The Arden Syntax standard for clinical decision support: experiences and directions.
Arden Syntax is a widely recognized standard for representing clinical and scientific knowledge in an executable format. It has a history that reaches back until 1989 and is currently maintained by the Health Level 7 (HL7) organization. We created a production-ready development environment, compiler, rule engine and application server for Arden Syntax. Over the course of several years, we have applied this Arden - Syntax - based CDS system in a wide variety of clinical problem domains, such as hepatitis serology interpretation, monitoring of nosocomial infections or the prediction of metastatic events in melanoma patients. We found the Arden Syntax standard to be very suitable for the practical implementation of CDS systems. Among the advantages of Arden Syntax are its status as an actively developed HL7 standard, the readability of the syntax, and various syntactic features such as flexible list handling. A major challenge we encountered was the technical integration of our CDS systems in existing, heterogeneous health information systems. To address this issue, we are currently working on incorporating the HL7 standard GELLO, which provides a standardized interface and query language for accessing data in health information systems. We hope that these planned extensions of the Arden Syntax might eventually help in realizing the vision of a global, interoperable and shared library of clinical decision support knowledge.


A hierarchy for relational reasoning in the prefrontal cortex.
The human brain possesses a unique capacity to reason about abstract relationships among items in our environment. The neural organization of reasoning abilities has remained elusive. Two approaches toward investigating human reasoning have involved studying visuo-spatial reasoning abilities and studying analogical reasoning. These approaches have both revealed anterior prefrontal cortex (PFC) involvement, but no prior studies have jointly investigated these two forms of reasoning to understand any potential convergence of activation within the PFC. Using fMRI, we tested the extent to which these two forms of reasoning (visuo-spatial and analogical) overlap in PFC activation. We conducted a visuo-spatial reasoning task that required processing multiple changes across three abstract pictures. This task activated a progressively anterior series of PFC regions when multiple relations had to be integrated. We also conducted a four-term analogy task in a stage-wise manner and compared results from this task to semantic and perceptual control conditions that did not require integrating relations across the problems. We found greater activation for analogical reasoning in the series of PFC regions that were sequentially involved in the visuo-spatial reasoning task. These findings indicate that stages of neural processing overlap for different domains within human reasoning. The pattern of differences across the analogy task suggests a hierarchical organization for relational reasoning across domains in which posterior frontal cortex is active across concrete reasoning tasks, while progressively more anterior regions are recruited to process increasingly abstract representations in reasoning.


Cage occupancies, lattice constants, and guest chemical potentials for structure II hydrogen clathrate hydrate from Gibbs ensemble Monte Carlo simulations.
In this paper, equilibrium properties of structure II hydrates of hydrogen were determined from Monte Carlo simulations in the isothermal-isobaric Gibbs ensemble. Water and hydrogen molecules are described by the TIP4P/Ice and Silvera-Goldman models, respectively. The use of the Gibbs ensemble has many key advantages for the simulation of hydrates. By the separation of hydrogen vapor and hydrate phases into their own domains, coupled with transfer moves of hydrogen molecules between domains, cage occupancies were determined. Furthermore, the choice of this ensemble also allows equilibrium lattice constants and guest molecule chemical potentials to be straightforwardly estimated. Results for hydrogen mass fractions indicate reasonable agreement with prior simulation data and theoretical models, while detailed analysis of cage occupancy distributions and neighboring cage pair occupancy combinations gives valuable insight into the behavior of this hydrate at the inter-cage scale. These results will aid in the construction of theoretical models, for which knowledge of the occupancy of neighboring cages is of great importance. In support of previous experimental and theoretical works, we also find evidence of double occupancy of a few small cages inside of the hydrate stability zone, albeit at very high pressures; approximately 0.1% of small cages are doubly occupied at 300 MPa, for temperatures of 225 K and 250 K.


Neuroimaging findings in the at-risk mental state: a review of recent literature.
The at-risk mental state (ARMS) has been the subject of much interest during the past 15 years. A great deal of effort has been expended to identify neuroimaging markers that can inform our understanding of the risk state and to help predict who will transition to frank psychotic illness. Recently, there has been an explosion of neuroimaging literature from people with an ARMS, which has meant that reviews and meta-analyses lack currency. Here we review papers published in the past 2 years, and contrast their findings with previous reports. While it is clear that people in the ARMS do show brain alterations when compared with healthy control subjects, there is an overall lack of consistency as to which of these alterations predict the development of psychosis. This problem arises because of variations in methodology (in patient recruitment, region of interest, method of analysis, and functional task employed), but there has also been too little effort put into replicating previous research. Nonetheless, there are areas of promise, notably that activation of the stress system and increased striatal dopamine synthesis seem to mark out patients in the ARMS most at risk for later transition. Future studies should focus on these areas, and on network-level analysis, incorporating graph theoretical approaches and intrinsic connectivity networks.


Analysing outcomes through orthopaedic trauma registry - A prospective cohort study.
To develop a registry for recording injury-specific data to identify gaps and improve care. The prospective cohort study was conducted at Aga Khan University Hospital, Karachi, from June 2015 to July 2018 though enrollment of patients with limb trauma is continuing to date. Data on injuries and management related to Tibia shaft fractures was collected from medical records, and outcomes were assessed on follow-up visits. Internationally validated injury-specific scores were utilised for assessing functional, clinical and radiological outcomes. SPSS version 19 was used for data analysis. There were 763 patients with 825 limb injuries. Of the injuries, 310(37.6%) related to upper limbs and 515(62.4%) to the lower limbs. Management was surgical for 741(89.9%) and conservative for 84(10.1%) injuries. Overall, 12(1.57%) patients died, and in 7(0.91%) cases mortality was unrelated to trauma and its management. There were 105 patients with tibia shaft fractures. Of them, 88(83.8%) were males and 17(16.2%) were females. At one-year follow-up excellent-to-good results were 12(92%) for intramedullary nailing followed by 7(78%) for open reduction and internal fixation. Registry data can be used to develop preventive strategies and to improve management protocols.


Clinical pharmacokinetics of fluoxetine.
Fluoxetine is well absorbed after oral intake, is highly protein bound, and has a large volume of distribution. The elimination half-life of fluoxetine is about 1 to 4 days, while that of its metabolite norfluoxetine ranges from 7 to 15 days. Fluoxetine has a nonlinear pharmacokinetic profile. Therefore, the drug should be used with caution in patients with a reduced metabolic capability (i.e. hepatic dysfunction). In contrast with its effect on the pharmacokinetics of other antidepressants, age does not affect fluoxetine pharmacokinetics. This finding together with the better tolerability profile of fluoxetine (compared with tricyclic antidepressants) makes this drug particularly suitable for use in elderly patients with depression. Furthermore, the pharmacokinetics of fluoxetine are not affected by either obesity or renal impairment. On the basis of results of plasma concentration-clinical response relationship studies, there appears to be a therapeutic window for fluoxetine. Concentrations of fluoxetine plus norfluoxetine above 500 micrograms/L appear to be associated with a poorer clinical response than lower concentrations. Fluoxetine interacts with some other drugs. Concomitant administration of fluoxetine increased the blood concentrations of antipsychotics or antidepressants. The interactions between fluoxetine and lithium, tryptophan and monoamine oxidase inhibitors, in particular, are potentially serious, and can lead to the 'serotonergic syndrome'. This is because of synergistic pharmacodynamic effects and the influence of fluoxetine on the bioavailability of these compounds.


Effects of Game Situation-Dependent Emotions on Sport Spectators' Food Craving.
This study sought to challenge prevalent accounts of emotional eating by exploring the effects of situation-dependent emotions on consumers' food craving. Four specific game situations in the context of spectator sports, each corresponding to the four types of emotional coping (outcome-desire conflict, avoidance, fulfillment, and pursuit), were identified as follows: decisive victories, decisive losses, close victories, and close losses. By employing laboratory-based virtual reality spectatorship, Study 1 tested the causal effects of happiness (fulfillment), anger (conflict), sadness (conflict), fear (avoidance), and hope (pursuit) on food craving. Study 2 further designed fans' previous association between emotions and eating as a moderating mechanism in the context of online sport viewership. The results of the two experiments supported the three theoretical principles of eating behavior, including the "food as fuel" principle of anger, the hedonic eating principle of happiness, and the self-regulation principle of hope. However, the results rejected the escape awareness principle of sadness and fear. The study concludes with a discussion of context-dependent emotional positioning and intervention strategies for marketers and policy makers.


Outcome of conservative and surgical management of navicular stress fracture in athletes. Eighty-six cases proven with computerized tomography.
Eighty-two athletes with 86 clinical navicular stress fractures, all imaged with computerized tomography, were followed for an average of 33 months (range, 6 to 108) after diagnosis. Initial treatment consisted of at least 6 weeks of nonweightbearing cast immobilization for 22 fractures, at least 6 weeks of limitation of activity with continued weightbearing for 34 fractures, and a period of less than 6 weeks of conservative treatment for another 19 fractures. Five patients attempted to continue playing sports. Six patients had immediate surgery. Nineteen of 22 patients (86%) who had initial non-weightbearing cast immobilization treatment returned to sports, compared with only 9 of 34 patients (26%) who initially continued weightbearing with limited activity (P < 0.001). After failure of the latter treatment, successful outcomes were seen for 6 of 7 patients (86%) treated with nonweightbearing cast immobilization, while 11 of 15 patients (73%) who had one surgical procedure were able to return to sports. These results indicate that nonweightbearing cast immobilization is the treatment of choice for navicular stress fractures. Also, this treatment compares favorably with surgical treatment for patients who present after failed weightbearing treatments. Computerized tomographic appearances of healing fractures do not necessarily mirror clinical union, and postimmobilization management should be monitored clinically.


Effects of fat feeding on epinephrine secretion in the rat.
Adrenal medullary activity increases with fasting, although a role for diet in the regulation of epinephrine (Epi) secretion is otherwise unknown. The current studies examined the effects of dietary fat on adrenal medullary function in male CD rats. Addition of lard to a lab chow diet (+50% of chow energy) for 4 days lowered Epi excretion by 14% (P = 0.0005). Two weeks' exposure to diet containing 33% lard (by energy) reduced urinary Epi compared with that in animals fed an isoenergetic amount of chow. Epi levels in plasma obtained by indwelling catheter from unanesthetized unrestrained rats were lower in lard-fed rats than in chow-fed controls. The plasma Epi response to intravenous administration of d-fenfluramine (4 mg/kg), however, was exaggerated in the lard-fed rats. Plasma NE levels also rose after d-fenfluramine, but responses did not differ between diet groups. Urinary Epi was also measured after exposure to other fats. Beef tallow, like lard, suppressed Epi excretion, but safflower, medium-chain triglyceride, coconut, and soybean oils did not. These results suggest that fats of animal origin, in contrast to those derived from plants, suppress adrenal medullary function, possibly via alteration in central serotonergic pathways.


Genome-Wide Association Studies and Genomic Selection in Pearl Millet: Advances and Prospects.
Pearl millet is a climate-resilient, drought-tolerant crop capable of growing in marginal environments of arid and semi-arid regions globally. Pearl millet is a staple food for more than 90 million people living in poverty and can address the triple burden of malnutrition substantially. It remained a neglected crop until the turn of the 21st century, and much emphasis has been placed since then on the development of various genetic and genomic resources for whole-genome scan studies, such as the genome-wide association studies (GWAS) and genomic selection (GS). This was facilitated by the advent of sequencing-based genotyping, such as genotyping-by-sequencing (GBS), RAD-sequencing, and whole-genome re-sequencing (WGRS) in pearl millet. To carry out GWAS and GS, a world association mapping panel called the Pearl Millet inbred Germplasm Association Panel (PMiGAP) was developed at ICRISAT in partnership with Aberystwyth University. This panel consisted of germplasm lines, landraces, and breeding lines from 27 countries and was re-sequenced using the WGRS approach. It has a repository of circa 29 million genome-wide SNPs. PMiGAP has been used to map traits related to drought tolerance, grain Fe and Zn content, nitrogen use efficiency, components of endosperm starch, grain yield, etc. Genomic selection in pearl millet was jump-started recently by WGRS, RAD, and tGBS (tunable genotyping-by-sequencing) approaches for the PMiGAP and hybrid parental lines. Using multi-environment phenotyping of various training populations, initial attempts have been made to develop genomic selection models. This mini review discusses advances and prospects in GWAS and GS for pearl millet.


Applied vascular anatomy of the colon and rectum: clinical implications for the surgical oncologist.
Surgery remains the most radical method of treatment of many solid tumors, including colorectal cancer; in these tumors, surgery is the only method that can offer the chance of cure. To avoid early postoperative morbidity (mainly, anastomotic leak) and to achieve good long-term results (low incidence of tumor recurrence, long overall and disease-free survival, and optimal quality of life), the surgeon should have an in-depth knowledge of vascular anatomy of the colon and rectum. This essential requirement is based on the fact that the actual course followed by lymph fluid drainage from any part of the colon/rectum is determined by its blood supply; therefore, the extent of resection for colorectal cancer follows the principles of blood supply and lymphatic drainage. Knowledge of the colorectal vascular anatomy and its variations is of vital importance in the planning of radical surgical treatment and in appropriately performing colorectal resections, particularly in the patient who underwent in the past colectomy or aortic surgery that has changed the usual pattern of collateral blood supply to the colon. This review summarizes currently available data regarding vascular anatomy of the colon and rectum, from a surgical perspective.


[Anti-reflux surgery: indications, principles and contribution of laparoscopy].
Surgery is indicated when gastro-oesophageal reflux disease (GORD) is resistant to medical treatment. Manometry, upper GI series, pH-metry, gastric emptying studies and gastric acid sampling are performed in order to demonstrate that GORD is caused by a deficient gastro-oesophageal valve mechanism, and hence that surgical treatment will be beneficial. The surgical principle is restoring an anti-reflux barrier by recreating a sufficient pressure gradient in the distal oesophagus, and by correcting the gastro-oesophageal Hiss. Nissen' fundoplication is probably the most efficient anti-reflux procedure. However, it can cause dysphagia, gas bloating and inability to burp. One hundred and fifty-six laparoscopic Nissen fundoplications have been performed by the author. Operating time average 120 min. No perioperative death was observed. There were 3 conversions to laparotomy and 4 peroperative complications: 1 gastric perforation, 2 lesions of the pleura and 1 liver laceration. Four postoperative complications occurred: 1 pneumonia, 1 necrosis of the wrap, 1 small bowel perforation and 1 obstruction due to migration of the entire stomach into the chest. Hospitalisation time ranged between 2 and 14 days (median 2), with a follow up of a median of 10 months. Long-term postoperative complications were: 1 recurrent heartburn 6 months postoperatively and 2 severe dysphagia.


Clinical Predictors of Response to Magnetic Seizure Therapy in Depression: A Preliminary Report.
Magnetic seizure therapy (MST) is a novel convulsive brain stimulation method in clinical testing, which is used as an alternative for electroconvulsive therapy in patients with treatment-resistant depression (TRD). Preliminary studies have suggested that MST leads to fewer cognitive adverse effects than electroconvulsive therapy but has similar efficacy. However, the clinical predictors of response to MST have not been evaluated yet. This study aimed to investigate whether these predictors can be identified in patients with TRD. Thirty-eight patients with TRD were included. As clinical predictors for treatment response, we used the diagnosis, sex, age, family history, and severity of depression, as well as the melancholic, psychotic, anxiety, and atypical depression symptoms. A response was defined as an improvement higher than 50% on the 28-item Hamilton Rating Scale for Depression. The binary logistic regression, stepwise linear regression, and effect sizes were calculated. We found that 68.4% of the patients responded to MST. The responders had significantly fewer previous depressive episodes, less severe depression, and fewer melancholic (anhedonia) and anxiety symptoms than the nonresponders. In addition, responders were more likely to have a positive family history of depression than nonresponders. In particular, the number of previous episodes and a family history of depression were significant predictors of the response to MST. We demonstrate that the chronicity, severity, and family history of depression, as well as the presence of melancholic and anxiety symptoms, can serve as clinical predictors of the response to MST. Further research with a larger sample size will be required to verify these preliminary findings.


Excessive Daytime Sleepiness and Cardiovascular Mortality in US Adults: A NHANES 2005-2008 Follow-Up Study.
Excessive daytime sleepiness is highly prevalent and has been associated with increased risk of cardiovascular diseases, but evidence for its association with cardiovascular mortality is limited and inconsistent. We aimed to determine whether excessive daytime sleepiness is independently associated with cardiovascular mortality in general adult population. A prospective study of 10,330 adult participants (aged ≥20 years) from National Health and Nutrition Examination Survey (NHANES) 2005-2006 and 2007-2008 was followed up until December 31st, 2015. Excessive daytime sleepiness was defined as the self-reported feeling of being overly sleepy often or always during the day. Cox proportional hazard ratios (HRs) with 95% confidence interval (CI) were estimated to assess risk for cardiovascular mortality. A total of 10,330 participants with mean age of 47.3 years (95% CI, 46.0 to 48.1) were included in this analysis. Approximately, 18.5% of US adults reported excessive daytime sleepiness. Over a mean follow-up of 8.3 years, 262 cardiovascular deaths occurred. Participants with excessive daytime sleepiness had 2.85-times greater risk (95% CI, 1.33-6.09) of cardiovascular death than those without daytime sleepiness in multivariable analysis corrected for sociodemographic factors, comorbidities and cardiovascular risk factors including depression. Further adjustment for self-reported sleep disorders and sleep duration only slightly attenuated this association (HR, 2.55; 95% CI, 1.23-5.27). No interactions between excessive daytime sleepiness and age, sex or cardiovascular disease at study entry were observed (all Ps>0.05). Excessive daytime sleepiness is highly prevalent among US adults and is independently associated with an approximately two-and-a-half-fold increased risk of cardiovascular mortality in a large national sample. Screening for excessive daytime sleepiness may be a simple and cost-effective tool for identifying individuals at high risk of cardiovascular death.


The next Sub Saharan African epidemic? A case study of the determinants of cervical cancer knowledge and screening in Kenya.
Early cervical cancer screening has been shown to be beneficial in reducing cervical cancer related deaths. Despite the benefits of early cervical cancer screening, uptake remains limited, with wide disparities in access and uptake in most developing countries. As part of a larger study, this paper uses a socio-ecological framework to explain the determinants of cervical cancer knowledge and screening among women of reproductive age (15-49 years) in Kenya. We conducted a multilevel analysis of cervical cancer knowledge (n = 11,138) and screening (n = 10,333) using the 2014 Kenya Demographic and Health Survey (KDHS). Results show regional disparities in cancer knowledge and the utilization of cervical cancer screening services; regions with high wealth inequality (OR = 0.70, 95% CI [0.56-0.87]) emerged as vulnerable regions where women were less likely to screen for cervical cancer. Gender equity, health insurance coverage and education level significantly predicted cervical cancer screening rates. Results further revealed regional as well as rural-urban wealth inequalities in cervical cancer screening. We argue that given that Kenyan women are highly exposed to human papilloma virus (HPV) due to the legacy of human immunodeficiency virus (HIV) in the country, cervical cancer may be the next epidemic if integrated measures are not adopted to increase cervical cancer knowledge and overcome the barriers to utilizing early screening services. The paper concludes with policy recommendations and directions for future research.


Enteric pathogens in malnourished children with diarrhoea.
Enteric pathogens were determined from stools of 273 children aged less than 5 years at Kenyatta National Hospital (KNH), 43.6% (119/273) of whom were malnourished according to the Wellcome criteria. Rotavirus was detected by ELISA test, Salmonella, Shigella and E. coli by culture on MacConkey and Salmonella-Shigella agar at 37 degrees C overnight and Campylobacter on Skirrow's selective media at 42 degrees C for 48 hrs. These were identified by biochemical tests and serotyping using specific antisera. Whereas isolation rate for Campylobacter (0.0% vs 5.0%, p = 0.006), well malnourished ETEC-LT (0.6% vs 5.0%, p = 0.003) and T. hominis (0.0% vs 3.4%, p = 0.03) was higher in the malnourished children, EPEC (30.5% vs 10.1%, p < 0.001) and Salmonella+ETEC-LT (7.8% vs 1.7%, p = 0.02) was higher in children. The other enteric pathogens were equally isolated from normal and malnourished children. A larger proportion of malnourished children had diarrhoea of unknown aetiology compared to the well nourished (26.6% vs 50.4%, p < 0.001). Campylobacter and T. hominis may be opportunistic infections due to immuno-suppression in malnutrition. Diarrhoea of unknown aetiology may be due to aetiological agents that were not determined in this study.


Green synthesis of silver nanoparticles using Thymbra spicata L. var. spicata (zahter) aqueous leaf extract and evaluation of their morphology-dependent antibacterial and cytotoxic activity.
Silver (Ag) nanoparticles (NPs) were green synthesized at room temperature using different concentrations of the Thymbra spicata L. var. spicata (Zahter) aqueous leaf extracts for the first time. With the synthesis of AgNPs using the leaf extract of Cynara scolymus (Artichoke) and Mentha piperita (Peppermint), the biological activities of the nanoparticles synthesized using leaf extract of three economically significant plants have been studied comparatively. Nanoparticles were characterized by different spectroscopic and microscopic analysis. TEM analysis of the biosynthesized AgNPs revealed that the size and shape of the AgNPs were changed with the plant extract concentration. Biologically synthesized AgNPs from leaf extracts of the three different plants displayed significant differences in antibacterial activity against two different gram-negative and gram-positive bacteria. Also, the results from this study show the shape dependence of the antibacterial and cytotoxic activity of silver nanoparticles synthesized using T. spicata leaf extract. The nanoparticles with different shapes exhibited the strongest antibacterial and cytotoxic activity compared to mostly spherical nanoparticles. Present results clearly indicate that biological activities of silver nanoparticles were affected by nanoparticle shape and the source of the plant extract used in the synthesis.


Metabolomics analysis and biosynthesis of rosmarinic acid in Agastache rugosa Kuntze treated with methyl jasmonate.
This study investigated the effect of methyl jasmonate (MeJA) on metabolic profiles and rosmarinic acid (RA) biosynthesis in cell cultures of Agastache rugosa Kuntze. Transcript levels of phenylpropanoid biosynthetic genes, i.e., ArPAL, Ar4CL, and ArC4H, maximally increased 4.5-fold, 3.4-fold, and 3.5-fold, respectively, compared with the untreated controls, and the culture contained relatively high amounts of RA after exposure of cells to 50 µM MeJA. RA levels were 2.1-, 4.7-, and 3.9-fold higher after exposure to 10, 50, and 100 µM MeJA, respectively, than those in untreated controls. In addition, the transcript levels of genes attained maximum levels at different time points after the initial exposure. The transcript levels of ArC4H and Ar4CL were transiently induced by MeJA, and reached a maximum of up to 8-fold at 3 hr and 6 hr, respectively. The relationships between primary metabolites and phenolic acids in cell cultures of A. rugosa treated with MeJA were analyzed by gas chromatography coupled with time-of-flight mass spectrometry. In total, 45 metabolites, including 41 primary metabolites and 4 phenolic acids, were identified from A. rugosa. Metabolite profiles were subjected to partial least square-discriminate analysis to evaluate the effects of MeJA. The results indicate that both phenolic acids and precursors for the phenylpropanoid biosynthetic pathway, such as aromatic amino acids and shikimate, were induced as a response to MeJA treatment. Therefore, MeJA appears to have an important impact on RA accumulation, and the increased RA accumulation in the treated cells might be due to activation of the phenylpropanoid genes ArPAL, ArC4H, and Ar4CL.


Pathotyping the Zoonotic Pathogen Streptococcus suis: Novel Genetic Markers To Differentiate Invasive Disease-Associated Isolates from Non-Disease-Associated Isolates from England and Wales.
Streptococcus suis is one of the most important zoonotic bacterial pathogens of pigs, causing significant economic losses to the global swine industry. S. suis is also a very successful colonizer of mucosal surfaces, and commensal strains can be found in almost all pig populations worldwide, making detection of the S. suis species in asymptomatic carrier herds of little practical value in predicting the likelihood of future clinical relevance. The value of future molecular tools for surveillance and preventative health management lies in the detection of strains that genetically have increased potential to cause disease in presently healthy animals. Here we describe the use of genome-wide association studies to identify genetic markers associated with the observed clinical phenotypes (i) invasive disease and (ii) asymptomatic carriage on the palatine tonsils of pigs on UK farms. Subsequently, we designed a multiplex PCR to target three genetic markers that differentiated 115 S. suis isolates into disease-associated and non-disease-associated groups, that performed with a sensitivity of 0.91, a specificity of 0.79, a negative predictive value of 0.91, and a positive predictive value of 0.79 in comparison to observed clinical phenotypes. We describe evaluation of our pathotyping tool, using an out-of-sample collection of 50 previously uncharacterized S. suis isolates, in comparison to existing methods used to characterize and subtype S. suis isolates. In doing so, we show our pathotyping approach to be a competitive method to characterize S. suis isolates recovered from pigs on UK farms and one that can easily be updated to incorporate global strain collections.


Characterization of a Tetrahymena thermophila mutant strain unable to develop normal thermotolerance.
For Tetrahymena thermophila cells to survive extended periods of time at 43 degrees C, they must continuously synthesize heat shock proteins. For its translational machinery to function at 43 degrees C, T. thermophila requires either prior nonlethal heat shock treatment or brief treatment with partially inhibiting doses of cycloheximide or emetine. We have identified and characterized a mutant strain of T. thermophila (MC-3) in which prior nonlethal heat shock does not prevent protein synthesis inactivation at 43 degrees C. In addition, treatment of MC-3 cells with either of the antibiotics that normally confer 43 degrees C thermoprotection on wild-type cells elicited no similar thermoprotective response in these cells. Despite these phenotypic characteristics, by other criteria MC-3 synthesized a normal, functional array of heat shock proteins at 40 degrees C, a nonlethal heat shock protein-inducing temperature. The mutation in MC-3 which prevents the thermostabilization of protein synthesis by nonlethal heat shock is, by genetic criteria, most likely the same one which prevents the induction of thermotolerance by drug treatments. We present evidence that this mutation may affect some ribosome-associated functions.


Heat stress in atlanta: preparing for the olympic worst.
The weather might provide the toughest competition for endurance athletes at the Summer Olympic Games in Atlanta next month. The heat stress is likely to be higher than in any of the last several summer games. Here's a report on the expected conditions and how medical officials for the games are preparing.


V-doped SnS2: a new intermediate band material for a better use of the solar spectrum.
Intermediate band materials can boost photovoltaic efficiency through an increase in photocurrent without photovoltage degradation thanks to the use of two sub-bandgap photons to achieve a full electronic transition from the valence band to the conduction band of a semiconductor structure. After having reported in previous works several transition metal-substituted semiconductors as able to achieve the electronic structure needed for this scheme, we propose at present carrying out this substitution in sulfides that have bandgaps of around 2.0 eV and containing octahedrally coordinated cations such as In or Sn. Specifically, the electronic structure of layered SnS(2) with Sn partially substituted by vanadium is examined here with first principles quantum methods and seen to give favourable characteristics in this respect. The synthesis of this material in nanocrystalline powder form is then undertaken and achieved using solvothermal chemical methods. The insertion of vanadium in SnS(2) is found to produce an absorption spectrum in the UV-Vis-NIR range that displays a new sub-bandgap feature in agreement with the quantum calculations. A photocatalytic reaction-based test verifies that this sub-bandgap absorption produces highly mobile electrons and holes in the material that may be used for the solar energy conversion, giving experimental support to the quantum calculations predictions.


Risk Assessment of Arsenic in Rice Cereal and Other Dietary Sources for Infants and Toddlers in the U.S.
Currently, there are no set standards or quantitative guidelines available in the U.S. for arsenic levels in rice cereal, one of the most common first solid foods for infants. The objective of this study was to evaluate whether the detected levels of inorganic arsenic (As(i)) in rice cereal in the U.S. market are safe for consumption by infants and toddlers. A risk assessment was conducted based on literature reviews of the reported As(i) in rice cereal from the U.S. Food and Drug Administration's (FDA) survey and the recommended daily intake of rice cereal by body weight, for infants and toddlers between four and 24 months old. As a part of risk management, a maximum contaminant level (MCL) for Asi in rice cereal was computed considering overall exposure sources including drinking water, infant formula, and other infant solid foods. Hazard quotients (HQs) for acute and chronic exposures were calculated based on the U.S. Agency for Toxic Substances and Disease Registry's (ATSDR) Minimal Risk Level (MRL)(acute) (5.0 × 10(-3) mg/kg/day) and MRL(chronic) (3.0 × 10(-4) mg/kg/day). A cancer slope or potency factor of 1.5 mg/kg/day was used to predict an incremental lifetime cancer risk (ILCR). Exposure assessment showed that the largest source of As(i) for infants and toddlers between four and 24 months old was rice cereal (55%), followed by other infant solid food (19%), and drinking water (18%). Infant formula was the smallest source of As(i) for babies (9%) at the 50th percentile based on Monte Carlo simulations. While HQ(acute) were consistently below 1.0, HQ(chronic) at the 50 and 75th percentiles exceeded 1.0 for both rice cereal and total sources. ILCR ranged from 10(-6) (50th) to 10(-5) (75th percentile). MCLs for As(i) in rice cereal ranged from 0.0 (chronic) to 0.4 mg/kg (acute exposures).


Perioperative Opioid Consumption and Clinical Outcomes in Surgical Patients With a Pre-existing Opioid-Based Intrathecal Drug Delivery System.
Intrathecal drug delivery systems (IDDS) have been utilized for over 3 decades for management of chronic pain and spasticity. Patients with IDDS may present for surgical procedures unrelated to the IDDS device, although data are limited regarding perioperative outcomes. This is a historical matched cohort study conducted between January 1, 2007 and December 31, 2016 of patients with an opioid-based IDDS versus matched control patients undergoing surgery excluding interventional pain procedures. Patients in the IDDS group were matched with up to 2 patients without an IDDS. Multivariable regression analyses were utilized to assess differences in the primary outcome of cumulative perioperative opioid consumption (ie, intraoperative and postanesthesia care unit [PACU] opioid consumption), and opioid consumption during the first 24 and 72 postoperative hours. Postoperative clinical outcomes were also assessed including escalating oxygen requirements, naloxone administration, pain-sedation mismatch, and perioperative pain service consultation. A total of 321 surgeries were included, 112 with IDDS and 209 controls, with median (interquartile range [IQR]) age of 57 (49-64) years. Compared to matched controls, patients with an IDDS had greater perioperative opioid consumption (median [IQR] oral morphine milligram equivalents [OME] of 110 [60-163] vs 93 [IQR, 53-142]; adjusted multiplicative increase 1.28 [95% confidence interval {CI}, 1.03-1.59]; P = .026). IDDS patients also had greater opioid consumption in the first 24 and 72 postoperative hours (multiplicative increases of 2.23 [95% CI, 1.36-3.63], P = .001, and 2.46 [95% CI, 1.41-4.32], P = .002, respectively). There were no significant differences in postoperative oxygen requirements, naloxone administration, or pain-sedation mismatch. Inpatient pain medicine consultation was more frequent in IDDS patients compared to controls (51.8% vs 6.2%; P < .001). Patients with opioid-based IDDS received more perioperative opioids and were more likely to receive postoperative pain service consultation compared to matched controls. There were no significant differences in clinical safety outcomes, suggesting tolerance for higher opioid doses. Further research is warranted to optimize perioperative outcomes in those with IDDS.


A Molecular Networking Based Discovery of Diketopiperazine Heterodimers and Aspergillicins from Aspergillus caelatus.
The number of species in Aspergillus section Flavi has recently increased to 36 and includes some of the most important and well-known species in the genus Aspergillus. Numerous secondary metabolites, especially mycotoxins, have been reported from species such as A. flavus; however many of the more recently described species are less studied from a chemical point of view. This paper describes the use of MS/MS-based molecular networking to investigate the metabolome of A. caelatus leading to the discovery of several new diketopiperazine dimers and aspergillicins. An MS-guided isolation procedure yielded six new compounds, including asperazines D-H (1-5) and aspergillicin H (6). Asperazines G and H are artifacts derived from asperazines E and F formed during the separation process by formic acid. Two known compounds, aspergillicins A and C (7 and 8), were isolated from the same strain. Structures were elucidated by analyzing their HR-MS/MS and NMR spectroscopic data. The absolute configuration of asperazines D-F and aspergillicin H were deduced from the combination of NMR, Marfey's method, and ECD analyses.


Intrarenal cytokine mRNA expression and location in normal and IgA nephropathy tissue: TGF alpha, TGF beta, IGF 1, IL-4 and IL-6.
Peptide regulatory factors (PRFs) are critical components in the regulation of glomerular inflammatory response to immune injury and may also have a primary role in modulating intrinsic cell proliferation and matrix synthesis. Dysregulation of PRFs and glomerular infiltration with inflammatory, including mononuclear, cells occur in models of nephritis, but direct evidence for their role is not established in normal and diseased tissue in man. Using in situ hybridization techniques capable of detecting specific cellular messenger RNA we have evaluated normal human and IgA nephropathy diseased renal tissue for expression and location of PRF encoding mRNA. Permeabilized tissue was examined by autoradiography using 35S labelled-antisense, and -sense riboprobes for TGF alpha, TGF beta, IGF 1, IL-4, and IL-6 encoding mRNA. TGF beta was constitutively expressed in normal glomerular mesangium, capillary loop, Bowman's capsule, and vascular endothelial and tubular cells, but was downregulated in IgA nephropathy tissue. In contrasting and distinct patterns, TGF alpha encoding mRNA was found in neither tissue, whereas IGF 1 mRNA was expressed in normal and also in diseased tissue. IGF 1 mRNA activity was intense within tubular cell cytoplasm in normals, with similar characteristics in IgA nephropathy. Cytokines IL-4 and IL-6 mRNAs were absent in normals, with IL-4 detectable throughout renal substance in disease; IL-6 gene transcription was intense in glomerular and vascular endothelial sites in IgA nephropathy. These findings implicate selective gene induction and suppression in disease, suggesting functional downregulation of glomerular TGF beta, coincident with autocrine functions for IL-6 and IL-4 in the pathogenesis of IgA-related nephropathy.


Novel method for detection of glycogen in cells.
Glycogen, a branched polymer of glucose, functions as an energy reserve in many living organisms. Abnormalities in glycogen metabolism, usually excessive accumulation, can be caused genetically, most often through mutation of the enzymes directly involved in synthesis and degradation of the polymer leading to a variety of glycogen storage diseases (GSDs). Microscopic visualization of glycogen deposits in cells and tissues is important for the study of normal glycogen metabolism as well as diagnosis of GSDs. Here, we describe a method for the detection of glycogen using a renewable, recombinant protein which contains the carbohydrate-binding module (CBM) from starch-binding domain containing protein 1 (Stbd1). We generated a fusion protein containing g lutathione S-transferase, a cM c eptitope and the tbd1 BM (GYSC) for use as a glycogen-binding probe, which can be detected with secondary antibodies against glutathione S-transferase or cMyc. By enzyme-linked immunosorbent assay, we demonstrate that GYSC binds glycogen and two other polymers of glucose, amylopectin and amylose. Immunofluorescence staining of cultured cells indicate a GYSC-specific signal that is co-localized with signals obtained with anti-glycogen or anti-glycogen synthase antibodies. GYSC-positive staining inside of lysosomes is observed in individual muscle fibers isolated from mice deficient in lysosomal enzyme acid alpha-glucosidase, a well-characterized model of GSD II (Pompe disease). Co-localized GYSC and glycogen signals are also found in muscle fibers isolated from mice deficient in malin, a model for Lafora disease. These data indicate that GYSC is a novel probe that can be used to study glycogen metabolism under normal and pathological conditions.


[Cytochemical study of dehydrogenase activity in the tissues of the pig female genital system after injection of xenogenic cerebrospinal fluid (a cytochemical study)].
The experimental study was performed to evaluate the biological effects of parenteral injection of cerebrospinal fluid (SCF) on the uterus, uterine tubes and the ovary of piglets aged 60 days. Lactating cows aged 4-6 years after first calving were taken as SCF donors, since their SCF contained maximal spectrum of biologically active substances. For injection the whole SCF, SCF after passage through bacterial filters and SCF supernatant were used. The effect of SCF was assessed using histological and histochemical (succinate- and lactate dehydrogenases demonstration) methods. It was found that SCF preparations studied had differential effect on oxidative-reduction processes in the tissues of reproductive system organs of immature pigs, that is associated with the broad spectrum of biologically active substances in mammalian SCF.


The neuroligins and the synaptic pathway in Autism Spectrum Disorder.
The genetics underlying autism spectrum disorder (ASD) is complex and heterogeneous, and de novo variants are found in genes converging in functional biological processes. Neuronal communication, including trans-synaptic signaling involving two families of cell-adhesion proteins, the presynaptic neurexins and the postsynaptic neuroligins, is one of the most recurrently affected pathways in ASD. Given the role of these proteins in determining synaptic function, abnormal synaptic plasticity and failure to establish proper synaptic contacts might represent mechanisms underlying risk of ASD. More than 30 mutations have been found in the neuroligin genes. Most of the resulting residue substitutions map in the extracellular, cholinesterase-like domain of the protein, and impair protein folding and trafficking. Conversely, the stalk and intracellular domains are less affected. Accordingly, several genetic animal models of ASD have been generated, showing behavioral and synaptic alterations. The aim of this review is to discuss the current knowledge on ASD-linked mutations in the neuroligin proteins and their effect on synaptic function, in various brain areas and circuits.


Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study.
Exercise training reduces the symptoms of chronic heart failure. Which exercise intensity yields maximal beneficial adaptations is controversial. Furthermore, the incidence of chronic heart failure increases with advanced age; it has been reported that 88% and 49% of patients with a first diagnosis of chronic heart failure are >65 and >80 years old, respectively. Despite this, most previous studies have excluded patients with an age >70 years. Our objective was to compare training programs with moderate versus high exercise intensity with regard to variables associated with cardiovascular function and prognosis in patients with postinfarction heart failure. Twenty-seven patients with stable postinfarction heart failure who were undergoing optimal medical treatment, including beta-blockers and angiotensin-converting enzyme inhibitors (aged 75.5+/-11.1 years; left ventricular [LV] ejection fraction 29%; VO2peak 13 mL x kg(-1) x min(-1)) were randomized to either moderate continuous training (70% of highest measured heart rate, ie, peak heart rate) or aerobic interval training (95% of peak heart rate) 3 times per week for 12 weeks or to a control group that received standard advice regarding physical activity. VO2peak increased more with aerobic interval training than moderate continuous training (46% versus 14%, P<0.001) and was associated with reverse LV remodeling. LV end-diastolic and end-systolic volumes declined with aerobic interval training only, by 18% and 25%, respectively; LV ejection fraction increased 35%, and pro-brain natriuretic peptide decreased 40%. Improvement in brachial artery flow-mediated dilation (endothelial function) was greater with aerobic interval training, and mitochondrial function in lateral vastus muscle increased with aerobic interval training only. The MacNew global score for quality of life in cardiovascular disease increased in both exercise groups. No changes occurred in the control group. Exercise intensity was an important factor for reversing LV remodeling and improving aerobic capacity, endothelial function, and quality of life in patients with postinfarction heart failure. These findings may have important implications for exercise training in rehabilitation programs and future studies.


Amino acid metabolism in intestinal bacteria: links between gut ecology and host health.
Bacteria in the gastrointestinal (GI) tract play an important role in the metabolism of dietary substances in the gut and extraintestinal tissues. Amino acids (AA) should be taken into consideration in the development of new strategies to enhance efficiency of nutrient utilization because they are not only major components in the diet and building blocks for protein but also regulate energy and protein homeostasis in organisms. The diversity of the AA-fermenting bacteria and their metabolic redundancy make them easier to survive and interact with their neighboring species or eukaryotic host during transition along GI tract. The outcomes of the interactions have important impacts on gut health and whole-body homeostasis. The AA-derived molecules produced by intestinal bacteria affect host health by regulating either host immunity and cell function or microbial composition and metabolism. Emerging evidence shows that dietary factors, such as protein, non-digestible carbohydrates, probiotics, synbiotics and phytochemicals, modulate AA utilization by gut microorganisms. Interdisciplinary research involving nutritionists and microbiologists is expected to rapidly expand knowledge about crucial roles for AA in gut ecology and host health.


The role of HIRA-dependent H3.3 deposition and its modifications in the somatic hypermutation of immunoglobulin variable regions.
The H3.3 histone variant and its chaperone HIRA are involved in active transcription, but their detailed roles in regulating somatic hypermutation (SHM) of immunoglobulin variable regions in human B cells are not yet fully understood. In this study, we show that the knockout (KO) of HIRA significantly decreased SHM and changed the mutation pattern of the variable region of the immunoglobulin heavy chain (IgH) in the human Ramos B cell line without changing the levels of activation-induced deaminase and other major proteins known to be involved in SHM. Except for H3K79me2/3 and Spt5, many factors related to active transcription, including H3.3, were substantively decreased in HIRA KO cells, and this was accompanied by decreased nascent transcription in the IgH locus. The abundance of ZMYND11 that specifically binds to H3.3K36me3 on the IgH locus was also reduced in the HIRA KO. Somewhat surprisingly, HIRA loss increased the chromatin accessibility of the IgH V region locus. Furthermore, stable expression of ectopic H3.3G34V and H3.3G34R mutants that inhibit both the trimethylation of H3.3K36 and the recruitment of ZMYND11 significantly reduced SHM in Ramos cells, while the H3.3K79M did not. Consistent with the HIRA KO, the H3.3G34V mutant also decreased the occupancy of various elongation factors and of ZMYND11 on the IgH variable and downstream switching regions. Our results reveal an unrecognized role of HIRA and the H3.3K36me3 modification in SHM and extend our knowledge of how transcription-associated chromatin structure and accessibility contribute to SHM in human B cells.


Cancer Treatment Helpline: a retrospective study of the NHS Tayside experience.
Treatment-related toxicity and delays in the management of this toxicity can impact the outcomes of patient with cancer. In Scotland, a national cancer helpline was established to provide triage assessment for patients receiving systemic anticancer therapy (SACT) in an attempt to minimise delays in toxicity management. In this article, we describe the use and impact of the helpline in our region over the last 5 years. Patients who contacted the NHS Tayside cancer helpline between 1 January 2016 and 31 December 2020 were retrospectively identified. Patient demographics as well as the reason and outcome of each call was recorded. A descriptive analysis was performed. 6562 individual patients received SACT and 8385 calls were recorded during the time period. Median age of callers was 63 years (range 17-98) and 59.2% were women. Use of the helpline increased by 83.6% between 2016 and 2020, driven by an increase in in-hours calls. 41% of calls required review by a healthcare professional only, 24% required review and admission and the remaining 35% telephone advice only. The majority of cases (85%) were either assessed or advised solely by oncology. The proportional use of general practitioner services has decreased. The helpline provides a way for patients to report symptoms directly to their clinical team and receive appropriate specialist advice at an early stage. We demonstrate that most of these calls can be managed solely by our oncology team. This system can reduce pressure on other parts of the local health system.


Dorsal hindbrain 5'-adenosine monophosphate-activated protein kinase as an intracellular mediator of energy balance.
The fuel-sensing enzyme AMP-activated protein kinase (AMPK) has been implicated in central nervous system control of energy balance. Hypothalamic AMPK activity is increased by food deprivation, and this elevation is inhibited by refeeding or by leptin treatment. The contribution of extrahypothalamic AMPK activity in energy balance control has not been addressed. Here, we investigate the effects of physiological state on the AMPK activity in hindbrain nucleus tractus solitarius (NTS) neurons because treatments that reduce energy availability in these neurons trigger behavioral, endocrine, and autonomic responses to restore energy balance. Food-deprived rats showed significantly increased AMPK activity in both NTS- and hypothalamus-enriched lysates compared with those that were ad libitum fed. Pharmacological inhibition of AMPK activity in medial NTS neurons, by intraparenchymal injection of compound C, suppressed food intake and body weight gain compared with vehicle. Fourth ventricle (4th i.c.v.) compound C delivery increased heart rate and spontaneous activity in free-moving rats. Suppression of AMPK activity has been implicated in leptin's anorectic action in the hypothalamus. Given the role of leptin signaling in food intake inhibition within the medial NTS, we also examined whether stimulation of hindbrain AMPK by 4th i.c.v. administration of 5-aminoimidazole-4-carboxamide-riboside (AICAR), an AMP-mimicking promoter of AMPK activity, could attenuate the inhibition of food intake by 4th i.c.v. leptin. The intake-suppressive effects of leptin (at 2 and 4 h) were completely reversed by AICAR. We conclude that 1) hindbrain AMPK activity contributes to energy balance control through regulation of food intake and energy expenditure, 2) leptin's intake-reducing effects in the NTS are mediated by AMPK, and 3) central nervous system AMPK controls whole-body homeostasis at anatomically distributed sites across the neuraxis.


Early recovery trajectories after fast-track primary total hip arthroplasty: the role of patient characteristics.
Background and purpose - Little is known about heterogeneity in early recovery after primary total hip arthroplasty (THA). Therefore, we characterized subgroups of patients according to their hip function trajectory during the first 6 weeks after THA in a fast-track setting. Patients and methods - 94 patients (median age 65 years [41-82], 56 women) from a single hospital participated in a diary study. Patients recorded their severity of hip problems (Oxford Hip Score, OHS) weekly for 6 weeks after THA. Latent class growth modelling (LCGM) was used to identify patients with the same hip function trajectory and to compare these subgroups on patient characteristics. Results - LCGM revealed a fast (n = 17), an average (n = 53), and a slow (n = 24) recovery subgroup. Subgroups differed on the estimated weekly growth rate during the first 2 weeks (fast: 9.5; average: 5.3; slow: 2.7), with fewer differences between groups in the last 4 weeks (fast: 0.90; average: 2.0; slow: 1.7). Patients in the slow recovery group could be characterized as women of older age (mean age =69) who rated their health as lower preoperatively, needed more assistance during recovery, and were less satisfied with the outcomes of the surgery. Interpretation - We identified distinct recovery trajectories in the first 6 weeks after fast-track primary THA which were associated with patient characteristics.


Influences of monocular and binocular vision on postural stability.
To compare the influences of monocular vision versus binocular vision on postural control, twenty-seven otherwise healthy adults, aged from 19 to 38 years, with corrected visual acuity of better than or equal to 20/20, were recruited. Body sway for standing 30 seconds on a force platform in 3 conditions was recorded for each participant: one with both eyes open (BEO), one with left eye open (LEO) and the other with both eyes closed (BEC). Postural stability was subsequently evaluated by measuring the total track length (TL) and surface area (SA) of center of pressure of body sway. The results show that the values of TL and SA of BEC were significantly greater than those of LEO and BEO. Moreover, the values of TL and SA of BEO were significantly smaller than those of LEO (p < 0.05, one-way repeated measures ANOVA and post hoc of Fisher's LSD procedure). The Romberg coefficient of LEO was also significantly greater than that of BEO (p < 0.05, paired sample t-test). We concluded that optimal binocular vision provides more information for keeping balance than monocular vision according to the results revealed in our study. Assessment of visual acuity is recommended before doing a posturographic test in the clinical setting. However, the long-term impact of blindness on controlling posture is uncertain and needs further investigation.


Profile of hepatocellular carcinoma in the Republic of Moldova: first-hand information on the presentation, distribution and etiologies.
Moldova is the European country with the highest incidence of hepatocellular carcinoma (HCC) in both sexes. There is, however, no data comprehensively describing the presentation and the risk factors of HCC in the country. We decided to analyze cases of HCC recently received in a tertiary healthcare Institution from Chisinau, the Moldovian capital. A series of 148 primary liver tumors including 139 cases of HCC were retrospectively analyzed for demographic features, serological and biochemical data, and clinical presentation. The mean age of patients was 59 ± 10 years (range: 19-66) with a M:F sex ratio of 1.9. Tumors appeared on full-blown liver cirrhosis in 83% of cases and were composed of multiple nodules at diagnosis in 36% of patients. Serum Alpha-fetoprotein was exceeding 10ng/mL in 76% of cases. Liver tumor and hepatitis were co-discovered in 34% of cases. More than 81% of hepatocellular carcinomas were associated with at least one hepatitis virus. Carriers of anti-hepatitis C virus were predominating (55% of cases) over patients seropositive for hepatitis B virus surface antigen (36%). Half of the latter were also infected with hepatitis Delta virus. In total, dual or triple infections were present in 24% and 7% of cases. The burden of infections with hepatitis viruses is particularly important in Moldova and corresponds to a situation commonly observed in countries of the Southern hemisphere. A pro-active policy of screening for persistent liver infection targeting population at risk of HCC (> 50 years) and coupled with the distribution of antivirals in positive cases should be rapidly implemented in Moldova to reduce incidence or primary liver cancer.


Finding the K best synthesis plans.
In synthesis planning, the goal is to synthesize a target molecule from available starting materials, possibly optimizing costs such as price or environmental impact of the process. Current algorithmic approaches to synthesis planning are usually based on selecting a bond set and finding a single good plan among those induced by it. We demonstrate that synthesis planning can be phrased as a combinatorial optimization problem on hypergraphs by modeling individual synthesis plans as directed hyperpaths embedded in a hypergraph of reactions (HoR) representing the chemistry of interest. As a consequence, a polynomial time algorithm to find the K shortest hyperpaths can be used to compute the K best synthesis plans for a given target molecule. Having K good plans to choose from has many benefits: it makes the synthesis planning process much more robust when in later stages adding further chemical detail, it allows one to combine several notions of cost, and it provides a way to deal with imprecise yield estimates. A bond set gives rise to a HoR in a natural way. However, our modeling is not restricted to bond set based approaches-any set of known reactions and starting materials can be used to define a HoR. We also discuss classical quality measures for synthesis plans, such as overall yield and convergency, and demonstrate that convergency has a built-in inconsistency which could render its use in synthesis planning questionable. Decalin is used as an illustrative example of the use and implications of our results.


Longitudinal Associations Between Grit, Academic Outcomes, and Residency Match Rates Among Pharmacy Students.
Objective. To characterize Grit-S scores in pharmacy students, determine whether Grit-S scores change within individual pharmacy students and cohorts over time, and investigate the relationship between Grit-S scores, academic outcomes, and professional outcomes. Methods. A survey was conducted in fall 2016 and again in fall 2017 to determine Grit-S scores in first- through fourth-year pharmacy students. Participant demographic variables, grade point average (GPA), advanced pharmacy practice experience (APPE) ratings, and residency match results were collected. Results. Over the study period, 852 survey responses were completed by 85% of students surveyed. The mean Grit-S scores of each cohort ranged from 3.5 to 3.7 (on a 5-point scale with 5 representing the highest level of grit). Underrepresented minorities had slightly higher Grit-S scores and first-generation college students had slightly lower Grit-S scores. Two hundred eighty-seven students responded to both the 2016 and 2017 surveys. Among these paired responses, small but significant changes in individual Grit-S scores over time that varied in direction and magnitude by school year were noted. Higher Grit-S scores were not associated with higher GPA or superior APPE performance, nor were they predictive of a student matching to a postgraduate pharmacy residency. Conclusion. Significant associations between grit and measures of academic or professional achievement were not detected in this pharmacy student cohort. The presence of small but significant changes in Grit-S scores over time, in the absence of any intervention, has implications that further research should be conducted in this area.


Neuronal thread protein regulation and interaction with microtubule-associated proteins in SH-Sy5y neuronal cells.
In Alzheimer's disease (AD), neuronal thread protein (NTP) accumulates in cortical neurons and colocalizes with phospho- tau-immunoreactive cytoskeletal lesions that correlate with dementia. To generate additional information about the potential role of NTP in AD, we characterized its expression and regulation in human SH-Sy5y neuronal cells. Quantitative real-time reverse transcription-polymerase chain reactin and Western blot analysis demonstrated prominent insulin, moderate insulin-like growth factor, type 1 (IGF-1) and minimal nerve growth factor stimulation of NTP expression. In addition, NTP protein was more stable and it progressively accumulated in cells that were stimulated with insulin for 24 or 48 h. Metabolic labeling and phospho-amino acid analysis demonstrated phosphorylation of NTP on Serine residues, 30-60 min after insulin or IGF-1 stimulation, when glycogen synthase kinase 3beta (GSK-3beta) activity would no longer have been suppressed. Kinase inhibitor and in vitro phosphorylation studies demonstrated a role for GSK-3beta in the positive regulation of NTP expression and phosphorylation. Coimmunoprecipitation studies demonstrated physical interactions between NTP and tau or microtubule-associated protein 1b (MAP-1b), and ubiquitin immunoreactivity in NTP immunoprecipitates. In summary, these studies showed that (i) NTP expression is regulated at the level of transcription by insulin and IGF-1 stimulation; (ii) NTP is phosphorylated by GSK-3beta; (iii) NTP can physically interact with tau and MAP-1b and (iv) NTP-MAP complexes are ubiquitinated. The results suggest a functional role for NTP in relation to the turnover or processing of neuronal cytoskeletal proteins, attributes that may be modulated by insulin/IGF-1-mediated signaling.


Essentials for ATP synthesis by F1F0 ATP synthases.
The majority of cellular energy in the form of adenosine triphosphate (ATP) is synthesized by the ubiquitous F(1)F(0) ATP synthase. Power for ATP synthesis derives from an electrochemical proton (or Na(+)) gradient, which drives rotation of membranous F(0) motor components. Efficient rotation not only requires a significant driving force (DeltamuH(+)), consisting of membrane potential (Deltapsi) and proton concentration gradient (DeltapH), but also a high proton concentration at the source P side. In vivo this is maintained by dynamic proton movements across and along the surface of the membrane. The torque-generating unit consists of the interface of the rotating c ring and the stator a subunit. Ion translocation through this unit involves a sophisticated interplay between the c-ring binding sites, the stator arginine, and the coupling ions on both sides of the membrane. c-ring rotation is transmitted to the eccentric shaft gamma-subunit to elicit conformational changes in the catalytic sites of F(1), leading to ATP synthesis.


A SARS-CoV-2 sequence submission tool for the European Nucleotide Archive.
Many aspects of the global response to the COVID-19 pandemic are enabled by the fast and open publication of SARS-CoV-2 genetic sequence data. The European Nucleotide Archive (ENA) is the European recommended open repository for genetic sequences. In this work, we present a tool for submitting raw sequencing reads of SARS-CoV-2 to ENA. The tool features a single-step submission process, a graphical user interface, tabular-formatted metadata and the possibility to remove human reads prior to submission. A Galaxy wrap of the tool allows users with little or no bioinformatics knowledge to do bulk sequencing read submissions. The tool is also packed in a Docker container to ease deployment. CLI ENA upload tool is available at github.com/usegalaxy-eu/ena-upload-cli (DOI 10.5281/zenodo.4537621); Galaxy ENA upload tool at toolshed.g2.bx.psu.edu/view/iuc/ena_upload/382518f24d6d and github.com/galaxyproject/tools-iuc/tree/master/tools/ena_upload (development); and ENA upload Galaxy container at github.com/ELIXIR-Belgium/ena-upload-container (DOI 10.5281/zenodo.4730785).


Enantioselective divergent syntheses of several polyhalogenated Plocamium monoterpenes and evaluation of their selectivity for solid tumors.
The family of polyhalogenated monoterpenes from Plocamium counts over a hundred known members. Using glyceraldehyde acetonide as a chiral-pool precursor, an enantioselective and divergent strategy was developed that provides a blueprint for the synthesis of many of the small yet complex acyclic members of this family. The broad applicability of this approach is demonstrated with the short, eight-step synthesis of four natural products and three analogues. These syntheses are the first of any members of the acyclic polyhalogenated Plocamium monoterpenes and permitted the evaluation of their selectivity against a range of tumor cell lines.


Perceptions of the dental profession: a comparative analysis through scale development.
Dentistry is a science-based profession that has a close interaction with people and society. However, despite this close interaction, perceptions of the dental profession by both patients and dental professionals have received little research attention. The purpose of this study was to compare the perceptions of dentists, dental students, and patients toward the dental profession through the development and testing of the Dental Profession Perceptions Scale (DPPS). The DPPS contains a total of 17 items measured on a 5-point Likert response scale. The DPPS showed excellent internal reliability (Cronbach's α = 0.92) and test-retest reliability (r = 0.93). Explanatory and confirmatory factor analyses of the DPPS showed that dentists', dental students', and patients' perceptions of the dental profession could be grouped according to 'status', 'human', and 'scientific' factors. There were no statistically significant differences between participants' DPPS total or sub-scale scores according to dental group, gender, or income. The DPPS developed can be used in future studies as a psychometrically sound measuring tool. Further studies should examine the factors that may affect the perceptions of the dental profession in different societies and cultures.


Complex regulatory role of DNA methylation in caste- and age-specific expression of a termite.
The reproductive castes of eusocial insects are often characterized by extreme lifespans and reproductive output, indicating an absence of the fecundity/longevity trade-off. The role of DNA methylation in the regulation of caste- and age-specific gene expression in eusocial insects is controversial. While some studies find a clear link to caste formation in honeybees and ants, others find no correlation when replication is increased across independent colonies. Although recent studies have identified transcription patterns involved in the maintenance of high reproduction throughout the long lives of queens, the role of DNA methylation in the regulation of these genes is unknown. We carried out a comparative analysis of DNA methylation in the regulation of caste-specific transcription and its importance for the regulation of fertility and longevity in queens of the higher termite Macrotermes natalensis. We found evidence for significant, well-regulated changes in DNA methylation in mature compared to young queens, especially in several genes related to ageing and fecundity in mature queens. We also found a strong link between methylation and caste-specific alternative splicing. This study reveals a complex regulatory role of fat body DNA methylation both in the division of labour in termites, and during the reproductive maturation of queens.


Characteristics of pole impacts to side of passenger cars in European traffic accidents and assessment of injury mechanisms--analysis of German and UK in-depth data.
The national accident statistics demonstrate that the situation of passenger car side impacts is dominated by car-to-car accidents. Car side-to-pole impacts are relatively infrequent events but result in disproportionate rates of serious and fatal injuries when compared to those in car-to-car side impact. Hence their importance has been highlighted in recent studies. For the present study two approaches were undertaken to better understand the scenario of car-to-pole impacts in Germany. The German in-depth database GIDAS (German In-Depth-Accident Study) and the UK-based database CCIS (Co-operative Crash Injury Study) were used. The first part or the study is a statistical analysis of passenger car side-to-pole impacts to describe the characteristics and their importance relevant to other types of impact and to gain further knowledge about the main factors influencing the accident outcome. The second part contains a case-by-case review of passenger cars first registered 1998 and onwards to further investigate this type of impact, including regression analysis to assess the relationship between injury severity and pole impact relevant factors. The study uses a methodology that merges in-depth-accident data from different nations and shows how in-depth cases can be used for finding injury-related technical parameters like deformation pattern, load circumstances for impact locations, and directions on the vehicle for the assessment of current and prospective test regulations. Delta-v can be identified as the most significant influencing factor for MAIS, especially for injury severity for thr thorax and abdomen. The vast majority of severe and fatal injuries are in accidents involving damage to the passenger compartment. The depth of deformation has significant influence on the injury severity level of the extremities. The most frequent direction of impact in car side-to-pole impacts is perpendicular (90 degrees +/-15 degrees ).


[Use of etretinate (RO-10-9359) in intermittent doses and follow-up for 1 year in patients with psoriasis. Final report].
p6e results of the treatment of 21 cases of psoriasis with etretinate are reported. The initial doses was 1 mg./Kg./daily for 8 weeks and, after control of the disease, minimal doses alternative with placebo administration. This method permits to obtain good results with minimal side effects.


Cardiovascular biomarkers in patients with COVID-19.
The coronavirus disease 2019 (COVID-19) pandemic has increased awareness that severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) may have profound effects on the cardiovascular system. COVID-19 often affects patients with pre-existing cardiac disease, and may trigger acute respiratory distress syndrome (ARDS), venous thromboembolism (VTE), acute myocardial infarction (AMI), and acute heart failure (AHF). However, as COVID-19 is primarily a respiratory infectious disease, there remain substantial uncertainty and controversy whether and how cardiovascular biomarkers should be used in patients with suspected COVID-19. To help clinicians understand the possible value as well as the most appropriate interpretation of cardiovascular biomarkers in COVID-19, it is important to highlight that recent findings regarding the prognostic role of cardiovascular biomarkers in patients hospitalized with COVID-19 are similar to those obtained in studies for pneumonia and ARDS in general. Cardiovascular biomarkers reflecting pathophysiological processes involved in COVID-19/pneumonia and its complications have a role evaluating disease severity, cardiac involvement, and risk of death in COVID-19 as well as in pneumonias caused by other pathogens. First, cardiomyocyte injury, as quantified by cardiac troponin concentrations, and haemodynamic cardiac stress, as quantified by natriuretic peptide concentrations, may occur in COVID-19 as in other pneumonias. The level of those biomarkers correlates with disease severity and mortality. Interpretation of cardiac troponin and natriuretic peptide concentrations as quantitative variables may aid in risk stratification in COVID-19/pneumonia and also will ensure that these biomarkers maintain high diagnostic accuracy for AMI and AHF. Second, activated coagulation as quantified by D-dimers seems more prominent in COVID-19 as in other pneumonias. Due to the central role of endothelitis and VTE in COVID-19, serial measurements of D-dimers may help physicians in the selection of patients for VTE imaging and the intensification of the level of anticoagulation from prophylactic to slightly higher or even therapeutic doses.


Patellofemoral pain: Challenging current practice - A case report.
Patellofemoral pain (PFP) is a common problem in young people, with 1 in 6 suffering at any one time. It is unclear which management approach is the optimal method for treating PFP in the long term, with traditional physiotherapy examination focusing on assessing for specific structural dysfunction. A rationale for a different assessment and treatment approach, one that moves the focus away from a biomedical/tissue pathology model towards one directed at the neurophysiology of pain, has been suggested. The patient was a 21 year old male with a 6 year history of PFP with previous failed physiotherapeutic treatment. He reported previous multiple healthcare practitioners' advice to avoid activities that were painful as reasons for being unable to participate in sporting activities. No specific structural testing was performed, such as specific muscle strength, length, foot position, patella movement and position, or movement patterns. Descriptions of tissue based pathology models of pain, e.g. patella mal-tracking, were actively discouraged and challenged. The patient was taught to perform one uncomfortable/painful exercise as part of his rehabilitation programme twice a day. The patient achieved 80% improvement in his symptoms over 7 appointments and a return to physical activity following a 5 month rehabilitation programme purposively designed to elicit pain by means of gradually exercising and loading the tissues. This case report highlights the need for further research into exercise protocols for patients suffering with PFP based upon neurophysiology models of pain.


Roughness parameters for standard description of surface nanoarchitecture.
The nanoarchitecture and surface roughness of metallic thin films prepared by magnetron sputtering were analyzed to determine the topographical statistics that give the optimum description of their nanoarchitechture. Nanoscale topographical profiles were generated by performing atomic force microscopy (AFM) scans of 1 μm × 1 μm areas of titanium and silver films of three different thicknesses (3 nm, 12 nm, and 150 nm). Of the titanium films, the 150-nm film had the highest average roughness (R(a) = 2.63 nm), more than four times that of the 3-nm and 12-nm titanium films. When silver films were coated on top of 150-nm titanium films, the average roughness increased further; the 3-nm (R(a) = 4.96 nm) and 150-nm (R(a) = 4.65 nm) silver films average roughnesses were approximately twice that of the 150-nm titanium film. For topographical analysis, seven statistical parameters were calculated. These parameters included commonly used roughness measurements, as well as some less commonly used measurements, in order to determine which combination of parameters gave the best overall description of the nanoarchitecture of the films presented. Skewness (R(skw)), surface area increase (R(sa)), and peak counts (R(pc)) provided the best description of horizontal surface dimensions, and in conjunction with vertical descriptors R(a) and R(q) gave the best characterization of surface architecture. The five roughness parameters R(a), R(q), R(skw), R(sa), and R(pc) are proposed as a new standard for describing surface nanoarchitecture.


Inhibition of ice recrystallization and cryoprotective activity of wheat proteins in liver and pancreatic cells.
Efficient cryopreservation of cells at ultralow temperatures requires the use of substances that help maintain viability and metabolic functions post-thaw. We are developing new technology where plant proteins are used to substitute the commonly-used, but relatively toxic chemical dimethyl sulfoxide. Recombinant forms of four structurally diverse wheat proteins, TaIRI-2 (ice recrystallization inhibition), TaBAS1 (2-Cys peroxiredoxin), WCS120 (dehydrin), and TaENO (enolase) can efficiently cryopreserve hepatocytes and insulin-secreting INS832/13 cells. This study shows that TaIRI-2 and TaENO are internalized during the freeze-thaw process, while TaBAS1 and WCS120 remain at the extracellular level. Possible antifreeze activity of the four proteins was assessed. The "splat cooling" method for quantifying ice recrystallization inhibition activity (a property that characterizes antifreeze proteins) revealed that TaIRI-2 and TaENO are more potent than TaBAS1 and WCS120. Because of their ability to inhibit ice recrystallization, the wheat recombinant proteins TaIRI-2 and TaENO are promising candidates and could prove useful to improve cryopreservation protocols for hepatocytes and insulin-secreting cells, and possibly other cell types. TaENO does not have typical ice-binding domains, and the TargetFreeze tool did not predict an antifreeze capacity, suggesting the existence of nontypical antifreeze domains. The fact that TaBAS1 is an efficient cryoprotectant but does not show antifreeze activity indicates a different mechanism of action. The cryoprotective properties conferred by WCS120 depend on biochemical properties that remain to be determined. Overall, our results show that the proteins' efficiencies vary between cell types, and confirm that a combination of different protection mechanisms is needed to successfully cryopreserve mammalian cells.


Biochemical analysis of a beta-D-xylosidase and a bifunctional xylanase-ferulic acid esterase from a xylanolytic gene cluster in Prevotella ruminicola 23.
Prevotella ruminicola 23 is an obligate anaerobic bacterium in the phylum Bacteroidetes that contributes to hemicellulose utilization within the bovine rumen. To gain insight into the cellular machinery that this organism elaborates to degrade the hemicellulosic polymer xylan, we identified and cloned a gene predicted to encode a bifunctional xylanase-ferulic acid esterase (xyn10D-fae1A) and expressed the recombinant protein in Escherichia coli. Biochemical analysis of purified Xyn10D-Fae1A revealed that this protein possesses both endo-beta-1,4-xylanase and ferulic acid esterase activities. A putative glycoside hydrolase (GH) family 3 beta-D-glucosidase gene, with a novel PA14-like insertion sequence, was identified two genes downstream of xyn10D-fae1A. Biochemical analyses of the purified recombinant protein revealed that the putative beta-D-glucosidase has activity for pNP-beta-D-xylopyranoside, pNP-alpha-L-arabinofuranoside, and xylo-oligosaccharides; thus, the gene was designated xyl3A. When incubated in combination with Xyn10D-Fae1A, Xyl3A improved the release of xylose monomers from a hemicellulosic xylan substrate, suggesting that these two enzymes function synergistically to depolymerize xylan. Directed mutagenesis studies of Xyn10D-Fae1A mapped the catalytic sites for the two enzymatic functionalities to distinct regions within the polypeptide sequence. When a mutation was introduced into the putative catalytic site for the xylanase domain (E280S), the ferulic acid esterase activity increased threefold, which suggests that the two catalytic domains for Xyn10D-Fae1A are functionally coupled. Directed mutagenesis of conserved residues for Xyl3A resulted in attenuation of activity, which supports the assignment of Xyl3A as a GH family 3 beta-D-xylosidase.


[Primary non-Hodgkin's lymphoma of the duodenum].
We report a case of duodenal primary non-Hodgkin lymphoma classified as a polymorphic B lymphoma with a low degree of malignancy. It was studied by ultrasound, computed tomography and simple contrast study. We review the radiologic appearance, sites of origin, and the role of Imagiology in staging and differential diagnosis.


Clearing the surgical backlog caused by COVID-19 in Ontario: a time series modelling study.
To mitigate the effects of coronavirus disease 2019 (COVID-19), jurisdictions worldwide ramped down nonemergent surgeries, creating a global surgical backlog. We sought to estimate the size of the nonemergent surgical backlog during COVID-19 in Ontario, Canada, and the time and resources required to clear the backlog. We used 6 Ontario or Canadian population administrative sources to obtain data covering part or all of the period between Jan. 1, 2017, and June 13, 2020, on historical volumes and operating room throughput distributions by surgery type and region, and lengths of stay in ward and intensive care unit (ICU) beds. We used time series forecasting, queuing models and probabilistic sensitivity analysis to estimate the size of the backlog and clearance time for a +10% (+1 day per week at 50% capacity) surge scenario. Between Mar. 15 and June 13, 2020, the estimated backlog in Ontario was 148 364 surgeries (95% prediction interval 124 508-174 589), an average weekly increase of 11 413 surgeries. Estimated backlog clearance time is 84 weeks (95% confidence interval [CI] 46-145), with an estimated weekly throughput of 717 patients (95% CI 326-1367) requiring 719 operating room hours (95% CI 431-1038), 265 ward beds (95% CI 87-678) and 9 ICU beds (95% CI 4-20) per week. The magnitude of the surgical backlog from COVID-19 raises serious implications for the recovery phase in Ontario. Our framework for modelling surgical backlog recovery can be adapted to other jurisdictions, using local data to assist with planning.


Materials for microfabricated implantable devices: a review.
The application of microfabrication to the development of biomedical implants has produced a new generation of miniaturized technology for assisting treatment and research. Microfabricated implantable devices (μID) are an increasingly important tool, and the development of new μIDs is a rapidly growing field that requires new microtechnologies able to safely and accurately function in vivo. Here, we present a review of μID research that examines the critical role of material choice in design and fabrication. Materials commonly used for μID production are identified and presented along with their relevant physical properties and a survey of the state-of-the-art in μID development. The consequence of material choice as it pertains to microfabrication and biocompatibility is discussed in detail with a particular focus on the divide between hard, rigid materials and soft, pliable polymers.


Humoral and cellular immune responses of pigs inoculated with Mycoplasma hyopneumoniae.
Cellular and humoral immune responses of pigs inoculated with Mycoplasma hyopneumoniae were investigated at postinoculation weeks (PIW) 2, 4, and 6. The response of blood lymphocytes (BL) and bronchial lymph node lymphocytes (LNL) to stimulation by M hyopneumoniae antigens was evaluated by a lymphocyte-stimulation test. Specific antibodies in serum and lung washing samples were assayed by ELISA. Immunoglobulin-positive cells in lungs and bronchial lymph nodes were identified by indirect fluorescent antibody test, using isotype-specific monoclonal antibodies. At PIW 0 to 6, BL from control and M hyopneumoniae-inoculated pigs were stimulated by M hyopneumoniae cells; however, BL from inoculated pigs generally had higher stimulation indices, especially at PIW 6. The response of LNL was influenced by previous exposure to M hyopneumoniae, as indicated by higher stimulation indices (P less than 0.01) of LNL from inoculated pigs killed at PIW 2 and 6. Specific ELISA antibodies to M hyopneumoniae in lung washings from inoculated pigs consisted mainly of IgG and IgA isotypes. Examination of lung sections by indirect immunofluorescence revealed that cells producing IgM and IgA were in controls as well as M hyopneumoniae-inoculated pigs, but IgG-positive cells were only in lungs of inoculated pigs. Resolution of pneumonia appeared to correlate with development of increased sensitization of BL, as well as development of marked increases in immunoglobulins, particularly IgG in lung washings at PIW 6.


Superior continuous quantity discrimination in a freshwater turtle.
Quantity discrimination, the ability to discriminate a magnitude of difference or discrete numerical information, plays a key role in animal behavior. While quantitative ability has been well documented in fishes, birds, mammals, and even in previously unstudied invertebrates and amphibians, it is still poorly understood in reptiles and has never been tested in an aquatic turtle despite the fact that evidence is accumulating that reptiles possess cognitive skills and learning ability. To help address this deficiency in reptiles, we investigated the quantitative ability of an Asian freshwater turtle, Mauremys sinensis, using red cubes on a white background in a trained quantity discrimination task. While spontaneous quantity discrimination methods are thought to be more ecologically relevant, training animals on a quantity discrimination task allows more comparability across taxa. We assessed the turtles' quantitative performance in a series of tests with increasing quantity ratios and numerosities. Surprisingly, the turtles were able to discriminate quantities of up to 9 versus 10 (ratio = 0.9), which shows a good quantitative ability that is comparable to some endotherms. Our results showed that the turtles' quantitative performance followed Weber's law, in which success rate decreased with increasing quantity ratio across a wide range of numerosities. Furthermore, the gradual improvement of their success rate across different experiments and phases suggested that the turtles possess learning ability. Reptile quantitative ability has long been ignored and therefore is likely under-estimated. More comparative research on numerical cognition across a diversity of species will greatly contribute to a clearer understanding of quantitative ability in animals and whether it has evolved convergently in diverse taxa.


Religious Involvement and Allostatic Resilience: Findings from a Community Study of Black and White Americans.
Wide inequities in stress and health have been documented between Black and White women and men in the United States. This study asks: How does religion factor into these inequities? We approach this open question from a biopsychosocial perspective, developing three hypotheses for the stress-coping effects of religiosity between groups. We then test our hypotheses with survey and biomarker data from the Nashville Stress and Health Study (2011-2014), a probability sample of Black and White women and men from Davidson County, Tennessee. We find that Black women score the highest on all indicators of religiosity, followed by Black men, White women, and White men. We also find that increased divine control and religious coping predict higher levels of resiliency biomarkers for Black women only and lower levels for White respondents, especially White men. We discuss how our findings inform broader population health inequities and outline several avenues for future research.


Randomized Lasso Links Microbial Taxa with Aquatic Functional Groups Inferred from Flow Cytometry.
High-nucleic-acid (HNA) and low-nucleic-acid (LNA) bacteria are two operational groups identified by flow cytometry (FCM) in aquatic systems. A number of reports have shown that HNA cell density correlates strongly with heterotrophic production, while LNA cell density does not. However, which taxa are specifically associated with these groups, and by extension, productivity has remained elusive. Here, we addressed this knowledge gap by using a machine learning-based variable selection approach that integrated FCM and 16S rRNA gene sequencing data collected from 14 freshwater lakes spanning a broad range in physicochemical conditions. There was a strong association between bacterial heterotrophic production and HNA absolute cell abundances (R 2 = 0.65), but not with the more abundant LNA cells. This solidifies findings, mainly from marine systems, that HNA and LNA bacteria could be considered separate functional groups, the former contributing a disproportionately large share of carbon cycling. Taxa selected by the models could predict HNA and LNA absolute cell abundances at all taxonomic levels. Selected operational taxonomic units (OTUs) ranged from low to high relative abundance and were mostly lake system specific (89.5% to 99.2%). A subset of selected OTUs was associated with both LNA and HNA groups (12.5% to 33.3%), suggesting either phenotypic plasticity or within-OTU genetic and physiological heterogeneity. These findings may lead to the identification of system-specific putative ecological indicators for heterotrophic productivity. Generally, our approach allows for the association of OTUs with specific functional groups in diverse ecosystems in order to improve our understanding of (microbial) biodiversity-ecosystem functioning relationships.IMPORTANCE A major goal in microbial ecology is to understand how microbial community structure influences ecosystem functioning. Various methods to directly associate bacterial taxa to functional groups in the environment are being developed. In this study, we applied machine learning methods to relate taxonomic data obtained from marker gene surveys to functional groups identified by flow cytometry. This allowed us to identify the taxa that are associated with heterotrophic productivity in freshwater lakes and indicated that the key contributors were highly system specific, regularly rare members of the community, and that some could possibly switch between being low and high contributors. Our approach provides a promising framework to identify taxa that contribute to ecosystem functioning and can be further developed to explore microbial contributions beyond heterotrophic production.


Identification of Novel Chemical Entities for Adenosine Receptor Type 2A Using Molecular Modeling Approaches.
Adenosine Receptor Type 2A (A2AAR) plays a role in important processes, such as anti-inflammatory ones. In this way, the present work aimed to search for compounds by pharmacophore-based virtual screening. The pharmacokinetic/toxicological profiles of the compounds, as well as a robust QSAR, predicted the binding modes via molecular docking. Finally, we used molecular dynamics to investigate the stability of interactions from ligand-A2AAR. For the search for A2AAR agonists, the UK-432097 and a set of 20 compounds available in the BindingDB database were studied. These compounds were used to generate pharmacophore models. Molecular properties were used for construction of the QSAR model by multiple linear regression for the prediction of biological activity. The best pharmacophore model was used by searching for commercial compounds in databases and the resulting compounds from the pharmacophore-based virtual screening were applied to the QSAR. Two compounds had promising activity due to their satisfactory pharmacokinetic/toxicological profiles and predictions via QSAR (Diverset 10002403 pEC50 = 7.54407; ZINC04257548 pEC50 = 7.38310). Moreover, they had satisfactory docking and molecular dynamics results compared to those obtained for Regadenoson (Lexiscan®), used as the positive control. These compounds can be used in biological assays (in vitro and in vivo) in order to confirm the potential activity agonist to A2AAR.


Insights into schizophrenia using positron emission tomography: building the evidence and refining the focus.
Schizophrenia involves dysregulation in dopaminergic transmission. Studies show heightened presynaptic striatal dopaminergic function and elevated striatal D(2)/D(3) receptor density in the brain. Cognitive impairments result from hypostimulation of D(1) receptors and are associated with dysfunction in the prefrontal cortex. Here we discuss relevant positron emissions tomography (PET) studies and provide future directions.


Unsupervised EEG Artifact Detection and Correction.
Electroencephalography (EEG) is used in the diagnosis, monitoring, and prognostication of many neurological ailments including seizure, coma, sleep disorders, brain injury, and behavioral abnormalities. One of the primary challenges of EEG data is its sensitivity to a breadth of non-stationary noises caused by physiological-, movement-, and equipment-related artifacts. Existing solutions to artifact detection are deficient because they require experts to manually explore and annotate data for artifact segments. Existing solutions to artifact correction or removal are deficient because they assume that the incidence and specific characteristics of artifacts are similar across both subjects and tasks (i.e., "one-size-fits-all"). In this paper, we describe a novel EEG noise-reduction method that uses representation learning to perform patient- and task-specific artifact detection and correction. More specifically, our method extracts 58 clinically relevant features and applies an ensemble of unsupervised outlier detection algorithms to identify EEG artifacts that are unique to a given task and subject. The artifact segments are then passed to a deep encoder-decoder network for unsupervised artifact correction. We compared the performance of classification models trained with and without our method and observed a 10% relative improvement in performance when using our approach. Our method provides a flexible end-to-end unsupervised framework that can be applied to novel EEG data without the need for expert supervision and can be used for a variety of clinical decision tasks, including coma prognostication and degenerative illness detection. By making our method, code, and data publicly available, our work provides a tool that is of both immediate practical utility and may also serve as an important foundation for future efforts in this domain.


Analysis of rice Act1 5' region activity in transgenic rice plants.
The 5' region of the rice actin 1 gene (Act1) has been developed as an efficient regulator of foreign gene expression in transgenic rice plants. To determine the pattern and level of rice Act1 5' region activity, transgenic rice plants containing the Act1 5' region fused to a bacterial beta-glucuronidase (Gus) coding sequence were generated. Two independent clonal lines of transgenic rice plants were analyzed in detail. Quantitative analysis showed that tissue from these transgenic rice plants have a level of GUS protein that represents as much as 3% of total soluble protein. We were able to demonstrate that Act1-Gus gene expression is constitutive throughout the sporophytic and gametophytic tissues of these transgenic rice plants. Plants from one transgenic line were analyzed for the segregation of GUS activity in pollen by in situ histochemical staining, and the inheritance and stability of Act1-Gus expression were assayed in subsequently derived progeny plants.


An analysis of 6 decades of hygiene-related advertising: 1940-2000.
To describe and analyze trends in hygiene-related advertisements and examine potential social and regulatory changes that might be associated with these trends. From 1940 to 2000, advertisements in January issues of 2 widely read magazines were analyzed every fifth year, and 2 additional magazines only available from 1960 to 2000 were also analyzed every fifth year. In a content analysis, the total number of advertisements were determined and specific advertisements were grouped into categories (personal hygiene, dishwashing, laundry, and house cleaning) and further examined for the presence of 4 key claims (aesthetics, health effects, time-saving, and microbial effects). From 1940 to 2000 for all magazines combined, 10.4% of the advertisements were devoted to hygiene products. After 1960 there were significantly fewer hygiene advertisements as compared with 1940 to 1955, and there was a significant increase after 1980 (P <.00001). Throughout all 6 decades, most advertisements related to personal hygiene. There were no significant differences over time in the proportion of advertisements that made claims related to health, microbial effects, or aesthetics, but significantly more advertisements before 1960 made time-savings claims (P =.009). This content analysis reflects a cyclical attention in consumer advertising to personal and home hygiene products during the past 6 decades, with a waning of interest in the decades from 1960 to 1980 and an apparent resurgence of advertisements from 1985 to 2000. The potential contributions of federal regulatory bodies and societal changes (e.g., new marketing strategies and options, product development, new and re-emerging infectious diseases, increasing concern about antimicrobial resistance, and increasing recognition that infectious diseases are unlikely to be eradicated) to these marketing trends are discussed.