvenile X-linked retinoschisis (XLRS). Nine subjects with XLRS and 10 visually normal individuals participated. Luminance thresholds were measured at 15 locations along the horizontal visual field meridian. Locations were grouped into four regions for analysis: foveal, parafoveal (2°), perifoveal (5°-10°), and peripheral (10°-60°). For spatial integration measurements, stimulus duration was 100 ms, and size ranged from 0.01 to 2.32 deg2 (Goldmann I-V). For temporal integration measurements, stimulus size was 0.15 deg2 (Goldmann III), and duration ranged from 12 to 800 ms. The effect of stimulus size and duration on the subjects' threshold was described using integration models. Luminance thresholds for the XLRS group were more elevated for small targets (2.0×-12.6×) than for large targets (1.25×-3.2×) compared to controls for all locations. Likewise, thresholds for the XLRS group were more elevated for short durations (6.3×) than for long durations (4.0×) in the fovea and parafovea but were similarly elevated at all durations (2.0×-2.5×) in the perifovea and periphery. For both the size and duration experiments, thresholds measured in the fovea, parafovea, and perifovea of XLRS subjects were highly similar to those measured from the peripheral field of the controls. Spatial and temporal integration characteristics of the XLRS fovea, parafovea, and perifovea are similar to those of the normal periphery. The results also indicate that scaling stimulus size equates thresholds for the XLRS and control subjects throughout the visual field, but scaling duration does not.


Detection of implausible phylogenetic inferences using posterior predictive assessment of model fit.
Systematic phylogenetic error caused by the simplifying assumptions made in models of molecular evolution may be impossible to avoid entirely when attempting to model evolution across massive, diverse data sets. However, not all deficiencies of inference models result in unreliable phylogenetic estimates. The field of phylogenetics lacks a direct method to identify cases where model specification adversely affects inferences. Posterior predictive simulation is a flexible and intuitive approach for assessing goodness-of-fit of the assumed model and priors in a Bayesian phylogenetic analysis. Here, I propose new test statistics for use in posterior predictive assessment of model fit. These test statistics compare phylogenetic inferences from posterior predictive data sets to inferences from the original data. A simulation study demonstrates the utility of these new statistics. The new tests reject the plausibility of inferred tree lengths or topologies more often when data/model combinations produce biased inferences. I also apply this approach to exemplar empirical data sets, highlighting the value of the novel assessments.


Ciguatera and scombroid fish poisoning in the United States.
Ciguatera and scombroid fish poisonings are common causes of fish-related foodborne illness in the United States; however, existing surveillance systems underestimate the overall human health impact. This study aimed to describe existing data on ciguatera and scombroid fish poisonings from outbreak and poison control center reports and to estimate the overall number of ciguatera and scombroid fish-poisoning illnesses, hospitalizations, and deaths in the United States. We analyzed outbreak data from the Foodborne Disease Outbreak Surveillance Systems (FDOSS) from 2000 to 2007 and poison control center call data from the National Poison Data System (NPDS) from 2005 to 2009 for reports of ciguatera and scombroid fish poisonings. Using a statistical model with many inputs, we adjusted the outbreak data for undercounting due to underreporting and underdiagnosis to generate estimates. Underreporting and underdiagnosis multipliers were derived from the poison control call data and the published literature. Annually, an average of 15 ciguatera and 28 scombroid fish-poisoning outbreaks, involving a total of 60 and 108 ill persons, respectively, were reported to FDOSS (2000-2007). NPDS reported an average of 173 exposure calls for ciguatoxin and 200 exposure calls for scombroid fish poisoning annually (2005-2009). After adjusting for undercounting, we estimated 15,910 (90% credible interval [CrI] 4140-37,408) ciguatera fish-poisoning illnesses annually, resulting in 343 (90% CrI 69-851) hospitalizations and three deaths (90% CrI 1-7). We estimated 35,142 (90% CrI: 10,496-78,128) scombroid fish-poisoning illnesses, resulting in 162 (90% CrI 0-558) hospitalizations and 0 deaths. Ciguatera and scombroid fish poisonings affect more Americans than reported in surveillance systems. Although additional data can improve these assessments, the estimated number of illnesses caused by seafood intoxication illuminates this public health problem. Efforts, including education, can reduce ciguatera and scombroid fish poisonings.


Beyond molecular nitrogen: revelation of two ambient-pressure metastable single- and double-bonded nitrogen allotropes built from three-membered rings.
In this study, we present a crystal structure prediction and characterization for two novel single- and double-bonded nitrogen allotropes (denoted as CubN and DobN) bearing three-membered nitrogen cycles. These materials are ambient-pressure metastable robust solids with strong cohesive energies. Due to the presence of strained nitrogen cycles, these allotropes are high-lying phases, which retain high energy densities at least up to 200 GPa, when CubN becomes lower in energy than ζ-N2. The studied allotropes are indirect wide-bandgap semiconductors. A detailed spectral characterization of these materials is also presented herein. Due to their extremely high heats of formation and crystal densities, CubN and DobN demonstrate excellent detonation properties that are comparable to those of previously reported phases (cg-N and TrigN). Propulsive properties (including specific impulse and characteristic velocity) of CubN and DobN as solid monopropellants were also estimated. Thus, if synthesized, the present nitrogen allotropes will have great potential for practical applications and achieving fundamental knowledge about nitrogen as a chemical element.


Activity and therapeutic potential of ORI-1001 antisense oligonucleotide on human papillomavirus replication utilizing a model of dysplastic human epithelium.
Human Papillomaviruses (HPVs) are small double-stranded DNA viruses that infect the cutaneous or mucosal epithelium. The high-risk genital HPVs are associated with squamous intraepithelial lesions of the anogenital region that can progress to cancer. Cervical cancer is the third leading cause of cancer death in women worldwide, yet there are no specific therapeutic treatments for HPV-associated malignancies. Development of specific antisense oligonucleotides as antiviral agents is an alternative therapeutic strategy. We utilized the organotypic raft culture system which recapitulates the entire HPV life cycle, including the production of infectious virions. We studied the effect of the ORI-1001 antisense phosphorothioate oligonucleotide designed against the E1 mRNA translation start site of low-risk HPV6 and HPV11, and tested it against high-risk HPV31b and HPV16 vegetative replication and oncogene promoter activity. ORI-1001 significantly inhibited HPV31b genome amplification. In contrast, HPV16 genome amplification was unaffected. In addition, ORI-1001 significantly downregulated transcriptional activity from a HPV31b p99 early promoter luciferase reporter construct, and inhibited E1 and E6E7 transcript expression from the wild-type genome. Our results support the idea that the antisense activity of OR-1001 can target HPV31b functional activities in the differentiation dependent life cycle of this virus. Our results predict that binding stability between antisense oligonucleotides with partial homology to HPV genes may mediate targeting of multiple HPV types. Our studies also highlight the utility of the raft culture system in defining the parameters for testing antisense oligonucleotides against HPV.


Developing a Health Impact Model for Adult Lead Exposure and Cardiovascular Disease Mortality.
Lead (Pb) is a highly toxic pollutant. Evidence suggests it is associated with cardiovascular disease (CVD)-related mortality. We present a rigorous approach for identifying concentration-response functions that relate adult Pb exposures to CVD mortality to inform a health impact model (HIM). We then use the model in a proof-of-concept example. Building on previously conducted government literature reviews and a de novo supplemental literature review, we compiled and evaluated the available data on Pb and CVD mortality in humans. We applied a set of predefined selection criteria to identify studies that would be most useful in understanding the impact of Pb exposure on CVD mortality risk in adults. Once we identified the studies, we derived a HIM and used each study's concentration-response function in a proof-of-concept example. Our literature search identified 15 studies for full-text review. Of those 15 studies, 4 fit our criteria for use in the HIM. Using population and CVD mortality rates for 40- to 80-y-olds in 2014, we estimated that 34,000-99,000 deaths have been avoided due to the lowering of blood Pb levels from 1999 to 2014. Based on these values we estimated that approximately 16%-46% of the decreased CVD-related death rate from 1999 to 2014 may be attributable to decreased blood Pb levels. Our results demonstrate that decreases in Pb exposure can result in large benefits for the adult population. We have provided a HIM that can be used in a variety of applications from burden-of-disease estimates to regulatory impact assessments and have demonstrated its sensitivity to the choice of concentration-response function. https://doi.org/10.1289/EHP6552.


Measurement of optical properties of materials in the vacuum ultraviolet spectral region.
Measurement of optical properties in the VUV depends on photometric data rather than a mixture of photometric and relative phase data. Generally the measurement technique is that of measuring the reflected intensity at a number of angles of incidence and fitting these data to a calculated reflectance curve. The actual measured reflectance values need not always be known but are helpful in the final analysis of the data. Other more specialized methods include a critical angle method and the determination of extinction coefficients from transmittance measurements. The accuracy of the reflectance methods depends on the optical properties of the material being measured and the angles of incidence at which reflectance measurements are made. Instrumental errors and the condition of the surface being measured can also cause appreciable errors in the results. Accurate values of the optical constants can be used to characterize the electronic structure of a material and to design special reflecting and transmitting coatings for use in EUV astronomy and laboratory applications and possibly for use with excimer lasers in the VUV.


The Clinical and Chest CT Features Associated With Severe and Critical COVID-19 Pneumonia.
The aim of this study was to investigate the clinical and computed tomography (CT) features associated with severe and critical coronavirus disease 2019 (COVID-19) pneumonia. Eighty-three patients with COVID-19 pneumonia including 25 severe/critical cases and 58 ordinary cases were enrolled. The chest CT images and clinical data of them were reviewed and compared. The risk factors associated with disease severity were analyzed. Compared with the ordinary patients, the severe/critical patients had older ages, higher incidence of comorbidities, cough, expectoration, chest pain, and dyspnea. The incidences of consolidation, linear opacities, crazy-paving pattern, and bronchial wall thickening in severe/critical patients were significantly higher than those of the ordinary patients. Besides, severe/critical patients showed higher incidences of lymph node enlargement, pericardial effusion, and pleural effusion than the ordinary patients. The CT scores of severe/critical patients were significantly higher than those of the ordinary patients (P < 0.001). Receiver operating characteristic curve showed that the sensitivity and specificity of CT score were 80.0% and 82.8%, respectively, for the discrimination of the 2 types. The clinical factors of age older than 50 years, comorbidities, dyspnea, chest pain, cough, expectoration, decreased lymphocytes, and increased inflammation indicators were risk factors for severe/critical COVID-19 pneumonia. Computed tomography findings of consolidation, linear opacities, crazy-paving pattern, bronchial wall thickening, high CT scores, and extrapulmonary lesions were features of severe/critical COVID-19 pneumonia. There are significant differences in clinical symptoms, laboratory examinations, and CT manifestations between the ordinary patients and the severe/critical patients. Many factors are related to the severity of the disease, which can help clinicians to judge the severity of the patient and evaluate the prognosis.


Fate of manuscripts declined by the Journal of the American Academy of Dermatology.
Submissions to the Journal of the American Academy of Dermatology (JAAD) undergo a rigorous peer-review process. However, little is known regarding the fate of manuscripts declined by the JAAD. We sought to: (1) determine the proportion of manuscripts declined by the JAAD that are subsequently published elsewhere; (2) identify the journals in which they were published; and (3) study whether the authors of declined manuscripts adopted in their final publications the changes suggested by the JAAD reviewers. We reviewed the outcomes of the 489 submissions declined by the JAAD during two 4-month periods: from March 1, 2004, to June 30, 2004, and from March 1, 2005, to June 30, 2005. Of the 981 manuscripts submitted to JAAD during the two 4-month periods studied, 489 manuscripts (50%) were declined. Among the declined manuscripts, 201 (41%) had been subsequently published in other medical journals as of March 1, 2007. Among the 55 journals that published manuscripts declined by JAAD, 23 (42%) were nondermatology journals. The median impact factor for these 55 journals was 1.638, compared with the JAAD's impact factor of 2.402. Among the declined manuscripts, Case Reports comprised the largest proportion (n = 149, 31%), followed by Original Research Reports (n = 90, 18%). Overall, 46 (51%) rejected Original Research Reports were subsequently published, compared with 145 (36%) rejected submissions in other categories that were later published (P < .01). Among the 101 subsequently published manuscripts for which full texts were available, 82% of the authors incorporated at least one change suggested by the JAAD reviewers. The manuscripts that adopted JAAD-reviewer suggestions were published in journals with higher impact factors than those that did not incorporate any JAAD-reviewer suggestions (P = .0305). It is possible that the average lag time of 28 months in this study is not sufficient for some rejected manuscripts to reach subsequent publication. Approximately half of the manuscripts rejected by the JAAD were subsequently published in other journals within 28 months, among which, roughly 40% went to nondermatology journals. The median impact factor of the journals that published JAAD-rejected manuscripts was lower than that of the JAAD. Rejected Original Research Reports have a significantly higher probability of being subsequently published than other category submissions. This may be a result of relative quality of Original Research Reports versus submissions for other sections of the journal (eg, Case Reports). Manuscripts that adopted JAAD-reviewer suggestions were subsequently published in journals with higher impact factors than those that did not incorporate JAAD-reviewer suggestions. This indicates that peer-reviewer comments can be useful and important for improving the quality of scientific publications.


Spinal cord sparing reirradiation with helical tomotherapy.
The purpose of this study was to present planning, feasibility, toxicity, and outcome of helical tomotherapy for spinal cord-sparing reirradiation of spinal metastases and tumors. Thirty-six patients with spinal metastases and tumors who had undergone previous radiotherapy were reirradiated with helical tomotherapy because of tumor progression, pain, or compromised stability. Mean spinal cord dose of previous radiotherapy was 36.3 grays (Gy) after a median time interval of 17.5 months. Mean prescribed dose of reirradiation was 34.8 Gy. Daily megavoltage computed tomography (CT) image guidance was performed to assure precise dose application. Mean beam time was 8.4 minutes; the dose maximum to the spinal cord at reirradiation could be limited to a 9.8-Gy median dose (minimum, 5.2 Gy; maximum, 21.8 Gy). Significant pain relief from a median value of 7 on the visual analogue scale before therapy to a median value of 3 at 6 weeks after radiotherapy was achieved. One- and 2-year local control was 76% and 63%; overall survival was 67% after 1 year and 58% after 2 years. One grade 2 skin toxicity and no grade 3 or higher toxicities were observed. Helical tomotherapy makes reirradiation of spinal metastases and excellent avoidance of the spinal cord possible and achieves good pain relief and local control. With a minimal distance of several millimeters between target volume and spinal cord, tailor-made dose distributions with steep dose gradients around previously irradiated tissue are obtained and precisely applied with daily megavoltage CT-based image guidance.


Female-specific flightless phenotype for mosquito control.
Dengue and dengue hemorrhagic fever are increasing public health problems with an estimated 50-100 million new infections each year. Aedes aegypti is the major vector of dengue viruses in its range and control of this mosquito would reduce significantly human morbidity and mortality. Present mosquito control methods are not sufficiently effective and new approaches are needed urgently. A "sterile-male-release" strategy based on the release of mosquitoes carrying a conditional dominant lethal gene is an attractive new control methodology. Transgenic strains of Aedes aegypti were engineered to have a repressible female-specific flightless phenotype using either two separate transgenes or a single transgene, based on the use of a female-specific indirect flight muscle promoter from the Aedes aegypti Actin-4 gene. These strains eliminate the need for sterilization by irradiation, permit male-only release ("genetic sexing"), and enable the release of eggs instead of adults. Furthermore, these strains are expected to facilitate area-wide control or elimination of dengue if adopted as part of an integrated pest management strategy.


The CSL112-2001 trial: Safety and tolerability of multiple doses of CSL112 (apolipoprotein A-I [human]), an intravenous formulation of plasma-derived apolipoprotein A-I, among subjects with moderate renal impairment after acute myocardial infarction.
CSL112 (apolipoprotein A-I [human]) is a plasma-derived apolipoprotein A-I developed for early reduction of cardiovascular risk following an acute myocardial infarction (AMI). The safety of CSL112 among AMI subjects with moderate, stage 3 chronic kidney disease (CKD) is unknown. CSL112_2001, a multicenter, placebo-controlled, parallel-group, double-blind, randomized phase 2 trial, enrolled patients with moderate CKD within 7 days following AMI. Enrollment was stratified on the basis of estimated glomerular filtration rate and presence of diabetes requiring treatment. Patients were randomized in a 2:1 ratio to receive 4 weekly infusions of CSL112 6 g or placebo. The co-primary safety end points were renal serious adverse events (SAEs) and acute kidney injury, defined as an increase ≥26.5 μmol/L in baseline serum creatinine for more than 24 hours, during the treatment period. A total of 83 patients were randomized (55 CSL112 vs 28 placebo). No increase in renal SAEs was observed in the CSL112 group compared with placebo (CSL112 = 1 [1.9%], placebo = 4 [14.3%]). Similarly, no increase in acute kidney injury events was observed (CSL112 = 2 [4.0%], placebo = 4 [14.3%]). Rates of other SAEs were similar between groups. CSL112 administration resulted in increases in ApoA-I and cholesterol efflux similar to those observed in patients with AMI and normal renal function or stage 2 CKD enrolled in the ApoA-I Event Reducing in Ischemic Syndromes I trial. These results demonstrate the acceptable safety of the 6-g dose of CSL112 among AMI subjects with moderate stage 3 CKD and support inclusion of these patients in a phase 3 cardiovascular outcomes trial powered to assess efficacy.


Regulation of Notch 1 signaling in THP-1 cells enhances M2 macrophage differentiation.
Macrophage polarization is emerging as an important area of research for the development of novel therapeutics to treat inflammatory diseases. Within the current study, the role of Notch1R in macrophage differentiation was investigated as well as downstream effects in THP-1 monocytes cultured in "inflammation mimicry" media. Interference of Notch signaling was achieved using either the pharmaceutical inhibitor DAPT or Notch1R small interfering RNA (siRNA), and Notch1R expression, macrophage phenotypes, and anti- and proinflammatory cytokine expression were evaluated. Data presented show that Notch1R expression on M1 macrophages as well as M1 macrophage differentiation is significantly elevated during cellular stress (P < 0.05). However, under identical culture conditions, interference to Notch signaling via Notch1R inhibition mitigated these results as well as promoted M2 macrophage differentiation. Moreover, when subjected to cellular stress, macrophage secretion of proinflammatory cytokines was significantly heightened (P < 0.05). Importantly, Notch1R inhibition not only diminished proinflammatory cytokine secretion but also enhanced anti-inflammatory protein release (P < 0.05). Our data suggest that Notch1R plays a pivotal role in M1 macrophage differentiation and heightened inflammatory responses. Therefore, we conclude that inhibition of Notch1R and subsequent downstream signaling enhances monocyte to M2 polarized macrophage outcomes and promotes anti-inflammatory mediation during cellular stress.


Water quality risks of 'improved' water sources: evidence from Cambodia.
The objective of this study was to investigate the quality of on-plot piped water and rainwater at the point of consumption in an area with rapidly expanding coverage of 'improved' water sources. Cross-sectional study of 914 peri-urban households in Kandal Province, Cambodia, between July-August 2011. We collected data from all households on water management, drinking water quality and factors potentially related to post-collection water contamination. Drinking water samples were taken directly from a subsample of household taps (n = 143), stored tap water (n = 124), other stored water (n = 92) and treated stored water (n = 79) for basic water quality analysis for Escherichia coli and other parameters. Household drinking water management was complex, with different sources used at any given time and across seasons. Rainwater was the most commonly used drinking water source. Households mixed different water sources in storage containers, including 'improved' with 'unimproved' sources. Piped water from taps deteriorated during storage (P < 0.0005), from 520 cfu/100 ml (coefficient of variation, CV: 5.7) E. coli to 1100 cfu/100 ml (CV: 3.4). Stored non-piped water (primarily rainwater) had a mean E. coli count of 1500 cfu/100 ml (CV: 4.1), not significantly different from stored piped water (P = 0.20). Microbial contamination of stored water was significantly associated with observed storage and handling practices, including dipping hands or receptacles in water (P < 0.005), and having an uncovered storage container (P = 0.052). The microbial quality of 'improved' water sources in our study area was not maintained at the point of consumption, possibly due to a combination of mixing water sources at the household level, unsafe storage and handling practices, and inadequately treated piped-to-plot water. These results have implications for refining international targets for safe drinking water access as well as the assumptions underlying global burden of disease estimates, which posit that 'improved' sources pose minimal risks of diarrhoeal diseases.


Bis[O-propan-2-yl (4-eth-oxy-phen-yl)dithio-phospho-nato-κ(2) S,S']nickel(II).
The title compound, [Ni(C11H16O2PS2)2], is a neutral four-coordinate mononuclear complex with a square-planar geometry. The complex lies on an inversion center. The metal atom is surrounded by two chelating isobidentate O-propan-2-yl (4-eth-oxy-phen-yl)dithio-phospho-nate ligands in a trans configuration binding through the S-donor atoms. The Ni-S bond lengths are 2.2328 (5) and 2.2369 (5) Å, an insignificant difference to be considered anisobidentate. The Ni⋯P separation is 2.8224 (5) Å and the S-P bond lengths are 2.0035 (7) and 2.0053 (7) Å. The S-Ni-S (chelating) and S-Ni-S (trans) bond angles are 88.321 (18) and 180°. The Ni-S-P bond angles are 83.26 (2) and 83.33 (2)°, indicating a very minor distortion from ideal square-planar geometry for the Ni atom. The P atom, however, is distorted quite significantly from an ideal tetra-hedral geometry, as reflected by the S-P-S and O-P-C bond angles of 101.93 (3) and 100.70 (7)°, respectively.


A synthetic peptide homologous to retroviral transmembrane envelope proteins depresses protein kinase C mediated lymphocyte proliferation and directly inactivated protein kinase C: a potential mechanism for immunosuppression.
CKS-17, an immunosuppressive peptide homologous to certain retroviral transmembrane envelope protein, has been shown to inhibit lymphocyte proliferation in response to mitogens or alloantigens when covalently attached to bovine serum albumin (CKS-17-BSA). To define its site of action, we determined if CKS-17 conjugated to human serum albumin (CKS-17-HSA) could block the direct activation of lymphocytes by phorbol-12-myristate-13-acetate (PMA) or by a synthetic diacylglycerol, dioctanoylglycerol (DiC8). CKS-17-HSA inhibited lymphocyte proliferation in response to PMA and ionomycin in a dose-dependent manner with up to 88% inhibition occurring with 15 microM CKS-17-HSA. The conjugated peptide also inhibited the proliferation of lymphocytes in response to DiC8 and ionomycin by up to 57% at 15 microM CKS-17-HSA. Based on these findings we investigated the effect of CKS-17-HSA on the activity of protein kinase C (PKC), an enzyme directly activated by PMA and DiC8. PKC was isolated chromatographically from the cytosol of human neutrophils or the human lymphoblastoid cell line Jurkat. CKS-17-HSA caused a dose-dependent enzyme inhibition with a concentration giving half-maximal inhibition (IC50) of ca.3 microM and greater than 95% inhibition at 15 microM CKS-17-HSA. Inhibition of PKC by the conjugated peptide was not reversed by increasing concentrations of Ca2+, Mg2+, phosphatidylserine, diolein, or adenosine triphosphate (ATP), indicating that the conjugated peptide did not function as a chelator or competitive inhibitor. In contrast to its effects on PKC, CKS-17-HSA did not inhibit the activity of adenosine 3':5'-cyclic monophosphate (cyclic AMP)-dependent protein kinase (PK-A) nor the calcium and phospholipid-independent form of PKC (PK-M). Moreover the peptide inhibited in vivo PKC activity in cytosol of intact cells and in membrane of PMA-stimulated cells. These results suggest that the inhibition of lymphocyte proliferation by CKS-17-HSA may be due to the direct inactivation of PKC.


Rapidly progressing breast cancer in Nigeria.
To test the hypothesis that the bleak prognosis of breast cancer in Nigeria may be due, in part, to a subset of patients with rapidly progressing type of breast cancer, a prospective study of 120 breast cancer patients was undertaken. Patients were staged by the UICC-TNM system and the PEV system. Eighty-one (67.5%) of the patients had non PEV while 39 (32.5%) had PEV breast cancer. Of the 24 patients in TNM stage IV, 21 had PEV. Also 17.5% of all breast cancer patient or 53.8% of PEV patients were in the PEV stage with the worst prognosis. Following similar treatment, the median survival of non PEV patients (14 months) was significantly greater than that of PEV patients (6 months). Overall median survival of the cancer patients was 9.5 months. It is concluded that the finding that fully one third of our breast cancer patients have rapidly progressing breast cancer contributes significantly to the poor prognosis of breast cancer in Nigeria.


The links between allergen skin test sensitivity, airway responsiveness and airway response to allergen.
The allergen-induced early asthmatic response [provocation concentration (PC)20, the concentration causing a 20% forced expiratory volume in 1 s (FEV)1 fall] depends on the level of IgE sensitivity and the degree of nonallergic airway hyperresponsiveness (AHR) and can be predicted from histamine PC20 and allergen skin test endpoint. We examined the relationships between allergen PC20, methacholine PC20, and allergen skin test endpoint and assessed the accuracy of both the histamine PC20-based prediction of allergen PC20 (using methacholine) and a new methacholine PC20-based prediction equation. From 158 allergen challenges, the allergen PC20, the methacholine PC20, and the skin test endpoint were recorded and relationships between these three were sought. We compared the measured allergen PC20 to that predicted from the previous histamine PC20-based and the new methacholine-based formulae. In single regressions, allergen PC20 correlated with both methacholine PC20 (r=0.25, P=0.0015) and skin test endpoint (r=0.52, P <0.00005). The relationship was improved by multiple regression of log-allergen PC20vs. log-methacholine PC20 and log-endpoint (r=0.61, P <0.00005). The histamine-based formula predicted allergen PC20 to within 2 doubling concentrations in 80% and within 3 in 92%. The new methacholine-based formula to within 2 and 3 concentrations in 81% and 94%, respectively; only nine of 158 subjects were outside the 3 concentrations. We have confirmed the dependence of the allergen-induced early asthmatic response upon the level of allergic sensitivity and the degree of AHR, the latter as assessed by methacholine challenge. The allergen PC20 can be predicted to within 3 doubling concentrations in 94% of cases.


TBX3 acts as tissue-specific component of the Wnt/β-catenin transcriptional complex.
BCL9 and PYGO are β-catenin cofactors that enhance the transcription of Wnt target genes. They have been proposed as therapeutic targets to diminish Wnt signaling output in intestinal malignancies. Here we find that, in colorectal cancer cells and in developing mouse forelimbs, BCL9 proteins sustain the action of β-catenin in a largely PYGO-independent manner. Our genetic analyses implied that BCL9 necessitates other interaction partners in mediating its transcriptional output. We identified the transcription factor TBX3 as a candidate tissue-specific member of the β-catenin transcriptional complex. In developing forelimbs, both TBX3 and BCL9 occupy a large number of Wnt-responsive regulatory elements, genome-wide. Moreover, mutations in Bcl9 affect the expression of TBX3 targets in vivo, and modulation of TBX3 abundance impacts on Wnt target genes transcription in a β-catenin- and TCF/LEF-dependent manner. Finally, TBX3 overexpression exacerbates the metastatic potential of Wnt-dependent human colorectal cancer cells. Our work implicates TBX3 as context-dependent component of the Wnt/β-catenin-dependent transcriptional complex.


Association of DNA strand breaks with accelerated terminal differentiation in mouse epidermal cells exposed to tumor promoters.
We have studied the appearance of single strand breaks (SSB) in DNA of mouse keratinocytes exposed in vitro to various tumor promoters. Mouse basal keratinocytes were selectively cultured in low calcium medium, prelabeled with [14C]thymidine, exposed to test agents, and SSB quantified by alkaline elution. 12-O-Tetradecanoylphorbol-13-acetate (TPA) caused a dose-dependent (10(-9)-10(-7) M) increase in SSB after 24 h but not after shorter exposures. DNA containing TPA-induced SSB was found only in cells which had detached from the culture plate as a consequence of TPA-induced terminal differentiation. Attached cells, resistant to the differentiation-inducing effects of TPA, had the low level of SSB found in DNA from vehicle-treated control cells. Attached cells were resistant to the formation of SSB and to induced differentiation when reexposed to TPA. Other tumor-promoting phorbol esters, mezerein and retinyl phorbol acetate, also produced SSB in detached cells, whereas phorbol or resiniferatoxin caused neither SSB or cell detachment. Retinoic acid, which blocks the induction of differentiation by TPA, inhibited the production of SSB by TPA; however, fluocinolone acetonide, chymostatin, catalase, or superoxide dismutase blocked neither TPA-induced SSB nor terminal differentiation. Epidermal cell lines resistant to TPA-induced differentiation were also resistant to SSB production by TPA. Benzoyl peroxide (BP) (10(-4) M) induced SSB in basal keratinocytes within 1 h, and attached cells showed extensive SSB by 12 h. Retinoic acid had only a slight effect on BP-induced SSB, and 1 of 3 TPA-resistant cell lines developed SSB when exposed to BP. These results suggest that TPA-induced SSB in epidermal cells are an indirect consequence of the induction of terminal differentiation, whereas BP produces SSB by a more direct mechanism of DNA damage.


Counting drugs to understand the disease: the case of measuring the diabetes epidemic.
Diabetes prevalence increases globally with severe consequences for afflicted individuals and societies. Data on diabetes incidence and diabetes related mortality on a population level are, however, scarce. As an alternative to dedicated studies it has been suggested to use pharmacoepidemiological databases that are readily available, at least in the Nordic countries. For all 470,000 inhabitants in Funen County, Denmark, in the period 1992-2003, data on gender, date of birth, death and migration to and from the county, and any filled prescriptions of an anti-diabetic medication was obtained from the Odense Pharmaco-Epidemiological Database. Prevalence odds for use of an anti-diabetic medication rose annually 3.5% (95% confidence interval: 3.1%, 3.9%) for females, 4.5% (4.0%, 4.9%) for males. Corresponding incidence rates annually rose 4.8% (3.8%, 5.8%) for females, 4.5% (3.5%, 5.4%) for males. Mortality rates among treated annually declined 2.8% (1.4%, 4.1%) among females, 2.2% (0.9%, 3.5%) among males. The disequilibrium in absolute numbers between incidence and mortality among treated was the main driver for the increasing prevalence, while concurrent trends in incidence and diabetes related mortality only marginally affected prevalence trends. Trend estimates were insensitive to varying the length of the run-in period used for determining treatment status, except when using the naive and methodologically flawed run-in period of variable length. While pharmacoepidemiological databases provide a useful tool for monitoring pharmacologically treated diabetes, a dedicated diabetes database covering all prevalents and incidents is needed for a more detailed analysis of underlying causes and trends.


A morphogenetic model for the development of cortical convolutions.
The convolutions of the mammalian cortex are one of its most intriguing characteristics. Their pattern is very distinctive for different species, and there seems to be a remarkable relationship between convolutions and the architectonic and functional regionalization of the cerebral cortex. Yet the mechanisms behind the development of convolutions and their association with the cortical regionalization are poorly understood. Here we propose a morphogenetic model for the development of cortical convolutions based on the structure of the cortex as a closed surface with glial and axonal fibres pulling radially, the fundamental mechanical properties of cortex and fibres (elasticity and plasticity), and the growth of the cortical surface. The computer simulations of this model suggest that convolutions are a natural consequence of cortical growth. The model reproduces several aspects of convolutional development, such as the relationship between cortical surface and brain volume among mammals, the period of compensation in the degree of convolution observed in gyrencephalic brains and the dependence of the degree of convolution on cortical thickness. We have also studied the effect of early cortical regionalization on the development of convolutions by introducing geometric, mechanic and growth asymmetries in the model. The morphogenetic model is thus able to reproduce the gradients in the degree of convolution, the development of primary, secondary and tertiary convolution, and the overproduction of sulci observed in animals with altered afferent cortical connections.


Sedentary time has a stronger impact on metabolic health than moderate to vigorous physical activity in adolescents with obesity: a cross-sectional analysis of the Beta-JUDO study.
Relationships between movement-related behaviours and metabolic health remain underexplored in adolescents with obesity. To compare profiles of sedentary time (more sedentary, SED+ vs. less sedentary, SED-), moderate to vigorous physical activity (MVPA) time (more active, MVPA+ vs. less active, MVPA-) and combinations of behaviours (SED-/MVPA+, SED-/MVPA-, SED+/MVPA+, SED+/MVPA-) in regard to metabolic health. One hundred and thirty-four subjects (mean age 13.4 ± 2.2 yrs, mean body mass index [BMI] 98.9 ± 0.7 percentile, 48.5% females) underwent 24 h/7 day accelerometry, anthropometric, body composition, blood pressure (BP), lipid profile and insulin resistance (IR) assessments. Metabolic health was better in SED- [lower fat mass (FM) percentage (p < 0.05), blood pressure (BP) (p < 0.05), homeostasis model assessment of insulin resistance (HOMA-IR) (p < 0.001) and metabolic syndrome risk score (MetScore) (p < 0.001), higher high-density lipoprotein-cholesterol (HDL-c) (p = 0.001)] vs. SED+ group and in MVPA+ [lower triglyceridemia (TG), (p < 0.05), HOMA-IR (p < 0.01) and MetScore (p < 0.001), higher HDL-c (p < 0.01)] vs. MVPA- group after adjustment with age, gender, maturation and BMI. SED-/MVPA+ group had the best metabolic health. While sedentary (p < 0.001) but also MVPA times (p < 0.001) were lower in SED-/MVPA- vs. SED+/MVPA+, SED-/MVPA- had lower FM percentage (p < 0.05), HOMA-IR (p < 0.01) and MetScore (p < 0.05) and higher HDL-c (p < 0.05), independently of BMI. Sedentary time was positively correlated with HOMA-IR and Metscore and negatively correlated with HDL-c after adjustment with MVPA (p < 0.05). MVPA was negatively correlated with HOMA-IR, BP and MetScore and positively correlated with HDL-c after adjustment with sedentary time (p < 0.05). Lower sedentary time is associated with a better metabolic health independently of MVPA and might be a first step in the management of pediatric obesity when increasing MVPA is not possible.


Vertical-cavity surface-emitting phase shifter.
This study proposes a novel technique for a 2D beam steering system using hybrid plasmonic phase shifters with a cylindrical configuration in a 2D periodic array suitable for LIDAR applications. A nanoscale VCSEP design facilitates a sub-wavelength spacing between individual phase shifters, yielding an expanded field of view and side lobes suppression. The proposed design includes a highly doped sub-micron silicon pillar covered by a thin layer of nonlinear material and an additional conductive metal layer. Characterization of a single VCSEP demonstrated a Free Spectral Range (FSR) of 53.28 ± 2.5 nm and a transmission variation of 3 dB, with VπL equal to 0.075 V-mm.


Gis and fuzzy logic applied to modelling forest fire risk.
Fire risk mapping is a basic planning and protection element. This study presents the application of fuzzy logic in a geographic information system (GIS) as an alternative multi-criteria analysis for determining the areas of highest risk of forest fire in natural forest remnants in the Brazil. In the decision-making process, a set of factors that are relevant to fire safety were identified in the study area. For each input variable chosen for the model, a pertinence function was defined that best described its influence on fire risk. Subsequently, the variables were combined for the presentation of the final fire risk map. Concluded in the study that an increased risk of fire occurs at the wildland - urban interface. A strong relationship was observed between the fire ignition points and proximity to roads and urban areas. The proposed model was efficient to integrate the variables and determine areas of greatest risk.


[Changes of catecholamine content in the myocardium in thyrotoxicosis].
Experimental thyrotoxicosis was induced in rats and rabbits. The content of catecholamines was significantly decreasing in the myocardium of rabbits in the presence of severe thyroidine-induced toxicosis. The noradrenaline concentration was especially low in the ventricles. The histochemical examination of the myocardium of rats revealed a reduction of catecholamines fluorescence, which indicates a decrease in their amount in the adrenergic structures.