In Vitro Antioxidant and Antimicrobial Properties of Composite Flour Formulations Developed Using Selected Local Grain Varieties.

The aim of this study was to determine the in vitro antioxidant potential of four extruded and domestically prepared composite flour formulations developed by composting selected locally available grain varieties in Sri Lanka. The potential of the flour extracts to scavenge free radicals were evaluated by performing DPPH, ABTS, and FRAP assays. Furthermore, the antimicrobial activities of the flour formulations against selected Gram-positive and Gram-negative pathogenic microorganisms were comparatively evaluated using agar well diffusion and disk diffusion assays. Ethanol and water extracts of the samples were evaluated for their antimicrobial potential. The results showed that extruded samples possessed high antioxidant properties than samples prepared using the conventional cooking. Furthermore, the antioxidant potential of the formulations evaluated using different assays was strongly correlated. Moreover, the formulations reported positive antimicrobial potential against tested Gram-negative and Gram-positive bacteria. The ethanol extracts of flour formulations exhibited higher susceptibility to tested microbes than that of water extracts while agar well diffusion resulted significantly high inhibition against pathogenic bacteria than that of agar disk diffusion method (p < 0.05). In overall, the highest inhibition zone of 17.64 mm was depicted by F4 against Salmonella, while the lowest diameter of 6.09 mm was depicted by F1 against Listeria. In conclusion, the developed flour formulations contained natural antimicrobial agents which can combat common food spoilage and pathogenic bacteria and can be promoted as value-added products with health benefits beyond nutrition.

Nutritional intake of sport undergraduates in Sabaragamuwa University of Sri Lanka.

BACKGROUND: Nutritional intake plays an important role in determining energy availability which is vital to health, wellbeing, and sports performance in an active population. This research assessed the sports undergraduates' nutritional intake compared to the Dietary Guidelines for Americans and nutrition goals provided by WHO. METHODS: This study is a quantitative, cross-sectional descriptive study. One hundred and one (n = 101) sports undergraduates aged between 20 to 23 years were recruited and the nutrient intake was assessed using the three-day food diary method and quantified the macro and micronutrients by the food composition database. One sample t-test was performed to compare the mean nutrient intakes with the lowest recommendation values. RESULTS: Though most undergraduates were able to meet the dietary requirements in carbohydrates, they were deficient in their protein intake and exceeded in fats intake. Further, both male and female students were deficient in their daily energy intake (1723 kcal, 1607 kcal) and dietary fiber intake (8 g, 11 g). The saturated fat intake was met by all students while 20% of males and 21% of females exceeded the recommendations (< 10%). The micronutrient intake of vitamins such as C, B1, B2, B9, and B12 and minerals such as Calcium, Magnesium, and Potassium, were significantly below the recommendations (p < 0.05) except for vitamin B3 niacin. CONCLUSIONS: Providing a nutritionally valuable meal is essentially required to maintain both physical and mental fitness. Our results revealed that the Sri Lankan sport science undergraduates do not have an adequate daily dietary intake of energy, proteins, calcium, magnesium, potassium, and vitamins such as C, B1, B2, B9, and B12.

Mormyrid fish as models for investigating sensory-motor integration: A behavioural perspective.

Animals possess senses which gather information from their environment. They can tune into important aspects of this information and decide on the most appropriate response, requiring coordination of their sensory and motor systems. This interaction is bidirectional. Animals can actively shape their perception with self-driven motion, altering sensory flow to maximise the environmental information they are able to extract. Mormyrid fish are excellent candidates for studying sensory-motor interactions, because they possess a unique sensory system (the active electric sense) and exhibit notable behaviours that seem to be associated with electrosensing. This review will take a behavioural approach to unpicking this relationship, using active electrolocation as an example where body movements and sensing capabilities are highly related and can be assessed in tandem. Active electrolocation is the process where individuals will generate and detect low-voltage electric fields to locate and recognise nearby objects. We will focus on research in the mormyrid Gnathonemus petersii (G. petersii), given the extensive study of this species, particularly its object recognition abilities. By studying object detection and recognition, we can assess the potential benefits of self-driven movements to enhance selection of biologically relevant information. Finally, these findings are highly relevant to understanding the involvement of movement in shaping the sensory experience of animals that use other sensory modalities. Understanding the overlap between sensory and motor systems will give insight into how different species have become adapted to their environments.

Biodeterioration of low-density polyethylene by mangrove-associated endolichenic fungi and their enzymatic regimes.

Fungal involvement in the biodeterioration of low-density polyethylene (LDPE) has received great attention in recent years. Among diverse groups of fungi, endolichenic fungi (ELF) are adapted to thrive in resource-limited conditions. The present study was designed to investigate the potential of mangrove-associated ELF, in the biodeterioration of LDPE and to quantify key-depolymerizing enzymes. A total of 31 ELF species, isolated from 22 lichens of mangrove ecosystems in Negombo lagoon, Sri Lanka were identified using DNA barcoding techniques. ELF were inoculated into a mineral salt medium, containing LDPE strips and incubated at 28 ± 2°C, for 21 days, under laboratory conditions. After incubation, biodeterioration was monitored based on percent reductions in weights and tensile properties, increments in the degree of water absorption, changes in peaks of infrared spectra and surface erosions using scanning electron microscopy. Out of 31 species, Chaetomium globosum, Daldinia eschscholtzii, Neofusicoccum occulatum, Phanerochaete chrysosporium, Schizophyllum commune and Xylaria feejeensis showed significant changes. Production of depolymerizing enzymes by these species was assayed qualitatively using plate-based methods and quantitatively by mass-level enzyme production. Among them, Phanerochaete chrysosporium showed the highest enzyme activities as (9·69 ± 0·04) × 10-3 , (1·96 ± 0·01) × 10-3 , (5·73 ± 0·03) × 10-3 , (0·88 ± 0·01), (0·64 ± 0·06), (1·43 ± 0·01) U ml-1 for laccase, lignin peroxidase, manganese peroxidase, amylase, lipase and esterase, respectively.

A translational model-based approach to inform the choice of the dose in phase 1 oncology trials: the case study of erdafitinib.

PURPOSE: Erdafitinib (JNJ-42756493, BALVERSA) is a tyrosine kinase inhibitor indicated for the treatment of advanced urothelial carcinoma. In this work, a translational model-based approach to inform the choice of the doses in phase 1 trials is illustrated. METHODS: A pharmacokinetic (PK) model was developed to describe the time course of erdafitinib plasma concentrations in mice and rats. Data from multiple xenograft studies in mice and rats were analyzed using the Simeoni tumor growth inhibition (TGI) model. The model parameters were used to derive a range of erdafitinib exposures that might inform the choice of the doses in oncology phase 1 trials. Conversion of exposures to doses was based on preliminary PK assessments from the first-in human (FIH) study. RESULTS: A one-compartment PK disposition model, with linear absorption and dose-dependent clearance, adequately described the PK data in both mice and rats via an allometric scaling approach. The TGI model was able to describe tumor growth dynamics, providing quantitative measurements of erdafitinib antitumor potency in mice and rats. Based on these estimates, ranges of efficacious unbound concentration were identified for erdafitinib in mice (0.642-5.364 µg/L) and rats (0.782-2.565 µg/L). Based on the FIH data, it was possible to transpose exposures into doses and doses of above 4 mg/day provided erdafitinib exposures associated with significant TGI in animals. The findings were in agreement with the results of the FIH trial, in which the first hints of clinical activities were observed at 6 mg. CONCLUSION: The successful modeling exercise of erdafitinib preclinical data showed how translational PK-PD modeling might be a tool to help to inform the choice of the doses in FIH studies.

Cryogenic spectrometer for measuring the far-IR to millimeter-wave absorptivity of cosmic analog dusts.

We report on the design, construction, and performance of a custom apparatus built to measure the frequency- and temperature-dependent absorptivity of millimeter-wave light by cosmic analog dusts. We highlight the unique challenges faced as well as a few key innovations that are part of the instrument. Among those is an ultra-compact Fourier transform spectrometer. We have measured its effective frequency range and FWHM resolution to be 150-2100 GHz and ∼45GHz, respectively. Another innovation is a cold sample positioner whose temperature can be controlled within the range of 3.7-50 K. The use of a pulse-tube cryocooler results in a pulse-synchronous signal that dominates the detector (bolometer) signal. Methods used to address that challenge are also presented.

Speech metrics, general disability, brain imaging and quality of life in multiple sclerosis.

BACKGROUND AND PURPOSE: Objective measurement of speech has shown promising results to monitor disease state in multiple sclerosis. In this study, we characterize the relationship between disease severity and speech metrics through perceptual (listener based) and objective acoustic analysis. We further look at deviations of acoustic metrics in people with no perceivable dysarthria. METHODS: Correlations and regression were calculated between speech measurements and disability scores, brain volume, lesion load and quality of life. Speech measurements were further compared between three subgroups of increasing overall neurological disability: mild (as rated by the Expanded Disability Status Scale ≤2.5), moderate (≥3 and ≤5.5) and severe (≥6). RESULTS: Clinical speech impairment occurred majorly in people with severe disability. An experimental acoustic composite score differentiated mild from moderate (P < 0.001) and moderate from severe subgroups (P = 0.003), and correlated with overall neurological disability (r = 0.6, P < 0.001), quality of life (r = 0.5, P < 0.001), white matter volume (r = 0.3, P = 0.007) and lesion load (r = 0.3, P = 0.008). Acoustic metrics also correlated with disability scores in people with no perceivable dysarthria. CONCLUSIONS: Acoustic analysis offers a valuable insight into the development of speech impairment in multiple sclerosis. These results highlight the potential of automated analysis of speech to assist in monitoring disease progression and treatment response.

Parcel-guided rTMS for depression.

Transcranial magnetic stimulation (TMS) is an approved intervention for treatment-resistant depression (TRD), but current targeting approaches are only partially successful. Our objectives were (1) to examine the feasibility of MRI-guided TMS in the clinical setting using a recently published surface-based, multimodal parcellation in patients with TRD who failed standard TMS (sdTMS); (2) to examine the neurobiological mechanisms and clinical outcomes underlying MRI-guided TMS compared to that of sdTMS. We used parcel-guided TMS (pgTMS) to target the left dorsolateral prefrontal cortex parcel 46. Resting-state functional connectivity (rsfc) was assessed between parcel 46 and predefined nodes within the default mode and visual networks, following both pgTMS and sdTMS. All patients (n = 10) who had previously failed sdTMS responded to pgTMS. Alterations in rsfc between frontal, default mode, and visual networks differed significantly over time between groups. Improvements in symptoms correlated with alterations in rsfc within each treatment group. The outcome of our study supports the feasibility of pgTMS within the clinical setting. Future prospective, double-blind studies of pgTMS vs. sdTMS appear warranted.

Combination of IKVAV, LRE, and GPQGIWGQ Bioactive Signaling Peptides Increases Human Induced Pluripotent Stem Cell Derived Neural Stem Cells Extracellular Matrix Remodeling and Neurite Extension.

Extracellular matrix (ECM) remodeling is emerging as a modulator of neural maturation and axon extension. Most studies have used rodent cells to develop matrices capable of manipulating extracellular matrix remodeling for regenerative applications. However, clinically relevant human induced pluripotent stem cell derived neural stem cells (hNSC) do not always behave in a similar manner as rodent cells. In this study, hNSC response to a hyaluronic acid matrix with laminin derived IKVAV and LRE peptide signaling that has previously shown to promote ECM remodeling and neurite extension by mouse embryonic stem cells is examined. The addition of enzymatically degradable cross linker GPQGIWGQ to the IKVAV and LRE containing hyaluronic acid matrix is necessary to promote neurite extension, hyaluronic acid degradation, and gelatinase expression over hyaluronic acid matrices containing GPQGIWGQ, IKVAV and LRE, or no peptides. Changes in peptide content alters a number of matrix properties that can contribute to the cellular response, but increases in mesh size are not observed with cross linker cleavage in this study. Overall, these data imply a complex interaction between IKVAV, LRE, and GPQGIWGQ to modulate hNSC behavior.

Effect of Laminin Derived Peptides IKVAV and LRE Tethered to Hyaluronic Acid on hiPSC Derived Neural Stem Cell Morphology, Attachment and Neurite Extension.

Low neural tissue extracellular matrix (ECM) content has led to the understudy of its effects on neural cells and tissue. Hyaluronic acid (HA) and laminin are major neural ECM components, but direct comparisons of their cellular effects could not be located in the literature. The current study uses human-induced pluripotent stem-cell-derived neural stem cells to assess the effects of HA, laminin, and HA with laminin-derived peptides IKVAV and LRE on cellular morphology, attachment, neurite extension and ECM remodeling. Increased attachment was observed on HA with and without IKVAV and LRE compared to laminin. Cellular morphology and neurite extension were similar on all surfaces. Using a direct binding inhibitor of Cav2.2 voltage gated calcium channel activity, a known binding partner of LRE, reduced attachment on HA with and without IKVAV and LRE and altered cellular morphology on surfaces with laminin or IKVAV and LRE. HA with IKVAV and LRE reduced the fluorescent intensity of fibronectin staining, but did not alter the localization of ECM remodeling enzymes matrix metalloprotease 2 and 9 staining compared to HA. Overall, the data indicate HA, IKVAV and LRE have complementary effects on human-induced pluripotent stem-cell-derived neural stem cell behavior.

Manipulation of Extracellular Matrix Remodeling and Neurite Extension by Mouse Embryonic Stem Cells Using IKVAV and LRE Peptide Tethering in Hyaluronic Acid Matrices.

Cellular remodeling of the matrix has recently emerged as a key factor in promoting neural differentiation. Most strategies to manipulate matrix remodeling focus on proteolytically cleavable cross-linkers, leading to changes in tethered biochemical signaling and matrix properties. Using peptides that are not the direct target of enzymatic degradation will likely reduce changes in the matrix and improve control of biological behavior. In this study, laminin-derived peptides, IKVAV and LRE, tethered to independent sites in hyaluronic acid matrices using Michael addition and strain-promoted azide-alkyne cycloaddition are sufficient to manipulate hyaluronic acid degradation, gelatinase expression, and protease expression, while promoting neurite extension through matrix metalloprotease-dependent mechanisms in mouse embryonic stem cells encapsulated in hyaluronic acid matrices using an oxidation-reduction reaction initiated gelation. This study provides the foundation for a new strategy to stimulate matrix remodeling that is not dependent on enzymatic cleavage targets.

Resting state functional connectivity predictors of treatment response to electroconvulsive therapy in depression.

There is increasing focus on use of resting-state functional connectivity (RSFC) analyses to subtype depression and to predict treatment response. To date, identification of RSFC patterns associated with response to electroconvulsive therapy (ECT) remain limited, and focused on interactions between dorsal prefrontal and regions of the limbic or default-mode networks. Deficits in visual processing are reported in depression, however, RSFC with or within the visual network have not been explored in recent models of depression. Here, we support prior studies showing in a sample of 18 patients with depression that connectivity between dorsal prefrontal and regions of the limbic and default-mode networks serves as a significant predictor. In addition, however, we demonstrate that including visual connectivity measures greatly increases predictive power of the RSFC algorithm (>80% accuracy of remission). These exploratory results encourage further investigation into visual dysfunction in depression, and use of RSFC algorithms incorporating the visual network in prediction of response to both ECT and transcranial magnetic stimulation (TMS), offering a new framework for the development of RSFC-guided TMS interventions in depression.

Polyethylene glycol in spinal cord injury repair: a critical review.

Polyethylene glycol (PEG) is a synthetic biocompatible polymer with many useful properties for developing therapeutics to treat spinal cord injury. Direct application of PEG as a fusogen to the injury site can repair cell membranes, mitigate oxidative stress, and promote axonal regeneration to restore motor function. PEG can be covalently or noncovalently conjugated to proteins, peptides, and nanoparticles to limit their clearance by the reticuloendothelial system, reduce their immunogenicity, and facilitate crossing the blood-brain barrier. Cross-linking PEG produces hydrogels that can act as delivery vehicles for bioactive molecules including growth factors and cells such as bone marrow stromal cells, which can modulate the inflammatory response and support neural tissue regeneration. PEG hydrogels can be cross-linked in vitro or delivered as an injectable formulation that can gel in situ at the site of injury. Chemical and mechanical properties of PEG hydrogels are tunable and must be optimized for creating the most favorable delivery environment. Peptides mimicking extracellular matrix protein such as laminin and n-cadherin can be incorporated into PEG hydrogels to promote neural differentiation and axonal extensions. Different hydrogel cross-linking densities and stiffness will also affect the differentiation process. PEG hydrogels with a gradient of peptide concentrations or Young's modulus have been developed to systematically study these factors. This review will describe these and other recent advancements of PEG in the field of spinal cord injury in greater detail.

Mechanical stabilization of proteolytically degradable polyethylene glycol dimethacrylate hydrogels through peptide interaction.

Balancing enhancement of neurite extension against loss of matrix support in synthetic hydrogels containing proteolytically degradable and bioactive signaling peptides to optimize tissue formation is difficult. Using a systematic approach, polyethylene glycol hydrogels containing concurrent continuous concentration gradients of the laminin derived bioactive signaling peptide, Ile-Lys-Val-Ala-Val (IKVAV), and collagen derived matrix metalloprotease degradable peptide, GPQGIWGQ, were fabricated and characterized. During proteolytic degradation of the concentration gradient hydrogels, the IKVAV and IWGQ cleavage fragment from GPQGIWGQ were found to interact and stabilize the bulk Young's Modulus of the hydrogel. Further testing of discrete samples containing GPQGIWGQ or its cleavage fragments, GPQG and IWGQ, indicates hydrophobic interactions between the peptides are not necessary for mechanical stabilization of the hydrogel, but changes in the concentration ratio between the peptides tethered in the hydrogel and salts and ions in the swelling solution can affect the stabilization. Encapsulation of human induced pluripotent stem cell derived neural stem cells did not reduce the mechanical properties of the hydrogel over a 14 day neural differentiation culture period, and IKVAV was found to maintain concentration dependent effects on neurite extension and mRNA gene expression of neural cytoskeletal markers, similar to previous studies. As a result, this work has significant implications for the analysis of biological studies in matrices, as the material and mechanical properties of the hydrogel may be unexpectedly temporally changing during culture due to interactions between peptide signaling elements, underscoring the need for greater matrix characterization during the degradation and cell culture. STATEMENT OF SIGNIFICANCE: Greater emulation of the native extracellular matrix is necessary for tissue formation. To achieve this, matrices are becoming more complex, often including multiple bioactive signaling elements. However, peptide signaling in polyethylene glycol matrices and amino acids interactions between peptides can affect hydrogel material and mechanical properties, but are rarely studied. The current study identifies such an interaction between laminin derived peptide, IKVAV, and collagen derived matrix metalloprotease degradable peptide, GPQGIWGQ. Previous studies using these peptides did not identify their interactions' ability to mechanically stabilize the hydrogel during degradation. This work underscores the need for greater matrix characterization and consideration of bioactive signaling element effects temporally on the matrix's material and mechanical properties, as they can contribute to cellular response.

Human Induced Pluripotent Stem Cell Derived Neural Stem Cell Survival and Neural Differentiation on Polyethylene Glycol Dimethacrylate Hydrogels Containing a Continuous Concentration Gradient of N-Cadherin Derived Peptide His-Ala-Val-Asp-Ile.

Although preclinical models of spinal cord injury have shown that matrix inclusion in stem cell therapy leads to greater neurological improvements than that including cells alone, there has been insufficient matrix optimization for human cells. N-Cadherin influences the development and maintenance of neural tissue, but the effects of N-cadherin derived peptide His-Ala-Val-Asp-Ile (HAVDI) on the survival, neurite extension, and expression of neural differentiation markers in human induced pluripotent stem cell derived neural stems (hNSC) have not been widely examined. Using polyethylene glycol hydrogels containing a continuous gradient of HAVDI, this study identifies concentration dependent effects on hNSC survival and neural differentiation.

Response to di-functionalized hyaluronic acid with orthogonal chemistry grafting at independent modification sites in rodent models of neural differentiation and spinal cord injury.

Hyaluronic acid (HA) with one reactive moiety grafted to the backbone is a commonly used matrix in tissue engineering. The addition of a second orthogonal moiety to the backbone allows for greater control in bioactive signal tethering and gelation. In this study, thiol and azide functional groups were grafted to the HA backbone at separate modification sites. NMR, FT-IR, colorimetric assay, and radio-TLC activity were used to confirm and quantify thiol and azide grafting to the HA backbone. Various ratios of di-functional HA (dif HA) and methacrylate HA (mHA) were used to encapsulate mouse embryonic stem cells in order to examine the neural differentiation of the cells. Greater neural maturation was observed in hydrogels containing a higher percentage of dif HA compared to mHA over a six day neural differentiation time course. This formulation was then tested in a contusion spinal cord injury model for biological effect and was found to reduce the ED1+ area in the spinal cord compared to control and allow for host axon extension into the matrix filled lesion area. These results indicate that dif HA is supportive of neural differentiation and can reduce inflammation without additional bioactive signal tethering. dif HA is a promising matrix base for the central nervous system, which should be further developed.

Three-dimensional spatial cognition in a benthic fish, Corydoras aeneus.

The way animals move through space is likely to affect the way they learn and remember spatial information. For example, a pelagic fish, Astyanax fasciatus, moves freely in vertical and horizontal space and encodes information from both dimensions with similar accuracy. Benthic fish can also move with six degrees of freedom, but spend much of their time travelling over the substrate; hence they might be expected to prioritise the horizontal dimension. To understand how benthic fish encode and deploy three-dimensional spatial information we used a fully rotational Y-maze to test whether Corydoras aeneus (i) encode space as an integrated three-dimensional unit or as separate elements, by testing whether they can decompose a three-dimensional trajectory into its vertical and horizontal components, and (ii) whether they prioritise vertical or horizontal information when the two conflict. In contradiction to the expectation generated by our hypothesis, our results suggest that C. aeneus are better at extracting vertical information than horizontal information from a three-dimensional trajectory, suggesting that the vertical axis is learned and remembered robustly. Our results also showed that C. aeneus prioritise vertical information when it conflicts with horizontal information. From these results, we infer that benthic fish attend preferentially to a cue unique to the vertical axis, and we suggest that this cue is hydrostatic pressure.

Met signaling regulates growth, repopulating potential and basal cell-fate commitment of mammary luminal progenitors: implications for basal-like breast cancer.

Basal-like breast cancer is an aggressive subtype of mammary carcinoma. Despite expressing basal markers, typical of mammary stem cells, this tumor has been proposed to originate from luminal progenitors, which are downstream of stem cells along the mammary epithelial hierarchy. This suggests that committed luminal progenitors may reacquire basal, stem-like characteristics, but the mechanisms that regulate this transition remain unclear. Using mouse models, we found that luminal progenitors express high levels of the Met receptor for hepatocyte growth factor (HGF), as compared with the other mammary epithelial sub-populations. Constitutive activation of Met led luminal progenitors to attain stem cell properties, including enhanced clonogenic activity in vitro and de novo ability to reconstitute mammary glands in repopulation assays in vivo. Moreover, in response to Met signaling, luminal progenitors gave rise to hyperplastic ductal morphogenesis and preferentially underwent basal lineage commitment at the expense of luminal cell-fate specification. Opposite and symmetric results were produced by systemic pharmacological inhibition of Met. Hence, Met signaling targets luminal progenitors for expansion, impairs their differentiation toward the mature luminal phenotype and enables their commitment toward the basal lineage. These results emphasize a critical role for Met in promoting deregulated proliferation and basal plasticity of normal luminal progenitors in the mammary gland, a complex of events that may be required for sustaining the functional and phenotypic properties of basal-like breast tumors.

State-dependent valuation learning in fish: banded tetras prefer stimuli associated with greater past deprivation.

Humans and some birds and insects sometimes prefer alternatives associated with greater past cost or need, sometimes affording losses. It has been proposed that this is widespread because learning may include knowledge about both the physical properties of alternatives and state-dependent fitness gains. We examine the phenomenon for the first time in a fish, the banded tetra (Astyanax fasciatus). During training we paired two different color cues to identical food rewards, one under greater deprivation than the other. We then tested preference between these cues under both deprivation states. Consistent with previous results in other taxa, the fish preferred the cue associated with previous greater deprivation regardless of the condition under which they were tested. These results provide further support to the view that organisms assign value using state-dependent increments in fitness during learning. Although generally adaptive, under experimental conditions state-dependent valuation learning can lead to paradoxical choices.