Assessment of genetic variation within a global collection of lentil (Lens culinaris Medik.) cultivars and landraces using SNP markers.
Lentil is a self-pollinated annual diploid (2n = 2× = 14) crop with a restricted history of genetic improvement through breeding, particularly when compared to cereal crops. This limited breeding has probably contributed to the narrow genetic base of local cultivars, and a corresponding potential to continue yield increases and stability. Therefore, knowledge of genetic variation and relationships between populations is important for understanding of available genetic variability and its potential for use in breeding programs. Single nucleotide polymorphism (SNP) markers provide a method for rapid automated genotyping and subsequent data analysis over large numbers of samples, allowing assessment of genetic relationships between genotypes. In order to investigate levels of genetic diversity within lentil germplasm, 505 cultivars and landraces were genotyped with 384 genome-wide distributed SNP markers, of which 266 (69.2%) obtained successful amplification and detected polymorphisms. Gene diversity and PIC values varied between 0.108-0.5 and 0.102-0.375, with averages of 0.419 and 0.328, respectively. On the basis of clarity and interest to lentil breeders, the genetic structure of the germplasm collection was analysed separately for cultivars and landraces. A neighbour-joining (NJ) dendrogram was constructed for commercial cultivars, in which lentil cultivars were sorted into three major groups (G-I, G-II and G-III). These results were further supported by principal coordinate analysis (PCoA) and STRUCTURE, from which three clear clusters were defined based on differences in geographical location. In the case of landraces, a weak correlation between geographical origin and genetic relationships was observed. The landraces from the Mediterranean region, predominantly Greece and Turkey, revealed very high levels of genetic diversity. Lentil cultivars revealed clear clustering based on geographical origin, but much more limited correlation between geographic origin and genetic diversity was observed for landraces. These results suggest that selection of divergent parental genotypes for breeding should be made actively on the basis of systematic assessment of genetic distance between genotypes, rather than passively based on geographical distance.


2-Aminopurine as a fluorescent probe of DNA conformation and the DNA-enzyme interface.
Nearly 50 years since its potential as a fluorescent base analogue was first recognized, 2-aminopurine (2AP) continues to be the most widely used fluorescent probe of DNA structure and the perturbation of that structure by interaction with enzymes and other molecules. In this review, we begin by considering the origin of the dramatic and intriguing difference in photophysical properties between 2AP and its structural isomer, adenine; although 2AP differs from the natural base only in the position of the exocyclic amine group, its fluorescence intensity is one thousand times greater. We then discuss the mechanism of interbase quenching of 2AP fluorescence in DNA, which is the basis of its use as a conformational probe but remains imperfectly understood. There are hundreds of examples in the literature of the use of changes in the fluorescence intensity of 2AP as the basis of assays of conformational change; however, in this review we will consider in detail only a few intensity-based studies. Our primary aim is to highlight the use of time-resolved fluorescence measurements, and the interpretation of fluorescence decay parameters, to explore the structure and dynamics of DNA. We discuss the salient features of the fluorescence decay of 2AP when incorporated in DNA and review the use of decay measurements in studying duplexes, single strands and other structures. We survey the use of 2AP as a probe of DNA-enzyme interaction and enzyme-induced distortion, focusing particularly on its use to study base flipping and the enhanced mechanistic insights that can be gained by a detailed analysis of the decay parameters, rather than merely monitoring changes in fluorescence intensity. Finally we reflect on the merits and shortcomings of 2AP and the prospects for its wider adoption as a fluorescence-decay-based probe.


Cephalometric analyses and flow-volume loops in obstructive sleep apnea patients.
Fifteen patients with obstructive sleep apnea syndrome (OSAS) and 10 controls were studied. Polygraphic monitoring during sleep confirmed the presence or absence of OSAS. Ten OSAS patients and five controls had cephalometric analysis and 12 OSAS patients and five controls had a flow-volume loop study during wakefulness. Seven OSAS patients were submitted to both analyses. Flow-volume loops were unable to detect extrathoracic airway obstruction in six out of 12 OSAS patients. One control was found with positive results. Six out of seven subjects with positive flow-volume loops were overweight (greater than or equal to 30% ideal weight). Cephalograms were very useful in demonstrating mandibular deficiencies in OSAS patients. The length of the soft palate and the position of the hyoid bone, together with the measurement of the posterior airway space, are criteria of great interest in OSAS patients. Cephalometric analysis is recommended in all OSAS patients scheduled for surgical procedure. None of these tests, however, whether alone or in combination, is capable of identifying all cases of OSAS.


Screening for inborn errors of metabolism in high-risk children: a 3-year pilot study in Zhejiang Province, China.
Tandem mass spectrometry (MS/MS) has been available in China for 8 years. This technique makes it possible to screen for a wide range of previously unscreened inborn errors of metabolism (IEM) using a single test. This 3-year pilot study investigated the screening, diagnosis, treatment and outcomes of IEM in symptomatic infants and children. All children encountered in the Newborn Screening Center of Zhejiang Province during a 3-year period with symptoms suspicious for IEM were screened for metabolic diseases. Dried blood spots were collected and analyzed by tandem mass spectrometry. The diagnoses were further confirmed by clinical symptoms and biochemical analysis. Neonatal intrahepatic cholestasis caused by citrin deficiency, ornithine transcarbamylase deficiency and primary carnitine deficiency were confirmed by DNA analysis. A total of 11,060 symptomatic patients (6,720 boys, 4,340 girls) with a median age of 28.8 months (range: 0.04-168.2 months) were screened. Among these, 62 were diagnosed with IEM, with a detection rate of 0.56%. Thirty-five were males and 27 females and the median age was 3.55 months (range 0.07-143.9 months). Of the 62 patients, 27 (43.5%) had aminoacidemias, 26 (41.9%) had organic acidemias and nine (14.5%) had fatty acid oxidation disorders. Because most symptomatic patients are diagnosed at an older age, mental retardation and motor delay are difficult to reverse. Additionally, poor medication compliance reduces the efficacy of treatment. More extensive newborn screening is thus imperative for ensuring early diagnosis and enhancing the treatment efficacy of IEM.


Types and quality of animals in cancer research.
In addition to studies in man, animal models may serve as important tools in the detection of the etiology, biology and treatment of certain types of human cancers. Various models have become available by performing life span studies on 2 rat strains, viz WAG/Rij, BN/Bi and (WAG x BN) F1 hybrid and on Praomys natalensis. Several of these models are described. A basic prerequisite for these types of studies is the availability of animals of good quality. After a general description of the quality of laboratory animals the desirable health status of animals in cancer research is discussed.


Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses.
Chikungunya virus (CHIKV) is an arthritogenic arbovirus of the Alphavirus genus, which has infected millions of people after its re-emergence in the last decade. In this study, a BHK cell line containing a stable CHIKV replicon with a luciferase reporter was used in a high-throughput platform to screen approximately 3000 compounds. Following initial validation, 25 compounds were chosen as primary hits for secondary validation with wild type and reporter CHIKV infection, which identified three promising compounds. Abamectin (EC50 = 1.5 μM) and ivermectin (EC50 = 0.6 μM) are fermentation products generated by a soil dwelling actinomycete, Streptomyces avermitilis, whereas berberine (EC50 = 1.8 μM) is a plant-derived isoquinoline alkaloid. They inhibited CHIKV replication in a dose-dependent manner and had broad antiviral activity against other alphaviruses--Semliki Forest virus and Sindbis virus. Abamectin and ivermectin were also active against yellow fever virus, a flavivirus. These compounds caused reduced synthesis of CHIKV genomic and antigenomic viral RNA as well as downregulation of viral protein expression. Time of addition experiments also suggested that they act on the replication phase of the viral infectious cycle.


The pivotal ripening gene SlDML2 participates in regulating disease resistance in tomato.
Fruit ripening and disease resistance are two essential biological processes for quality formation and maintenance. DNA methylation, in the form of 5-methylcytosine (5mC), has been elucidated to modulate fruit ripening, but its role in regulating fruit disease resistance remains poorly understood. In this study, we show that mutation of SlDML2, the DNA demethylase gene essential for fruit ripening, affects multiple developmental processes of tomato besides fruit ripening, including seed germination, leaf length and width and flower branching. Intriguingly, loss of SlDML2 function decreased the resistance of tomato fruits against the necrotrophic fungal pathogen Botrytis cinerea. Comparative transcriptomic analysis revealed an obvious transcriptome reprogramming caused by SlDML2 mutation during B. cinerea invasion. Among the thousands of differentially expressed genes, SlβCA3 encoding a β-carbonic anhydrase and SlFAD3 encoding a ω-3 fatty acid desaturase were demonstrated to be transcriptionally activated by SlDML2-mediated DNA demethylation and positively regulate tomato resistance to B. cinerea probably in the same genetic pathway with SlDML2. We further show that the pericarp tissue surrounding B. cinerea infection exhibited a delay in ripening with singnificant decrease in expression of ripening genes that are targeted by SlDML2 and increase in expression of SlβCA3 and SlFAD3. Taken together, our results uncover an essential layer of gene regulation mediated by DNA methylation upon B. cinerea infection and raise the possible that the DNA demethylase gene SlDML2, as a multifunctional gene, participates in modulating the trade-off between fruit ripening and disease resistance.


Extinguishing cue-controlled reward choice: Effects of Pavlovian extinction on outcome-selective Pavlovian-instrumental transfer.
Outcome-selective Pavlovian-instrumental transfer (PIT) refers to the finding that presenting Pavlovian predictors of outcomes can enhance the vigor of instrumental responding for those same outcomes. Three experiments examined the sensitivity of outcome-selective PIT to Pavlovian (stimulus-outcome) extinction. In Experiment 1, participants first learnt to perform different instrumental responses to earn different outcomes. In a separate Pavlovian training phase, certain stimuli were established as Pavlovian signals of the different outcomes. Some of these Pavlovian stimuli were then extinguished (they were presented alone, without any outcome), while others were not. A final transfer test measured the extent to which these Pavlovian cues biased instrumental response choice. Consistent with previous work, the observed PIT effects were immune to Pavlovian extinction; the non-extinguished and extinguished cues produced PIT effects that did not significantly differ in size. In Experiment 2, response choice was tested in the presence of compound stimuli that included both extinguished and non-extinguished cues. Response choice was highly sensitive to the extinction manipulation under these circumstances. Experiment 3 tested whether this sensitivity to Pavlovian extinction was a direct effect of the associative strength of the Pavlovian cues present, or an indirect effect of cue salience. The results provide unique evidence to suggest that PIT is a direct consequence of the strength of the Pavlovian associations. (PsycINFO Database Record


Proportional mixture of two rarefaction/extrapolation curves to forecast biodiversity changes under landscape transformation.
Progressive habitat transformation causes global changes in landscape biodiversity patterns, but can be hard to quantify. Rarefaction/extrapolation approaches can quantify within-habitat biodiversity, but may not be useful for cases in which one habitat type is progressively transformed into another habitat type. To quantify biodiversity patterns in such transformed landscapes, we use Hill numbers to analyse individual-based species abundance data or replicated, sample-based incidence data. Given biodiversity data from two distinct habitat types, when a specified proportion of original habitat is transformed, our approach utilises a proportional mixture of two within-habitat rarefaction/extrapolation curves to analytically predict biodiversity changes, with bootstrap confidence intervals to assess sampling uncertainty. We also derive analytic formulas for assessing species composition (i.e. the numbers of shared and unique species) for any mixture of the two habitat types. Our analytical and numerical analyses revealed that species unique to each habitat type are the most important determinants of landscape biodiversity patterns.


[Immune disturbances in acute pyelonephritis. Part I].
In the part I of a literature review of modern national and foreign publications dedicated to the problem of immune disorders in acute pyelonephritis, information on the role of innate and adaptive immunity in the pathogenesis of acute pyelonephritis is summarized and systematized. The relationship between the pathogens and immune system, in particular the ability of pathogens to overcome the protective immune mechanisms are discussed. The role of neutrophilic granulocytes as well as cellular immunity in the pathogenesis of acute pyelonephritis is shown. The changes in level of pro- and anti-inflammatory cytokines are separately highlighted. In conclusion, perspective directions for the studies in the area of immune disorders in acute pyelonephritis are proposed.


Declining genetic diversity of European honeybees along the twentieth century.
The European honeybee (Apis mellifera) is a key pollinator and has in the last decades suffered significant population decline. A combination of factors, including decrease in genetic diversity and introduction of Varroa mites, have been suggested to be responsible for these losses, but no definitive cause has yet been appointed. In Europe not only have wild colonies been severely affected, but managed hives have had a massive decline in numbers. To test the hypothesis that honeybees' genetic diversity has decreased in the recent past, we used reduced representation genome sequencing of 40 historical honeybee specimens collected in Natural History collections across Europe and compared them to genomic data from 40 individuals from extant populations (collected post 2006). Our results are consistent with the existence of five evolutionary lineages as previously described, and show a decrease in genetic diversity between historical and extant individuals of the same lineage, as well as high levels of admixture in historical specimens. Our data confirm that a loss of genetic diversity has occurred during the last century, potentially increasing honeybees' vulnerability to contemporary ecological and anthropogenic stressors.


Monocrotaline pyrrole induces apoptosis in pulmonary artery endothelial cells.
In the monocrotaline (MCT) model of pulmonary hypertension, the pulmonary vascular endothelium is the likely early target of the reactive metabolite monocrotaline pyrrole (MCTP). Incubation of cultured bovine pulmonary arterial endothelial cells (BPAEC) with MCTP results in covalent binding to DNA, cell cycle arrest, and delayed but progressive cell death. The mode of cell death in MCTP-induced endothelial damage has not been addressed previously. Since DNA damage is frequently associated with apoptosis, the presence or absence of apoptosis in adherent BPAEC was determined by several techniques, including morphologic and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling. Two concentrations of MCTP (5 and 34.5 microgram/ml) along with a vehicle control were examined with each assay. Both concentrations of MCTP induced increasing numbers of cells to undergo apoptosis over time beginning as early as 6 h after exposure to MCTP in the high concentration group. Control and vehicle control cells exhibited small amounts of apoptosis (1-2%), which did not change over the duration of the experiment. Additionally, cell membrane integrity was assessed over time by either exposure to membrane-impermeant dyes or measuring LDH release. By either method, BPAEC had increased membrane permeability after about 48 h of either low or high concentration MCTP exposure. We conclude that both a low or high concentration of MCTP causes cell death in BPAEC by inducing apoptosis.


The homogenization of the Metathesaurus schema and distribution format.
The third version of the UMLS Metathesaurus, Meta-1.2, to be released in October 1992, will have a simpler schema and simpler distribution formats than the first two versions, Meta-1.0 and Meta-1.1 released in October 1990 and 1991, respectively. For one thing, it will have only a single kind of entry (Concept), rather than three (Concept, Related, and Synonym). Further, the Relational Format, will consist of four logical relations, or tables, instead of the nearly three score different tables used to represent the same kind of information in Meta-1.1. These four tables will contain, respectively, (1) the names of each concept, (2) the relationships between concepts, (3) attributes of the concepts, and (4) a word-based index into the concept names. We argue that the new schema and formats provide a better conceptual model of the Metathesaurus, and represent the information contained there more uniformly. Even though these changes are incremental and evolutionary, both users and software developers should find the Meta-1.2 significantly easier to understand, and the information contained in it significantly easier to use.


Development of a Pediatric Fall Risk And Injury Reduction Program.
Fall prevention programs that include reliable, valid, and clinically tested screening tools have demonstrated more positive effects for adult and geriatric populations than those not including such assessment. In contrast, because falling is a natural part of growth and development for pediatric patients, progression toward effective prevention programs for this population has proven to be a challenge; a significant impediment is the lack of definition regarding what constitutes a reportable fall. This project explored pediatric health care providers' perceptions of patient falls in order to define a reportable pediatric fall and inform development of a prevention program. A concept analysis of defining attributes, antecedents, and consequences of pediatric falls from literature formed the basis for a set of questions; a convenience sample of 28 pediatric health care providers in an acute care hospital in New England participated in six moderated focus groups. Constant comparison method was used to code the qualitative data and develop themes. Participants unanimously agreed on several points; as expected, their years of experience in pediatric practice provided valuable insight. Three major themes emerged: patient characteristics, caregiver characteristics, and environmental characteristics. Based on factors identified by staff, a screening tool was adopted and integrated into the electronic medical record. Staff were actively engaged in developing definitions, selecting tools, and identifying next steps toward a comprehensive fall reduction program for their patients. As a result, they have embraced changes and advocated successfully for endorsement by the organization.


Impact of Storage Temperature on the Expression of Cell Survival Genes in Cultured ARPE-19 Cells.
The development of a suitable storage method for retinal pigment epithelium (RPE) is necessary in the establishment of future RPE replacement therapy, and storage temperature has proven to be pivotal for cell survival. ARPE-19, a widely used model for RPE, has been shown to yield the greatest number of viable cells when stored at 16°C compared to other storage temperatures. In this study, we analyze the gene expression profile of cultured ARPE-19 cells after seven days of storage at different temperatures in an effort to predict the gene-level consequences of storage of RPE transplants. ARPE-19 cells were cultured until confluence and then stored in minimum essential medium at 4°C, 16°C, and 37°C for seven days. The total RNA was isolated and the gene expression profile was determined using DNA microarrays. The Results were validated using qPCR. Principal component and hierarchical clustering analyses show that the gene expression profiles of cell cultures stored at different temperatures cluster into separate groups. Cultures stored at 4°C cluster closest to the control cultures that were not stored and display the least change in gene expression after storage (157 differentially expressed genes). Cultures stored at 16°C and 37°C display a much larger change in differential gene expression (1787 and 1357 differentially expressed genes, respectively). At 16°C, the expression of several genes with proposed tumor suppressor functions was markedly increased. Changes in regulation of several known signaling pathways and of oxidative stress markers were discovered at both 16°C and 37°C, and activation of the angiogenesis marker vascular endothelial growth factor (VEGF) was discovered at 37°C. There was no evidence of the activation of inflammatory processes in stored cell cultures. ARPE-19 cultures stored at 16°C show the greatest propensity to modulate their gene expression profile in a manner that supports cell survival during storage.


Differential susceptibility to inhaled pollutants: effects of demographics and diseases.
Inhaled pollutants and respiratory disease deserve particular attention at a conference focused on susceptibility and environmental risk. Inhaled air contains diverse biological, physical and chemical stressors which may cause upper and lower respiratory inflammation and exacerbate complex polygenic disorders such as asthma and sinusitis. This paper focuses on intrinsic susceptibility factors of demographics and diseases as well as genetic background. The National Health Information Survey shows that acute and chronic respiratory conditions are common at all ages, but their incidence and prevalence vary between age groups. Susceptibility is therefore not a fixed characteristic, but the aggregate effect of changing intrinsic factors such as age and disease. While ethnicity is often cited as a risk factor for disease prevalence or severity, recent research shows that measurable factors such as nasal ellipticity determine exposure-dose relationships, while the imperfect surrogate of ethnicity does not. Studies also show that exposure-dose relationships can be modified by recent exposures, and additional information is clearly needed in this area. We propose that evidence for the genetic contribution to pollutant susceptibility be sought in inter-individual variation in responses of homogenous, well characterized individuals to short term controlled pollutant exposure. Future improvements in risk assessment models will be based on a precise identification of factors that determine exposure-dose relationships, and a mechanistic understanding of the reasons that a demographic factor or disease appears to confer altered susceptibility.


Association of Snoring with Prediabetes and Type 2 Diabetes Mellitus: The Cardiovascular and Metabolic Diseases Etiology Research Center Cohort.
Evidence suggests that habitual snoring is an independent risk factor for poor glycemic health. We examined the associations between snoring with prediabetes and diabetes in Korean population. Self-reported snoring characteristics were collected from 3,948 middle-aged adults without prior cardiovascular diseases. Multivariable linear regression assessed the association of snoring intensity, frequency, disruptiveness, and disrupted breathing with fasting glucose and glycosylated hemoglobin (HbA1c) level. Then, multinomial regression evaluated how increasing snoring symptoms are associated with the risk for prediabetes and diabetes, adjusting for socioeconomic and behavioral risk factors of diabetes, obesity, hypertension, and other sleep variables. Higher snoring intensity and frequency were positively associated with fasting glucose and HbA1c levels. Participants presenting the most severe snoring were at 1.84 times higher risk (95% confidence interval [CI], 1.09 to 2.29) for prediabetes and 2.24 times higher risk (95% CI, 1.84 to 2.95) for diabetes, compared to non-snorers. Such graded association was also observed amongst the most frequent snorers with higher risk for prediabetes (odds ratio [OR], 1.78; 95% CI, 1.29 to 2.22) and diabetes (OR, 2.03; 95% CI, 1.45 to 2.85). Disruptive snoring (OR, 1.60; 95% CI, 1.12 to 2.28) and near-daily disruptive breathing (OR, 2.18; 95% CI, 1.02 to 4.19) were associated with higher odds for diabetes. Such findings remained robust after additional adjustment for sleep duration, excessive daytime sleepiness, unwakefulness, and sleep-deprived driving. Snoring is associated with impaired glucose metabolism even in otherwise metabolically healthy adults. Habitual snorers may require lifestyle modifications and pharmacological treatment to improve glycemic profile.


The effect of collaborative care on treatment outcomes of newly diagnosed tuberculosis patients with Type-2 diabetes mellitus and adverse drug reaction presentations: A prospective study.
The burdens of tuberculosis (TB) and diabetes mellitus (DM) in Nigeria are high. DM often goes unrecognized in TB patients, resulting in poorer treatment outcomes compared with TB patients only. This study set out to compare TB treatment outcomes and associated factors in TB only and TBDM patients when a collaborative care (CC) model is in place. A prospective quasi-experimental study, modeled after the World Health Organization and The Union's Collaborative Framework for Care and Control of TB and DM was carried out among TB patients in two chest clinics in Lagos state. Patients were grouped into TB only, who received the usual TB care, directly observed treatment, short course (DOTS), and TBDM, who received DOTS and CC. Data were analyzed with IBM Statistical Package for the Social Sciences, version 23.0. Chi-square and multivariate analysis determined the association between treatment success and CC. Statistical tests were calculated at 95% confidence intervals and considered significant when P value is < 0.05. Of 671 participants in the study, 52 (7.7%) had DM. At TB treatment completion, there was no statistically significant difference in outcomes between TBDM and TB-only patients (P = 0.40). Patients who received CC were about 32 (OR: 31.60, 95% CI: 3.38-293), and 5 times (OR: 5.08, 95% CI: 1.35-19.17) more likely to achieve success and cure, respectively, compared to those who did not. Provision of CC with DOTS ensured improved TB treatment outcomes in TBDM patients. Recommendations of WHO/The Union are feasible in our setting.


Classification of a body form of parasitic copepods.
The following classification of body form typical for parasitic copepods which could be useful when compiling the determinants describing supraspecific taxon was proposed. The cyclopoid body form for the families Bomolochidae, Taeniacanthidae, Ergasilidae, Myicolidae, Tegabomolochidae, Telsidae and Grandiunguidae; caligoid body form for Caligidae, Pandaridae, Euryphoridae, Cecropidae, Scienophilidae, Trebiidae and Dissonidae; eudactyloid body form for Eudactylinidae, Hatschekiidae and Pseudocynidae; the chondracanthoid body form for Hyponeoidae, Shiinoidae, Pharoidae and some Chondracanthidae; the lernanthropoid body form for Lernanthropidae and Anthosomatidae; the lernaeopodidoid body form for Lernaeopodidae and Naobranchiidae; the sphyriioid body form for Sphyriidae, Lernaeidae, Pennellidae and some Chondracanthidae; the philichthyioid body form for Philichthyidae are discussed.


Development of an eHealth System to Capture and Analyze Patient Sensor and Self-Report Data: Mixed-Methods Assessment of Potential Applications to Improve Cancer Care Delivery.
Capturing and Analyzing Sensor and Self-Report Data for Clinicians and Researchers (COMPASS) is an electronic health (eHealth) platform designed to improve cancer care delivery through passive monitoring of patients' health status and delivering customizable reports to clinicians. Based on data from sensors and context-driven administration of patient-reported outcome (PRO) measures, key indices of patients' functional status can be collected between regular clinic visits, supporting clinicians in the delivery of patient care. The first phase of this project aimed to systematically collect input from oncology providers and patients on potential clinical applications for COMPASS to refine the system. Ten clinicians representing various oncology specialties and disciplines completed semi-structured interviews designed to solicit clinician input on how COMPASS can best support clinical care delivery. Three cancer patients tested a prototype of COMPASS for 7 days and provided feedback. Interview data were tabulated using thematic content analysis to identify the most clinically relevant objective and PRO domains. Thematic content analysis revealed that clinicians were most interested in monitoring vital statistics, symptoms, and functional status, including the physical activity level (n=9), weight (n=5), fatigue (n=9), sleep quality (n=8), and anxiety (n=7). Patients (2 in active treatment and 1 in remission) reported that they would use such a device, were enthusiastic about their clinicians monitoring their health status, especially the tracking of symptoms, and felt knowing their clinicians were monitoring and reviewing their health status provided valuable reassurance. Patients would, however, like to provide some context to their data. Clinicians and patients both articulated potential benefits of the COMPASS system in improving cancer care. From a clinician standpoint, data need to be easily interpretable and actionable. The fact that patients and clinicians both see potential value in eHealth systems suggests wider adoption and utilization could prove to be a useful tool for improving care delivery.


Flagellar dynamics reveal fluctuations and kinetic limit in the Escherichia coli chemotaxis network.
The Escherichia coli chemotaxis network, by which bacteria modulate their random run/tumble swimming pattern to navigate their environment, must cope with unavoidable number fluctuations ("noise") in its molecular constituents like other signaling networks. The probability of clockwise (CW) flagellar rotation, or CW bias, is a measure of the chemotaxis network's output, and its temporal fluctuations provide a proxy for network noise. Here we quantify fluctuations in the chemotaxis signaling network from the switching statistics of flagella, observed using time-resolved fluorescence microscopy of individual optically trapped E. coli cells. This approach allows noise to be quantified across the dynamic range of the network. Large CW bias fluctuations are revealed at steady state, which may play a critical role in driving flagellar switching and cell tumbling. When the network is stimulated chemically to higher activity, fluctuations dramatically decrease. A stochastic theoretical model, inspired by work on gene expression noise, points to CheY activation occurring in bursts, driving CW bias fluctuations. This model also shows that an intrinsic kinetic ceiling on network activity places an upper limit on activated CheY and CW bias, which when encountered suppresses network fluctuations. This limit may also prevent cells from tumbling unproductively in steep gradients.


Addressing social drivers of HIV/AIDS for the long-term response: conceptual and methodological considerations.
A key component of the shift from an emergency to a long-term response to AIDS is a change in focus from HIV prevention interventions focused on individuals to a comprehensive strategy in which social/structural approaches are core elements. Such approaches aim to modify social conditions by addressing key drivers of HIV vulnerability that affect the ability of individuals to protect themselves and others from HIV. The development and implementation of evidence-based social/structural interventions have been hampered by both scientific and political obstacles that have not been fully explored or redressed. This paper provides a framework, examples, and some guidance for how to conceptualise, operationalise, measure, and evaluate complex social/structural approaches to HIV prevention to help situate them more concretely in a long-term strategy to end AIDS.


Complement Plays a Critical Role in Inflammation-Induced Immunoprophylaxis Failure in Mice.
Complement impacts innate and adaptive immunity. Using a model in which the human KEL glycoprotein is expressed on murine red blood cells (RBCs), we have shown that polyclonal immunoprophylaxis (KELIg) prevents alloimmunization to transfused RBCs when a recipient is in their baseline state of heath but with immunoprophylaxis failure occurring in the presence of a viral-like stimulus. As complement can be detected on antibody coated KEL RBCs following transfusion, we hypothesized that recipient complement synergizes with viral-like inflammation to reduce immunoprophylaxis efficacy. Indeed, we found recipient C3 and C1q were critical to immunoprophylaxis failure in the setting of a viral-like stimulus, with no anti-KEL IgG alloantibodies generated in C3-/- or C1q-/- mice following KELIg treatment and KEL RBC transfusion. Differences in RBC uptake were noted in mice lacking C3, with lower consumption by splenic and peripheral blood inflammatory monocytes. Finally, no alloantibodies were detected in the setting of a viral-like stimulus following KELIg treatment and KEL RBC transfusion in mice lacking complement receptors (CR1/2-/-), narrowing key cells for immunoprophylaxis failure to those expressing these complement receptors. In-vitro studies showed complement fixed opsonized RBCs were significantly less likely to bind to B-cells from CR1/2-/- than wild type mice, potentially implicating lowered B-cell activation threshold in the presence of complement as being responsible for these findings. We thus propose a two-hit model for inflammation-induced immunoprophylaxis failure, where the first "hit" is recipient inflammation and the second "hit" is complement production/sensing. These results may have translational relevance to antigen-antibody interactions in humans.


Immunologic mechanisms of uveitis. New targets for immunomodulation.
The uvea consists of the choroid, ciliary body, and iris, and inflammation of the uveal tract is termed uveitis. Nevertheless, uveitis is commonly used to more generally describe intraocular inflammation involving not only the uvea, but also the retina, vitreous, and sclera. Fifty years ago, infectious organisms such as syphilis and tuberculosis were thought to be the cause of most forms of uveitis. Since that time, many causes of uveitis have been described as infectious and noninfectious. Scientists have shown that the immune response plays a critical role in the development of infectious and noninfectious forms of the disease. With a more detailed understanding of the immune mechanisms leading to the development of uveitis, we are now able to develop new therapeutic approaches based on targeting various components of the immune response.


Immunosuppression for delayed or slow graft function in primary cadaveric renal transplantation: use of low dose tacrolimus therapy with post-operative administration of anti-CD25 monoclonal antibody.
Patients who develop delayed graft function (DGF) following cadaveric renal transplantation have inferior survival to those who do not. Calcineurin inhibitors (CNI) may prolong recovery from DGF. Patients with DGF are therefore routinely treated with either polyclonal antilymphocyte preparations or monoclonal anti-CD3 monoclonal antibodies and delayed introduction of CNI. The purpose of this study was to evaluate the efficacy of the anti-CD25 monoclonal antibody basiliximab (BSLIX) started post-operatively in patients at high risk for DGF combined with low dose tacrolimus (TAC). Patients who received a primary cadaveric renal transplant only after August 1998 were included in this retrospective study (n = 143). All patients received TAC and mycophenolate Mofetil (MMF) pre-operatively. At 6 h post-operatively, graft function was assessed clinically by urine output and serum creatinine. Those patients who had a urine output < 300 cc/6 h or a rising serum creatinine were presumed to be at risk for DGF (n = 46). These patients were treated with 20 mg BSLIX and had TAC dose reduced to maintain a trough blood level of < 5 ng/mL. Basiliximab was repeated at day 5. Patients not felt to be at risk for DGF were treated with standard TAC dose with trough level target of 9-12 ng/mL. Patients at risk were classified as DGF if they needed dialysis or as slow graft function (SGF) if they did not. The combined group (SGF/DGF) were analysed together. Patients with SGF/DGF had their TAC dose increased to achieve trough levels of 9-12 ng/mL when renal function improved. Patient groups were compared for demographics, need for dialysis, serum creatinine, glomerular filtration rate (GFR), TAC trough levels, MMF dosage, complications and 1- and 2-yr actuarial graft survival. Patients with SGF/DGF had a longer length of stay (8 vs. 5.7 d), were more likely to be black (41.3 vs. 25.7%), and required more post-operative haemodialysis (HD) (52.2 vs. 4.1%). SGF/DGF and non-SGF/DGF patients had similar rates of rejection (28.2 vs. 19.6%, p = 0.28) and steroid resistant rejection (SRR) (6.5 vs. 2.1%, p = 0.32). There were no differences in the rate of cytomegalovirus (CMV) infection (4.3 vs. 6.1%). Serum creatinine was higher and GFR lower at all time points in the SGF/DGF patients. The 1 and 2 yr actuarial survival in the non-SGF/DGF patients was 97.6 and 97.6% compared with 1 and 2 yrs actuarial survival of 94.1% and 80.0% in the SGF/DGF patients, p = 0.04. There were no differences in patient survival. There were no differences in actuarial survival for the SGF/DGF patients who received dialysis compared with those who did not receive dialysis. Comparison of patients who received HD (n = 28) to those who did not (n = 115), regardless of group demonstrated no difference in 1 and 2 yrs actuarial survival, 100 and 94.1% in HD patients vs. 98.2 and 92.5% in non-HD patients. The clinical diagnosis of SGF/DGF can be made 6 h post-operatively based on urine output and serum creatinine. Basiliximab can be started post-operatively in these patients and decreased levels of TAC can be used to achieve acceptably low rates of rejection in these patients. However, SGF/DGF patients, regardless of their need for dialysis, have worse function at 1 yr and lower 2-yr actuarial graft survival compared with non-SGF/DGF patients. Most of the poor survival can be attributed to the SGF group. Further strategies to either prevent SGF/DGF or to optimize treatment in these patients are needed.


Prevalence and Antifungal Susceptibility of Pathogenic Yeasts in China: A 10-Year Retrospective Study in a Teaching Hospital.
To determine the dynamic changes of pathogenic yeast prevalence and antifungal susceptibility patterns in tertiary hospitals in China, we analyzed 527 yeast isolates preserved in the Research Center for Medical Mycology at Peking University, Beijing, China, between Jan 2010 and Dec 2019 and correctly identified 19 yeast species by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and ribosomal DNA sequencing. Antifungal susceptibility testing was performed following a Sensititre YeastOne colorimetric microdilution panel with nine clinically available antifungals. The Clinical and Laboratory Standards Institute (CLSI)-approved standard M27-A3 (S4) and newly revised clinical breakpoints or species-specific and method-specific epidemiological cutoff values were used for the interpretation of susceptibility test data. In this study, although Candida albicans was the predominant single species, non-C. albicans species constituted >50% of isolates in 6 out of 10 years, and more rare species were present in the recent 5 years. The non-C. albicans species identified most frequently were Candida parapsilosis sensu stricto, Candida tropicalis, and Candida glabrata. The prevalence of fluconazole and voriconazole resistance in the C. parapsilosis sensu stricto population was <3%, but C. tropicalis exhibited decreased susceptibility to fluconazole (42, 57.5%) and voriconazole (31, 42.5%), and 22 (30.1%) C. tropicalis isolates exhibited wild-type minimum inhibitory concentrations (MICs) to posaconazole. Furthermore, fluconazole and voriconazole cross-resistance prevalence in C. tropicalis was 19 (26.1%). The overall prevalence of fluconazole resistance in the C. glabrata population was 14 (26.9%), and prevalence of isolates exhibiting voriconazole non-wild-type MICs was 33 (63.5%). High-level echinocandin resistance was mainly observed in C. glabrata, and the prevalence rates of isolate resistance to anidulafungin, micafungin, and caspofungin were 5 (9.6%), 5 (9.6%), and 4 (7.7%), respectively. Moreover, one C. glabrata isolate showed multidrug resistant to azoles, echinocandins, and flucytosine. Overall, the 10-year surveillance study showed the increasing prevalence of non-C. albicans species over time; the emergence of azole resistance in C. tropicalis and multidrug resistance in C. glabrata over the years reinforced the need for epidemiological surveillance and monitoring.


Effect of gender, body composition, and equilibration time on the 2H-to-18O dilution space ratio.
Physiological sources of variation in the 2H-to-18O dilution space ratio (DSR) were examined in 34 males and 20 females (4-78 yr; 14.7-143.2 kg; 1.8-61.0% body fat). Dilution spaces were obtained by time 0 extrapolation of isotope washout over 10-14 days, and body composition was obtained by underwater weight (adults) or bioelectrical impedance (children). The mean DSR was 1.050 +/- 0.015 (range 1.029-1.111), significantly higher (P < 0.001) than the traditionally assumed value of 1.029 based on exchange over 4 h. Use of the value 1.029 causes a systematic 8% overestimate of energy expenditure from doubly labeled water, relative to use of the value 1.05. The DSR was not related to body composition or age but was significantly higher (P < 0.05) in males (1.052 +/- 0.016) than in females (1.044 +/- 0.012). This gender effect was not explained by differences in the number of exchangeable hydrogens in the body. We conclude 1) variation in the 2H-to-18O DSR is not explained by body composition but is influenced by the chemical availability of exchangeable hydrogens to undergo exchange; 2) because the DSR is not easily predicted, use of the observed dilution spaces are recommended; 3) if a fixed DSR is used, values of 1.044 and 1.052 are recommended in females and males, respectively.


Infections in the compromised child.
Children receiving chemotherapy for malignant diseases show different patterns of infection depending on their underlying disease and its therapy. Granulocytopenia carries the risk of bacterial infection, and also, if prolonged, of fungal infection. Impairment of cell-mediated immunity predisposes to infections with Pneumocystis carinii and is thought to be responsible for severe primary infections with varicella and measles, as well as the severe cytomegalovirus infections seen after allogeneic bone marrow transplantation. Absence or impairment of splenic function predisposes to overwhelming septicaemia with encapsulated organisms, while defects in the normal mechanical barriers to infection provide routes for bacterial and fungal invasion. Despite the lack of physical signs of a normal inflammatory response, clinical evaluation may be critical to the localization of infection in the immunocompromised child. Blood culture and biopsy remain pivotal investigations in the achievement of a microbiological diagnosis. Empirical treatment with a combination of antibiotics has been shown in comparative studies to be effective in initial management of the febrile neutropenic patient: continuing studies are evaluating the role of monotherapy and of different antibiotic combinations, particularly in the light of changing patterns of bacterial infections. Empirical antifungal therapy has been shown to be necessary for persistent or recurrent fever, particularly as persistent fungal infection may compromise the outcome of continuing cytotoxic therapy. Continuing uncertainties over many aspects of management of the infected immunocompromised child provide scope for clinical trials in parallel with trials evaluating new anticancer regimens. The use of new diagnostic methods, the role of prophylaxis, the most appropriate empirical regimen, the evaluation of new antimicrobial agents, all require careful evaluation for efficacy and safety. Perhaps the greatest dilemma of all is how far results from trials in adults can be extrapolated to paediatric practice.


Exploiting the nano-sized features of microfibrillated cellulose (MFC) for the development of controlled-release packaging.
Microfibrillated cellulose (MFC) was used in this study to prepare films containing an active molecule, lysozyme, which is a natural antimicrobial agent. The main goal of this research was to assess the potential for exploiting the nano-sized dimension of cellulose fibrils to slow the release of the antimicrobial molecule, thus avoiding a too-quick release into the surrounding medium, which is a major disadvantage of most release systems. For this purpose, the release kinetics of lysozyme over a 10-day period in two different media (pure water and water/ethanol 10wt.%) were obtained, and the experimental data was fitted with a solution of Fick's second law to quantify the apparent diffusion coefficient (D). The results indicate that the MFC retained lysozyme, presumably due to electrostatic, hydrogen, and ion-dipole interactions, with the largest release of lysozyme-approximately 14%-occurring from the initial amount loaded on the films. As expected, ethanol as a co-solvent slightly decreased the diffusion of lysozyme from the MFC polymer network. The addition of two potential modulating release agents-glycerol and sodium chloride-was also evaluated. Findings from this work suggest that MFC-based films can be considered a suitable candidate for use in controlled-release packaging systems.


Mast cells in the labial salivary glands of patients with Sjögren's syndrome: a histochemical, immunohistochemical, and electron microscopical study.
Mast cells in labial salivary glands obtained from patients with xerostomia with or without focal sialadenitis/Sjögren's syndrome were studied. There was no significant correlation between the intensity of local lymphocyte infiltration and the morphometrically analysed number of mast cells staining positive with toluidine blue. Histamine staining with heterologous 11C antiserum showed significantly fewer positive cells than staining with toluidine blue (mean (SD) 62 (10) v 138 (30)). This suggests heterogeneity of the mast cell population. Furthermore, there was a correlation between the focus score and the number of mast cells containing histamine. This suggests that the proliferation of mast cells containing histamine may be locally regulated by the immune inflammation, possibly through mediators from macrophages and fibroblasts. In contrast, the number of mast cells staining positive with toluidine blue could not be used as a marker of the degree of local inflammation. Although transmission electron microscopic analysis did not disclose signs of 'en masse' mast cell degranulation, mast cells may have a role in the local disease process.


Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis.
Bruton's tyrosine kinase (BTK) regulates the functions of B cells and myeloid cells that are implicated in the pathogenesis of multiple sclerosis. Evobrutinib is a selective oral BTK inhibitor that has been shown to inhibit B-cell activation both in vitro and in vivo. In this double-blind, randomized, phase 2 trial, we assigned patients with relapsing multiple sclerosis to one of five groups: placebo, evobrutinib (at a dose of 25 mg once daily, 75 mg once daily, or 75 mg twice daily), or open-label dimethyl fumarate (DMF) as a reference. The primary end point was the total (cumulative) number of gadolinium-enhancing lesions identified on T1-weighted magnetic resonance imaging at weeks 12, 16, 20, and 24. Key secondary end points included the annualized relapse rate and change from baseline in the score on the Expanded Disability Status Scale (EDSS). A total of 267 patients were randomly assigned to a trial group. The mean (±SD) total number of gadolinium-enhancing lesions during weeks 12 through 24 was 3.85±5.44 in the placebo group, 4.06±8.02 in the evobrutinib 25-mg group, 1.69±4.69 in the evobrutinib 75-mg once-daily group, 1.15±3.70 in the evobrutinib 75-mg twice-daily group, and 4.78±22.05 in the DMF group. The baseline adjusted rate ratios for the total number of lesions over time as compared with placebo were 1.45 in the evobrutinib 25-mg group (P = 0.32), 0.30 in the evobrutinib 75-mg once-daily group (P = 0.005), and 0.44 in the evobrutinib 75-mg twice-daily group (P = 0.06). The unadjusted annualized relapse rate at week 24 was 0.37 in the placebo group, 0.57 in the evobrutinib 25-mg group, 0.13 in the evobrutinib 75-mg once-daily group, 0.08 in the evobrutinib 75-mg twice-daily group, and 0.20 in the DMF group. There was no significant effect of trial group on the change from baseline in the EDSS score. Elevations in liver aminotransferase values were observed with evobrutinib. Patients with relapsing multiple sclerosis who received 75 mg of evobrutinib once daily had significantly fewer enhancing lesions during weeks 12 through 24 than those who received placebo. There was no significant difference with placebo for either the 25-mg once-daily or 75-mg twice-daily dose of evobrutinib, nor in the annualized relapse rate or disability progression at any dose. Longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis. (Funded by EMD Serono; ClinicalTrials.gov number, NCT02975349.).


[Two cases of lung infection due to Mycobacterium chelonae subsp. abscessus].
Two cases of lung infection due to Mycobacterium chelonae subsp. abscessus are reported. Case 1, a 50-year-old female, was a secondary infection-type, and case 2, a 53-year-old female, was a primary infection-type. The 16 cases reported, between the ages of 29 and 76 years, there were 6 males and 10 females. The roentgenographic examinations, revealed that the ratio of the primary and secondary infection-type was 3:1. Effective agents for this organism has not been yet confirmed. In the present study, we treated two patients with AMK and IPM/CS, and obtained negative conversion of the sputum culture as well as improvement of roentgenographic features.


Bivalent attachment of antibody onto poliovirus leads to conformational alteration and neutralization.
The treatment of nonsaturating, neutralizing antibody-poliovirus complexes with papain generally led to the loss of viral neutralization and to the loss of the neutralization-associated change in the isoelectric point (pI) of the virion. Subsequent treatment with anti-immunoglobulin G antibodies restored the neutralization of the virus and the alteration of the viral pI. It appears that, under nonsaturating conditions, poliovirus neutralization by an antibody is dependent upon the ability of the antibody to bivalently attach to the virion. Exceptions are monospecific neutralizing antibodies with an affinity for capsid protein VP3.


Nitrate reduction by organotrophic Anammox bacteria in a nitritation/anammox granular sludge and a moving bed biofilm reactor.
The effects of volatile fatty acids (VFAs) on nitrogen removal and microbial community structure in nitritation/anammox process were compared within a granular sludge reactor and a moving bed biofilm reactor. Nitrate productions in both systems were lower by 40-68% in comparison with expected nitrate production. Expected sludge production on VFAs was estimated to be 67-77% higher if heterotrophs were the main acetate degraders suggesting that Anammox bacteria used its organotrophic capability and successfully competed with general heterotrophs for organic carbon, which led to a reduced sludge production. FISH measurements showed a population consisting of mainly Anammox and AOB in both reactors and oxygen uptake rate (OUR) tests also confirmed that flocculent biomass consisted of a minor proportion of heterotrophs with a large proportion of AOBs. The dominant Anammox bacterium was Candidatus "Brocadia fulgida" with a minor fraction of Candidatus "Anammoxoglobus propionicus", both known to be capable of oxidizing VFAs.


Variation in surgical and anaesthetic technique and associations with operative risk in the European carotid surgery trial: implications for trials of ancillary techniques.
several ancillary surgical techniques, such as shunting and patching, are used in association with carotid endarterectomy. However, the balance of risks and benefits of these techniques is uncertain because of the lack of large randomised controlled trials (RCTs). To assess the potential for further trials, we studied the variation in use of these techniques by surgeon and by country in the European Carotid Surgery Trial (ECST). use of each ancillary technique was assessed by surgeon and by country. For each technique, the relationships between the use of the technique and baseline patient characteristics, use of other techniques, and the 30-day operative risk of stroke and death were determined. there was considerable variation between surgeons in the use of ancillary operative techniques both within (p<0.001 for shunting and patching), and between countries (p<0.001 for shunting and patching). Some surgeons used techniques selectively, and so the characteristics of patients differed depending on which techniques were used. Use of each technique was also significantly associated with the use of other techniques. Multiple regression analysis, taking into account all these factors, found no statistically significant associations between operative risk and the use of shunting, patching, intra-operative EEG monitoring, or type of anaesthetic. The only surgical technique significantly associated with an increased operative risk was not using intra-operative anticoagulation (hazard ratio=2.33, 95% CI=1.4-4.2). Other factors associated with an increased risk were an operation time of less than 1 h, or greater than 1.5 h, and the surgeons' subjective assessment that the operation was difficult. in the ECST, operative risk was more closely related to patient characteristics, length of surgery, and the surgeons' perception of the difficulty of the operation, than to the use of particular ancillary operative techniques. The considerable variation between surgeons, and between countries, in the use of ancillary techniques is in keeping with the lack of convincing data from RCTs, and suggests that there should be sufficient uncertainty to make large pragmatic trials possible.


Lectin microarrays identify cell-specific and functionally significant cell surface glycan markers.
Glycosylation is among the most complex posttranslational modifications with an extremely high level of diversity that has made it refractory to high-throughput analyses. Despite its resistance to high-throughput techniques, glycosylation is important in many critical cellular processes that necessitate a productive approach to their analysis. To facilitate studies in glycosylation, we developed a high-throughput lectin microarray for defining mammalian cell surface glycan signatures. Using the lectin microarray we established a binary analysis of cell binding and hierarchical organization of 24 mammalian cell lines. The array was also used to document changes in cell surface glycosylation during cell development and differentiation of primary murine immune system cells. To establish the biological and clinical importance of glycan signatures, the lectin microarray was applied in two systems. First, we analyzed the cell surface glycan signatures and were able to predict mannose-dependent tropism using a model pathogen. Second, we used the glycan signatures to identify novel lectin biomarkers for cancer stem-like cells in a murine model. Thus, lectin microarrays are an effective tool for analyzing diverse cell processes including cell development and differentiation, cell-cell communication, pathogen-host recognition, and cell surface biomarker identification.


Mapping the receptor site for alpha-scorpion toxins on a Na+ channel voltage sensor.
The α-scorpions toxins bind to the resting state of Na(+) channels and inhibit fast inactivation by interaction with a receptor site formed by domains I and IV. Mutants T1560A, F1610A, and E1613A in domain IV had lower affinities for Leiurus quinquestriatus hebraeus toxin II (LqhII), and mutant E1613R had ~73-fold lower affinity. Toxin dissociation was accelerated by depolarization and increased by these mutations, whereas association rates at negative membrane potentials were not changed. These results indicate that Thr1560 in the S1-S2 loop, Phe1610 in the S3 segment, and Glu1613 in the S3-S4 loop in domain IV participate in toxin binding. T393A in the SS2-S6 loop in domain I also had lower affinity for LqhII, indicating that this extracellular loop may form a secondary component of the receptor site. Analysis with the Rosetta-Membrane algorithm resulted in a model of LqhII binding to the voltage sensor in a resting state, in which amino acid residues in an extracellular cleft formed by the S1-S2 and S3-S4 loops in domain IV interact with two faces of the wedge-shaped LqhII molecule. The conserved gating charges in the S4 segment are in an inward position and form ion pairs with negatively charged amino acid residues in the S2 and S3 segments of the voltage sensor. This model defines the structure of the resting state of a voltage sensor of Na(+) channels and reveals its mode of interaction with a gating modifier toxin.


The origin and underlying driving forces of the SARS-CoV-2 outbreak.
SARS-CoV-2 began spreading in December 2019 and has since become a pandemic that has impacted many aspects of human society. Several issues concerning the origin, time of introduction to humans, evolutionary patterns, and underlying force driving the SARS-CoV-2 outbreak remain unclear. Genetic variation in 137 SARS-CoV-2 genomes and related coronaviruses as of 2/23/2020 was analyzed. After correcting for mutational bias, the excess of low frequency mutations on both synonymous and nonsynonymous sites was revealed which is consistent with the recent outbreak of the virus. In contrast to adaptive evolution previously reported for SARS-CoV during its brief epidemic in 2003, our analysis of SARS-CoV-2 genomes shows signs of relaxation. The sequence similarity in the spike receptor binding domain between SARS-CoV-2 and a sequence from pangolin is probably due to an ancient intergenomic introgression that occurred approximately 40 years ago. The current outbreak of SARS-CoV-2 was estimated to have originated on 12/11/2019 (95% HPD 11/13/2019-12/23/2019). The effective population size of the virus showed an approximately 20-fold increase from the onset of the outbreak to the lockdown of Wuhan (1/23/2020) and ceased to increase afterwards, demonstrating the effectiveness of social distancing in preventing its spread. Two mutations, 84S in orf8 protein and 251 V in orf3 protein, occurred coincidentally with human intervention. The former first appeared on 1/5/2020 and plateaued around 1/23/2020. The latter rapidly increased in frequency after 1/23/2020. Thus, the roles of these mutations on infectivity need to be elucidated. Genetic diversity of SARS-CoV-2 collected from China is two times higher than those derived from the rest of the world. A network analysis found that haplotypes collected from Wuhan were interior and had more mutational connections, both of which are consistent with the observation that the SARS-CoV-2 outbreak originated in China. SARS-CoV-2 might have cryptically circulated within humans for years before being discovered. Data from the early outbreak and hospital archives are needed to trace its evolutionary path and determine the critical steps required for effective spreading.


A Bayesian semiparametric approach for inference on the population partly conditional mean from longitudinal data with dropout.
Studies of memory trajectories using longitudinal data often result in highly nonrepresentative samples due to selective study enrollment and attrition. An additional bias comes from practice effects that result in improved or maintained performance due to familiarity with test content or context. These challenges may bias study findings and severely distort the ability to generalize to the target population. In this study, we propose an approach for estimating the finite population mean of a longitudinal outcome conditioning on being alive at a specific time point. We develop a flexible Bayesian semiparametric predictive estimator for population inference when longitudinal auxiliary information is known for the target population. We evaluate the sensitivity of the results to untestable assumptions and further compare our approach to other methods used for population inference in a simulation study. The proposed approach is motivated by 15-year longitudinal data from the Betula longitudinal cohort study. We apply our approach to estimate lifespan trajectories in episodic memory, with the aim to generalize findings to a target population.


Schema model of the self-concept.
The centrality of the self-concept in maintaining physical and psychosocial well-being is widely recognized in nursing. Despite its importance, progress in the development of an empirically-supported and clinically-relevant theoretical framework has been limited by difficulties in defining and measuring the construct. The schema model of the self-concept is presented as a theoretical framework that has the potential for explaining how the self-concept functions to influence emotional and behavioral responses to events relevant to health and well-being.


Sarcopterygian fin ontogeny elucidates the origin of hands with digits.
How the hand and digits originated from fish fins during the Devonian fin-to-limb transition remains unsolved. Controversy in this conundrum stems from the scarcity of ontogenetic data from extant lobe-finned fishes. We report the patterning of an autopod-like domain by hoxa13 during fin development of the Australian lungfish, the most closely related extant fish relative of tetrapods. Differences from tetrapod limbs include the absence of digit-specific expansion of hoxd13 and hand2 and distal limitation of alx4 and pax9, which potentially evolved through an enhanced response to shh signaling in limbs. These developmental patterns indicate that the digit program originated in postaxial fin radials and later expanded anteriorly inside of a preexisting autopod-like domain during the evolution of limbs. Our findings provide a genetic framework for the transition of fins into limbs that supports the significance of classical models proposing a bending of the tetrapod metapterygial axis.


Relationship between testate amoeba (protist) communities and atmospheric heavy metals accumulated in Barbula indica (bryophyta) in Vietnam.
We studied the relationships between testate amoeba communities and heavy metal (Pb, Cd, Zn, Ni, Cu, Mn, and Fe) concentrations in the moss Barbula indica sampled at 29 sites in and around the city of Hanoi (Vietnam). Our first approach was to compare the heavy metal concentrations and testate amoeba variables between the city (zone 1) and the surrounding (zone 2). Mean moss concentrations of Pb, Cd, Zn, Ni, and Cu were significantly higher and testate amoeba species richness and abundance were significantly lower in zone 1 and the abundance of eight taxa differed significantly between the two zones. We then studied the correlation between heavy metals and testate amoebae. Species richness and abundance were correlated negatively to Pb concentration. Shannon H' was negatively correlated to both Pb and Cd. The abundance of several species was negatively correlated with Pb, Cd, Zn, and Ni; however, at the community level, Pb emerged as the only significant variable in a redundancy analysis. Our results suggest that testate amoebae are sensitive to and may be good bioindicators for heavy metal pollution, especially lead. Further research is needed to understand the causal relationships underlying the observed patterns.


Adjuvant therapy in patients with resected poor-risk head and neck cancer.
In patients with locally or regionally advanced head and neck carcinomas, postoperative radiotherapy has historically been the adjuvant therapy applied for patients with prognostically worrisome pathologic features. Any improvement in therapeutic index achieved by adding cytotoxic agents to postoperative radiotherapy remained controversial. However, two recent randomized trials, conducted in parallel in Europe and the United States, produced level I evidence regarding improved efficacy in this setting for the concurrent administration of chemotherapy and radiotherapy. High-dose cisplatin and irradiation can now be considered the standard therapeutic approach for resected poor-risk disease. The presence of positive margins and/or nodal extracapsular spread in the surgical specimens are the subgroups that appear to benefit in the most significant way from the addition of chemotherapy to radiation. Many questions regarding the optimization of adjuvant treatments still remain unanswered, especially with respect to improvement of patient compliance, integration of novel drugs targeting both locoregional and systemic control, and modulation of treatment intensity according to risk levels.


Neutrophils as a Therapeutic Target in Cancer.
Neutrophils are the most abundant population of white blood cells in the human circulation. They are terminally differentiated myeloid cells which were traditionally associated with fighting infections and inflammatory processes. While this perception of neutrophils is still widely prevalent, in the past decade it has become clear that neutrophils also play a critical role in tumor growth and progression. The unique tumor microenvironment, consisting of the non-malignant stroma that surrounds tumor cells, is shaped by numerous cues emanating from both tumor cells and stromal cells which support the growing tumor. Various immune cells, including neutrophils, make up a significant proportion of the tumor stroma. Immune cells exist for the protection of the host against various threats including the detection and elimination of cancerous cells. However, in the context of cancer immune cells are often coerced into a tumor supportive phenotype. This is also the case for neutrophils, which are often described to possess tumor promoting properties and to associate with poorer prognosis. The fact that neutrophils may contribute to tumor growth and progression suggests they may be targets for anti-cancer therapies. This review discusses the various functions neutrophils may play in cancer and the possibility of targeting these functions as a novel mode of immunotherapy.


Multi-scale and multi-site resampling of a study area in spatial genetics: implications for flying insect species.
The use of multiple sampling areas in landscape genetic analysis has been recognized as a useful way of generalizing the patterns of environmental effects on organism gene flow. It reduces the variability in inference which can be substantially affected by the scale of the study area and its geographic location. However, empirical landscape genetic studies rarely consider multiple sampling areas due to the sampling effort required. In this study, we explored the effects of environmental features on the gene flow of a flying long-horned beetle (Monochamus galloprovincialis) using a landscape genetics approach. To account for the unknown scale of gene flow and the multiple local confounding effects of evolutionary history and landscape changes on inference, we developed a way of resampling study areas on multiple scales and in multiple locations (sliding windows) in a single large-scale sampling design. Landscape analyses were conducted in 3*104 study areas ranging in scale from 220 to 1,000 km and spread over 132 locations on the Iberian Peninsula. The resampling approach made it possible to identify the features affecting the gene flow of this species but also showed high variability in inference among the scales and the locations tested, independent of the variation in environmental features. This method provides an opportunity to explore the effects of environmental features on organism gene flow on the whole and reach conclusions about general landscape effects on their dispersal, while limiting the sampling effort to a reasonable level.


Regeneration of cervical epithelium after laser vaporization.
The process of reepithelialization after laser vaporization of normal cervical squamous epithelium was examined using light and electron microscopy. Tissue specimens were obtained from seven patients at time intervals ranging from seven to 16 days after laser vaporization. Immature squamous epithelium appeared at the edge of the laser crater between seven and 14 days, and by 14 to 16 days, the immature epithelium covered the entire crater area. The observations made in this study concur with those of other studies of the healing process of squamous epithelium, whereby immature cells from the surrounding undamaged epithelium migrate into the damaged area, eventually differentiating into a full thickness of epithelium.


Structural color from pigment-loaded nanostructures.
Color can originate from wavelength-dependence in the absorption of pigments or the scattering of nanostructures. While synthetic colors are dominated by the former, vivid structural colors found in nature have inspired much research on the latter. However, many of the most vibrant colors in nature involve the interactions of structure and pigment. Here, we demonstrate that pigment can be exploited to efficiently create bright structural color at wavelengths outside its absorption band. We created pigment-enhanced Bragg reflectors by sequentially spin-coating layers of poly-vinyl alcohol (PVA) and polystyrene (PS) loaded with β-carotene (BC). With only 10 double layers, we achieved a peak reflectance over 0.8 at 550 nm and normal incidence. A pigment-free multilayer made of the same materials would require 25 double layers to achieve the same reflectance. Further, pigment loading suppressed the Bragg reflector's characteristic iridescence. Using numerical simulations, we further show that similar pigment loadings could significantly expand the gamut of non-iridescent colors addressable by photonic glasses.


Effects of mercury contaminated rice from typical chemical plant area in China on nitric oxide changes and c-fos expression of rats brain.
China is one of countries with the highest mercury production in the world. The Guizhou Province in Southwestern China is currently one of the world's most important mercury production areas. In order to study the neurotoxicity of rice from Qingzhen Chemical Plant area and probe into the signal transduction molecular mechanism of injury in rat brain stimulation by mercury contaminated rice. The rats were exposed to mercury contaminated rice for 20 d. Both of the measurements of NO and NOS were processed according to the protocol of the kit. The effect of Hg contaminated rice on the expression of c-fos mRNA in rat brain and the expression of c-FOS protein in cortex, hippocampus were observed using reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemical methods. The results showed the neural transmitter NO and NOS in brain were significantly change between exposure groups and control group; the mercury polluted rice induced significantly the expression of c-fos mRNA; the c-FOS positive cells in hippocampus and cortex of exposure groups were significant different from control group (p < 0.01). It could be concluded that nitric oxide was involved in mercury contaminated rice induced immediate early gene c-fos expressions in the rat brain. Through food chain, local ecosystem and health of local people iave been deteriorated seriously by mercury. This serious situation will last a long period. In order to alleviate mercury pollution, more work needs to do.


Role of proliferation in HER2 status predicted response to doxorubicin.
The role of HER2 in predicting response to doxorubicin (DXR) therapy in breast cancer was evaluated in vivo in a series of breast carcinomas from 220 patients with tumors larger than 2.5 cm and treated with 3 cycles of DXR (75 mg/m(2)) as neoadjuvant chemotherapy. Patients with HER2-positive tumors were more frequently responsive to DXR treatment compared with HER2-negative patients (p = 0.05; Mantel-Haenszel Chi(2) = 0.009). Progesterone receptor (PgR) negativity, but not mutated p53, was also associated with response to DXR (p = 0.05; Mantel-Haenszel Chi(2) = 0.004). Further analysis of those correlations using breast carcinoma cell lines characterized for different biologic parameters revealed a trend between HER2 positivity/PgR negativity and greater DXR sensitivity, but the strongest direct correlation was found between the proliferation rate and sensitivity to DXR (r = 0.82, p = 0.00009). Neither p53 nor the DXR target molecule topoisomerase-II-alpha was significantly associated with in vitro sensitivity to DXR. Thus, whereas data showed that the major biologic parameter associated with in vitro response to DXR in breast cancer cells appears to be the tumor proliferation rate, HER2 expression together with PgR negativity may serve as the counterpart of the proliferation marker in predicting the in vivo response to DXR.


Development of a shear force measurement dummy for seat comfort.
Seat comfort is one of the main factors that consumers consider when purchasing a car. In this study, we develop a dummy with a shear-force sensor to evaluate seat comfort. The sensor has dimensions of 25 mm × 25 mm × 26 mm and is made of S45C. Electroless nickel plating is employed to coat its surface in order to prevent corrosion and oxidation. The proposed sensor is validated using a qualified load cell and shows high accuracy and precision (measurement range: -30-30 N; sensitivity: 0.1 N; linear relationship: R = 0.999; transverse sensitivity: <1%). The dummy is manufactured in compliance with the SAE standards (SAE J826) and incorporates shear sensors into its design. We measure the shear force under four driving conditions and at five different speeds using a sedan; results showed that the shear force increases with speed under all driving conditions. In the case of acceleration and deceleration, shear force significantly changes in the lower body of the dummy. During right and left turns, it significantly changes in the upper body of the dummy.


Combined fluorescence and reflectance spectroscopy for in vivo quantification of cancer biomarkers in low- and high-grade glioma surgery.
Biomarkers are indicators of biological processes and hold promise for the diagnosis and treatment of disease. Gliomas represent a heterogeneous group of brain tumors with marked intra- and inter-tumor variability. The extent of surgical resection is a significant factor influencing post-surgical recurrence and prognosis. Here, we used fluorescence and reflectance spectral signatures for in vivo quantification of multiple biomarkers during glioma surgery, with fluorescence contrast provided by exogenously-induced protoporphyrin IX (PpIX) following administration of 5-aminolevulinic acid. We performed light-transport modeling to quantify multiple biomarkers indicative of tumor biological processes, including the local concentration of PpIX and associated photoproducts, total hemoglobin concentration, oxygen saturation, and optical scattering parameters. We developed a diagnostic algorithm for intra-operative tissue delineation that accounts for the combined tumor-specific predictive capabilities of these quantitative biomarkers. Tumor tissue delineation achieved accuracies of up to 94% (specificity = 94%, sensitivity = 94%) across a range of glioma histologies beyond current state-of-the-art optical approaches, including state-of-the-art fluorescence image guidance. This multiple biomarker strategy opens the door to optical methods for surgical guidance that use quantification of well-established neoplastic processes. Future work would seek to validate the predictive power of this proof-of-concept study in a separate larger cohort of patients.


HSF1 down-regulates XAF1 through transcriptional regulation.
Studies have indicated the role of HSF1 (heat-shock transcription factor 1) in repressing the transcription of some nonheat shock genes. XAF1 (XIAP-associated factor 1) was an inhibitor of apoptosis-interacting protein with the effect of antagonizing the cytoprotective role of XIAP. XAF1 expression was lower in gastrointestinal cancers than in normal tissues with the mechanism unclear. Here we showed that gastrointestinal cancer tissues expressed higher levels of HSF1 than matched normal tissues. The expression of XAF1 and HSF1 was negatively correlated in gastrointestinal cancer cell lines. Stress stimuli, including heat, hypo-osmolarity, and H2O2, significantly suppressed the expression of XAF1, whereas the alteration of HSF1 expression negatively correlated with XAF1 expression. We cloned varying lengths of the 5'-flanking region of the XAF1 gene into luciferase reporter vectors, and we evaluated their promoter activities. A transcription silencer was found between the -592- and -1414-nucleotide region that was rich in nGAAn/nT-TCn elements (where n indicates G, A, T, or C). A high affinity and functional HSF1-binding element within the -862/-821-nucleotide region was determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Inactivation of this "heat-shock element" by either site-directed mutation or an HSF1 inhibitor, pifithrin-alpha, restored the promoter activity of the silencer structure. Moreover, pretreatment with antioxidants suppressed HSF1 binding activity and increased the transcriptional activity and expression of XAF1. These findings suggested that endogenous stress pressure in cancer cells sustained the high level expression of HSF1 and subsequently suppressed XAF1 expression, implicating the synergized effect of two anti-apoptotic protein families, HSP and inhibitors of apoptosis, in cytoprotection under stress circumstances.


Herbal-Based Formulation Containing Eurycoma longifolia and Labisia pumila Aqueous Extracts: Safe for Consumption?
A combined polyherbal formulation containing tongkat ali (Eurycoma longifolia) and kacip fatimah (Labisia pumila) aqueous extracts was evaluated for its safety aspect. A repeated dose 28-day toxicity study using Wistar rats was conducted where the polyherbal formulation was administered at doses 125, 500 and 2000 mg/kg body weight to male and female treatment groups daily via oral gavage, with rats receiving only water as the control group. In-life parameters measured include monitoring of food and water consumption and clinical and functional observations. On day 29, blood was collected for haematological and biochemical analysis. The rats were necropsied and the organs were collected for histopathological examination. This study showed that the combined formulation did not induce any significant toxicity effect at any dose level in terms of morbidity, mortality, behaviour, functional observation, body weight, food and water consumption, whole blood haematology and serum biochemistry. However, there were some microscopic changes in the histopathological examinations of some organs given 2000 mg/kg body weight, which may suggest an early response to the polyherbal formulation. From this study, the no observed adverse effect level is estimated to be more than 500 mg/kg body weight but not exceeding 2000 mg/kg body weight. The observed effects at the highest dose indicate the need for further study of longer dosing duration.


Coupled molecular dynamics-Monte Carlo model to study the role of chemical processes during laser ablation of polymeric materials.
The coarse grained chemical reaction model is enhanced to build a molecular dynamics (MD) simulation framework with an embedded Monte Carlo (MC) based reaction scheme. The MC scheme utilizes predetermined reaction chemistry, energetics, and rate kinetics of materials to incorporate chemical reactions occurring in a substrate into the MD simulation. The kinetics information is utilized to set the probabilities for the types of reactions to perform based on radical survival times and reaction rates. Implementing a reaction involves changing the reactants species types which alters their interaction potentials and thus produces the required energy change. We discuss the application of this method to study the initiation of ultraviolet laser ablation in poly(methyl methacrylate). The use of this scheme enables the modeling of all possible photoexcitation pathways in the polymer. It also permits a direct study of the role of thermal, mechanical, and chemical processes that can set off ablation. We demonstrate that the role of laser induced heating, thermomechanical stresses, pressure wave formation and relaxation, and thermochemical decomposition of the polymer substrate can be investigated directly by suitably choosing the potential energy and chemical reaction energy landscape. The results highlight the usefulness of such a modeling approach by showing that various processes in polymer ablation are intricately linked leading to the transformation of the substrate and its ejection. The method, in principle, can be utilized to study systems where chemical reactions are expected to play a dominant role or interact strongly with other physical processes.


A Comparison of Antibacterial Properties of Tachyplesin, Thanatin, and Enterocin P on Enterococcus faecalis.
Enterococcus faecalis (E. faecalis) is one of the persistent microorganisms responsible for the failure of root canal treatments. This study investigated the antibacterial property, the time-killing of 3 peptides, namely Tachyplesin, Thanatin, and Enterocin P, on E. faecalis. In this study, recombinant peptides were synthesized via secretory synthesis. The peptides were then purified and isolated using affinity chromatography after which their purification was evaluated through SDS-PAGE. The antimicrobial activity of peptides against E. faecalis was tested using the minimum inhibitory concentration test (MIC), the minimum bactericidal concentration test (MBC), and the time-killing assay. Based on antimicrobial tests, a similar value was observed for the MIC and MBC in the recombinant peptide of Enterocin P. The concentration of MBC was twice as much as that of MIC for Tanatin and Tachyplesin. The time-killing-assay antimicrobial test showed that Enterocin P has a better pattern and antimicrobial activity than the other two peptides; all three peptides have weaker antimicrobial activities than sodium hypochlorite. Considering the equivalence of MIC and MBC in the recombinant peptide of Enterocin P, it can be a viable replacement for traditional disinfectants and medicaments used in root canal treatment procedures.


Transcriptional Controls for Early Bolting and Flowering in Angelica sinensis.
The root of the perennial herb Angelica sinensis is a widely used source for traditional Chinese medicines. While the plant thrives in cool-moist regions of western China, early bolting and flowering (EBF) for young plants significantly reduces root quality and yield. Approaches to inhibit EBF by changes in physiology during the vernalization process have been investigated; however, the mechanism for activating EBF is still limited. Here, transcript profiles for bolted and unbolted plants (BP and UBP, respectively) were compared by transcriptomic analysis, expression levels of candidate genes were validated by qRT-PCR, and the accumulations of gibberellins (GA1, GA4, GA8, GA9 and GA20) were also monitored by HPLC-MS/MS. A total of over 72,000 unigenes were detected with ca. 2600 differentially expressed genes (DEGs) observed in the BP compared with UBP. While various signaling pathways participate in flower induction, it is genes associated with floral development and the sucrose pathway that are observed to be coordinated in EBF plants, coherently up- and down-regulating flowering genes that activate and inhibit flowering, respectively. The signature transcripts pattern for the developmental pathways that drive flowering provides insight into the molecular signals that activate plant EBF.


Rett syndrome from quintuple and triple deletions within the MECP2 deletion hotspot region.
Rett syndrome results from mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene, which are nearly always lethal in males and lead to regression and reduced life expectancy in females. Herein we report one propositus with five tandem deletions and a second propositus with three tandem deletions within MECP2 exon 4 that encode truncated protein products resulting in classic Rett syndrome. These deletion breakpoints and single deletions in 3 other patients were all found within a 185-bp region along with 64 of 69 other reported deletion breakpoints in the MECP2 gene. Illegitimate recombination resulting in deletion at a substantial proportion of the shared MECP2 sites is enhanced by repeated guanosine (G) DNA sequences in the antisense direction, consistent with reports at other gene loci that polypurine (multiple guanosine or adenosine (A)) basepairs enhance sequence deletion. Multiple deletions at the same poly G recombination sites confirm the existence of deletion hotspots in this gene region with numerous repeated antisense sites that are enriched 26- to 161-fold. Deletion by illegitimate recombination within a single allele can occur during mitotic or meiotic cell cycles. Although prone to disease-causing deletion, this region is unique in humans and highly conserved among mammals for the last 75 000 000 years to maintain the MECP2 gene's critical function.


PDGF receptors on cells of the oligodendrocyte-type-2 astrocyte (O-2A) cell lineage.
It has been shown previously that cultures of rat optic nerve contain three types of macroglial cells--oligodendrocytes and two types of astrocytes. Type-1 astrocytes develop from their own precursor cells beginning before birth, while oligodendrocytes and type-2 astrocytes develop postnatally from a common bipotential precursor called the O-2A progenitor cell. Proliferating O-2A progenitor cells give rise to postmitotic oligodendrocytes beginning around birth, and to type-2 astrocytes beginning in the second postnatal week. Studies in vitro have suggested that platelet-derived growth factor (PDGF), secreted by type-1 astrocytes, plays an important part in timing oligodendrocyte development: PDGF seems to keep O-2A progenitor cells proliferating until an intrinsic clock in the progenitor cells initiates the process leading to oligodendrocyte differentiation. The clock apparently determines when a progenitor cell becomes unresponsive to PDGF, at which point the cell stops dividing and, as a consequence, automatically differentiates into an oligodendrocyte. Here we have used radiolabelled PDGF to show that O-2A progenitor cells have PDGF receptors, suggesting that these cells respond directly to PDGF. The receptors resemble the type A PDGF receptor previously described on human fibroblasts and are initially retained when progenitor cells stop dividing and develop in vitro into oligodendrocytes. The latter finding indicates that receptor loss is not the reason that progenitor cells initially become mitotically unresponsive to PDGF.


Role of Folic Acid in the Therapeutic Action of Nanostructured Porous Silica Functionalized with Organotin(IV) Compounds Against Different Cancer Cell Lines.
The synthesis, characterization and cytotoxic activity against different cancer cell lines of various mesoporous silica-based materials containing folate targeting moieties and a cytotoxic fragment based on a triphenyltin(IV) derivative have been studied. Two different mesoporous nanostructured silica systems have been used: firstly, micronic silica particles of the MSU-2 type and, secondly, mesoporous silica nanoparticles (MSNs) of about 80 nm. Both series of materials have been characterized by different methods, such as powder X-ray diffraction, X-ray fluorescence, absorption spectroscopy and microscopy. In addition, these systems have been tested against four different cancer cell lines, namely, OVCAR-3, DLD-1, A2780 and A431, in order to observe if the size of the silica-based systems and the quantity of incorporated folic acid influence their cytotoxic action. The results show that the materials are more active when the quantity of folic acid is higher, especially in those cells that overexpress folate receptors such as OVCAR-3 and DLD-1. In addition, the study of the potential modulation of the soluble folate receptor alpha (FOLR1) by treatment with the synthesized materials has been carried out using OVCAR-3, DLD-1, A2780 and A431 tumour cell lines. The results show that a relatively high concentration of folic acid functionalization of the nanostructured silica together with the incorporation of the cytotoxic tin fragment leads to an increase in the quantity of the soluble FOLR1 secreted by the tumour cells. In addition, the studies reported here show that this increase of the soluble FOLR1 occurs presumably by cutting the glycosyl-phosphatidylinositol anchor of membrane FR-α and by the release of intracellular FR-α. This study validates the potential use of a combination of mesoporous silica materials co-functionalized with folate targeting molecules and an organotin(IV) drug as a strategy for the therapeutic treatment of several cancer cells overexpressing folate receptors.


Strategies for success in academic surgery.
A growing concern among university surgeons is a perceived threat to the traditional academician role. Factors that have led to this concern include (1) changes in reimbursement and patient referral patterns, both of which have resulted in reduced income; (2) mounting external pressure from the departmental chairperson/dean to generate professional fees; (3) pervasive ambiguity in the criteria for promotion and tenure; (4) intensified competition for research dollars in recent years; and (5) a perception that fellow academicians view surgeons as operating room technicians incapable of laboratory research. These cogent issues have the means to place academic goals in jeopardy. Potentially they lead to dissatisfaction, unhappiness, and eventual departure from academia. A healthy solution to the problem includes departmental recognition and reward for whichever primary role/s the academic surgeon embraces--clinical, educational, research, or administrative. Clear chairperson-faculty communication on the issues of expectation and reward is a key ingredient in the solution. A mail survey was conducted with chairpersons of surgical departments and academic surgeons addressing the issues of retention, promotion, and benefits. Results revealed significant differences in perceptions, suggesting the need for improved communication between faculty and chairpersons and a team approach to help maintain academic viability in the future. When the quadruple threat can be mutually described as a departmental rather than individual quality, the joys and rewards of academic surgery can be considerable for faculty and chairpersons alike.


Balance and Gait Impairment in Transient Ischemic Attack and Minor Stroke.
There has been little research into gait and balance impairment in transient ischemic attack (TIA) and minor stroke, despite these conditions affecting large numbers of people and the potential impact on function. The aim of this study was to determine the impact of TIA and minor stroke on gait and balance. Twelve people with TIA or minor stroke without previous gait/balance problems and 12 age- and sex-matched controls were recruited. Participants (mean age 67 years) underwent a comprehensive assessment including physiological, balance, and gait measures (clinical and computerized [NeuroCom/GAITRite]). Matched-pairs analysis was undertaken. Groups were similar in body mass index, vision, leg proprioception/strength, and reaction time. Cognition was worse in the TIA/minor stroke group: mean Montreal Cognitive Assessment score 22.2 versus 26.6, P = .001. People with TIA/minor stroke were significantly worse on all but one clinical test. Median scores for TIA/minor stroke versus control were as follows: Timed Up and Go (TUG), 9.4 versus 7.6 seconds, P = .019; TUG dual task, 12.3 versus 8.5 seconds, P = .012; Four Square Step Test, 10.9 versus 7.2 seconds, P = .006. Mean Step Test score for TIA/minor stroke versus control was 14.1 versus 17.7, P = .021. The TIA/minor stroke group also had significantly worse performance on computerized tests: increased turn time/sway, increased step length, slower comfortable/fast gait speeds, and greater proportion of gait cycle spent in double support. This study found that people with TIA/minor stroke have gait and balance dysfunction despite having no obvious physiological impairments. Intervention studies aimed at improving balance and gait in this population are needed.


Multi-site genetic analysis of diffusion images and voxelwise heritability analysis: a pilot project of the ENIGMA-DTI working group.
The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium was set up to analyze brain measures and genotypes from multiple sites across the world to improve the power to detect genetic variants that influence the brain. Diffusion tensor imaging (DTI) yields quantitative measures sensitive to brain development and degeneration, and some common genetic variants may be associated with white matter integrity or connectivity. DTI measures, such as the fractional anisotropy (FA) of water diffusion, may be useful for identifying genetic variants that influence brain microstructure. However, genome-wide association studies (GWAS) require large populations to obtain sufficient power to detect and replicate significant effects, motivating a multi-site consortium effort. As part of an ENIGMA-DTI working group, we analyzed high-resolution FA images from multiple imaging sites across North America, Australia, and Europe, to address the challenge of harmonizing imaging data collected at multiple sites. Four hundred images of healthy adults aged 18-85 from four sites were used to create a template and corresponding skeletonized FA image as a common reference space. Using twin and pedigree samples of different ethnicities, we used our common template to evaluate the heritability of tract-derived FA measures. We show that our template is reliable for integrating multiple datasets by combining results through meta-analysis and unifying the data through exploratory mega-analyses. Our results may help prioritize regions of the FA map that are consistently influenced by additive genetic factors for future genetic discovery studies. Protocols and templates are publicly available at (http://enigma.loni.ucla.edu/ongoing/dti-working-group/).


In situ localization of DNA topoisomerase II, a major polypeptide component of the Drosophila nuclear matrix fraction.
DNA topoisomerase II has been immunochemically identified on protein blots as a major polypeptide component of the Drosophila nuclear matrix-pore complex-lamina fraction. Indirect immunofluorescence analyses of larval cryosections have confirmed the nuclear localization of topoisomerase II in situ. Although apparently excluded from the nucleolus, the topoisomerase protein is otherwise distributed throughout the interior of interphase nuclei. Similar immunocytochemical studies performed with permeabilized whole giant cells from third-instar larval salivary glands have shown topoisomerase II to be largely restricted to the polytene chromosomes. Upon nuclear disassembly during mitosis, the topoisomerase polypeptide appears to redistribute diffusely throughout the cell. Faint immunofluorescent staining of mitotic chromosomes is also observed.


Are Artificial Dendrites Useful in Neuro-Evolution?
The significant role of dendritic processing within neuronal networks has become increasingly clear. This letter explores the effects of including a simple dendrite-inspired mechanism into neuro-evolution. The phenomenon of separate dendrite activation thresholds on connections is allowed to emerge under an evolutionary process. It is shown how such processing can be positively selected for, particularly for connections between the hidden and output layers, and increases performance.