In structure-based virtual screening, compound ranking through a consensus of scores from a variety of docking programs or scoring functions, rather than ranking by scores from a single program, ...provides better predictive performance and reduces target performance variability. Here we compare traditional consensus scoring methods with a novel, unsupervised gradient boosting approach. We also observed increased score variation among active ligands and developed a statistical mixture model consensus score based on combining score means and variances. To evaluate performance, we used the common performance metrics ROCAUC and EF1 on 21 benchmark targets from DUD-E. Traditional consensus methods, such as taking the mean of quantile normalized docking scores, outperformed individual docking methods and are more robust to target variation. The mixture model and gradient boosting provided further improvements over the traditional consensus methods. These methods are readily applicable to new targets in academic research and overcome the potentially poor performance of using a single docking method on a new target.
The electronic properties of thiol‐functionalized 2D MoS2 nanosheets are investigated. Shifts in the valence and conduction bands and Fermi levels are observed while bandgaps remain unaffected. These ...findings allow the tuning of energy barriers between 2D MoS2 and other materials, which can lead to improved control over 2D MoS2‐based electronic and optical devices and catalysts.
Approximately 800 million people worldwide are infected with one or more species of skin-penetrating nematodes. These parasites persist in the environment as developmentally arrested third-stage ...infective larvae (iL3s) that navigate toward host-emitted cues, contact host skin, and penetrate the skin. iL3s then reinitiate development inside the host in response to sensory cues, a process called activation. Here, we investigate how chemosensation drives host seeking and activation in skin-penetrating nematodes. We show that the olfactory preferences of iL3s are categorically different from those of free-living adults, which may restrict host seeking to iL3s. The human-parasitic threadworm Strongyloides stercoralis and hookworm Ancylostoma ceylanicum have highly dissimilar olfactory preferences, suggesting that these two species may use distinct strategies to target humans. CRISPR/Cas9-mediated mutagenesis of the S. stercoralis
tax-4 gene abolishes iL3 attraction to a host-emitted odorant and prevents activation. Our results suggest an important role for chemosensation in iL3 host seeking and infectivity and provide insight into the molecular mechanisms that underlie these processes.
Objective
Aberrant glutamate and γ‐aminobutyric acid (GABA) neurotransmission contribute to seizure generation and the epileptic state. However, whether levels of these neurochemicals are abnormal in ...epileptic patients is unknown. Here, we report on interictal levels of glutamate, glutamine, and GABA in epilepsy patients at seizure onset and nonepileptic sites, cortical lesions, and from patients with poorly localized neocortical epilepsies.
Methods
Subjects (n = 79) were medically refractory epilepsy patients undergoing intracranial electroencephalogram evaluation. Microdialysis probes (n = 125) coupled to depth electrodes were implanted within suspected seizure onset sites and microdialysis samples were obtained during interictal periods. Glutamate, glutamine, and GABA were measured using high‐performance liquid chromatography. Probe locations were subsequently classified by consensus of expert epileptologists.
Results
Glutamate levels were elevated in epileptogenic (p = 0.03; n = 7), nonlocalized (p < 0.001), and lesional cortical sites (p < 0.001) when compared to nonepileptogenic cortex. Glutamate was also elevated in epileptogenic (p < 0.001) compared to nonepileptogenic hippocampus. There were no statistical differences in GABA or glutamine, although GABA levels showed high variability across patients and groups.
Interpretation
Our findings indicate that chronically elevated extracellular glutamate is a common pathological feature among epilepsies with different etiology. Contrary to our predictions, GABA and glutamine levels were not decreased in any of the measured areas. Whereas variability in GABA levels may in part be attributed to the use of GABAergic antiepileptic drugs, the stability in glutamine across patient groups indicate that extracellular glutamine levels are under tighter metabolic regulation than previously thought. Ann Neurol 2016;80:35–45
Nitrosamine formation has been associated with wastewater-impacted waters, but specific precursors within wastewater effluents have not been identified. Experiments indicated that nitrosamines form ...in low yields from quaternary amines, and that the nitrosamines form from the quaternary amines themselves, not just lower order amine impurities. Polymeric and benzylated quaternary amines were more potent precursors than monomeric quaternary alkylamines. Pretreatment of quaternary amines with ozone or free chlorine, which deactivate lower order amine impurities, did not significantly reduce nitrosamine formation. The nitrosamine formation pathway is unclear but experiments indicated that transformation of quaternary amines to lower order amine precursors via Hofmann elimination was not involved. Experiments suggest that the pathway may involve quaternary amine degradation by amidogen or chloramino radicals formed from chloramines. Quaternary amines are significant constituents of consumer products, including shampoos, detergents, and fabric softeners. Although quaternary amines may be removed by sedimentation during wastewater treatment, their importance should be evaluated on a case-by-case basis. The high loadings from consumer products may enable the portion not removed to serve as precursors.
The post-harvest fumigant, sulfuryl fluoride (SO2F2), is a >1000-fold more potent greenhouse gas than carbon dioxide and methane. Pilot studies have shown that SO2F2 fumes vented from fumigation ...chambers can be captured and hydrolyzed by hydroxide (OH–) and hydrogen peroxide (H2O2) at pH ∼ 12 in a scrubber, producing SO4 2– and F– as waste salts. To reduce the costs and challenges associated with purchasing and mixing these reagents onsite, this study evaluates the electrochemical generation of OH– and H2O2 within spent scrubbing solution, taking advantage of the waste SO4 2– and F– as free sources of electrolyte. The study used a gas diffusion electrode constructed from carbon paper coated with carbon black as a catalyst selective for the reduction of O2 to H2O2. Under galvanostatic conditions, the study evaluated the effect of electrochemical conditions, including applied cathodic current density and electrolyte strength. Within an electrolyte containing 200 mM SO4 2– and 400 mM F–, comparable to the waste salts generated by a SO2F2 scrubbing event, the system produced 250 mM H2O2 at pH 12.6 within 4 h with a Faradaic efficiency of 98.8% for O2 reduction to H2O2. In a scrubbing-water sample from lab-scale fumigation, the system generated ∼200 mM H2O2 at pH 13.5 within 4 h with a Faradaic efficiency of 75.6%. A comparison of the costs to purchase NaOH and H2O2 against the electricity costs for electrochemical treatment indicated that the electrochemical approach could be 38–71% lower, depending on the local cost of electricity.
The aim of this pilot study was to determine the effect of individual complex carbohydrate taste sensitivity on cycling performance with complex carbohydrate oral rinsing. Ten male participants ...completed five cycling time trials in a fasted state with a seven-day washout period between each trial. Participants completed a fixed amount of work (738.45 ± 150.74 kJ) as fast as possible on a cycle ergometer while rinsing with an oral rinse for 10 s every 12.5% of the trial. An oral rinse (maltodextrin, oligofructose, glucose, sucralose or water control) was given per visit in a randomised, crossover, blinded design. Afterwards, participants had their taste assessed with three stimuli, complex carbohydrate (maltodextrin), sweet (glucose) and sour (citric acid), using taste assessment protocol to determine individual taste sensitivity status. Participants were subsequently grouped according to their complex carbohydrate taste sensitivity and complex carbohydrate taste intensity. There were no significant effects of the oral rinses on cycling performance time (
= 0.173). Participants who did not have improvements in exercise performance with the maltodextrin rinse experienced a stronger taste intensity with complex carbohydrate stimuli at baseline (
= 0.047) and overall (
= 0.047) than those who did have improvements in performance. Overall, a carbohydrate oral rinse was ineffective in significantly improving cycling performance in comparison with a water control. However, when participants were grouped according to complex carbohydrate taste intensity, differences in exercise performance suggest that individual sensitivity status to complex carbohydrates could impact the efficacy of a carbohydrate-based oral rinse.
Genetic code redundancy allows most amino acids to be encoded by multiple codons that are non-randomly distributed along coding sequences. An accepted theory explaining the biological significance of ...such non-uniform codon selection is that codons are translated at different speeds. Thus, varying codon placement along a message may confer variable rates of polypeptide emergence from the ribosome, which may influence the capacity to fold toward the native state. Previous studies report conflicting results regarding whether certain codons correlate with particular structural or folding properties of the encoded protein. This is partly due to different criteria traditionally utilized for predicting translation speeds of codons, including their usage frequencies and the concentration of tRNA species capable of decoding them, which do not always correlate. Here, we developed a metric to predict organism-specific relative translation rates of codons based on the availability of tRNA decoding mechanisms: Watson–Crick, non-Watson–Crick or both types of interactions. We determine translation rates of messages by pulse-chase analyses in living Escherichia coli cells and show that sequence engineering based on these concepts predictably modulates translation rates in a manner that is superior to codon usage frequency, which occur during the elongation phase, and significantly impacts folding of the encoded polypeptide. Finally, we demonstrate that sequence harmonization based on expression host tRNA pools, designed to mimic ribosome movement of the original organism, can significantly increase the folding of the encoded polypeptide. These results illuminate how genetic code degeneracy may function to specify properties beyond amino acid encoding, including folding.
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► Relative translation elongation rates can be predicted if tRNA genes are known. ► Translation rate acceleration observed in E. coli by pulse‐chase analysis. ► Elongation rates depend on wobble content and number of tRNA, not codon frequency. ► Synonymously recoded accelerations decrease heterologous folding yield in E. coli. ► Recapitulating endogenous rates increases heterologous folding yield in E. coli.
Sacral neuromodulation (SNM) is an advanced therapy that stimulates sacral spinal nerves to modulate bladder or bowel dysfunction and is approved for the treatment of overactive bladder, fecal ...incontinence, and non-obstructive urinary retention. Prior to implantation, a successful trial period must be performed via percutaneous nerve evaluation (PNE) or a staged trial to assess treatment efficacy. Ideal lead placement in the S3 foramen is imperative to produce an adequate response and successful outcome. Traditional lead placement with fluoroscopic guidance utilizes the anteroposterior (AP) and lateral views. In this abstract we describe an additional modification which may aid lead placement.
This video demonstrates the bullseye technique to obtain S3 foramen access for optimal lead placement in SNM.
Begin the procedure by placing the patient in the prone position. The medial edges of the S3 foramen are marked bilaterally in the AP view followed by a horizontal marking at the level of S3. The pelvis is imaged with live fluoroscopy starting at 0 degrees and then rotating the C-arm to 30 degrees. This rotation allows the “opening up” of the S3 foramen from an ellipsoid to an oval. The surgeon grasps the needle with a Kelly clamp, placing it at the level of the skin approximately 2 cm cephalad from the horizontal marking. Live fluoroscopy is performed to align the needle with the image intensifier to form the bullseye. Once the correct angle is identified, the needle is advanced. The procedure is repeated on the contralateral foramen.
The bullseye technique allows quick and predictable access into S3. It can potentially decrease operating time, minimize needle entries in PNE, and allows the surgeon to access S3 while maintaining proper medial orientation.
The bullseye technique can assist surgeons in obtaining optimal access in SNM and can quickly be integrated into current practices.
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