Systematic analysis of the entire second extracellular loop of the V(1a) vasopressin receptor: key residues, conserved throughout a G-protein-coupled receptor family, identified.
The roles of extracellular residues of G-protein-coupled receptors (GPCRs) are not well defined compared with residues in transmembrane helices. Nevertheless, it has been established that extracellular domains of both peptide-GPCRs and amine-GPCRs incorporate functionally important residues. Extracellular loop 2 (ECL2) has attracted particular interest, because the x-ray structure of bovine rhodopsin revealed that ECL2 projects into the binding crevice within the transmembrane bundle. Our study provides the first comprehensive investigation into the role of the individual residues comprising the entire ECL2 domain of a small peptide-GPCR. Using the V(1a) vasopressin receptor, systematic substitution of all of the ECL2 residues by Ala generated 30 mutant receptors that were characterized pharmacologically. The majority of these mutant receptor constructs (24 in total) had essentially wild-type ligand binding and intracellular signaling characteristics, indicating that these residues are not critical for normal receptor function. However, four aromatic residues Phe(189), Trp(206), Phe(209), and Tyr(218) are important for agonist binding and receptor activation and are highly conserved throughout the neurohypophysial hormone subfamily of peptide-GPCRs. Located in the middle of ECL2, juxtaposed to the highly conserved disulfide bond, Trp(206) and Phe(209) project into the binding crevice. Indeed, Phe(209) is part of the Cys-X-X-X-Ar (where Ar is an aromatic residue) motif, which is well conserved in both peptide-GPCRs and amine-GPCRs. In contrast, Phe(189) and Tyr(218), located at the extreme ends of ECL2, may be important for determining the position of the ECL2 cap over the binding crevice. This study provides mechanistic insight into the roles of highly conserved ECL2 residues.


Proceedings: Persepectives on adolescent medicine: concepts and program design.
The concepts and goals of a program in adolescent medicine should include development of a capability to focus on current health needs of youth in a variety of settings; to plan clinical services to meet those needs with the flexibility necessary to respond to changing future requirements; and to deliver service within such a context while simulataneously creating a milieu conducive to education and investigation into the very process and definition of adolescence. The Division of Adolescent Medicine at Montefiore Hospital and Medical Center was designed 7 years ago to fulfill these goals and consequently may serve others as a functional model for health care delivery to teenagers. The Division is comprised of: (1) a 37 bed in-patient unit; (2) a hospital-based ambulatory program including general diagnostic and follow-up services, as well as a speciality service capability in the areas of gynecology and family planning, cardiology, gastroenterology and nutrition; (3) primary care health services within teenage dentention and prison facilities; (4) addictive disease diagnostic and treatment programs; (5) school health programs from intermediate school through college levels, and (6) the division also performs supportive and consultative functions for a variety of community-based agencies. Within the programatic design approximately 70,000 adolescents have been served. The cornerstone of the educational and investigative efforts has been the concept that all the above six functional units are clinical laboratories and classrooms so that training and research activities are integral parts of each of the service areas. This program design is continually undergoing revision and refinement so as to remain ever-responsive to new and emerging problems to meet additional training demands and, most importantly, to permit and encourage creativity and growth patients and staff.


Increasing viral burden in CD4+ T cells from patients with human immunodeficiency virus (HIV) infection reflects rapidly progressive immunosuppression and clinical disease.
To determine over time the relation between viral burden and immunologic decline in patients with asymptomatic human immunodeficiency virus (HIV) infection. Blind analysis of cell samples from matched cohorts for HIV proviral DNA by polymerase chain reaction, retrospective analysis of clinical data on patients, and prospective follow-up of patients seropositive for the human immunodeficiency virus type 1 (HIV-1). National research clinic and academic medical centers. Cohort 1 included 12 healthy HIV-1-seropositive patients (average follow-up, 14 months): Six patients had stable disease and 6 developed rapidly progressive disease. Cohort 2 included 15 healthy HIV-1-seropositive patients from the Multi-center AIDS Cohort Study (average follow-up, 32 months): Eight patients had stable disease and 7 developed rapidly progressive disease. LABORATORY STUDIES: Quantitative polymerase chain reaction was done to determine the HIV-1 viral burden in sort-purified CD4+ T cells obtained from patients at various timepoints. In patients who remained asymptomatic, frequencies of HIV-infected CD4+ T cells were low (less than 1/10,000 to 1/1000) at study entry and increased only minimally (none higher than 1/1000). In contrast, among patients who developed HIV-related symptoms including the acquired immunodeficiency syndrome (AIDS) despite having similar CD4 counts, frequencies of HIV-infected CD4+ T cells were higher at entry (greater than 1/1000) and increased substantially (greater than 1/100) in most within 3 months of developing progressive disease. This increase in HIV burden coincided with a significant decline over time in the percent of T4 cells (31% to 16%), whereas the percent of T4 cells was unchanged in persons who remained asymptomatic (33% to 34%). Increasing viral burden in peripheral blood CD4+ T-cells is directly associated with a progressive decline in CD4+ T cells and deteriorating clinical course in HIV-infected patients.


Multiple vaginal wall cysts: diagnosis and surgical management.
Simple cysts of the female genital tract may become symptomatic and require surgical removal. A 20-year-old woman had complaints of a vaginal bulge, pelvic pressure, dyspareunia, and stress urinary incontinence. Two cystic masses were seen in the vagina. A magnetic resonance imaging scan revealed 2 additional larger cysts. Urodynamic evaluation was significant for stress incontinence at 200 mL and a Valsalva leak-point pressure of 51 cm H(2)0. The 2 smaller cysts were removed intact through a superficial incision. The larger cysts were intentionally ruptured and dissected out. Histologic examination revealed a low cuboidal or a ciliated columnar epithelium that stained positive with mucicarmine, consistent with müllerian origin. One year after surgical excision, the patient remained symptom free with no urinary incontinence and no recurrence of the cysts. Magnetic resonance imaging was useful in delineating the course and anatomic arrangement of the vaginal cysts, but more importantly, identified another cyst that was not readily apparent at physical examination.


The "MS-ROM/IFAST" Model, a Novel Parallel Nonlinear EEG Analysis Technique, Distinguishes ASD Subjects From Children Affected With Other Neuropsychiatric Disorders With High Degree of Accuracy.
Background and Objective. In a previous study, we showed a new EEG processing methodology called Multi-Scale Ranked Organizing Map/Implicit Function As Squashing Time (MS-ROM/IFAST) performing an almost perfect distinction between computerized EEG of Italian children with autism spectrum disorder (ASD) and typically developing children. In this study, we assessed this system in distinguishing ASD subjects from children affected with other neuropsychiatric disorders (NPD). Methods. At a psychiatric practice in Texas, 20 children diagnosed with ASD and 20 children diagnosed with NPD were entered into the study. Continuous segments of artifact-free EEG data lasting 10 minutes were entered in MS-ROM/IFAST. From the new variables created by MS-ROM/IFAST, only 12 has been selected according to a correlation criterion. The selected features represent the input on which supervised machine learning systems (MLS) acted as blind classifiers. Results. The overall predictive capability in distinguishing ASD from other NPD cases ranged from 93% to 97.5%. The results were confirmed in further experiments in which Italian and US data have been combined. In this analysis, the best MLS reached 95.0% global accuracy in 1 out of 3 classes distinction (ASD, NPD, controls). This study demonstrates the value of EEG processing with advanced MLS in the differential diagnosis between ASD and NPD cases. The results were not affected by age, ethnicity and technicalities of EEG acquisition, confirming the existence of a specific EEG signature in ASD cases. To further support these findings, it was decided to test the behavior of already trained neural networks on 10 Italian very young ASD children (25-37 months). In this test, 9 out of 10 cases have been correctly recognized as ASD subjects in the best case. Conclusions. These results confirm the possibility of an early automatic autism detection based on standard EEG.


Transformations of count data for tests of interaction in factorial and split-plot experiments.
In applied entomological experiments, when the response is a count-type variable, certain transformation remedies such as the square root, logarithm (log), or rank transformation are often used to normalize data before analysis of variance. In this study, we examine the usefulness of these transformations by reanalyzing field-collected data from a split-plot experiment and by performing a more comprehensive simulation study of factorial and split-plot experiments. For field-collected data, significant interactions were dependent upon the type of transformation. For the simulation study, Poisson distributed errors were used for a 2 by 2 factorial arrangement, in both randomized complete block and split-plot settings. Various sizes of main effects were induced, and type I error rates and powers of the tests for interaction were examined for the raw response values, log-, square root-, and rank-transformed responses. The aligned rank transformation also was investigated because it has been shown to perform well in testing interactions in factorial arrangements. We found that for testing interactions, the untransformed response and the aligned rank response performed best (preserved nominal type I error rates), whereas the other transformations had inflated error rates when main effects were present. No evaluations of the tests for main effects or simple effects have been conducted. Potentially these transformations will still be necessary when performing these tests.


Chemical synthesis, folding, and structural insights into O-fucosylated epidermal growth factor-like repeat 12 of mouse Notch-1 receptor.
Notch receptors are cell surface glycoproteins that play key roles in a number of developmental cascades in metazoa. The extracellular domains of Notch-1 receptors are composed of 36 tandem epidermal growth factor (EGF)-like repeats, many of which are modified at highly conserved consensus sites by an unusual form of O-glycan, with O-fucose. The O-fucose residues on certain EGF repeats may be elongated. In mammalian cells this can be a tetrasaccharide, Siaα2,3Galβ1,4GlcNAcβ1,3Fucα1→. This elongation process is initiated by the action of O-fucose-specific β1,3 N-acetylglucosaminyltransferases of the Fringe family. There is evidence that the addition of GlcNAc by Fringe serves as an essential modulator of the interaction of Notch with its ligands and the triggering of activation. Here we describe the efficient synthesis, folding, and structural characterization of EGF repeat 12 (EGF 12) of a mouse Notch-1 receptor bearing different O-fucose glycan chains. We demonstrate that the three disulfide bonds, Cys(456)-Cys(467) (C1-C3), Cys(461)-Cys(476) (C2-C4), and Cys(478)-Cys(487) (C5-C6) were correctly formed in the nonglycosylated as well as the O-fucosylated forms of EGF 12. Three-dimensional structural studies by NMR reveal that the methyl group of fucose is in close contact with ILe(475), Met(477), Pro(478) residues and this stabilizes the conformation of the antiparallel β-sheet of EGF 12. The addition of the GlcNAc residue on O-fucosylated EGF 12 induces a significant conformational change in the adjacent tripeptide sequence, Gln(462)Asn(463)Asp(464), which is a motif involved in the natural, enzymatic O-fucosylation at the conserved site (Cys(461)X(4)Ser/ThrCys(467)).


Molecularly Defined Adult Granulosa Cell Tumor of the Ovary: The Clinical Phenotype.
The histopathologic features of adult granulosa cell tumors (AGCTs) are relatively nonspecific, resulting in misdiagnosis of other cancers as AGCT, a problem that has not been well characterized. FOXL2 mutation testing was used to stratify 336 AGCTs from three European centers into three categories: 1) FOXL2 mutant molecularly defined AGCT (MD-AGCT) (n = 256 of 336), 2) FOXL2 wild-type AGCT (n = 17 of 336), 3) misdiagnosed other tumor types (n = 63 of 336). All statistical tests were two-sided. The overall and disease-specific survival of the misdiagnosed cases was lower than in the MD-AGCTs (P < .001). The misdiagnosed cases accounted for 71.9% of disease-specific deaths within five years. In the population-based cohort, overall survival of MD-AGCT patients was not different from age-matched, population-based controls. Even though 35.2% of all the MD-AGCT patients in our study experienced a relapse, AGCT is usually an indolent disease. The historical, premolecular data underpinning our clinical understanding of AGCT was likely skewed by inclusion of misdiagnosed cases, and future management strategies should reflect the potential for surgical cure and long survival even after relapse.


Far-Reaching Dispersal of Borrelia burgdorferi Sensu Lato-Infected Blacklegged Ticks by Migratory Songbirds in Canada.
Lyme disease has been documented in northern areas of Canada, but the source of the etiological bacterium, Borrelia burgdorferi sensu lato (Bbsl) has been in doubt. We collected 87 ticks from 44 songbirds during 2017, and 24 (39%) of 62 nymphs of the blacklegged tick, Ixodes scapularis, were positive for Bbsl. We provide the first report of Bbsl-infected, songbird-transported I. scapularis in Cape Breton, Nova Scotia; Newfoundland and Labrador; north-central Manitoba, and Alberta. Notably, we report the northernmost account of Bbsl-infected ticks parasitizing a bird in Canada. DNA extraction, PCR amplification, and DNA sequencing reveal that these Bbsl amplicons belong to Borrelia burgdorferi sensu stricto (Bbss), which is pathogenic to humans. Based on our findings, health-care providers should be aware that migratory songbirds widely disperse B. burgdorferi-infected I. scapularis in Canada's North, and local residents do not have to visit an endemic area to contract Lyme disease.


Tomotherapy improves local control and changes failure patterns in locally advanced malignant pleural mesothelioma.
The purpose of the study was to determine whether intensity modulated radiation therapy delivered via helical tomotherapy improves local control (LC) after pleurectomy/decortication (P/D) for malignant pleural mesothelioma compared with 3-dimensional conformal radiation therapy (3D-CRT). Forty-five consecutive patients were treated with adjuvant radiation to 45 Gy in 1.8 Gy fractions after P/D between 2006 and 2014; 23 received 3D-CRT, and 22 received tomotherapy. Kaplan-Meier analysis was used to calculate overall survival, time to in-field or local failure (LF), and time to out-of-field failure. The Student t test and Fisher exact test were used to detect between-group differences. Median follow-up time was 19.4 months and 12.7 months for the 3D-CRT and tomotherapy groups, respectively. Eighty-two percent of patients had T3/T4 disease, and 64% had positive nodes; 17.4% and 41% of patients in the 3D-CRT and tomotherapy groups had nonepithelioid histology, respectively. Mean planning target volume dose, percentage of planning target volume receiving 100% of the prescription dose, and lung doses were significantly greater with tomotherapy (P < .05), but toxicity rates (including radiation pneumonitis rates) were equivalent. LC was significantly improved with tomotherapy on Kaplan-Meier analysis with outcomes censored at 2 years (P < .05); uncensored, this became a trend (P = .06). Median time to LF was 19 months with tomotherapy and 10.9 months in 3D-CRT (the latter interval being less than the median follow-up in the tomotherapy group). On univariate analysis, treatment modality was the only significant predictor of LC (P < .05). Isolated LF was significantly more frequent with 3D-CRT (P < .05). Conversely, isolated out-of-field failure was significantly more frequent with tomotherapy (P < .05). Overall survival and out-of-field control were not significantly different. Tomotherapy after P/D for malignant pleural mesothelioma is associated with improved target coverage that translates into improved LC compared with 3D-CRT. This is related to a change in failure patterns, with isolated LF being more common in the 3D-CRT group and isolated out-of-field failures predominating in the tomotherapy group.


[Preparation and transdermal diffusion of ursolic acid ethosomes].
To prepare ursolic acid ethosomes and investigate the penetration characteristics of ursolic ethosomes as a transdermal vehicle. Ursolic acid ethosomes were prepared by injection method, and the shape and particle size of the ethosomes were analyzed. Ursolic acid permeation tests in vitro through the skin of rats were performed in TP-3 diffusion cell. The accumulated permeation amounts of ursolic acid 10% isopropanol solution, ursolic acid liposomes, ursolic acid ethosomes were compared. The average encapsulation percentage, particle size, and Zeta potential of the ethosomes were (95.83 +/- 0.86)%, (87.5 +/- 7.5) nm and - (38.4 +/- 3.6) mV, respectively. The accumulated permeation amount of the ethosomes in 12 h was 146.49 microg x cm(-2), and its transdermal permeability in 12 h was 12.17 microg x cm(-2) x h(-1). The encapsulation percentage of the ethosomes is good, and the stability of the ursolic acid ethosomes is fine. Ethosomes can significantly enhance the diffusion rate of ursolic acid through the skin of rats.


Autocrine selection of a GLP-1R G-protein biased agonist with potent antidiabetic effects.
Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists have emerged as treatment options for type 2 diabetes mellitus (T2DM). GLP-1R signals through G-protein-dependent, and G-protein-independent pathways by engaging the scaffold protein β-arrestin; preferential signalling of ligands through one or the other of these branches is known as 'ligand bias'. Here we report the discovery of the potent and selective GLP-1R G-protein-biased agonist, P5. We identified P5 in a high-throughput autocrine-based screening of large combinatorial peptide libraries, and show that P5 promotes G-protein signalling comparable to GLP-1 and Exendin-4, but exhibited a significantly reduced β-arrestin response. Preclinical studies using different mouse models of T2DM demonstrate that P5 is a weak insulin secretagogue. Nevertheless, chronic treatment of diabetic mice with P5 increased adipogenesis, reduced adipose tissue inflammation as well as hepatic steatosis and was more effective at correcting hyperglycaemia and lowering haemoglobin A1c levels than Exendin-4, suggesting that GLP-1R G-protein-biased agonists may provide a novel therapeutic approach to T2DM.


Comprehensive analysis of the genome transcriptome and proteome landscapes of three tumor cell lines.
We here present a comparative genome, transcriptome and functional network analysis of three human cancer cell lines (A431, U251MG and U2OS), and investigate their relation to protein expression. Gene copy numbers significantly influenced corresponding transcript levels; their effect on protein levels was less pronounced. We focused on genes with altered mRNA and/or protein levels to identify those active in tumor maintenance. We provide comprehensive information for the three genomes and demonstrate the advantage of integrative analysis for identifying tumor-related genes amidst numerous background mutations by relating genomic variation to expression/protein abundance data and use gene networks to reveal implicated pathways.


Differential inhibition of membrane type 3 (MT3)-matrix metalloproteinase (MMP) and MT1-MMP by tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-3 rgulates pro-MMP-2 activation.
The membrane type (MT)-matrix metalloproteinases (MMPs) constitute a subgroup of membrane-anchored MMPs that are major mediators of pericellular proteolysis and physiological activators of pro-MMP-2. The MT-MMPs also exhibit differential inhibition by members of the tissue inhibitor of metalloproteinase (TIMP) family. Here we investigated the processing, catalytic activity, and TIMP inhibition of MT3-MMP (MMP-16). Inhibitor profile and mutant enzyme studies indicated that MT3-MMP is regulated on the cell surface by autocatalytic processing and ectodomain shedding. Inhibition kinetic studies showed that TIMP-3 is a high affinity inhibitor of MT3-MMP when compared with MT1-MMP (K(i) = 0.008 nm for MT3-MMP versus K(i) = 0.16 nm for MT1-MMP). In contrast, TIMP-2 is a better inhibitor of MT1-MMP. MT3-MMP requires TIMP-2 to accomplish full pro-MMP-2 activation and this process is enhanced in marimastatpretreated cells, consistent with regulation of active enzyme turnover by synthetic MMP inhibitors. TIMP-3 also enhances the activation of pro-MMP-2 by MT3-MMP but not by MT1-MMP. TIMP-4, in contrast, cannot support pro-MMP-2 activation with either enzyme. Affinity chromatography experiments demonstrated that pro-MMP-2 can assemble trimolecular complexes with a catalytic domain of MT3-MMP and TIMP-2 or TIMP-3 suggesting that pro-MMP-2 activation by MT3-MMP involves ternary complex formation on the cell surface. These results demonstrate that TIMP-3 is a major regulator of MT3-MMP activity and further underscores the unique interactions of TIMPs with MT-MMPs in the control of pericellular proteolysis.


Developing an anterior cervical diskectomy and fusion simulator for neurosurgical resident training.
Surgical simulators are useful in many surgical disciplines to augment residency training. Duty hour restrictions and increasing emphasis on patient safety and attending oversight have changed neurosurgical education from the traditional apprenticeship model. The Congress of Neurological Surgeons Simulation Committee has been developing neurosurgical simulators for the purpose of enhancing resident education and assessing proficiency. To review the initial experience with an anterior cervical diskectomy and fusion (ACDF) simulator. The first ACDF training module was implemented at the 2012 Congress of Neurological Surgeons Annual Meeting. The 90-minute curriculum included a written pretest, didactics, a practical pretest on the simulator, hands-on training, a written posttest, a practical posttest, and postcourse feedback. Didactic material covered clinical indications for ACDF, comparison with other cervical procedures, surgical anatomy and approach, principles of arthrodesis and spinal fixation, and complication management. Written pretests and posttests were administered to assess baseline knowledge and evidence of improvement after the module. Qualitative evaluation of individual performance on the practical (simulator) portion was included. Three neurosurgery residents, 2 senior medical students, and 1 attending neurosurgeon participated in the course. The pretest scores were an average 9.2 (range, 6-13). Posttest scores improved to 11.0 (range, 9-13; P = .03). Initial experience with the ACDF simulator suggests that it may represent a meaningful training module for residents. Simulation will be an important training modality for residents to practice surgical technique and for teachers to assess competency. Further development of an ACDF simulator and didactic curriculum will require additional verification of simulator validity and reliability.


Brain Atrophy Estimated from Structural Magnetic Resonance Imaging as a Marker of Large-Scale Network-Based Neurodegeneration in Aging and Stroke.
Brain atrophy is a normal part of healthy aging, and stroke appears to have neurodegenerative effects, accelerating this atrophy to pathological levels. The distributed pattern of atrophy in healthy aging suggests that large-scale brain networks may be involved. At the same time, the network wide effects of stroke are beginning to be appreciated. There is now widespread use of network methods to understand the brain in terms of coordinated brain activity or white matter connectivity. Examining brain morphology on a network level presents a powerful method of understanding brain structure and has been successfully applied to charting the course of brain development. This review will introduce recent advances in structural magnetic resonance imaging (MRI) acquisition and analyses that have allowed for reliable and reproducible estimates of atrophy in large-scale brain networks in aging and after stroke. These methods are currently underutilized despite their ease of acquisition and potential to clarify the progression of brain atrophy as a normal part of healthy aging and in the context of stroke. Understanding brain atrophy at the network level may be key to clarifying healthy aging processes and the pathway to neurodegeneration after stroke.


Changes in lipid composition and arachidonic acid turnover during the life cycle of the yeast Dipodascopsis uninucleata.
Ungerminated ascospores of Dipodascopsis uninucleata contained 18 times more lipid (5.5 % dry wt) than germinated cells; the lipid comprised 58 % (w/w) glycolipids, 28 % (w/w) neutral lipids (mainly triacylglycerols)and 14 % (w/w) phospholipids (mainly phosphatidylcholine and phosphatidylethanolamine). During germination the absolute amounts of all three lipid fractions fell sharply but, during the subsequent initiation of hyphal growth,the amount of phospholipids increased. As these hyphae began to differentiate for the sexual stage of the life cycle,the amount of neutral lipid then increased. The fatty acyl groups of the glyco-, neutral and phospholipid fractions throughout the life cycle were mainly palmitate (16:0), oleate (18: 1) and linoleate (18:2). The percentage of 16:O remained constant during the life cycle while the relative amounts of 18:2 plus alpha-linolenate (18:3) in the glyco-,neutral and phospholipid fractions first increased during initiation of growth and then decreased during the onset of differentiation. The opposite trend occurred with 18: 1. When [(3)H]arachidonic acid (ARA) and [1-(14)C]181: were fed separately to D. uninucleata, both were rapidly incorporated into phospholipids. Highest incorporation of ARA was in the growth phase; during the onset and remainder of the differentiation phase, the amount of ARA decreased in this fraction. Incorporation of 18: 1 increased during growth and differentiation, with a significant proportion(49% to 57%) being incorporated into triacylglycerols compared to a much smaller proportion (12% to 17%) of ARA.


Re-characterization of mono-2-ethylhexyl phthalate hydrolase belonging to the serine hydrolase family.
A novel bacterium assimilating di-2-ethylhexyl phthalate as a sole carbon source was isolated, and identified as a Rhodococcus species and the strain was named EG-5. The strain has a mono-2-ethylhexyl phthalate (MEHP) hydrolase (EG-5 MehpH), which exhibits some different enzymatic features when compared with the previously reported MEHP hydrolase (P8219 MehpH) from Gordonia sp. These differences include different pH optimum activity, maximal reaction temperature and heat stability. The Km and Vmax values of EG-5 MehpH were significantly higher than those of P8219 MehpH. The primary structure of EG-5 MehpH showed the highest sequence identity to that of P8219 MehpH (39%) among hydrolases. The phylogenetic tree suggested that EG-5 MehpH and P8219 MehpH were categorized in different groups of the novel MEHP hydrolase family. Mutation of a conserved R(109) residue of EG-5 MehpH to a hydrophobic residue resulted in a dramatic reduction in the Vmax value towards MEHP without affecting the Km value. These results indicate that this residue may neutralize the negative charge of a carboxylate anion of MEHP, and thus inhibit the catalytic nucleophile from attacking the ester bond. In other words, the R residue blocks inhibition from the carboxylate anion of MEHP. Recently, registered hypothetical proteins exhibiting 98% or 99% identities for EG-5 MehpH or for P8219 MehpH were found from some pathogens belonging to Actinomycetes. The protein may have other activities besides MEHP hydrolysis and function in other physiological reactions in some Actinomycetes.


Exploring neural dysfunction in 'clinical high risk' for psychosis: a quantitative review of fMRI studies.
Individuals at clinical high risk (CHR) of developing psychosis present with widespread functional abnormalities in the brain. Cognitive deficits, including working memory (WM) problems, as commonly elicited by n-back tasks, are observed in CHR individuals. However, functional MRI (fMRI) studies, comprising a heterogeneous cluster of general and social cognition paradigms, have not necessarily demonstrated consistent and conclusive results in this population. Hence, a comprehensive review of fMRI studies, spanning almost one decade, was carried out to observe for general trends with respect to brain regions and cognitive systems most likely to be dysfunctional in CHR individuals. 32 studies were included for this review, out of which 22 met the criteria for quantitative analysis using activation likelihood estimation (ALE). Task related contrast activations were firstly analysed by comparing CHR and healthy control participants in the total pooled sample, followed by a comparison of general cognitive function studies (excluding social cognition paradigms), and finally by only looking at n-back working memory task based studies. Findings from the ALE implicated four key dysfunctional and distinct neural regions in the CHR group, namely the right inferior parietal lobule (rIPL), the left medial frontal gyrus (lmFG), the left superior temporal gyrus (lSTG) and the right fronto-polar cortex (rFPC) of the superior frontal gyrus (SFG). Narrowing down to relatively few significant dysfunctional neural regions is a step forward in reducing the apparent ambiguity of overall findings, which would help to target specific neural regions and pathways of interest for future research in CHR populations.


Forecasting Hotspots-A Predictive Analytics Approach.
Current visual analytics systems provide users with the means to explore trends in their data. Linked views and interactive displays provide insight into correlations among people, events, and places in space and time. Analysts search for events of interest through statistical tools linked to visual displays, drill down into the data, and form hypotheses based upon the available information. However, current systems stop short of predicting events. In spatiotemporal data, analysts are searching for regions of space and time with unusually high incidences of events (hotspots). In the cases where hotspots are found, analysts would like to predict how these regions may grow in order to plan resource allocation and preventative measures. Furthermore, analysts would also like to predict where future hotspots may occur. To facilitate such forecasting, we have created a predictive visual analytics toolkit that provides analysts with linked spatiotemporal and statistical analytic views. Our system models spatiotemporal events through the combination of kernel density estimation for event distribution and seasonal trend decomposition by loess smoothing for temporal predictions. We provide analysts with estimates of error in our modeling, along with spatial and temporal alerts to indicate the occurrence of statistically significant hotspots. Spatial data are distributed based on a modeling of previous event locations, thereby maintaining a temporal coherence with past events. Such tools allow analysts to perform real-time hypothesis testing, plan intervention strategies, and allocate resources to correspond to perceived threats.


Nutrient variation in an urban lake chain and its consequences for phytoplankton production.
In the Central Arizona-Phoenix (CAP) ecosystem, managers divert mixed stream water and groundwater to maintain an artificial lake chain in Indian Bend Wash (IBW), a historically flashy, ephemeral, desert stream. Nutrient concentrations in the CAP ecosystem's groundwater, stream water, and floodwater differ: stream water has low concentrations of both inorganic N and P, while groundwater is low in inorganic P but rich in nitrate (NO(3)(-)). Consequently, groundwater contribution drives inorganic N concentrations in the lake chain. In contrast, floodwater typically has high P concentrations while remaining low in N. Thus we expected N and P concentrations in IBW lakes to vary with the mix of water flowing through them. Elevated NO(3)(-) and low inorganic P concentrations were predicted when groundwater pumping was pronounced and this prediction was supported. We hypothesized that these predictable changes in water chemistry would affect nutrient limitation of phytoplankton. Laboratory nutrient-addition bioassays demonstrated that phytoplankton growth was P-limited throughout the summer of 2003 when N/P was high. However, after a late-season flood drove N/P below 31:1, the expected threshold between N and P limitation, N limitation was observed. Our results indicate that effects of floods, the preeminent historic drivers of Sonoran Desert stream biogeochemistry, are mitigated in urban ecosystems by decisions about which spigots to turn. Consequently, nutrient limitation of urban streams is driven as much by management decisions as by natural hydrologic variation.


Effectiveness of Menthacarin on symptoms of irritable bowel syndrome.
Irritable bowel syndrome (IBS) and functional dyspepsia (FD) are common functional gastrointestinal disorders with overlapping symptoms. Effectiveness and safety of Menthacarin (Menthacarin® is the active ingredient of the product Carmenthin® [Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany]) in FD treatment were already demonstrated. We assessed the effectiveness of Menthacarin in reducing concomitant IBS-associated symptoms in FD patients. A systematic search to identify eligible double-blind, randomized controlled trials (RCTs) investigating Menthacarin in FD patients and focusing on IBS-associated symptoms was performed. Three out of five identified RCTs included a total of 111 eligible subjects, which allowed for summary statistics and inclusion into subgroup analysis for FD patients with IBS-associated symptoms. With pain intensity values decreasing by 50-75% on average during 28 days of treatment in patients with accompanying IBS, the subgroup analysis indicates beneficial treatment effects of Menthacarin that are similar to those found for FD patients in the primary analyses. The reduction of IBS-associated symptoms in FD patients suggests Menthacarin as a treatment option for IBS patients.


Lack of orientation and direction selectivity in a subgroup of fast-spiking inhibitory interneurons: cellular and synaptic mechanisms and comparison with other electrophysiological cell types.
Neurons in cat area 17 can be grouped in 4 different electrophysiological cell classes (regular spiking, intrinsically bursting, chattering, and fast spiking [FS]). However, little is known of the functional properties of these different cell classes. Here we compared orientation and direction selectivity between these cell classes in cat area 17 and found that a subset of FS inhibitory neurons, usually with complex receptive fields, exhibited little selectivity in comparison with other cell types. Differences in occurrence and amplitude of gamma-range membrane fluctuations, as well as in numbers of action potentials in response to optimal visual stimuli, did not parallel differences observed for orientation and direction selectivity. Instead, differences in selectivity resulted mostly from differences in tuning of the membrane potential responses, although variations in spike threshold also contributed: weakly selective FS neurons exhibited both a lower spike threshold and more broadly tuned membrane potential responses in comparison with the other cell classes. Our results are consistent with the hypothesis that a subgroup of FS neurons receives connections and possesses intrinsic properties allowing the generation of weakly selective responses. The existence of weakly selective inhibitory neurons is consistent with orientation selectivity models that rely on broadly tuned inhibition.


Multicomposition EPSR: Toward Transferable Potentials To Model Chalcogenide Glass Structures.
The structure of xAs40Se60-(1 - x)As40S60 glasses, where x = 1.000, 0.667, 0.500, 0.333, 0.250, and 0.000, is investigated using a combination of neutron and X-ray diffraction coupled with computational modeling using multicomposition empirical potential structure refinement (MC-EPSR). Traditional EPSR (T-EPSR) produces a set of empirical potentials that drive a structural model of a particular composition to agreement with diffraction experiments. The work presented here establishes the shortcomings in generating such a model for a ternary chalcogenide glass composition. In an enhancement to T-EPSR, MC-EPSR produces a set of pair potentials that generate robust structural models across a range of glass compositions. The structures obtained vary with composition in a much more systematic way than those taken from T-EPSR. For example, the average arsenic-sulfur bonding distances vary between 2.28 and 2.46 Å in T-EPSR but are 2.29 ± 0.02 Å in MC-EPSR. Similarly, the arsenic-selenium bond lengths from T-EPSR vary between 2.28 and 2.43 Å but are consistently 2.40 ± 0.02 Å in the MC-EPSR results. Analysis of these models suggests that the average separation of the chalcogen (S or Se) atoms is the structural origin of the changes in nonlinear refractive index with glass composition.


Looking beyond age and co-morbidities as predictors of outcomes in paraesophageal hernia repair.
Paraesophageal hernia (PEH) repair is a technically challenging operation. These patients are typically older and have more co-morbidities than patients undergoing anti-reflux operations for gastroesophageal reflux disease (GERD), and these factors are usually cited as the reason for worse outcomes for PEH patients. Clinically, it would be useful to identify potentially modifiable variables leading to improved outcomes. We performed a retrospective analysis of a representative sample from 37 states, using the Nationwide Inpatient Sample database over a 5-year period (2001-2005). Patients undergoing any anti-reflux operation with or without hiatal hernia repair were included, and comparison was made based on primary diagnoses of PEH or GERD. Exclusion criteria were diagnosis codes not associated with reflux disease or diaphragmatic hernia, emergency admissions, and age <18. Primary outcome was in-hospital mortality. Two sets of multivariate analyses were performed; one set adjusting for pre-treatment variables (age, gender, race, Charlson Comorbidity Index, hospital teaching status, hospital volume of anti-reflux surgery, calendar year) and a second set adjusting further for post-operative complications (splenectomy, esophageal laceration, pneumothorax, hemorrhage, cardiac, pulmonary, and thromboembolic events, (VTE)). Of the 23,458 patients, 6,706 patients had PEH. PEH patients are older (60.4 vs. 49.1, p < 0.001) and have significantly more co-morbidities than GERD patients. On multivariate analysis, adjusting for pre-treatment variables, PEH patients are more likely to die and have significantly worse outcomes than GERD patients. However, further adjustment for pulmonary complications, VTE, and hemorrhage eliminates the mortality difference between PEH and GERD patients, while adjustment for cardiac complications or pneumothorax did not eliminate the difference. While PEH patients have worse post-operative outcomes than GERD patients, we note that differences in mortality are explained by pulmonary complications, VTE, and hemorrhage. The impact of hemorrhagic complications on this group underscores the importance of careful dissection. Additionally, age and co-morbidities alone should not preclude a patient from PEH repair; rather, attention should be focused on peri-operative optimization of pulmonary status and prophylaxis of thromboembolic events.


Plasma insulin and cardiovascular mortality in non-diabetic European men and women: a meta-analysis of data from eleven prospective studies.
We examined the association between plasma insulin and cardiovascular mortality in non-diabetic European men and women based on data from eleven prospective studies. The study population comprised 6156 men and 5351 women aged 30-89 years. Baseline measurements included oral glucose tolerance test, fasting and 2-h plasma insulin, and conventional risk factors. Cox models were used to calculate hazard ratios (HRs) and their 95% confidence intervals, and overall HRs were assessed by meta-analyses. During the 8.8-year follow-up, 362 men and 70 women died from cardiovascular disease. The age- and smoking-adjusted overall HR of cardiovascular mortality for the highest vs the lower quartiles of fasting insulin was 1.58 (95% CI: 1.26-1.97) in men and 2.64 (1.54-4.51) in women. Adjusting for other risk factors in addition, the HR was 1.54 (1.16-2.03) in men and 2.66 (1.45-4.90) in women. For 2-h insulin these HRs were 1.28 (0.99-1.66), 1.87 (0.87-4.02), and 0.85 (0.60-1.21), 1.36 (0.53-3.45). The overall HRs for interquartile ranges for fasting and 2-h insulin, with full adjustment, were 1.13 (1.05-1.22) and 1.11 (1.01-1.23) in men, and 1.25 (1.08-1.45) and 1.11 (0.91-1.36) in women. Hyperinsulinaemia, defined by the highest quartile cut-off for fasting insulin, was significantly associated with cardiovascular mortality in both men and women independently of other risk factors. Associations between high 2-h insulin and cardiovascular mortality were weaker and non-significant. Weak positive associations of fasting and 2-h insulin with cardiovascular mortality over interquartile ranges were, however, more similar.


Concept and first experimental results of a new ferromagnetic assist device for extra-aortic counterpulsation.
Based on a ferromagnetic silicone cuff for extra-aortic counterpulsation, a new assist device concept was developed. The driving force is generated by an external magnetic field, which leads to contraction of a soft magnetic cuff. The force generation capacity of the device was tested in a silicone aorta model. Magnetic elastomers can be constructed through dispersion of micro- or nanoparticles in polymer matrices and were designed to act as soft actuators. Two magnetically active silicone cuffs were produced with a nanomagnet loading of 250 wt% (Cuff 1) and a micromagnet loading of 67 wt% (Cuff 2). The magnetic cuffs were applied on a silicone aorta model and contracted against hydrostatic pressure. A full contraction of Cuff 1 was possible against a maximal hydrostatic pressure of 30 cmH₂O (22 mmHg) at a magnetic flux density of 0.4 T (Tesla) and 65 cmH₂O (48 mmHg) at a magnetic flux density of 1.2 T. A 50% contraction of Cuff 2 was possible against a maximal hydrostatic pressure of 80 cmH₂O (59 mmHg) at a magnet-cuff-distance (MCD) of 0 cm. At MCDs of 1 and 2 cm a 50% contraction was possible against 33 cmH₂O (24 mmHg) and 10 cmH₂O (7 mmHg), respectively. Combining the advantages of magnetic elastomers with the principle of extra-aortic counterpulsation in a new assist device concept avoids the need for anticoagulation (no contact with bloodstream). With regard to the magnetic principle of action, no intra- to extracorporeal connection is needed. More experimental work is needed to further increase the force generated by the silicone cuff and to transfer the device concept into an in vivo setting.


The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia.
An internal tandem duplication in the fms-like tyrosine kinase 3 gene (FLT3/ITD) is associated with poor prognosis in acute myeloid leukemia (AML), but the impact of mutant level, size, and interaction with nucleophosmin 1 (NPM1) mutations remains controversial. We evaluated these characteristics in a large cohort of young adult AML patients. There was a highly significant trend for worsening in relapse risk (RR) and overall survival (OS) with increasing FLT3/ITD mutant level (P < .001 for both), and even in the low level mutant group (1%-24% of total FLT3 alleles), RR was significantly worse than in the FLT3 wild-type (WT) group (P < .001). In multivariate analysis, mutant level was the most powerful prognostic factor for RR. Mutant size and number had no significant impact on outcome. The beneficial impact of an NPM1 mutation on RR and OS was seen in FLT3/ITD(+) as well as FLT3/WT patients; both markers were highly significant independent predictors of outcome (P < .001). Stratification using both markers identified 3 prognostic groups: good (FLT3/ITD(-)NPM1(+)), intermediate (FLT3/ITD(-)NPM1(-) or FLT3/ITD(+)NPM1(+)), and poor (FLT3/ITD(+)NPM1(-)). Patients with high FLT3/ITD mutant level (greater than 50%) or FLT3/ITD(+) in the absence of an NPM1 mutation may be good candidates for more experimental therapeutic approaches.


Donor locus selection during Saccharomyces cerevisiae mating type interconversion responds to distant regulatory signals.
Mating type interconversion in homothallic strains of the yeast Saccharomyces cerevisiae results from directed transposition of a mating type allele from one of the two silent donor loci, HML and HMR, to the expressing locus, MAT. Cell type regulates the selection of the particular donor locus to be utilized during mating type interconversion: MATa cells preferentially select HML alpha and MAT alpha cells preferentially select HMRa. Such preferential selection indicates that the cell is able to distinguish between HML and HMR during mating type interconversion. Accordingly, we designed experiments to identify those features perceived by the cell to discriminate HML and HMR. We demonstrate that discrimination does not derive from the different structures of the HML and HMR loci, from the unique sequences flanking each donor locus nor from any of the DNA distal to the HM loci on chromosome III. Moreover, we find that the sequences flanking the MAT locus do not function in the preferential selection of one donor locus over the other. We propose that the positions of the donor loci on the left and right arms of chromosome III is the characteristic utilized by the cell to distinguish HML and HMR. This positional information is not generated by either CEN3 or the MAT locus, but probably derives from differences in the chromatin structure, chromosome folding or intranuclear localization of the two ends of chromosome III.


The role of peritoneal dialysis catheter configuration in preventing catheter tip migration.
Migration of the peritoneal dialysis (PD) catheter from the pelvis to the upper abdomen frequently results in peritoneal dialysis failure and removal of the catheter. Previous studies compared PD catheter survival in various catheter configurations. These studies included single-cuff and double-cuff, straight-end and curled-end catheters, and showed an incidence of catheter migration ranging from 5%-35% depending on the catheter type. Recent studies demonstrated that the double-cuff, Swan-neck, curled-end configuration is associated with a considerably lower incidence of migration. Most of these studies, however, had a small patient sample or no control group, or they compared nonequivalent catheters (for example, Swan-neck, curled-end versus straight, non-curled-end). Over a six-year period, we examined two similar double-cuff, curled-end catheters: Group I catheters had a straight segment between the two cuffs, and Group II catheters had a 60 degrees Swan-neck bend between the two cuffs (Quinton Instrument Co., Bothell, WA, U.S.A.). The two catheters were identical, except for the presence or absence of the Swan-neck bend. All catheters were placed by the closed laparoscopic technique. In the two groups of patients in whom the catheters were implanted, no statistically significant difference was observed in primary disease, age, sex, race, weight, prior abdominal surgery, or duration of dialysis before catheter migration. In group I, 33 of the 219 patients developed catheter migration (15%); in group II, 2 patients of 243 patients developed catheter migration (less than 1%, p = 0.002). In conclusion, the Swan-neck configuration presents an independent factor in preventing PD catheter migration. Review of previous studies and the data from our study, show that double-cuff, curled-end, Swan-neck PD catheters are superior to other catheters in regard to prevention of catheter migration and should be the catheter of choice in PD patients.


Clinical outcomes from the texting for relapse prevention (T4RP) in schizophrenia and schizoaffective disorder study.
This 6 month randomized control trial investigated whether a novel text-messaging program impacted targeted clinical outcomes in patients with schizophrenia and schizoaffective disorder (SAD). Forty patients were enrolled and completed baseline, 3-month and 6-month assessments. The intervention group received daily symptom check-in text messages, plus, a medication reminder or, inspirational quote text. The control group had treatment as usual. At 6 months the Positive and Negative Syndrome Scale mean positive score was significantly lower and injectable medication compliance was significantly higher in the intervention group. Recovery scores were significantly higher at 3 months. Results suggest that this program may benefit individuals with schizophrenia/SAD who use text messaging. Further investigation in a larger sample appears warranted.


A comparative analysis of role attainment and impairment in binge-eating disorder and bulimia nervosa: results from the WHO World Mental Health Surveys.
Background. Cross-national population data from the WHO World Mental Health surveys are used to compare role attainments and role impairments associated with binge-eating disorder (BED) and bulimia nervosa (BN). Methods. Community surveys assessed 23 000 adults across 12 countries for BED, BN and ten other DSM-IV mental disorders using the WHO Composite International Diagnostic Interview. Age-of-onset was assessed retrospectively. Ten physical disorders were assessed using standard conditions checklists. Analyses examined reciprocal time-lagged associations of eating disorders (EDs) with education, associations of early-onset (i.e., prior to completing education) EDs with subsequent adult role attainments and cross-sectional associations of current EDs with days of role impairment. Results. BED and BN predicted significantly increased education (females). Student status predicted increased risk of subsequent BED and BN (females). Early-onset BED predicted reduced odds of current (at time of interview) marriage (females) and reduced odds of current employment (males). Early-onset BN predicted increased odds of current work disability (females and males). Current BED and BN were both associated with significantly increased days of role impairment (females and males). Significant BED and BN effects on adult role attainments and impairments were explained by controls for comorbid disorders. Conclusions. Effects of BED on role attainments and impairments are comparable with those of BN. The most plausible interpretation of the fact that these associations are explained by comorbid disorders is that causal effects of EDs are mediated through secondary disorders. Controlled treatment effectiveness studies are needed to trace out long-term effects of BED-BN on secondary disorders.


Are healthcare professionals working in Australia's immigration detention centres condoning torture?
Australian immigration detention centres are in secluded locations, some on offshore islands, and are subject to extreme secrecy, comparable with 'black sites' elsewhere. There are parallels between healthcare professionals working in immigration detention centres and healthcare professionals involved with or complicit in torture. In both cases, healthcare professionals are conflicted between a duty of care to improve the health of patients and the interests of the government. While this duality of interests has been recognised previously, the full implications for healthcare professionals working in immigration detention have not been addressed. The Australian Government maintains that immigration detention is needed for security checks, but the average duration of immigration detention has increased from 10 weeks to 14 months, and detainees are not informed of the progress of their application for refugee status. Long-term immigration detention causes major mental health problems, is illegal in international law and arguably fulfils the recognised definition of torture. It is generally accepted that healthcare professionals should not participate in or condone torture. Australian healthcare professionals thus face a major ethical dilemma: patients in immigration detention have pressing mental and physical health needs, but providing healthcare might support or represent complicity in a practice that is unethical. Individual healthcare professionals need to decide whether or not to work in immigration detention centres. If they do so, they need to decide for how long and to what extent restrictive contracts and gagging laws will constrain them from advocating for closing detention centres.


Alternative versus standard packages of antenatal care for low-risk pregnancy.
The number of visits for antenatal (prenatal) care developed without evidence of how many visits are necessary. The content of each visit also needs evaluation. To compare the effects of antenatal care programmes with reduced visits for low-risk women with standard care. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2010), reference lists of articles and contacted researchers in the field. Randomised trials comparing a reduced number of antenatal visits, with or without goal-oriented care, with standard care. Two authors assessed trial quality and extracted data independently. We included seven trials (more than 60,000 women): four in high-income countries with individual randomisation; three in low- and middle-income countries with cluster randomisation (clinics as the unit of randomisation). The number of visits for standard care varied, with fewer visits in low- and middle- income country trials. In studies in high-income countries, women in the reduced visits groups, on average, attended between 8.2 and 12 times. In low- and middle- income country trials, many women in the reduced visits group attended on fewer than five occasions, although in these trials the content as well as the number of visits was changed, so as to be more 'goal oriented'.Perinatal mortality was increased for those randomised to reduced visits rather than standard care, and this difference was borderline for statistical significance (five trials; risk ratio (RR) 1.14; 95% confidence interval (CI) 1.00 to 1.31). In the subgroup analysis, for high-income countries the number of deaths was small (32/5108), and there was no clear difference between the groups (2 trials; RR 0.90; 95% CI 0.45 to 1.80); for low- and middle-income countries perinatal mortality was significantly higher in the reduced visits group (3 trials RR 1.15; 95% CI 1.01 to 1.32). Reduced visits were associated with a reduction in admission to neonatal intensive care that was borderline for significance (RR 0.89; 95% CI 0.79 to 1.02). There were no clear differences between the groups for the other reported clinical outcomes.Women in all settings were less satisfied with the reduced visits schedule and perceived the gap between visits as too long. Reduced visits may be associated with lower costs. In settings with limited resources where the number of visits is already low, reduced visits programmes of antenatal care are associated with an increase in perinatal mortality compared to standard care, although admission to neonatal intensive care may be reduced. Women prefer the standard visits schedule. Where the standard number of visits is low, visits should not be reduced without close monitoring of fetal and neonatal outcome.


Cytology of fine needle aspirates of primary extragonadal germ cell tumors.
To describe the characteristic cytologic features of fine needle aspirates (FNAs) of primary extragonadal germ cell tumors (PEGCTs). Thirteen patients with PEGCTs, including 2 seminomas, 2 mixed germ cell tumors, 3 immature teratomas, 1 choriocarcinoma and 5 yolk sac tumors (YSTs) were studied. The final diagnosis of PEGCT in all cases was established by histologic examination of the tumor tissues. Fine needle aspiration was done on either the primary tumor or metastatic foci. The aspirates were stained with one of the Romanovsky stains and Papanicolaou stain. Each type of PEGCT has its own morphologic characteristics. In seminoma, the tumor cells are large and noncohesive, with one to several distinct nucleoli; some lymphocytes are also present. YSTs show many pleomorphic cells with vacuoles in the cytoplasm and nuclei; tumor cells frequently aggregate in a microglandular or papillary pattern. Choriocarcinoma consists of syncytiotrophoblasts and cytotrophoblasts. The former are very large cells with eosinophilic cytoplasm, one to several nuclei and distinct nucleoli; the latter are medium-sized cells with vacuolated, basophilic cytoplasm and eccentric nuclei. Immature teratomas are composed of a mixture of cell types, including elongated epithelioid cells, mesenchymal cells and many large, naked, amorphous nuclei with a homogeneous chromatin pattern. Diagnosis of mixed germ cell tumor is difficult but can be made if two or more subtypes of tumor cells are observed in the FNA. Cytologic examination of FNAs of primary or metastatic lesions of PEGCTs, stained either with Romanovsky or Papanicolaou stain, is of diagnostic value for such diseases. The use of immunochemistry can help to confirm the cytologic impression.


Global estimates of the need for rehabilitation based on the Global Burden of Disease study 2019: a systematic analysis for the Global Burden of Disease Study 2019.
Rehabilitation has often been seen as a disability-specific service needed by only few of the population. Despite its individual and societal benefits, rehabilitation has not been prioritised in countries and is under-resourced. We present global, regional, and country data for the number of people who would benefit from rehabilitation at least once during the course of their disabling illness or injury. To estimate the need for rehabilitation, data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 were used to calculate the prevalence and years of life lived with disability (YLDs) of 25 diseases, impairments, or bespoke aggregations of sequelae that were selected as amenable to rehabilitation. All analyses were done at the country level and then aggregated to seven regions: World Bank high-income countries and the six WHO regions (ie, Africa, the Americas, Southeast Asia, Europe, Eastern Mediterranean, and Western Pacific). Globally, in 2019, 2·41 billion (95% uncertainty interval 2·34-2·50) individuals had conditions that would benefit from rehabilitation, contributing to 310 million [235-392] YLDs. This number had increased by 63% from 1990 to 2019. Regionally, the Western Pacific had the highest need of rehabilitation services (610 million people [588-636] and 83 million YLDs [62-106]). The disease area that contributed most to prevalence was musculoskeletal disorders (1·71 billion people [1·68-1·80]), with low back pain being the most prevalent condition in 134 of the 204 countries analysed. To our knowledge, this is the first study to produce a global estimate of the need for rehabilitation services and to show that at least one in every three people in the world needs rehabilitation at some point in the course of their illness or injury. This number counters the common view of rehabilitation as a service required by only few people. We argue that rehabilitation needs to be brought close to communities as an integral part of primary health care to reach more people in need. Bill & Melinda Gates Foundation.


Web based distance learning at Faculty of Medicine of Sarajevo University.
The time in which we live is defined by the significant influence of the information technologies on our lives, changes and development of society and the efficacy of all the organization systems. Increase and development of distance learning (DL) technologies over the past decade has exposed the potential and the efficiency of new technologies. Number of events has organized by teaching staff from Cathedrae for Medical Informatics in order to promote distance learning and web based education are very extensive: professional-scientific events, workshops and congresses, first tele-exam at the Medical Faculty, Introducing of Distance learning in curriculum at biomedical faculties, etc. At the University in Sarajevo in year 2003 was opened the e-learning center for the support to the faculties the distance studies by use of the information technology. At Medical Faculty of University of Sarajevo at Cathedrae for Medical Informatics since 2002 is in progress realization of the project named: "Possibilities of introducing distance learning in medical curriculum", approved by the Federal and the Cantonal ministry of science and education. Pilot project was realized during three past school years, theoretical and practical education of subject Medical informatics are adapted to the new concepts of education using world trends of education from the distance. One group of students was included in the project finalized by electronic exam registration and electronic exam on 20 June 2005, publicly, in the Physiology amphitheatre of the Medical Faculty in Sarajevo.


Diversity and distribution of Wolbachia in relation to geography, host plant affiliation and life cycle of a heterogonic gall wasp.
The maternally inherited endosymbiont Wolbachia is widespread in arthropods and nematodes and can play an important role in the ecology and evolution of its host through reproductive manipulation. Here, we survey Wolbachia in Belonocnema treatae, a widely distributed North American cynipid gall forming wasp that exhibits regional host specialization on three species of oaks and alternation of sexually and asexually reproducing generations. We investigated whether patterns of Wolbachia infection and diversity in B. treatae are associated with the insect's geographic distribution, host plant association, life cycle, and mitochondrial evolutionary history. Screening of 463 individuals from 23 populations including sexual and asexual generations from all three host plants across the southern U.S. showed an average infection rate of 56% with three common Wolbachia strains: wTre1-3 and an additional rare variant wTre4. Phylogenetic analysis based on wsp showed that these strains are unrelated and likely independently inherited. We found no difference in Wolbachia infection frequency among host plant associated populations or between the asexual and sexual generations, or between males and females of the sexual generation. Partially incomplete Wolbachia transmission rates might explain the occurrence of uninfected individuals. A parallel analysis of the mitochondrial cytochrome oxidase I gene in B. treatae showed high mtDNA haplotype diversity in both infected and uninfected populations suggesting an ancestral infection by Wolbachia as well as a clear split between eastern and western B. treatae mtDNA clades with a sequence divergence of > 6%. The strain wTre1 was present almost exclusively in the western clade while wTre2 and wTre3 occur almost exclusively in eastern populations. In contrast, the same strains co-occur as double-infections in Georgia and triple-infections in two populations in central Florida. The diversity of Wolbachia across geographically and genetically distinct populations of B. treatae and the co-occurrence of the same strains within three populations highlights the complex infection dynamics in this system. Moreover, the association of distinct Wolbachia strains with mitochondrial haplotypes of its host in populations infected by different Wolbachia strains suggests a potential role of the endosymbiont in reproductive isolation in B. treatae.


Stochastic transparency.
Stochastic transparency provides a unified approach to order-independent transparency, antialiasing, and deep shadow maps. It augments screen-door transparency using a random sub-pixel stipple pattern, where each fragment of transparent geometry covers a random subset of pixel samples of size proportional to alpha. This results in correct alpha-blended colors on average, in a single render pass with fixed memory size and no sorting, but introduces noise. We reduce this noise by an alpha correction pass, and by an accumulation pass that uses a stochastic shadow map from the camera. At the pixel level, the algorithm does not branch and contains no read-modify-write loops, other than traditional z-buffer blend operations. This makes it an excellent match for modern massively parallel GPU hardware. Stochastic transparency is very simple to implement and supports all types of transparent geometry, able without coding for special cases to mix hair, smoke, foliage, windows, and transparent cloth in a single scene.


Poor geographical match between the distributions of host diversity and parasite discovery effort.
Mapping global parasite diversity is crucial to identify geographical hotspots of emerging disease, and guide public health and conservation efforts. In principle, assuming a bottom-up coupling between the diversity of resources and consumers, the geographical distribution of parasite diversity should match that of host diversity. We test the expected spatial congruence between host and parasite diversity for helminth parasites of vertebrate hosts, across grid cells of a global map. Using high-resolution databases on host species distributions and newly compiled data on the geographical distribution of parasite species discovery, we found positive covariation between host species richness and the number of parasite species discovered, for all vertebrate groups, regardless of the analytical method used, spatial autocorrelation, and spatial resolution. However, all associations were very weak, indicating a poor match between host species richness and parasite species discovery. The research deficit in parasite discovery peaks in areas corresponding to hotspots of host diversity, where disproportionately fewer new parasites are discovered than expected based on local host richness. This spatially biased research effort prevents a full inventory of parasite biodiversity, and impedes predictions of where new diseases may emerge. The host taxon-specific maps we produced, however, can guide future efforts to uncover parasite biodiversity.


Increase in asialoganglioside- and monosialoganglioside-reactive antibodies in chronic Chagas' disease patients.
Antibodies reactive with the core glycan of asialoganglioside (GA1), monosialoganglioside (GM1), and disialoganglioside (GD1a) were studied in human sera. In healthy individuals, GA1-, GM1-, and GD1a-reactive antibodies were mainly of the IgM class, but also of the IgA and IgG classes, and were present at low titers in the serum of 68%, 79%, and 91% of the individuals studied, respectively. Levels of anti-GA1 and anti-GM1 antibodies, mainly of the IgA and IgG classes, were significantly elevated (P < 0.001) in 62% and 72% of subjects, respectively, chronically infected with Trypanosoma cruzi, with no association found with the degree of myocardial damage. No significant increase in anti-GA1 and anti-GM1 antibodies was found in dilated cardiomyopathy patients. The level of anti-GD1a antibody was not significantly different between healthy controls and chronic chagasic or dilatatory cardiomyopathy patients. Since the peripheral nervous system is very rich in gangliosides, it is possible that the increases in GA1- and GM1-specific antibodies that develop during chronic T. cruzi infection are involved in the pathology of peripheral neuropathy in Chagas' disease.


The translation initiation factor eIF4E regulates the sex-specific expression of the master switch gene Sxl in Drosophila melanogaster.
In female fruit flies, Sex-lethal (Sxl) turns off the X chromosome dosage compensation system by a mechanism involving a combination of alternative splicing and translational repression of the male specific lethal-2 (msl-2) mRNA. A genetic screen identified the translation initiation factor eif4e as a gene that acts together with Sxl to repress expression of the Msl-2 protein. However, eif4e is not required for Sxl mediated repression of msl-2 mRNA translation. Instead, eif4e functions as a co-factor in Sxl-dependent female-specific alternative splicing of msl-2 and also Sxl pre-mRNAs. Like other factors required for Sxl regulation of splicing, eif4e shows maternal-effect female-lethal interactions with Sxl. This female lethality can be enhanced by mutations in other co-factors that promote female-specific splicing and is caused by a failure to properly activate the Sxl-positive autoregulatory feedback loop in early embryos. In this feedback loop Sxl proteins promote their own synthesis by directing the female-specific alternative splicing of Sxl-Pm pre-mRNAs. Analysis of pre-mRNA splicing when eif4e activity is compromised demonstrates that Sxl-dependent female-specific splicing of both Sxl-Pm and msl-2 pre-mRNAs requires eif4e activity. Consistent with a direct involvement in Sxl-dependent alternative splicing, eIF4E is associated with unspliced Sxl-Pm pre-mRNAs and is found in complexes that contain early acting splicing factors--the U1/U2 snRNP protein Sans-fils (Snf), the U1 snRNP protein U1-70k, U2AF38, U2AF50, and the Wilms' Tumor 1 Associated Protein Fl(2)d--that have been directly implicated in Sxl splicing regulation.


Computer vision tools for low-cost and noninvasive measurement of autism-related behaviors in infants.
The early detection of developmental disorders is key to child outcome, allowing interventions to be initiated which promote development and improve prognosis. Research on autism spectrum disorder (ASD) suggests that behavioral signs can be observed late in the first year of life. Many of these studies involve extensive frame-by-frame video observation and analysis of a child's natural behavior. Although nonintrusive, these methods are extremely time-intensive and require a high level of observer training; thus, they are burdensome for clinical and large population research purposes. This work is a first milestone in a long-term project on non-invasive early observation of children in order to aid in risk detection and research of neurodevelopmental disorders. We focus on providing low-cost computer vision tools to measure and identify ASD behavioral signs based on components of the Autism Observation Scale for Infants (AOSI). In particular, we develop algorithms to measure responses to general ASD risk assessment tasks and activities outlined by the AOSI which assess visual attention by tracking facial features. We show results, including comparisons with expert and nonexpert clinicians, which demonstrate that the proposed computer vision tools can capture critical behavioral observations and potentially augment the clinician's behavioral observations obtained from real in-clinic assessments.


The map-based sequence of the rice genome.
Rice, one of the world's most important food plants, has important syntenic relationships with the other cereal species and is a model plant for the grasses. Here we present a map-based, finished quality sequence that covers 95% of the 389 Mb genome, including virtually all of the euchromatin and two complete centromeres. A total of 37,544 non-transposable-element-related protein-coding genes were identified, of which 71% had a putative homologue in Arabidopsis. In a reciprocal analysis, 90% of the Arabidopsis proteins had a putative homologue in the predicted rice proteome. Twenty-nine per cent of the 37,544 predicted genes appear in clustered gene families. The number and classes of transposable elements found in the rice genome are consistent with the expansion of syntenic regions in the maize and sorghum genomes. We find evidence for widespread and recurrent gene transfer from the organelles to the nuclear chromosomes. The map-based sequence has proven useful for the identification of genes underlying agronomic traits. The additional single-nucleotide polymorphisms and simple sequence repeats identified in our study should accelerate improvements in rice production.


Histone deacetylase inhibition alters histone methylation associated with heat shock protein 70 promoter modifications in astrocytes and neurons.
The mood-stabilizing and anticonvulsant drug valproic acid (VPA) inhibits histone deacetylases (HDACs). The aim of the present study was to determine the effect of HDAC inhibition on overall and target gene promoter-associated histone methylation in rat cortical neurons and astrocytes. We found that VPA and other HDAC inhibitors, including sodium butyrate (SB), trichostatin A (TSA), and the Class I HDAC inhibitors MS-275 and apicidin all increased levels of histone 3 lysine 4 dimethylation and trimethylation (H3K4Me2 and H3K4Me3); these processes are linked to transcriptional activation in rat cortical neurons and astrocytes. VPA, SB, TSA, MS-275, and apicidin also upregulated levels of the neuroprotective heat shock protein 70 (HSP70) in rat astrocytes. Moreover, Class I HDAC inhibition by VPA and MS-275 increased H3K4Me2 levels at the HSP70 promoter in astrocytes and neurons. We also found that VPA treatment facilitated the recruitment of acetyltransferase p300 to the HSP70 promoter and that p300 interacted with the transcription factor NF-Y in astrocytes. Taken together, the results suggest that Class I HDAC inhibition is key to upregulating overall and gene-specific H3K4 methylation in primary neuronal and astrocyte cultures. In addition, VPA-induced activation of the HSP70 promoter in astrocytes appears to involve an increase in H3K4Me2 levels and recruitment of p300. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.


Phase-matched nonlinear diffraction.
We report on a new (to our knowledge) configuration incorporating both birefringence and quasi-phase-matching, enabling efficient phase-matched nonlinear diffraction in one-dimensional periodically poled nonlinear crystals. We demonstrate the method experimentally, showing an efficient nonlinear diffraction to the first few orders in two types of crystals, MgO doped congruent lithium niobate and congruent lithium niobate, and characterize its efficiency dependence on the fundamental power, the propagation angle, and the crystal temperature. This configuration can increase efficiencies observed in nonlinear diffraction experiments, enables ferroelectric domain characterization by nonlinear microscopy, and can be used to determine the duty cycles of periodically poled nonlinear crystals.


Prevalence and Characteristics of Subclinical Atrial Fibrillation in a Community-Dwelling Elderly Population: The ARIC Study.
The prevalence of subclinical atrial fibrillation (AF) in the elderly general population is unclear. We sought to define the prevalence of subclinical AF in a community-based elderly population and to characterize subclinical AF and the incremental diagnostic yield of 4 versus 2 weeks of continuous ECG monitoring. We conducted a cross-sectional analysis within the community-based multicenter observational ARIC study (Atherosclerosis Risk in Communities) using visit 6 (2016-2017) data. The 2616 ARIC study participants who wore a leadless, ambulatory ECG monitor (Zio XT Patch) for up to 2 weeks were aged 79±5 years, 42% men, and 26% black. In a subset, 386 participants without clinically recognized AF wore the monitor twice, each time for up to 2 weeks. We characterized the prevalence of subclinical AF (ie, AF detected on the Zio XT Patch without clinically recognized AF) over 2 weeks of monitoring and the diagnostic yield of 4 versus 2 weeks of monitoring. The prevalence of subclinical AF was 2.5%; the prevalence of subclinical AF was 3.3% among white men, 2.5% among white women, 2.1% among black men, and 1.6% among black women. Subclinical AF was mostly intermittent (75%). Among those with intermittent subclinical AF, 91% had AF burden ≤10% during the monitoring period. In a subset of 386 participants without clinical AF, 78% more subclinical AF was detected by 4 weeks versus 2 weeks of ECG monitoring. In our study, the prevalence of subclinical AF was lower than previously reported and monitoring beyond 2 weeks provided substantial incremental diagnostic yield. Future studies should focus on individuals with higher risk to increase diagnostic yield and consider continuous monitoring duration longer than 2 weeks.


Acute corneal hydrops in keratoconus: a national prospective study of incidence and management.
PurposeTo determine incidence and management of acute corneal hydrops in the UK.MethodsWe used the BOSU report card system to survey cases of acute corneal hydrops in patients with keratoconus that occurred in the UK between November 2009 and December 2010. Ophthalmologists who reported a case were sent an initial questionnaire, with a follow-up questionnaire after 6 months. We collected information on the demographics, complications, changes in visual acuity, and management. The 2011 National Census was used as a source for population and ethnicity in the UK.ResultsThere were 73 incident cases of acute corneal hydrops, with a response to the initial questionnaire for 64 (88%) patients and follow-up data at 6 months for 57 (78%) patients. For the 64 confirmed cases the median (interquartile range) age of onset was 31.9 (23.2, 41.3) years and 48 (75%) of the cases occurred in males. A total of 42 (66%) patients were white, 14 (22%) were South Asian, and 7 (11%) were black. The proportion of South Asian and black patients with acute corneal hydrops was significantly higher than in the general population (P<0.001). The minimum estimated annual incidence of acute corneal hydrops in patients with keratoconus was estimated to be 1.43 (1.10, 1.83) per 1000. At 6 months following acute corneal hydrops a decision to proceed with keratoplasty had been made for 12 (20.3%) patients.ConclusionsThis is the first population-based estimate of the incidence of acute corneal hydrops in keratoconus.


Probabilistic encoding of stimulus strength in astrocyte global calcium signals.
Astrocyte calcium signals can range in size from subcellular microdomains to waves that spread through the whole cell (and into connected cells). The differential roles of such local or global calcium signaling are under intense investigation, but the mechanisms by which local signals evolve into global signals in astrocytes are not well understood, nor are the computational rules by which physiological stimuli are transduced into a global signal. To investigate these questions, we transiently applied receptor agonists linked to calcium signaling to primary cultures of cerebellar astrocytes. Astrocytes repetitively tested with the same stimulus responded with global signals intermittently, indicating that each stimulus had a defined probability for triggering a response. The response probability varied between agonists, increased with agonist concentration, and could be positively and negatively modulated by crosstalk with other signaling pathways. To better understand the processes determining the evolution of a global signal, we recorded subcellular calcium "puffs" throughout the whole cell during stimulation. The key requirement for puffs to trigger a global calcium wave following receptor activation appeared to be the synchronous release of calcium from three or more sites, rather than an increasing calcium load accumulating in the cytosol due to increased puff size, amplitude, or frequency. These results suggest that the concentration of transient stimuli will be encoded into a probability of generating a global calcium response, determined by the likelihood of synchronous release from multiple subcellular sites.


Antibodies to voltage-gated potassium and calcium channels in epilepsy.
To determine the prevalence of antibodies to ion channels in patients with long standing epilepsy. Although the CNS is thought to be protected from circulating antibodies by the blood brain barrier, glutamate receptor antibodies have been reported in Rasmussen's encephalitis, glutamic acid decarboxylase (GAD) antibodies have been found in a few patients with epilepsy, and antibodies to voltage-gated potassium channels (VGKC) have been found in a non-paraneoplastic form of limbic encephalitis (with amnesia and seizures) that responds to immunosuppressive therapy. We retrospectively screened sera from female epilepsy patients (n=106) for autoantibodies to VGKC (Kv 1.1, 1.2 or 1.6), voltage-gated calcium channels (VGCC) (P/Q-type), and GAD. All positive results, based on the values of control data [McKnight, K., Jiang, Y., et al. (2005). Serum antibodies in epilepsy and seizure-associated disorders. Neurology 65, 1730-1735], were retested at lower serum concentrations, and results compared with previously published control data. Demographics, medical history, and epilepsy related information was gathered. The studied group consisted predominantly of patients with long standing drug resistant epilepsy. VGKC antibodies were raised (>100 pM) in six patients. VGCC antibodies (>45 pM) were slightly raised in only one patient. GAD antibodies were <3 U/ml in all patients. The clinical features of the patients with VGKC antibodies differed from previously described patients with limbic encephalitis-like syndrome, and were not different with respect to seizure type, age at first seizure, duration of epilepsy, or use of anti-epileptic drugs from the VGKC antibody negative patients. The results demonstrate that antibodies to VGKC are present in 6% of patients with typical long-standing epilepsy, but whether these antibodies are pathogenic or secondary to the primary disease process needs to be determined.


HIV infection among members of the US Army Reserve Components with medical and health occupations.
Over 58,000 members of the US Army Reserve Components tested for human immunodeficiency virus (HIV) antibody had military or civilian medical occupations. The availability of HIV status and occupational information permits the assessment of prevalence and incidence of infection in this population. Levels of infection were not higher among women or among currently married men with medical occupations compared with those with nonmedical occupations. Prevalence and incidence were elevated among never-married men with either military or civilian medical occupations compared with never-married men with nonmedical occupations. Based on reported civilian occupation, male registered nurses and men with other medical occupations, excluding physicians and dentists, had a significantly higher prevalence of infection than men with nonmedical occupations. The patterns of infection suggest that the higher levels of infection found among never-married men with medical occupations may not be entirely due to occupational exposure. These findings may have applications in the design and interpretation of results of health care worker HIV surveillance programs.


Left atrial posterior wall isolation in conjunction with pulmonary vein isolation using cryoballoon for treatment of persistent atrial fibrillation (PIVoTAL): study rationale and design.
There is growing evidence in support of pulmonary vein isolation (PVI) with concomitant posterior wall isolation (PWI) for the treatment of patients with symptomatic persistent atrial fibrillation (persAF). However, there is limited data on the safety and efficacy of this approach using the cryoballoon. The aim of this multicenter, investigational device exemption trial (G190171) is to prospectively evaluate the acute and long-term outcomes of PVI versus PVI+PWI using the cryoballoon in patients with symptomatic persAF. The PIVoTAL is a prospective, randomized controlled study ( ClinicalTrials.gov : NCT04505163) in which patients with symptomatic persAF refractory/intolerant to ≥ 1 class I-IV antiarrhythmic drug, undergoing first-time catheter ablation, will be randomized to PVI (n = 183) versus PVI+PWI (n = 183) using the cryoballoon in a 1:1 fashion. The design will be double-blind until randomization immediately after PVI, beyond which the design will transform into a single-blind. PVI using cryoballoon will be standardized using a pre-specified dosing algorithm. Other empiric ablations aside from documented arrhythmias/arrhythmias spontaneously induced during the procedure will not be permitted. The primary efficacy endpoint is defined as AF recurrence at 12 months, after a single procedure and a 90-day blanking period. Arrhythmia outcomes will be assessed by routine electrocardiograms and 7-14 day ambulatory electrocardiographic monitoring at 3, 6, and 12 months post-ablation. The PIVoTAL is a prospective, randomized controlled trial designed to evaluate the outcomes of PVI alone versus PVI+PWI using the cryoballoon, in patients with symptomatic persAF. We hypothesize that PVI+PWI will prove to be superior to PVI alone for prevention of AF recurrence.


Size, skills, and suffrage: Motivated distortions in perceived formidability of political leaders.
Research shows that perception of physical size and status are positively associated. The current study was developed to replicate and extend earlier research on height perceptions of political leaders, indicating that supporters perceive their leaders as taller than non-supporters do, and winners are perceived as taller after the elections, while losers are perceived as shorter after the elections (winner/loser effects). Individuals use greater height and strength as indications of greater physical formidability. We hypothesized that in-group leaders' height and strength, but not weight, would be overestimated more compared to out-group leaders', and that this status-size association is not only driven by dominance, but also by prestige. We also tested whether previously found gender effects in estimates were due to using one's own height as an anchor, and we used an improved methodological approach by relying on multiple measurements of physical formidability and a within-subject design for testing winner/loser effects. The results of a two-part longitudinal study (self-selected sample via voting advice website; NWave1 = 2,011; NWave2 = 322) suggest that estimated physical formidability of political leaders is affected by motivated perception, as prestige was positively associated with estimated formidability, and in-group leaders were estimated more formidable than out-group leaders. We conclude that distortions in judged formidability related to social status are the result of motivated social perception in order to promote group functioning and leadership. Although we did not replicate a winner-effect (greater estimations of formidability after winning the elections), we did find some evidence for a loser-effect. Earlier suggestions that men make larger estimations than women because of their own larger body size are not supported. Implications for theory and future research are discussed.


From fish to modern humans--comparative anatomy, homologies and evolution of the head and neck musculature.
In a recent paper Diogo (2008) reported the results of the first part of an investigation of the comparative anatomy, homologies and evolution of the head and neck muscles of osteichthyans (bony fish + tetrapods). That report mainly focused on actinopterygian fish, but also compared these fish with certain non-mammalian sarcopterygians. The present paper focuses mainly on sarcopterygians, and particularly on how the head and neck muscles have evolved during the transitions from sarcopterygian fish and non-mammalian tetrapods to monotreme and therian mammals, including modern humans. The data obtained from our dissections of the head and neck muscles of representative members of sarcopterygian fish, amphibians, reptiles, monotremes and therian mammals, such as rodents, tree-shrews, colugos and primates, including modern humans, are compared with the information available in the literature. Our observations and comparisons indicate that the number of mandibular and true branchial muscles (sensu this work) present in modern humans is smaller than that found in mammals such as tree-shrews, rats and monotremes, as well as in reptiles such as lizards. Regarding the pharyngeal musculature, there is an increase in the number of muscles at the time of the evolutionary transition leading to therian mammals, but there was no significant increase during the transition leading to the emergence of higher primates and modern humans. The number of hypobranchial muscles is relatively constant within the therian mammals we examined, although in this case modern humans have more muscles than other mammals. The number of laryngeal and facial muscles in modern humans is greater than that found in most other therian taxa. Interestingly, modern humans possess peculiar laryngeal and facial muscles that are not present in the majority of the other mammalian taxa; this seems to corroborate the crucial role played by vocal communication and by facial expressions in primate and especially in human evolution. It is hoped that by compiling, in one paper, data about the head and neck muscles of a wide range of sarcopterygians, the present work could be useful to comparative anatomists, evolutionary biologists and functional morphologists and to researchers working in other fields such as developmental biology, genetics and/or evolutionary developmental biology.


The worldwide holoparasitic Apodanthaceae confidently placed in the Cucurbitales by nuclear and mitochondrial gene trees.
Of the c. 450 families of flowering plants, only two are left "unplaced" in the most recent APG classification of angiosperms. One of these is the Apodanthaceae, a clade of c. 19 holoparasitic species in two or three genera occurring in North and South America, Africa, the Near East, and Australia. Because of lateral gene transfer between Apodanthaceae and their hosts it has been difficult to infer the family's true closest relatives. Here we report a phylogenetic analysis of 16 accessions representing six species of Apodanthaceae from the United States, Chile, Iran, and Australia, using the mitochondrial matR gene and the nuclear 18S gene. Data matrices include 190 matR sequences from up to 95 families in 39 orders of flowering plants and 197 18S sequences from 101 families representing the 16 orders of rosids. Analyses were performed at the nucleotide and at the amino acid level. Both gene trees agree with angiosperm phylogenies found in other studies using more genes. Apodanthaceae and the seven families of the order Cucurbitales form a clade with 100% bootstrap support from matR and 56% from 18 S. In addition, the Apodanthaceae and Cucurbitales matR gene sequences uniquely share two non-synonymous codon changes and one synonymous change, as well as a codon insertion, already found by Barkman et al. (2007). Apodanthaceae belong in the Cucurbitales with which they share inferior ovaries, parietal placentation and a dioecious mating system, traits that are ancestral in Cucurbitales and which can now be interpreted as possible synapomorphies of an enlarged order Cucurbitales. The occurrence of Apodanthaceae in the Americas, Africa, the Near East, and Australia, and their adaptation to distantly related host species in the Fabaceae and Salicaceae suggest a long evolutionary history.


Beta1 integrin establishes endothelial cell polarity and arteriolar lumen formation via a Par3-dependent mechanism.
Maintenance of single-layered endothelium, squamous endothelial cell shape, and formation of a patent vascular lumen all require defined endothelial cell polarity. Loss of beta1 integrin (Itgb1) in nascent endothelium leads to disruption of arterial endothelial cell polarity and lumen formation. The loss of polarity is manifested as cuboidal-shaped endothelial cells with dysregulated levels and mislocalization of normally polarized cell-cell adhesion molecules, as well as decreased expression of the polarity gene Par3 (pard3). beta1 integrin and Par3 are both localized to the endothelial layer, with preferential expression of Par3 in arterial endothelium. Luminal occlusion is also exclusively noted in arteries, and is partially rescued by replacement of Par3 protein in beta1-deficient vessels. Combined, our findings demonstrate that beta1 integrin functions upstream of Par3 as part of a molecular cascade required for endothelial cell polarity and lumen formation.


Junior Investigators Thinking About Quitting Research: A Survey.
Junior tenure-track faculty report high levels of stress and low satisfaction; the increasingly competitive funding environment compounds this discontent. We examined factors associated with junior investigators who were thinking about quitting research. Data were collected as part of a program evaluation of an interdisciplinary research mentoring program in an academic medical center. Of the 62 mentees, 44 responded to the survey (71%). When asked "In the past year, have you considered quitting research?" 39 mentees answered the question; 17 (44%) answered in the affirmative. Those who had considered quitting had lower scores on the Clinical Research Appraisal Inventory-12 (CRAI-12) and job satisfaction and higher scores on burnout. In a regression model, we found that only CRAI-12 scores were significantly, inversely associated with thinking about quitting. Factors associated with thinking about quitting included lower confidence in research skills, reduced job satisfaction, and higher levels of burnout.


Terahertz-pulse generation by photoionization of air with laser pulses composed of both fundamental and second-harmonic waves.
Intense radiation in the terahertz (THz) frequency range can be generated by focusing of an ultrashort laser pulse composed of both a fundamental wave and its second-harmonic field into air, as reported previously by Cook et al. [Opt. Lett. 25, 1210 (2000)]. We identify a threshold for THz generation that proves that generation of a plasma is required and that the nonlinearity of air is insufficient to explain our measurements. An additional THz field component generated in the type I beta-barium borate crystal used for second-harmonic generation has to be considered if one is to avoid misinterpretation of this kind of experiment. We conclude with a comparison that shows that the plasma emitter is competitive with other state-of-the-art THz emitters.


Tailoring the chain packing in ultrathin polyelectrolyte films formed by sequential adsorption: nanoscale probing by positron annihilation spectroscopy.
Depth profiling experiments by positron annihilation spectroscopy have been used to investigate the free volume element size and concentration in films assembled using the layer-by-layer (LbL) adsorption method. Films prepared from strong polyelectrolytes, weak polyelectrolytes, hydrogen-bonding polymers, and blended polyelectrolyte multilayers have different chain packing that is reflected in the free volume characteristics. The influence of various parameters on free volume, such as number of bilayers, salt concentration, solution pH, and molecular weight, has been systematically studied. The free volume cavity diameters vary from 4 to 6 Å, and the free volume concentrations vary from (1.1-4.3) × 10(20) cm(-3), depending on the choice of assembly polymers and conditions. Films assembled from strong polyelectrolytes have fewer free volume cavities with a larger average size than films prepared from weak polyelectrolytes. Blending the weak polyanion poly(acrylic acid), PAA, with the strong polyanion poly(styrene sulfonate), PSS, to layer alternately with the polycation poly(allyamine hydrochloride), PAH, is shown to be a viable method to achieve intermediate free volume characteristics in these LbL films. An increase in salt concentration of the adsorption solutions for films prepared from strong polyelectrolytes makes these films tend toward weaker polyelectrolyte free volume characteristics. Hydrogen-bonded layered films show larger free volume element size and concentration than do their electrostatically bonded counterparts, while reducing the molecular weight of these hydrogen-bonded polymers results in slightly reduced free volume size and concentration. A study of the effect of solution pH on films prepared from weak polyelectrolytes shows that when both polyelectrolytes are substantially charged in solution (assembly pH = 7.5), the chains pack similarly to strong polyelectrolytes (i.e., lower free volume concentration), but with smaller average cavity sizes. These results give, for the first time, a clear indication of how the free volume profile develops in LbL thin films, offering numerous methods to tailor the Ångström-scale free volume properties by judicious selection of the assembly polymers and conditions. These findings can be potentially exploited to tailor the properties of thin polymer films for applications spanning membranes, sensing, and drug delivery.