Effect of phospholipid liposomes on prion fragment (106-128) amyloid formation.

Misfolding and aggregation of cellular prion protein (PrPc) is a major molecular process involved in the pathogenesis of prion diseases. Here, we studied the aggregation properties of a prion fragment peptide PrP(106-128). The results show that the peptide aggregates in a concentration-dependent manner in an aqueous solution and that the aggregation is sensitive to pH and the preformed amyloid seeds. Furthermore, we show that the zwitterionic POPC liposomes moderately inhibit the aggregation of PrP(106-128), whereas POPC/cholesterol (8:2) vesicles facilitate peptide aggregation likely due to the increase of the lipid packing order and membrane rigidity in the presence of cholesterol. In addition, anionic lipid vesicles of POPG and POPG/cholesterol above a certain concentration accelerate the aggregation of the peptide remarkably. The strong electrostatic interactions between the N-terminal region of the peptide and POPG may constrain the conformational plasticity of the peptide, preventing insertion of the peptide into the inner side of the membrane and thus promoting fibrillation on the membrane surface. The results suggest that the charge properties of the membrane, the composition of the liposomes, and the rigidity of lipid packing are critical in determining peptide adsorption on the membrane surface and the efficiency of the membrane in catalyzing peptide oligomeric nucleation and amyloid formation. The peptide could be used as an improved model molecule to investigate the mechanistic role of the crucial regions of PrP in aggregation in a membrane-rich environment and to screen effective inhibitors to block key interactions between these regions and membranes for preventing PrP aggregation.

Finite Element Modelling of a Gram-Negative Bacterial Cell and Nanospike Array for Cell Rupture Mechanism Study.

Inspired by nature, it is envisaged that a nanorough surface exhibits bactericidal properties by rupturing bacterial cells. In order to study the interaction mechanism between the cell membrane of a bacteria and a nanospike at the contact point, a finite element model was developed using the ABAQUS software package. The model, which saw a quarter of a gram-negative bacteria (Escherichia coli) cell membrane adhered to a 3 × 6 array of nanospikes, was validated by the published results, which show a reasonably good agreement with the model. The stress and strain development in the cell membrane was modeled and were observed to be spatially linear and temporally nonlinear. From the study, it was observed that the bacterial cell wall was deformed around the location of the nanospike tips as full contact was generated. Around the contact point, the principal stress reached above the critical stress leading to a creep deformation that is expected to cause cell rupture by penetrating the nanospike, and the mechanism is envisaged to be somewhat similar to that of a paper punching machine. The obtained results in this project can provide an insight on how bacterial cells of a specific species are deformed when they adhere to nanospikes, and how it is ruptured using this mechanism.

Effects of Charged Polyelectrolytes on Amyloid Fibril Formation of a Tau Fragment.

The microtubule-associated protein tau is involved in more than 20 different neurological disorders characterized by aberrant intracellular aggregation of tau in the brain. Here, we investigated the aggregation of a novel 20-residue model peptide, tau298-317, which is derived from the key microtubule binding domain of the full sequence tau. Our results show that tau298-317 highly mimics the physical and aggregation properties of tau. Under normal physiological conditions, the peptide maintains a disordered random coil without aggregation. The presence of polyanionic heparin (Hep) significantly promotes the aggregation of this peptide to form amyloid fibrils. The Hep-induced aggregation is sensitive to the ionic strength of the solution and the introduction of the negatively charged phosphate group on a serine (Ser305) residue in the sequence, suggesting an important role of electrostatic interactions in the mechanism of Hep-mediated aggregation. In addition, two positively charged polysaccharides, chitosan (CHT) and its quaternary derivative N-trimethyl chitosan (TMC), were found to effectively inhibit Hep-induced aggregation of tau298-317 in a concentration-dependent manner. Attractive electrostatic interactions between the positively charged moieties in CHT/TMC and the negatively charged residues of Hep play a critical role in inhibiting Hep-peptide interactions and suppressing peptide aggregation. Our results suggest that positively charged polyelectrolytes with optimized charged groups and charge distribution patterns can serve as effective molecular candidates to block tau-Hep interactions and prevent aggregation of tau induced by Hep and other polyanions.

Effects of zinc and carnosine on aggregation kinetics of Amyloid-ß40 peptide.

The accumulation and amyloid formation of amyloid-ß (Aß) peptides is closely associated with the pathology of Alzheimer's disease. The physiological environment wherein Aß aggregation happens is crowded with a large variety of metal ions including Zn2+. In this study, we investigated the role of Zn2+ in regulating the aggregation kinetics of Aß40 peptide. Our results show that Zn2+ can shift a typical single sigmoidal aggregation kinetics of Aß40 to a biphasic aggregation process. Zn2+ aids in initiating the rapid self-assembly of monomers to form oligomeric intermediates, which further grow into amyloid fibrils in the first aggregation phase. The presence of Zn2+ also retards the appearance of the second aggregation phase in a concentration dependent manner. In addition, our results show that a natural dipeptide, carnosine, can greatly alleviate the effect of Zn2+ on Aß aggregation kinetics, most likely by coordinating with the metal ion to form chelates. These results suggest a potential in vivo protective effect of carnosine against the cytotoxicity of Aß by suppressing Zn2+-induced rapid formation of Aß oligomers.

Tau liquid-liquid phase separation: At the crossroads of tau physiology and tauopathy.

Abnormal deposition of tau in neurons is a hallmark of Alzheimer's disease and several other neurodegenerative disorders. In the past decades, extensive efforts have been made to explore the mechanistic pathways underlying the development of tauopathies. Recently, the discovery of tau droplet formation by liquid-liquid phase separation (LLPS) has received a great deal of attention. It has been reported that tau condensates have a biological role in promoting and stabilizing microtubule (MT) assembly. Furthermore, it has been hypothesized that the transition of phase-separated tau droplets to a gel-like state and then to fibrils is associated with the pathology of neurodegenerative diseases. In this review, we outline LLPS, the structural disorder that facilitates tau droplet formation, the effects of posttranslational modification of tau on condensate formation, the physiological function of tau droplets, the pathways from droplet to toxic fibrils, and the therapeutic strategies for tauopathies that might evolve from toxic droplets. We expect a deeper understanding of tau LLPS will provide additional insights into tau physiology and tauopathies.

Modeling the fecal contamination (fecal coliform bacteria) in transboundary waters using the scenario matrix approach: a case study of Sutlej River, Pakistan.

Surface water quality is among the significant challenges in the Sutlej River basin, passing through Pakistan's most densely populated province. Currently, the overall surface water quality is grossly polluted, mainly due to the direct discharge of wastewater from the urban areas to the Sutlej River directly or through stream networks. Escherichia coli concentrations vary under extreme weather events like floods and droughts and socioeconomic circumstances like urbanization, population growth, and treatment options. This paper assesses the future E. coli load and concentrations using the Soil and Water Assessment Tool (SWAT) along with scenarios based on Shared Socioeconomic Pathways (SSPs) and Representative Concentration Pathways (RCPs) developed by the Intergovernmental Panel on Climate Change (IPCC). E. coli concentrations according to a more polluted scenario disclose a near and mid future increase by 108% and 173%, and far future increases up to 251% compared to the reference period (baseline) concentrations. The E. coli concentration is reduced by - 54%, - 68%, and - 81% for all the projected time steps compared to the baseline concentrations. While highly improved sewerage and manure management options are adapted, the concentration is further reduced by - 96%, - 101%, and - 105%, respectively, compared to the baseline. Our modeling and scenario matrix study shows that reducing microbiological concentrations in the surface water is possible. Still, it requires rigorous sanitation and treatment options, and socioeconomic variables play an essential role besides climate change to determine the microbiological concentration of water resources and be included in future studies whenever water quality and health risks are considered.

Therapeutic strategies for tauopathies and drug repurposing as a potential approach.

Tauopathies are neurodegenerative diseases characterized by the deposition of abnormal tau in the brain. To date, there are no disease-modifying therapies approved by the U.S. Food and Drug Administration (US FDA) for the treatment of tauopathies. In the past decades, extensive efforts have been provided to develop disease-modifying therapies to treat tauopathies. Specifically, exploring existing drugs with the intent of repurposing for the treatment of tauopathies affords a reasonable alternative to discover potent drugs for treating these formidable diseases. Drug repurposing will not only reduce formulation and development stage effort and cost but will also take a key advantage of the established toxicological studies, which is one of the main causes of clinical trial failure of new molecules. In this review, we provide an overview of the current treatment strategies for tauopathies and the recent progress in drug repurposing as an alternative approach to treat tauopathies.

Sustainable food drying technologies based on renewable energy sources.

Waste in the food supply chain is estimated to be about 30-40% of the total food production, which aggravates the world hunger and increases waste management burden and environmental impact. Despite the dire food scarcity, majority of this food waste takes place in developing countries because of the lack of appropriate and affordable preservation techniques. Traditional open sun drying is the most popular food-reservation technique to the local farmers due to near-zero capital cost and cheap labor cost. However, this method is highly energy intensive, unhygienic, and time demanding. The high energy consumption resulting from uncontrolled simultaneous heat, mass, and momentum transfer processes in traditional drying systems highlights the necessity of pursuing sustainability in drying process targeting reduced energy consumption, environmental and social impacts. This paper presents a comprehensive review on the sustainable food drying technologies based on renewable energy sources, with emphasis on the developing countries. It was observed that the integration of thermal energy storage with heat pump makes the integrated drying system more efficient, and dries food with better quality. Likewise, advanced integrated drying systems, such as, solar with microwave, and heat pump with microwave make the drying process more cost and quality competent. Finally, impact of resource distribution and governmental incentives for renewable energy use in sustainable drying is discussed.

Performance of Graphite-Dispersed Li2CO3-K2CO3 Molten Salt Nanofluid for a Direct Absorption Solar Collector System.

Considered to be the next generation of heat transfer fluids (HTFs), nanofluids have been receiving a growing interest over the past decade. Molten salt nanofluids have been shown to have great potential as an HTF for use in high temperature applications such as direct absorption solar collector (DAC) system. Very few studies using molten salt nanofluids as the HTF in a DAC receiver can be found in the open literature. This study aimed to develop a 3D computational fluid dynamics model of the receiver of a DAC using graphite-nanoparticle-dispersed Li2CO3-K2CO3 molten salt nanofluid to investigate the effects of design and operation parameters on receiver performance. Receiver total efficiency using Li2CO3-K2CO3 salt was compared with that using solar salt nanofluid. Spectral properties of the base fluid and nanoparticles were modeled as wavelength-dependent and the absorption of the solar radiation was modeled as a volumetric heat release in the flowing heat transfer fluid. Initial results show that the receiver efficiency increases with increasing solar concentration, decreasing nanoparticle volume fraction, and decreasing receiver length. It was also found that the Carnot efficiency increases with increasing receiver length and nanoparticle volume fraction, and decreasing solar concentration and inlet velocity. Comparative study shows that solar salt HTF could provide higher total efficiency. However, a higher operating temperature of Li2CO3-K2CO3 will allow for a greater amount of thermal energy storage for a smaller volume of liquid.

Performance Investigation of High Temperature Application of Molten Solar Salt Nanofluid in a Direct Absorption Solar Collector.

Nanofluids have great potential in a wide range of fields including solar thermal applications, where molten salt nanofluids have shown great potential as a heat transfer fluid (HTF) for use in high temperature solar applications. However, no study has investigated the use of molten salt nanofluids as the HTF in direct absorption solar collector systems (DAC). In this study, a two dimensional CFD model of a direct absorption high temperature molten salt nanofluid concentrating solar receiver has been developed to investigate the effects design and operating variables on receiver performance. It has been found that the Carnot efficiency increases with increasing receiver length, solar concentration, increasing height and decreasing inlet velocity. When coupled to a power generation cycle, it is predicted that total system efficiency can exceed 40% when solar concentrations are greater than 100×. To impart more emphasis on the temperature rise of the receiver, an adjusted Carnot efficiency has been used in conjunction with the upper temperature limit of the nanofluid. The adjusted total efficiency also resulted in a peak efficiency for solar concentration, which decreased with decreasing volume fraction, implying that each receiver configuration has an optimal solar concentration.

Hyperinflation deteriorates arterial oxygenation and lung injury in a rabbit model of ARDS with repeated open endotracheal suctioning.

BACKGROUND: Hyperinflation (HI) is performed following open endotracheal suctioning (OES), whose goals include: to stimulate a cough, recover oxygenation and improve compliance. However, it may also induce unintended consequences, including: lung stress and strain, failure to maintain high distending pressure, and subsequently cycling recruitment and derecruitment. Here, our aim was to investigate the effects of hyperinflation after repeated OES on sequential alteration of arterial oxygenation and lung injury profile using a saline lavage-induced surfactant depleted ARDS rabbit model. METHODS: Briefly, 30 Japanese White Rabbits were anesthetized and ventilated in pressure-controlled setting with a tidal volume of 6-8 ml/kg. Animals were divided into four groups, i.e.; Control, ARDS, OES, and HI. Saline-lavage-induced lung injury was induced except for Control group. Thereafter, rabbits were ventilated with positive-end expiratory pressure (PEEP) at 10 cm H2O. The ARDS group received ventilation with the same PEEP without derecruitment. As intervention, OES and HI were performed in ARDS animals. OES was performed for 15 seconds at 150 mm Hg, whereas HI was performed with PEEP at 0 cm H2O and peak inspiratory pressure at +5 cm H2O for a minute. Total duration of the experiment was for 3 hours. OES and HI were performed every 15 minutes from beginning of the protocol. RESULTS: PaO2 was maintained at about 400 mm Hg in both control and ARDS groups for the duration of this study, while in both OES and HI groups, PaO2 decreased continuously up to 3 hours, dropped to a mean (±SD) of 226 ± 28.9 and 97.0 ± 30.7 mmHg at 3 h, respectively. HI group had the lowest PaO2 in the present investigation. Histological lung injury score was the highest in HI group than other three groups. Pulmonary TNF-α and IL-8 levels were the highest in HI group compared to other groups, but without significant alterations at circulatory level in all the experimental groups. CONCLUSIONS: We show in the present study that hyperinflation following repeated OES deteriorate arterial oxygenation and the severity of lung injury in a rabbit model of ARDS undergoing mechanical ventilation.

Effects of selective endothelin (ET)-A receptor antagonist versus dual ET-A/B receptor antagonist on hearts of streptozotocin-treated diabetic rats.

AIMS: The aim was to study the differences in the effectiveness of two types of endothelin (ET) receptor antagonists (selective ET-A or dual ET-A/B antagonists) on the hearts of streptozotocin (STZ)-induced diabetic rats (type I diabetes) at functional and biochemical/molecular levels. MAIN METHODS: Citrate saline (vehicle) or STZ was injected into rats. The ET-A/B dual receptor antagonist (SB209670, 1mg/kg/day) and the ET-A receptor antagonist (TA-0201, 1mg/kg/day) were then administered to these rats. One week after injection, the animals were separated into those receiving SB209670, TA-0201 or vehicle by 4-week osmotic mini-pump. KEY FINDINGS: The VEGF level and percent fractional shortening in the diabetic heart were significantly decreased compared to the non-diabetic heart, whereas SB209670 and TA-0201 treatments greatly and comparably prevented this decrease. SB209670 treatment was more effective in reversing decreased expressions of KDR and phosphorylated AKT, downstream of VEGF angiogenic signaling, than TA-0201 treatment. The eNOS levels in hearts were significantly higher in diabetic rats than in healthy rats, and this increase was significantly reduced by TA-0210 but not by SB209670 treatment. SIGNIFICANCE: Improvement of KDR mRNA and pAKT levels by SB209670 but not TA-0201 suggests that dual ET-A/-B blockade may be effective in improving intracellular systems of these components in the diabetic rat heart. However, the present study also showed that TA-0201 or SB209670 improved percent fractional shortening and VEGF levels of the diabetic hearts to a similar extent, suggesting that ET-A blockade and dual ET-A/-B blockade are similarly effective in improving cardiac dysfunction in the diabetic rats.

Effects of protease activated receptor (PAR)2 blocking peptide on endothelin-1 levels in kidney tissues in endotoxemic rat mode.

AIMS: Septic shock, the severe form of sepsis, is associated with development of progressive damage in multiple organs. Kidney can be injured and its functions altered by activation of coagulation, vasoactive-peptide and inflammatory processes in sepsis. Endothelin (ET)-1, a potent vasoconstrictor, is implicated in the pathogenesis of sepsis and its complications. Protease-activated receptors (PARs) are shown to play an important role in the interplay between inflammation and coagulation. We examined the time-dependent alterations of ET-1 and inflammatory cytokine, such as tumor necrosis factor (TNF)-α in kidney tissue in lipopolysaccharide (LPS)-induced septic rat model and the effects of PAR2 blocking peptide on the LPS-induced elevations of renal ET-1 and TNF-α levels. MAIN METHODS: Male Wistar rats at 8 weeks of age were administered with either saline solution or LPS at different time points (1, 3, 6 and 10h). Additionally, we treated LPS-administered rats with PAR2 blocking peptide for 3h to assess whether blockade of PAR2 has a regulatory role on the ET-1 level in septic kidney. KEY FINDINGS: An increase in ET-1 peptide level was observed in kidney tissue after LPS administration time-dependently. Levels of renal TNF-α peaked (around 12-fold) at 1h of sepsis. Interestingly, PAR2 blocking peptide normalized the LPS-induced elevations of renal ET-1 and TNF-α levels. SIGNIFICANCE: The present study reveals a distinct chronological expression of ET-1 and TNF-α in LPS-administered renal tissues and that blockade of PAR2 may play a crucial role in treating renal injury, via normalization of inflammation, coagulation and vaso-active peptide.