Biophysical characterisation of human LincRNA-p21 sense and antisense Alu inverted repeats.

Human Long Intergenic Noncoding RNA-p21 (LincRNA-p21) is a regulatory noncoding RNA that plays an important role in promoting apoptosis. LincRNA-p21 is also critical in down-regulating many p53 target genes through its interaction with a p53 repressive complex. The interaction between LincRNA-p21 and the repressive complex is likely dependent on the RNA tertiary structure. Previous studies have determined the two-dimensional secondary structures of the sense and antisense human LincRNA-p21 AluSx1 IRs using SHAPE. However, there were no insights into its three-dimensional structure. Therefore, we in vitro transcribed the sense and antisense regions of LincRNA-p21 AluSx1 Inverted Repeats (IRs) and performed analytical ultracentrifugation, size exclusion chromatography, light scattering, and small angle X-ray scattering (SAXS) studies. Based on these studies, we determined low-resolution, three-dimensional structures of sense and antisense LincRNA-p21. By adapting previously known two-dimensional information, we calculated their sense and antisense high-resolution models and determined that they agree with the low-resolution structures determined using SAXS. Thus, our integrated approach provides insights into the structure of LincRNA-p21 Alu IRs. Our study also offers a viable pipeline for combining the secondary structure information with biophysical and computational studies to obtain high-resolution atomistic models for long noncoding RNAs.

Distance geometry and protein loop modeling.

Due to the role of loops in protein function, loop modeling is an important problem in computational biology. We present a new approach to loop modeling based on a combinatorial version of distance geometry, where the search space of the associated problem is represented by a binary tree and a branch-and-prune method is defined to explore it, following an atomic ordering previously given. This ordering is used to calculate the coordinates of atoms from the positions of its predecessors. In addition to the theoretical development, computational results are presented to illustrate the advantage of the proposed method, compared with another approach of the literature. Our algorithm is freely available at https://github.com/michaelsouza/bpl.

Increased circulating butyrate and ursodeoxycholate during probiotic intervention in humans with type 2 diabetes.

BACKGROUND: An increasing body of evidence implicates the resident gut microbiota as playing a critical role in type 2 diabetes (T2D) pathogenesis. We previously reported significant improvement in postprandial glucose control in human participants with T2D following 12-week administration of a 5-strain novel probiotic formulation ('WBF-011') in a double-blind, randomized, placebo controlled setting (NCT03893422). While the clinical endpoints were encouraging, additional exploratory measurements were needed in order to link the motivating mechanistic hypothesis - increased short-chain fatty acids - with markers of disease. RESULTS: Here we report targeted and untargeted metabolomic measurements on fasting plasma (n = 104) collected at baseline and end of intervention. Butyrate and ursodeoxycholate increased among participants randomized to WBF-011, along with compelling trends between butyrate and glycated haemoglobin (HbA1c). In vitro monoculture experiments demonstrated that the formulation's C. butyricum strain efficiently synthesizes ursodeoxycholate from the primary bile acid chenodeoxycholate during butyrogenic growth. Untargeted metabolomics also revealed coordinated decreases in intermediates of fatty acid oxidation and bilirubin, potential secondary signatures for metabolic improvement. Finally, improvement in HbA1c was limited almost entirely to participants not using sulfonylurea drugs. We show that these drugs can inhibit growth of formulation strains in vitro. CONCLUSION: To our knowledge, this is the first description of an increase in circulating butyrate or ursodeoxycholate following a probiotic intervention in humans with T2D, adding support for the possibility of a targeted microbiome-based approach to assist in the management of T2D. The efficient synthesis of UDCA by C. butyricum is also likely of interest to investigators of its use as a probiotic in other disease settings. The potential for inhibitory interaction between sulfonylurea drugs and gut microbiota should be considered carefully in the design of future studies.

A large-scale evaluation of computational protein function prediction.

Automated annotation of protein function is challenging. As the number of sequenced genomes rapidly grows, the overwhelming majority of protein products can only be annotated computationally. If computational predictions are to be relied upon, it is crucial that the accuracy of these methods be high. Here we report the results from the first large-scale community-based critical assessment of protein function annotation (CAFA) experiment. Fifty-four methods representing the state of the art for protein function prediction were evaluated on a target set of 866 proteins from 11 organisms. Two findings stand out: (i) today's best protein function prediction algorithms substantially outperform widely used first-generation methods, with large gains on all types of targets; and (ii) although the top methods perform well enough to guide experiments, there is considerable need for improvement of currently available tools.

Pb(II) adsorption by biomass from chemically modified aquatic macrophytes, Salvinia sp. and Pistia stratiotes.

This study used two biosorbents obtained from the aquatic plants Salvinia sp. and Pistia stratiotes to establish a sustainable and alternative treatment for industrial wastewater and other water bodies that contain Pb(II). The biosorbent named Salvinia with NaOH (SOH) was obtained from Salvinia sp., and Salvinia and Pistia mixture with NaOH (SPOH) was obtained from a mixture of the two plants in a 1:1 ratio. The biosorbents were characterized by zeta potential, infrared (IR) spectroscopy, scanning electron microscopy (SEM), energy-dispersive spectroscopy and Boehm titration. The results of Boehm titration and IR analysis indicated the presence of basic functional groups, whereas those of SEM analysis indicated that the biosorbents have a structure conducive to adsorption. Batch adsorption experiments were performed to observe the effects of pH, contact time, initial lead concentration and temperature on the metal removal process. The results revealed that the biosorbents efficiently removed Pb(II) from aqueous solutions, with a maximum observed adsorption capacity (saturation limits, qmax) of 202 mg g(-1) and 210.1 mg g(-1) for SPOH and SOH, respectively. The Freundlich, Langmuir and Dubinin-Radushkevich models were applied to the data; these biosorbent studies did not satisfactorily adjust to either of the models, but the information obtained helped us understand the adsorption mechanism.

A Branch-and-Bound Algorithm for the Molecular Ordered Covering Problem.

The Discretizable Molecular Distance Geometry Problem (DMDGP) plays a key role in the construction of three-dimensional molecular structures from interatomic distances acquired through nuclear magnetic resonance (NMR) spectroscopy, with the primary objective of validating a sequence of distance constraints related to NMR data. This article addresses the escalating complexity of the DMDGP encountered with larger and more flexible molecules by introducing a novel strategy via the Molecular Ordered Covering Problem, which optimizes the ordering of distance constraints to improve computational efficiency in DMDGP resolution. This approach utilizes a specialized Branch-and-Bound (BB) algorithm, tested on both synthetic and actual protein structures from the protein data bank. Our analysis demonstrates the efficacy of the previously proposed greedy heuristic in managing complex molecular scenarios, highlighting the BB algorithm's utility as a validation mechanism. This research contributes to ongoing efforts in molecular structure analysis, with possible implications for areas such as protein folding, drug design, and molecular modeling.

Solving the molecular distance geometry problem with inaccurate distance data.

We present a new iterative algorithm for the molecular distance geometry problem with inaccurate and sparse data, which is based on the solution of linear systems, maximum cliques, and a minimization of nonlinear least-squares function. Computational results with real protein structures are presented in order to validate our approach.

Medical Food Assessment Using a Smartphone App With Continuous Glucose Monitoring Sensors: Proof-of-Concept Study.

BACKGROUND: Novel wearable biosensors, ubiquitous smartphone ownership, and telemedicine are converging to enable new paradigms of clinical research. A new generation of continuous glucose monitoring (CGM) devices provides access to clinical-grade measurement of interstitial glucose levels. Adoption of these sensors has become widespread for the management of type 1 diabetes and is accelerating in type 2 diabetes. In parallel, individuals are adopting health-related smartphone-based apps to monitor and manage care. OBJECTIVE: We conducted a proof-of-concept study to investigate the potential of collecting robust, annotated, real-time clinical study measures of glucose levels without clinic visits. METHODS: Self-administered meal-tolerance tests were conducted to assess the impact of a proprietary synbiotic medical food on glucose control in a 6-week, double-blind, placebo-controlled, 2×2 cross-over pilot study (n=6). The primary endpoint was incremental glucose measured using Abbott Freestyle Libre CGM devices associated with a smartphone app that provided a visual diet log. RESULTS: All subjects completed the study and mastered CGM device usage. Over 40 days, 3000 data points on average per subject were collected across three sensors. No adverse events were recorded, and subjects reported general satisfaction with sensor management, the study product, and the smartphone app, with an average self-reported satisfaction score of 8.25/10. Despite a lack of sufficient power to achieve statistical significance, we demonstrated that we can detect meaningful changes in the postprandial glucose response in real-world settings, pointing to the merits of larger studies in the future. CONCLUSIONS: We have shown that CGM devices can provide a comprehensive picture of glucose control without clinic visits. CGM device usage in conjunction with our custom smartphone app can lower the participation burden for subjects while reducing study costs, and allows for robust integration of multiple valuable data types with glucose levels remotely. TRIAL REGISTRATION: ClinicalTrials.gov NCT04424888; http://clinicaltrials.gov/ct2/show/NCT04424888.

Life History of Bedellia somnulentella (Lepidoptera: Bedelliidae) Feeding on Ipomoea batatas (Solanales: Convolvulaceae) Leaves and Survey of Parasitoids in Brazil.

The microlepidoptera, Bedellia somnulentella (Zeller), is an important pest of sweetpotato, Ipomoea batatas (L.) Lam. Damage by B. somnulentella occurs in the larval stage and when consuming the foliar mesophyll of I. batatas make the leaves brown, wrinkled, and reducing the photosynthetic area and the yield. The detection and management of this pest depends on knowing its biological cycle and identifying its natural enemies. The objectives of this study were to determine the life history of B. somnulentella feeding on I. batatas leaves and to survey parasitoids of this pest in the field. The duration and viability of B. somnulentella egg, larva, prepupa, pupa, and adult stages were evaluated under laboratory conditions. Cephalic capsule width was measured to determine the number of B. somnulentella instars, based on the Dyar rule and analyzed by the Akaike statistical model (AIC). The developmental period of B. somnulentella was 32.5 ± 0. 21 d with a viability of 75, 84, 100, and 84% for the egg, larva, prepupa, and pupa stages, respectively. The identification of this pest on the plants is possible from the third instar and in the pupal and adult stages. The parasitoid Conura sp. (Hymenoptera: Chalcididae) was identified parasitizing pupae of B. somnulentella and could be considered a potential natural enemy for the integrated management of this pest.

Biodefense Implications of New-World Hantaviruses.

Hantaviruses, part of the Bunyaviridae family, are a genus of negative-sense, single-stranded RNA viruses that cause two major diseases: New-World Hantavirus Cardiopulmonary Syndrome and Old-World Hemorrhagic Fever with Renal Syndrome. Hantaviruses generally are found worldwide with each disease corresponding to their respective hemispheres. New-World Hantaviruses spread by specific rodent-host reservoirs and are categorized as emerging viruses that pose a threat to global health and security due to their high mortality rate and ease of transmission. Incidentally, reports of Hantavirus categorization as a bioweapon are often contradicted as both US National Institute of Allergy and Infectious Diseases and the Centers for Disease Control and Prevention refer to them as Category A and C bioagents respectively, each retaining qualitative levels of importance and severity. Concerns of Hantavirus being engineered into a novel bioagent has been thwarted by Hantaviruses being difficult to culture, isolate, and purify limiting its ability to be weaponized. However, the natural properties of Hantaviruses pose a threat that can be exploited by conventional and unconventional forces. This review seeks to clarify the categorization of Hantaviruses as a bioweapon, whilst defining the practicality of employing New-World Hantaviruses and their effect on armies, infrastructure, and civilian targets.

Improvements to postprandial glucose control in subjects with type 2 diabetes: a multicenter, double blind, randomized placebo-controlled trial of a novel probiotic formulation.

INTRODUCTION: A growing body of evidence suggests that specific, naturally occurring gut bacteria are under-represented in the intestinal tracts of subjects with type 2 diabetes (T2D) and that their functions, like gut barrier stability and butyrate production, are important to glucose and insulin homeostasis. The objective of this study was to test the hypothesis that enteral exposure to microbes with these proposed functions can safely improve clinical measures of glycemic control and thereby play a role in the overall dietary management of diabetes. RESEARCH DESIGN AND METHODS: We evaluated whether a probiotic comprised of these anaerobic bacteria would enhance dietary management by (1) manufacturing two novel probiotic formulations containing three (WBF-010) or five (WBF-011) distinct strains in a Current Good Manufacturing Practice (cGMP) facility, (2) establishing consistent live-cell concentrations, (3) confirming safety at target concentrations dispensed in both animal and human studies and (4) conducting a 12-week parallel, double-blind, placebo-controlled, proof-of-concept study in which subjects previously diagnosed with T2D (n=76) were randomly assigned to a two times a day regimen of placebo, WBF-010 or WBF-011. RESULTS: No safety or tolerability issues were observed. Compared with the placebo group, subjects administered WBF-011 (which contains inulin, Akkermansia muciniphila, Clostridium beijerinckii, Clostridium butyricum, Bifidobacterium infantis and Anaerobutyricum hallii) significantly improved in the primary outcome, glucose total area under the curve (AUC): -36.1 mg/dL/180 min, p=0.0500 and also improved in secondary outcomes, glycated hemoglobin (A1c): -0.6, glucose incremental-AUC: -28.6 mg/dL/180 min. CONCLUSIONS: To our knowledge, this is the first randomized controlled trial to administer four of the five strains to human subjects with T2D. This proof-of-concept study (clinical trial number NCT03893422) shows that the intervention was safe and well tolerated and that supplementation with WBF-011 improves postprandial glucose control. The limited sample size and intersubject variability justifies future studies designed to confirm and expand on these observations.

Controlled retrieval and selection of action-relevant knowledge mediated by partially overlapping regions in left ventrolateral prefrontal cortex.

Information from long-term memory is used to identify appropriate responses to cues in the environment. Left ventrolateral prefrontal cortex (VLPFC) has been implicated in the effortful retrieval of semantic representations, as well as in the goal-directed selection between such representations. It has also been suggested that left posterior middle temporal gyrus (pMTG) stores the rules which VLPFC accesses to guide behavior. In the present event-related fMRI study, we examined the contributions of left VLPFC and pMTG in the controlled retrieval and selection of action-relevant knowledge associated with road signs. Controlled retrieval demands were manipulated by varying how recently the sign meaning was learned, and selection demands were manipulated by varying the number of competing meanings associated with a sign. Activation in anterior VLPFC was consistent with controlled retrieval, activation in posterior VLPFC was consistent with selection, and activation in mid-VLPFC was sensitive to both manipulations. Left pMTG, while active, was not sensitive to these manipulations. These findings highlight the role of left VLPFC in accessing and maintaining goal-relevant information for the control of action.

Assessment of a coastal lagoon metal distribution through natural and anthropogenic processes (SE, Brazil).

The present study intends to assess the metal pollution of a eutrophic coastal lagoon, analyzing the long-term and actual metal content in surface sediments, suspended particles, aquatic macrophyte and fish species, and the loads emitted from natural processes and anthropogenic sources, including the relative emission of domestic untreated sewage. Distribution indicated contamination of suspended particles with Cd and the predominance of Pb in the bioavailable form in surface sediments which may explain Cd and Pb contamination in fish. Domestic untreated sewage was an important source of Cu and due to the lagoon's management, this source may be increasing the metal content in the lagoon's surface sediments. Soil loss, atmospheric deposition and solid waste disposal also contributed to metal inputs to the lagoon. Extensive contamination has been prevented by the lagoon's management such as sandbar opening. Metal retention within the watershed soils reduce the effective metal transference and lagoon pollution.

Charts versus Discharge ICD-10 Coding for Sternal Wound Infection Following Coronary Artery Bypass Grafting.

BACKGROUND: Sternal wound infection (SWI) in patients undergoing coronary artery bypass grafting (CABG) can carry a significant risk of morbidity and mortality. The objective of this work is to describe the methods used to identify cases of SWI in an administrative database and to demonstrate the effectiveness of using an International Classification of Diseases, Tenth Revision (ICD-10) coding algorithm for this purpose. METHODS: ICD-10 codes were used to identify cases of SWI within one year of CABG between April 2002 and November 2009. We randomly chose 200 charts for detailed chart review (100 from each of the groups coded as having SWI and not having SWI) to determine the utility of the ICD-10 coding algorithm. RESULTS: There were 2,820 patients undergoing CABG. Of these, 264 (9.4 percent) were coded as having SWI. Thirty-eight cases of SWI were identified by chart review. The ICD-10 coding algorithm of T81.3 or T81.4 was able to identify incident SWI with a positive predictive value of 35 percent and a negative predictive value of 97 percent. The agreement between the ICD-10 coding algorithm and presence of SWI remained fair, with an overall kappa coefficient of 0.32 (95 percent confidence interval, 0.22-0.43). The effectiveness of identifying deep SWI cases is also presented. CONCLUSIONS: This article describes an effective algorithm for identifying a cohort of patients with SWI following open sternotomy in large databases using ICD-10 coding. In addition, alternative search strategies are presented to suit researchers' needs.

Hypereosinophilic thrombus causing aortic stenosis and myocardial infarction.

Hypereosinophilia can cause severe endomyocardial fibrosis with subsequent restrictive cardiac disease and endocardial lesions. We present a case of a 37-year-old man with known hypereosinophilia, followed with yearly echocardiograms, who presented acutely with myocardial infarction and aortic outflow tract obstruction. At surgery, a broad based eosinophilic thrombus was found that had obstructed the aortic outflow tract. The possibility of the rapid emergence of such obstructive thrombotic lesions in hypereosinophilic syndromes warrants very close echocardiographic surveillance.

Trends in postcoronary artery bypass graft sternal wound dehiscence in a provincial population.

BACKGROUND: It appears that the medical profile of patients undergoing coronary artery bypass graft (CABG) surgery has changed. The impact of this demographic shift on CABG outcomes, such as sternal wound dehiscence, is unclear. OBJECTIVES: To quantify the incidence and trends of sternal wound dehiscence, quantify the demographic shift of those undergoing CABG and identify patient factors predictive of disease. METHODS: A prospective analysis was performed on a historical cohort of consecutive patients who underwent CABG (without valve replacement) in Alberta between April 1, 2002 and November 30, 2009. The incidence and trends of sternal wound dehiscence were determined. In addition, the trend of the mean Charlson index score and European System for Cardiac Operative Risk Evaluation (EuroSCORE) (capturing patient comorbidities) was analyzed. Univariable analysis and multivariable models were performed to determine factors predictive of wound dehiscence. RESULTS: A total of 5815 patients underwent CABG during the study period. The incidence proportion of sternal wound dehiscence in Alberta was 1.86% and the incidence rate was 1.98 cases per 100 person-years. Although both the EuroSCORE and Charlson scores significantly increased over the study period, the incidence of sternal wound dehiscence did not change significantly. Factors predictive of sternal wound dehiscence were diabetes (OR 2.97 [95% CI 1.73 to 5.10]), obesity (OR 1.55 [95% CI 1.05 to 2.27]) and female sex (OR 1.90 [95% CI 1.26 to 2.87]). CONCLUSIONS: The incidence proportion of sternal wound dehiscence in Alberta was comparable with the incidence previously published in the literature. While patients undergoing CABG had worsening medical profiles, the incidence of sternal wound dehiscence did not appear to be increasing significantly.

HISTORIQUE: Il semble que le profil médical des patients qui subisent un pontage aortocoronarien (PAC) a changé. On ne connaît pas les effets de ce changement démographique sur les résultats des PAC, tels que la déhiscence sternale. OBJECTIF: Quantifier l'incidence et les tendances de déhiscence sternale, quantifier le changement démographique des personnes qui subissent un PAC et cerner les facteurs liés aux patients qui sont prédictifs de maladie. MÉTHODOLOGIE: Les chercheurs ont effectué une analyse prospective auprès d'une cohorte historique de patients consécutifs qui avaient subi un PAC (sans remplacement valvulaire) en Alberta entre le 1er avril 2002 et le 30 novembre 2009. Ils ont déterminé l'incidence et les tendances des déhiscences sternales. Ils ont analysé la tendance de l'indice moyen de Charlson et de l'EuroSCORE (European System for Cardiac Operative Risk Evaluation) (qui saisit les comorbidités des patients). Ils ont utilisé des analyses univariables et des modèles multivariables pour déterminer les facteurs prédictifs d'une déhiscence de la plaie. RÉSULTATS: Au total, 5 815 patients ont subi un PAC pendant la période de l'étude. La proportion de déhiscence sternale en Alberta était de 1,86 % et le taux d'incidence, de 1,98 cas sur 100 personnes-année. Même si l'EuroSCORE et l'indice de Charlson ont augmenté considérablement pendant la période de l'étude, l'incidence de déhiscence sternale n'a pas changé de manière significative. Le diabète (RC 2,97 [95 % IC 1,73 à 5,10]), l'obésité (RC 1,55 [95 % IC 1,05 à 2,27]) et le sexe féminin (RC 1,90 [95 % IC 1,26 à 2,87]) étaient les facteurs prédictifs de déhiscence sternale. CONCLUSIONS: La proportion de déhiscence sternale en Alberta était comparable à celle publiée par le passé. Le profil médical des patients qui subissent un PAC s'aggravait, mais l'incidence de déhiscence sternale ne semblait pas augmenter de manière significative.

Flexible rule use: common neural substrates in children and adults.

Flexible rule-guided behavior develops gradually, and requires the ability to remember the rules, switch between them as needed, and implement them in the face of competing information. Our goals for this study were twofold: first, to assess whether these components of rule-guided behavior are separable at the neural level, and second, to identify age-related differences in one or more component that could support the emergence of increasingly accurate and flexible rule use over development. We collected event-related fMRI data while 36 children aged 8-13 and adults aged 20-27 performed a task that manipulated rule representation, rule switching, and stimulus incongruency. Several regions - left dorsolateral prefrontal cortex (DLPFC), left posterior parietal cortex, and pre-supplementary motor area - were engaged by both the rule representation and the rule-switching manipulations. These regions were engaged similarly across age groups, though contrasting timecourses of activation in left DLPFC suggest that children updated task rules more slowly than did adults. These findings support the idea that common networks can contribute to a variety of executive functions, and that some developmental changes take the form of changes in temporal dynamics rather than qualitative changes in the network of brain regions engaged.

Silver nanoplate contrast agents for in vivo molecular photoacoustic imaging.

Silver nanoplates are introduced as a new photoacoustic contrast agent that can be easily functionalized for molecular photoacoustic imaging in vivo. Methods are described for synthesis, functionalization, and stabilization of silver nanoplates using biocompatible ("green") reagents. Directional antibody conjugation to the nanoplate surface is presented along with proof of molecular sensitivity in vitro with pancreatic cancer cells. Cell viability tests show the antibody-conjugated silver nanoplates to be nontoxic at concentrations up to 1 mg/mL. Furthermore, the silver nanoplates' potential for in vivo application as a molecularly sensitive photoacoustic contrast agent is demonstrated using an orthotopic mouse model of pancreatic cancer. Results of these studies suggest that the synthesized silver nanoplates are well suited for a host of biomedical imaging and sensing applications.