Attention Mobilization as a Modulator of Listening Effort: Evidence From Pupillometry.

Listening to speech in noise can require substantial mental effort, even among younger normal-hearing adults. The task-evoked pupil response (TEPR) has been shown to track the increased effort exerted to recognize words or sentences in increasing noise. However, few studies have examined the trajectory of listening effort across longer, more natural, stretches of speech, or the extent to which expectations about upcoming listening difficulty modulate the TEPR. Seventeen younger normal-hearing adults listened to 60-s-long audiobook passages, repeated three times in a row, at two different signal-to-noise ratios (SNRs) while pupil size was recorded. There was a significant interaction between SNR, repetition, and baseline pupil size on sustained listening effort. At lower baseline pupil sizes, potentially reflecting lower attention mobilization, TEPRs were more sustained in the harder SNR condition, particularly when attention mobilization remained low by the third presentation. At intermediate baseline pupil sizes, differences between conditions were largely absent, suggesting these listeners had optimally mobilized their attention for both SNRs. Lastly, at higher baseline pupil sizes, potentially reflecting overmobilization of attention, the effect of SNR was initially reversed for the second and third presentations: participants initially appeared to disengage in the harder SNR condition, resulting in reduced TEPRs that recovered in the second half of the story. Together, these findings suggest that the unfolding of listening effort over time depends critically on the extent to which individuals have successfully mobilized their attention in anticipation of difficult listening conditions.

A multicenter, randomized phase 2 study to establish combinations of CBP501, cisplatin and nivolumab for ≥3rd-line treatment of patients with advanced pancreatic adenocarcinoma.

BACKGROUND: There is no standard of care for ≥ 3rd-line treatment of metastatic pancreatic adenocarcinoma (PDAC). CBP501 is a novel calmodulin-binding peptide that has been shown to enhance the influx of platinum agents into tumor cells and tumor immunogenicity. This study aimed to (1) confirm efficacy of CBP501/cisplatin/nivolumab for metastatic PDAC observed in a previous phase 1 study, (2) identify combinations that yield 35% 3-month progression-free survival rate (3MPFS) and (3) define the contribution of CBP501 to the effects of combination therapy. METHODS: CBP501 16 or 25 mg/m2 (CBP(16) or CBP(25)) was combined with 60 mg/m2 cisplatin (CDDP) and 240 mg nivolumab (nivo), administered at 3-week intervals. Patients were randomized 1:1:1:1 to (1) CBP(25)/CDDP/nivo, (2) CBP(16)/CDDP/nivo, (3) CBP(25)/CDDP and (4) CDDP/nivo, with randomization stratified by ECOG PS and liver metastases. A Fleming two-stage design was used, yielding a one-sided type I error rate of 2.5% and 80% power when the true 3MPFS is 35%. RESULTS: Among 36 patients, 3MPFS was 44.4% in arms 1 and 2, 11.1% in arm 3% and 33.3% in arm 4. Two patients achieved a partial response in arm 1 (ORR 22.2%; none in other arms). Median PFS and OS were 2.4, 2.1, 1.5 and 1.5 months and 6.3, 5.3, 3.7 and 4.9 months, respectively. Overall, all treatment combinations were well tolerated. Most treatment-related adverse events were grade 1-2. CONCLUSIONS: The combination CBP(25)/(16)/CDDP/nivo demonstrated promising signs of efficacy and a manageable safety profile for the treatment of advanced PDAC. CLINICAL TRIAL REGISTRATION: NCT04953962.

Microplastics fouling and interaction with polymeric membranes: A review.

The emergence and accumulation of microplastics (MPs) in various aquatic environments have recently raised significant concerns. Wastewater treatment plants (WWTPs) have been identified as one of the major sources of MPs discharge to the environment, implying a substantial need to improve advanced techniques for more efficient removal of MPs. Polymeric membranes have been proven effective in MPs removal. However, fouling is the main drawback of membrane processes and MPs can foul the membranes due to their small size and specific surface properties. Hence, it is important to investigate the impacts of MPs on membrane fouling to develop efficient membrane-based techniques for MPs removal. Although membrane technologies have a high potential for MPs removal, the interaction of MPs with membranes and their fouling effects have not been critically reviewed. The purpose of this paper is to provide a state-of-the-art review of MPs interaction with membranes and facilitate a better understanding of the relevant limitations and prospects of the membrane technologies. The first section of this paper is dedicated to a review of recent studies on MPs occurrence in WWTPs aiming to determine the most frequent MPs. This is followed by a summary of recent studies on MPs removal using membranes and discussions on the impact of MPs on membrane fouling and other probable issues (abrasion, concentration polarisation, biofouling, etc.). Finally, some recommendations for further research in this area are highlighted. This study serves as a valuable reference for future research on the development of anti-fouling membranes considering these new emerging contaminates.

Carbohydrate binding modules enhance cellulose enzymatic hydrolysis by increasing access of cellulases to the substrate.

Plant biomass is a low-cost and abundant source of carbohydrates for production of fuels, "green" chemicals and materials. Currently, biochemical conversion of the biomass into sugars via enzymatic hydrolysis is the most viable technology. Here, the role of carbohydrate binding modules (CBMs) in the disruption of insoluble polysaccharide structures and their capacity to enhance cellulase-promoted lignocellulosic biomass hydrolysis was investigated. We show that CBM addition promotes generation of additional reducing ends in the insoluble substrate by cellulases. On the contrary, bovine serum albumin (BSA), widely used in prevention of a non-specific protein binding, causes an increase in soluble reducing-end production, when applied jointly with cellulases. We demonstrate that binding of CBMs to cellulose is non-homogeneous, irreversible and leads to its amorphisation. Our results also reveal effects of CBM-promoted amorphogenesis on cellulose hydrolysis by cellulases.

Does the association between substance use and sexual risk behaviors among high school students vary by sexual identity?

OBJECTIVE: Limited information exists on whether associations between substance use behaviors (SUBs) and sexual risk behaviors (SRBs) vary by sexual identity. METHODS: Data from the 2015 national Youth Risk Behavior Survey (n = 15,624), were analyzed to assess associations between SUBs (cigarette smoking, alcohol use, binge drinking, marijuana use, prescription drug misuse, injection drug use, illicit drug use) and SRBs (sexual activity, number of partners, condom use). Logistic regression models calculated adjusted prevalence ratios (aPR), stratified by sexual identity, and interaction effects for sexual identity were introduced to models to determine if associations varied by sexual identity. RESULTS: All SUBs had significant associations with current sexual activity and 4+ sexual partners for both heterosexual and LGB students. No condom use during last sexual intercourse was significantly associated with all SUBs except alcohol use among heterosexual students, while no condom use was only significantly associated with injection drug use among LGB students. Associations between current sexual activity and SUBs were significantly stronger among heterosexual compared to LGB students for smoking (aPR = 2.39;95% CI:2.15,2.65 vs aPR = 1.49;95% CI:1.14,1.95), marijuana use (2.41;2.15,2.71 vs 1.86;1.58,2.19) and prescription drug misuse (2.10;1.93,2.28 vs 1.60;1.28,2.00). Associations between no condom use and SUBs were significantly stronger for heterosexual compared to LGB students only for smoking (1.32;1.16,1.50 vs 0.96;0.73,1.25) and marijuana use (1.22;1.07,1.38 vs 0.90;0.72,1.12). CONCLUSIONS: The relationship between most SUBs and SRBs did not vary significantly by sexual identity. These findings underscore the importance coordinating school-based programs to prevent substance use and promote sexual health.

A resistive Q-switch for low-field NMR systems.

An NMR Q-switch was designed and constructed specifically for use with low-field NMR apparatus. This featured a comparatively simple resistive damping design. It served to reduce the r.f. probe ring-down time, and hence reduced the signal acquisition delay from 25 ms to 9 ms, on an Earth's magnetic field NMR system. The advantage of this earlier acquisition was demonstrated for both an aqueous suspension of iron oxide particles and using an NMR flow meter.

OncoPPi-informed discovery of mitogen-activated protein kinase kinase 3 as a novel binding partner of c-Myc.

Mitogen-activated protein kinase kinase 3 (MKK3) is a dual threonine/tyrosine protein kinase that regulates inflammation, proliferation and apoptosis through specific phosphorylation and activation of the p38 mitogen-activated protein kinase. However, the role of MKK3 beyond p38-signaling remains elusive. Recently, we reported a protein-protein interaction (PPI) network of cancer-associated genes, termed OncoPPi, as a resource for the scientific community to generate new biological models. Analysis of the OncoPPi connectivity identified MKK3 as one of the major hub proteins in the network. Here, we show that MKK3 interacts with a large number of proteins critical for cell growth and metabolism, including the major oncogenic driver MYC. Multiple complementary approaches were used to demonstrate the direct interaction of MKK3 with MYC in vitro and in vivo. Computational modeling and experimental studies mapped the interaction interface to the MYC helix-loop-helix domain and a novel 15-residue MYC-binding motif in MKK3 (MBM). The MBM in MKK3 is distinct from the known binding sites for p38 or upstream kinases. Functionally, MKK3 stabilized MYC protein, enhanced its transcriptional activity and increased expression of MYC-regulated genes. The defined MBM peptide mimicked the MKK3 effect in promoting MYC activity. Together, the exploration of OncoPPi led to a new biological model in which MKK3 operates by two distinct mechanisms in cellular regulation through its phosphorylation of p38 and its activation of MYC through PPI.

On the subtle tuneability of cellulose hydrogels: implications for binding of biomolecules demonstrated for CBM 1.

Cellulose-based hydrogel materials prepared by regeneration from cellulose solutions in ionic liquids, or ionic liquid containing solvent mixtures (organic electrolyte solutions), are becoming widely used in a range of applications from tissue scaffolds to membrane ionic diodes. In all such applications knowledge of the nature of the hydrogel with regards to porosity (pore size and tortuosity) and material structure and surface properties (crystallinity and hydrophobicity) is critical. Here we report significant changes in hydrogel properties, based on the choice of cellulose raw material (α- or bacterial cellulose - with differing degree of polymerization) and regeneration solvent (methanol or water). Focus is on bioaffinity applications, but the findings have wide ramifications, including in biomedical applications and cellulose saccharification. Specifically, we report that the choice of cellulose and regeneration solvent influences the surface area accessible to a family 1 carbohydrate-binding module (CBM), CBM affinity for the cellulose material, and rate of migration through the hydrogel. By regenerating bacterial cellulose in water, a maximum accessible surface area of 33 m2 g-1 was achieved. However, the highest CBM migration rate, 1.76 µm2 min-1, was attained by regenerating α-cellulose in methanol, which also resulted in the maximum affinity of the biomolecule for the material. Thus, it is clear that if regenerated cellulose hydrogels are to be used as support materials in bioaffinity (or other) applications, a balance between accessible surface area and affinity, or migration rate, must be achieved.

A low balance between microparticles expressing tissue factor pathway inhibitor and tissue factor is associated with thrombosis in Behçet's Syndrome.

Thrombosis is common in Behçet's Syndrome (BS), and there is a need for better biomarkers for risk assessment. As microparticles expressing Tissue Factor (TF) can contribute to thrombosis in preclinical models, we investigated whether plasma microparticles expressing Tissue Factor (TF) are increased in BS. We compared blood plasma from 72 healthy controls with that from 88 BS patients (21 with a history of thrombosis (Th+) and 67 without (Th-). Using flow cytometry, we found that the total plasma MP numbers were increased in BS compared to HC, as were MPs expressing TF and Tissue Factor Pathway Inhibitor (TFPI) (all p < 0.0001). Amongst BS patients, the Th+ group had increased total and TF positive MP numbers (both p ≤ 0.0002) compared to the Th- group, but had a lower proportion of TFPI positive MPs (p < 0.05). Consequently, the ratio of TFPI positive to TF positive MP counts (TFPI/TF) was significantly lower in Th+ versus Th- BS patients (p = 0.0002), and no patient with a TFPI/TF MP ratio >0.7 had a history of clinical thrombosis. We conclude that TF-expressing MP are increased in BS and that an imbalance between microparticulate TF and TFPI may predispose to thrombosis.

Transcriptome Analysis of Aspergillus flavus Reveals veA-Dependent Regulation of Secondary Metabolite Gene Clusters, Including the Novel Aflavarin Cluster.

The global regulatory veA gene governs development and secondary metabolism in numerous fungal species, including Aspergillus flavus. This is especially relevant since A. flavus infects crops of agricultural importance worldwide, contaminating them with potent mycotoxins. The most well-known are aflatoxins, which are cytotoxic and carcinogenic polyketide compounds. The production of aflatoxins and the expression of genes implicated in the production of these mycotoxins are veA dependent. The genes responsible for the synthesis of aflatoxins are clustered, a signature common for genes involved in fungal secondary metabolism. Studies of the A. flavus genome revealed many gene clusters possibly connected to the synthesis of secondary metabolites. Many of these metabolites are still unknown, or the association between a known metabolite and a particular gene cluster has not yet been established. In the present transcriptome study, we show that veA is necessary for the expression of a large number of genes. Twenty-eight out of the predicted 56 secondary metabolite gene clusters include at least one gene that is differentially expressed depending on presence or absence of veA. One of the clusters under the influence of veA is cluster 39. The absence of veA results in a downregulation of the five genes found within this cluster. Interestingly, our results indicate that the cluster is expressed mainly in sclerotia. Chemical analysis of sclerotial extracts revealed that cluster 39 is responsible for the production of aflavarin.

One step bioconversion of waste precious metals into Serratia biofilm-immobilized catalyst for Cr(VI) reduction.

OBJECTIVES: For reduction of Cr(VI) the Pd-catalyst is excellent but costly. The objectives were to prove the robustness of a Serratia biofilm as a support for biogenic Pd-nanoparticles and to fabricate effective catalyst from precious metal waste. RESULTS: Nanoparticles (NPs) of palladium were immobilized on polyurethane reticulated foam and polypropylene supports via adhesive biofilm of a Serratia sp. The biofilm adhesion and cohesion strength were unaffected by palladization and catalytic biofilm integrity was also shown by magnetic resonance imaging. Biofilm-Pd and mixed precious metals on biofilm (biofilm-PM) reduced 5 mM Cr(VI) to Cr(III) when immobilized in a flow-through column reactor, at respective flow rates of 9 and 6 ml/h. The lower activity of the latter was attributed to fewer, larger, metal deposits on the bacteria. Activity was lost in each case at pH 7 but was restored by washing with 5 mM citrate solution or by exposure of columns to solution at pH 2, suggesting fouling by Cr(III) hydroxide product at neutral pH. CONCLUSION: A 'one pot' conversion of precious metal waste into new catalyst for waste decontamination was shown in a continuous flow system based on the use of Serratia biofilm to manufacture and support catalytic Pd-nanoparticles.

The exaggerated inflammatory response in Behçet's syndrome: identification of dysfunctional post-transcriptional regulation of the IFN-γ/CXCL10 IP-10 pathway.

The mechanisms underlying the exaggerated inflammatory response in Behçet's syndrome (BS) remain poorly understood. We investigated the response of CD14(+) blood monocytes to interferon (IFN)-γ, focusing on the chemokine CXCL10. Chemokine synthesis and release were analysed at a protein and mRNA level following stimulation with IFN-γ. Findings in BS patients were compared with 25 healthy controls (HC), 15 rheumatoid arthritis (RA) and 15 systemic lupus erythematosus (SLE) disease control patients. BS monocytes produced significantly more CXCL10 protein than HC monocytes from 2 h following IFN-γ stimulation, despite equivalent quantities of mRNA, suggesting more efficient translation. This was significantly more pronounced in BS with high disease activity and in those with ocular and neurological clinical manifestations. The imbalance between CXCL10 protein and mRNA expression was not observed in either RA or SLE patients, and was not seen with other chemokines studied (CXCL9, CXCL11 and CCL2). Furthermore, BS monocytes treated with an alternative stimulant (LPS) did not show abnormal tumour necrosis factor (TNF)-α release. Sucrose density gradients to segregate monocyte CXCL10 mRNA into free RNA or polysome-associated RNA showed equal proportions in BS and HC samples, suggesting that the difference between BS and HC may be due to reduced negative control of CXCL10 translation in BS at a post-initiation level. We conclude that BS monocytes have dysfunctional post-transcriptional regulation of CXCL10 mRNA, resulting in over-expression of CXCL10 protein upon IFN-γ stimulation. As CXCL10 is a chemokine that recruits mononuclear cells, this abnormality may contribute to the exaggerated inflammatory responses that characterizes BS.

Magnetic resonance signal moment determination using the Earth's magnetic field.

We demonstrate a method to manipulate magnetic resonance data such that the moments of the signal spatial distribution are readily accessible. Usually, magnetic resonance imaging relies on data acquired in so-called k-space which is subsequently Fourier transformed to render an image. Here, via analysis of the complex signal in the vicinity of the centre of k-space we are able to access the first three moments of the signal spatial distribution, ultimately in multiple directions. This is demonstrated for biofouling of a reverse osmosis (RO) membrane module, rendering unique information and an early warning of the onset of fouling. The analysis is particularly applicable for the use of mobile magnetic resonance spectrometers; here we demonstrate it using an Earth's magnetic field system.

Interfacial tension measurements using MRI drop shape analysis.

Accurate interfacial tension data for fluid systems such as hydrocarbons and water is essential to many applications such as reservoir oil and gas recovery predictions. Conventional interfacial tension measurement techniques typically use optical images to analyze droplet shapes but require that the continuous-phase fluid be optically transparent and that the fluids are not refractive index matched. Magnetic resonance images obtain contrast between fluids using other mechanisms such as magnetic relaxation weighting, so systems that are impossible to measure with optical methods may be analyzed. In this article, we present high-field (9.4 T) MRI images of various droplets analyzed with axisymmetric drop shape analysis. The resultant interfacial tension data show good agreement with literature data. The method is subsequently demonstrated using both opaque continuous phases and refractive-index-matched fluids. We conclude with a brief consideration of the potential to extrapolate the methodology to lower magnetic fields (0.3 T), featuring more accessible hardware; although droplet imaging is possible, resolution and stability do not currently permit accurate interfacial tension measurements.

Monitoring bacterially induced calcite precipitation in porous media using magnetic resonance imaging and flow measurements.

A range of nuclear magnetic resonance (NMR) techniques are employed to provide novel, non-invasive measurements of both the structure and transport properties of porous media following a biologically mediated calcite precipitation reaction. Both a model glass bead pack and a sandstone rock core were considered. Structure was probed using magnetic resonance imaging (MRI) via a combination of quantitative one-dimensional profiles and three-dimensional images, applied before and after the formation of calcite in order to characterise the spatial distribution of the precipitate. It was shown through modification and variations of the calcite precipitation treatment that differences in the calcite fill would occur but all methods were successful in partially blocking the different porous media. Precipitation was seen to occur predominantly at the inlet of the bead pack, whereas precipitation occurred almost uniformly along the sandstone core. Transport properties are quantified using pulse field gradient (PFG) NMR measurements which provide probability distributions of molecular displacement over a set observation time (propagators), supplementing conventional permeability measurements. Propagators quantify the local effect of calcite formation on system hydrodynamics and the extent of stagnant region formation. Collectively, the combination of NMR measurements utilised here provides a toolkit for determining the efficacy of a biological-precipitation reaction for partially blocking porous materials.

Assessment of F-RNA coliphage as a potential indicator of enteric virus contamination of hog carcasses.

Hepatitis E virus (HEV) is common in pigs, and some swine HEV strains are closely related to human strains. The zoonotic transmission of HEV is now well established. HEV can be detected by molecular techniques, but the significance of the presence of viral nucleic acid is questionable when foods are subjected to virus inactivation treatments. F-RNA coliphages are attractive candidates as indicators for enteric viruses because they are similar in size and survival characteristics and can be rapidly cultured. Information on the contamination of hog carcasses with enteric or hepatic viruses during slaughter is lacking. The objective of this study was to compare the incidence and levels of contamination of hog carcasses with F-RNA coliphages, HEV, total aerobic bacteria, coliforms, and Escherichia coli at different stages of the dressing process. Hog carcasses entering the commercial slaughter facility are heavily contaminated with F-RNA coliphages and HEV. Subsequent processes such as scalding, singing, and pasteurization can reduce the incidence and levels of F-RNA coliphages and HEV substantially to almost undetectable levels. Large discrepancies between the amount of viral nucleic acid and infectious F-RNA coliphage particles, both at high levels and low levels of contamination, were observed. The prevalence and levels of viable F-RNA coliphages were lower than those of total aerobic bacteria, coliforms, and E. coli in the anal area and on random sites before pasteurization. At a research abattoir, there was no overall mean reduction of viable F-RNA coliphages recovered from random sites before pasteurization and after washing, whereas overall mean reductions of 1.2, 2.6, and 2.9 log CFU for total aerobic bacteria, coliforms, and E. coli, respectively, were obtained. These findings suggest that bacteria such as coliforms and E. coli may not be suitable as indicators for enteric viruses in a meat processing environment.

Emulsion droplet sizing using low-field NMR with chemical shift resolution and the block gradient pulse method.

Pulsed Field Gradient (PFG) measurements are commonly used to determine emulsion droplet size distributions based on restricted self-diffusion within the emulsion droplets. Such measurement capability is readily available on commercial NMR bench-top apparatus. A significant limitation is the requirement to selectively detect signal from the liquid phase within the emulsion droplets; this is currently achieved using either relaxation or self-diffusion contrast. Here we demonstrate the use of a 1.1 T bench-top NMR magnet, which when coupled with an rf micro-coil, is able to provide sufficient chemical shift resolution such that unambiguous signal selection is achieved from the dispersed droplet phase. We also improve the accuracy of the numerical inversion process required to produce the emulsion droplet size distribution, by employing the Block Gradient Pulse (bgp) method, which partially relaxes the assumptions of a Gaussian phase distribution or infinitely short gradient pulse application inherent in current application. The techniques are successfully applied to size 3 different emulsions.

Using non-invasive magnetic resonance imaging (MRI) to assess the reduction of Cr(VI) using a biofilm-palladium catalyst.

Industrial waste streams may contain contaminants that are valuable like Pd(II) and/or toxic and mutagenic like Cr(VI). Using Serratia sp. biofilm the former was biomineralized to produce a supported nanocrystalline Pd(0) catalyst, and this biofilm-Pd heterogeneous catalyst was then used to reduce Cr(VI) to less dangerous Cr(III) at room temperature, with formate as the electron donor. Cr(VI)((aq)) is non-paramagnetic while Cr(III)((aq)) is paramagnetic, which enabled spatial mapping of Cr species concentrations within the reactor cell using non-invasive magnetic resonance (MR) imaging experiments. Spatial reactivity heterogeneities were thus examined. In batch reactions, these could be attributed primarily to heterogeneity of Pd(0) distribution and to the development of gas bubbles within the reactor. In continuous flow reactions, spatial reactivity heterogeneities resulted primarily from heterogeneity of Cr(VI) delivery.

Nuclear magnetic resonance relaxation and diffusion in the presence of internal gradients: the effect of magnetic field strength.

It is known that internal magnetic field gradients in porous materials, caused by susceptibility differences at the solid-fluid interfaces, alter the observed effective Nuclear Magnetic Resonance transverse relaxation times T2,eff. The internal gradients scale with the strength of the static background magnetic field B0. Here, we acquire data at various magnitudes of B0 to observe the influence of internal gradients on T2-T2 exchange measurements; the theory discussed and observations made are applicable to any T2-T2 analysis of heterogeneous materials. At high magnetic field strengths, it is possible to observe diffusive exchange between regions of local internal gradient extrema within individual pores. Therefore, the observed exchange pathways are not associated with pore-to-pore exchange. Understanding the significance of internal gradients in transverse relaxation measurements is critical to interpreting these results. We present the example of water in porous sandstone rock and offer a guideline to determine whether an observed T2,eff relaxation time distribution reflects the pore size distribution for a given susceptibility contrast (magnetic field strength) and spin echo separation. More generally, we confirm that for porous materials T1 provides a better indication of the pore size distribution than T2,eff at high magnetic field strengths (B0>1 T), and demonstrate the data analysis necessary to validate pore size interpretations of T2,eff measurements.

Quantitative single point imaging with compressed sensing.

A novel approach with respect to single point imaging (SPI), compressed sensing, is presented here that is shown to significantly reduce the loss of accuracy of reconstructed images from under-sampled acquisition data. SPI complements compressed sensing extremely well as it allows unconstrained selection of sampling trajectories. Dynamic processes featuring short T2* NMR signal can thus be more rapidly imaged, in our case the absorption of moisture by a cereal-based wafer material, with minimal loss of image quantification. The absolute moisture content distribution is recovered via a series of images acquired with variable phase encoding times allowing extrapolation to time zero for each image pixel and the effective removal of T2* contrast.