Search

Graphene-based nanomaterials (GBNs) have been widely used in various fields nowadays. However, they are reported to be highly toxic to some aquatic organisms. However, the multi-organ toxicity caused by pristine graphene (pG) and graphene oxide (GO) to the developing zebrafish (Danio rerio) larvae or juvenile and the underlying mechanisms is not fully known. Therefore, in the present study, the effect of pG and GO with environmental concentrations (0, 5, 10, 15, 20, and 25 μg/L of pG; 0, 0.1, 0.2, 0.3, and 0.4 mg/mL of GO) on multi-organ system in developing zebrafish larvae was experimentally assessed. The pG and GO were found to accumulate in the brain tissue that also caused significant changes in the heart beat and survival rate. The sizes of hepatocytes were reduced. Altered axonal integrity, affecting axon length and pattern in "Tg(mbp:eGFP) transgenic lines" was also observed. In addition, the results indicated pathological effects in major organs and with disrupted mitochondrial structure was quite obvious. The pG and GO bioaccumulation leads to multi organ toxicity in zebrafish larvae. In future, the existence of the current study can be extrapolated to other aquatic system in general and in particularly to humans.

Bio-inspired approaches represent potentially transformational methods to fabricate and activate non-natural materials for applications ranging from biomedical diagnostics to energy harvesting platforms. Recently, bio-based methods for the exfoliation of graphene in water have been developed, resulting in peptide-capped nanosheets; however, a clear understanding of the reaction system and peptide ligand structure remains unclear, limiting the advance of such approaches. Here the effects of reaction solution conditions and peptide ligand structure were systematically examined for graphene exfoliation, identifying key parameters to optimize material production. For this, the P1 peptide, identified with affinity for graphene, was exploited to drive exfoliation of bulk graphite to generate the final materials. The peptide was modified at both the N- and C-terminus with a 10-carbon chain fatty acid to explore the effects of a hydrophobic domain on the exfoliation process. The system was examined as a function of sonication time, pH, reagent concentration, and graphite source, where the final materials were fully characterized using a suite of approaches. Collectively, these results demonstrated that maximum graphene production was achieved using the parent P1 peptide after 12 h of sonication under basic conditions. While the exfoliation efficiency was slightly lower for the fatty acid modified peptides, the graphene produced using these biomolecules had fewer defects incorporated, potentially from the wrapping of the nanosheet edge by the aliphatic domain. Such results are important to provide key reaction designs to optimize the reproducibility of graphene exfoliation using biomimetic approaches.

Bimetallic nanoparticles remain a promising avenue to achieve highly reactive catalysts. In this contribution, we demonstrate the use of a photoswitchable peptide for the production of PdAu bimetallic nanoparticles at a variety of Pd : Au ratios. Using this peptide, the biomolecular overlayer structure can be switched between two different conformations (cis vs. trans) via light irradiation, thus accessing two different surface structures. The composition and arrangement of the materials was fully characterized, including atomic-level analyses, after which the reactivity of the bimetallic materials was explored using the reduction of 4-nitrophenol as a model system. Using these materials, it was demonstrated that the reactivity was maximized for the particles prepared at a Pd : Au ratio of 1 : 3 and with the peptide in the cis conformation. Such results present routes to a new generation of catalysts that could be remotely activated for on/off reactivity as a function of the ligand overlayer conformation.

Ghee (milk fat) due to its high price and demand is highly susceptible to adulteration for economic gains. Further, due to advanced practices of adulteration, its detection is becoming difficult by any single method. In the present study, methods based upon physico-chemical (BR reading and RM value) and chromatography (fatty acid, triglycerides, and plant sterols profiling) were evaluated to detect adulteration. Pure ghee was adulterated @ 1%, 2.5%, 5%, and 10% with coconut, soya bean, groundnut, and sunflower oil. Results of physico-chemical methods indicated that BR reading crossed regulatory limit only @ 10% of sunflower and soya bean oil adulteration while for the other two oils it was within the acceptable range (FSSAI standards for Gujarat i.e. 40 to 43.5). In the case of RM value, adulteration was not detected with any oil up to 10% level of adulteration with respect to FSSAI regulation (i.e. minimum 24) for Gujarat. Among chromatographic methods, fatty acids marker molecules like lauric for coconut and linoleic for soya bean, groundnut, and sunflower oil showed an increase upon adulteration even @ 1%. Marker fatty acids % values were falling outside the range for lauric (i.e.2.3 to 3.2%) and linoleic (i.e.1 to 2%) as specified by FSSAI in the manual of analysis for milk and milk products 2016 however, natural variations might affect the results. Triglyceride profiling was found to be capable of detecting adulteration @ 5% for all the oils except groundnut which was detected @ 10%. Plant sterols (â-sitosterol and stigmasterol) based method was found suitable to detect adulteration @ 1% with sunflower and soya bean oil, @ 2.5% with groundnut oil, and @ 5% with coconut oil. All the methods appear to have their strengths and limitations; hence laboratories may apply a combination of techniques to detect advanced adulteration.

BACKGROUND No Food and Drug Administration-approved medication improves outcomes following traumatic brain injury (TBI). A forthcoming clinical trial that evaluated the effects of two prehospital tranexamic acid (TXA) dosing strategies compared with placebo demonstrated no differences in thromboelastography (TEG) values. We proposed to explore the impact of TXA on markers of coagulation and fibrinolysis in patients with moderate to severe TBI. METHODS Data were extracted from a placebo-controlled clinical trial in which patients 15 years or older with TBI (Glasgow Coma Scale, 3-12) and systolic blood pressure of ≥90 mm Hg were randomized prehospital to receive placebo bolus/placebo infusion (placebo), 1 g of TXA bolus/1 g of TXA infusion (bolus maintenance), or 2 g of TXA bolus/placebo infusion (bolus only). Thromboelastography was performed, and coagulation measures including prothrombin time, activated partial thromboplastin time, international ratio, fibrinogen, D-dimer, plasmin-antiplasmin (PAP), thrombin antithrombin, tissue plasminogen activator, and plasminogen activator inhibitor 1 were quantified at admission and 6 hours later. RESULTS Of 966 patients receiving study drug, 700 had laboratory tests drawn at admission and 6 hours later. There were no statistically significant differences in TEG values, including LY30, between groups (p > 0.05). No differences between prothrombin time, activated partial thromboplastin time, international ratio, fibrinogen, thrombin antithrombin, tissue plasminogen activator, and plasminogen activator inhibitor 1 were demonstrated across treatment groups. Concentrations of D-dimer in TXA treatment groups were less than placebo at 6 hours (p < 0.001). Concentrations of PAP in TXA treatment groups were less than placebo on admission (p < 0.001) and 6 hours (p = 0.02). No differences in D-dimer and PAP were observed between bolus maintenance and bolus only. CONCLUSION While D-dimer and PAP levels reflect a lower degree of fibrinolysis following prehospital administration of TXA when compared with placebo in a large prehospital trial of patients with TBI, TEG obtained on admission and 6 hours later did not demonstrate any differences in fibrinolysis between the two TXA dosing regimens and placebo. LEVEL OF EVIDENCE Diagnostic test, level III.

Genotoxic impurities (GIs) are chemical agents that have a DNA-interaction characteristic which can ultimately lead to cancer. Their presence in various drug substances had driven various regulatory authorities to guide monitor, control, and to limit their level in various drug products. The objective of this article is to review the analytical approaches and challenges faced while accessing, monitoring, and controlling GIs in pharmaceuticals and also a brief explanation such as low limits of GIs, matrix interference, non-volatility, and environmental conditions encountered during the analysis of GIs are also discussed in this paper. At present, several modern analytical techniques are being used for the analysis of GIs such as high-performance liquid chromatography, liquid chromatography-mass spectrometry, and gas chromatography-mass spectroscopy that have high selectivity and sensitivity, but at the same time, many researchers have reported several challenges while using these techniques. Impacts of GIs are very important and various international organizations such as the World Health Organization have set out rules for regulating these chemicals. Hence, we can conclude that analytical approaches and their challenges are essential to understand because they play a key role to develop robust analytical methods.

Background Alzheimer's disease (AD) is among the most prevalent forms of dementia in the world and neuropathological studies suggest similar high prevalence of mixed (AD + vascular) dementias. Approximately 25%-50% of individuals with AD develop psychosis sometime during their illness. The presence of psychosis in AD worsens outcomes. Currently there are no United States Food and Drug Administration (FDA) approved medications for the treatment of psychosis in AD. Pimavanserin, a novel atypical antipsychotic medication, was approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson disease psychosis and is currently in clinical trials for the treatment of psychosis in AD. Aim To evaluate the existing literature regarding the use of pimavanserin for treating psychosis among individuals with AD. Methods A literature review of clinical studies of pimavanserin treatment for psychosis in individuals with AD was performed using the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Trials were identified by systematically searching PubMed, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus through October 2019. The 5-point Jadad scoring system was used to assess the methodologic quality of the randomized placebo-controlled trials. Results A total of 499 citations were retrieved and pooled in EndNote and de-duplicated to 258 citations. This set was uploaded to Covidence for screening. Two separate screeners (Srinivasan S and Tampi RR) evaluated the titles, abstracts, and full text of eligible articles. Of the identified 258 abstracts, 98 articles underwent full text review and 2 publications from 1 randomized controlled trial (RCT) were included in the final analysis. The quality of evidence was assessed to be of good methodologic quality, scoring 4 out of 5 using the 5-point Jadad questionnaire with the Jadad Scoring calculation. This systematic review found only one RCT that evaluated the use of pimavanserin for the treatment of psychosis among individuals with AD. This phase 2 trial resulted in two publications, the second of which was a subgroup analysis from the original study. The evidence from these two publications showed that pimavanserin improves psychotic symptoms among individuals with AD when compared to placebo at week 6. Conclusion Pimavanserin may be a pharmacologic consideration for the treatment for psychosis in AD. Additional RCTs are needed to assess the evidence of effectiveness before pimavanserin is considered a standard treatment.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) provide clinical benefits over chemotherapy for lung cancer patients with EGFR activating mutations. Despite initial clinical responses, long‐term efficacy is not possible because of acquired resistance to these therapies. We have developed EGFR TKI drug‐tolerant (DT) human lung cancer cell lines as a model for de novo resistance. Mass spectroscopic analysis revealed that the cytochrome P450 protein, CYP51A1 (Lanosterol 14α‐demethylase), which is directly involved with cholesterol synthesis, was significantly upregulated in the DT cells. Total cellular cholesterol, and more specifically, mitochondrial cholesterol, were found to be upregulated in DT cells. We then used the CYP51A1 inhibitor, ketoconazole, to downregulate cholesterol synthesis. In both parental and DT cells, ketoconazole and EGFR TKIs acted synergistically to induce apoptosis and overcome the development of EGFR tolerance. Lastly, this combination therapy was shown to shrink the growth of tumors in an in vivo mouse model of EGFR TKI resistance. Thus, our study demonstrates for the first time that ketoconazole treatment inhibits upregulation of mitochondrial cholesterol and thereby overcomes EGFR‐TKI resistance in lung cancer cells.

N-(Propargyl)indole-2-carbonitriles undergo DBU-catalyzed addition of CH-acids to nitriles, followed by cyclization to give 9-aminopyrido[1,2-a]indoles. The reaction proceeds through the initial formation of a push-pull enamine, alkyne-allene rearrangement and intramolecular nucleophilic cyclization. Nitromethane and malonate esters can be employed as the CH-acids. The resulting compounds were found to exhibit fluorescence properties.

Nanosheet heterostructures offer emergent optical/electronic properties. These could be achieved using selective materials binding peptides, but lack of understanding of selectivity impedes advancement. Here we examine peptides with affinity for graphene or h-BN using quantitative experiments and molecular simulation to identify traits for design of 2D nanosheet selective peptides.

Cancer is the second deadliest cause among all ailments even after the development of modern research and technologies. This leads in search of alternative sources of treating cancer. Herbal formulations were considered to be the rich sources of treating agents for most of the ailments from agelong days. Bacterial Reverse Mutation method of evaluation is one among the preliminary phase incorporated to assess the mutagenic potential of herbal formulations. The selected Polyherbal Formulation (PF3) of Annona Squamosa, Zingiber Officinalis, and Triticum Aestivum in 1:1:1 ratio was evaluated for its mutagenic potential. The results with method I - Plate incorporation and method II - Preincubation indicate that, the PF3 extract at a maximum dose of 5 mg/plate did not cause a positive increase in the mean number of revertant colonies per plate with any of the tester strains either in the presence (+S9) or absence of metabolic activation (-S9). The rich flavonoids and other phytoconstituents of the formulation may be responsible for antimutative properties with the possible inactivation of mutagens or by interfering in the process of mutagenisis. The higher studies were needed to be proven further to authenticate the mutagenic potentialities.

Background Inflammation in the central nervous system (CNS) is observed in many neurological disorders. Nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO–sGC–cGMP) signaling plays an essential role in modulating neuroinflammation. CYR119 is a CNS-penetrant sGC stimulator that amplifies endogenous NO–sGC–cGMP signaling. We evaluated target engagement and the effects of CYR119 on markers of neuroinflammation in vitro in mouse microglial cells and in vivo in quinolinic acid (QA)-induced and high-fat diet-induced rodent neuroinflammation models. Methods Target engagement was verified in human embryonic kidney (HEK) cells, rat primary neurons, mouse SIM-A9 cells, and in rats by measuring changes in cGMP and downstream targets of sGC signaling [phosphorylated vasodilator-stimulated phosphoprotein (pVASP), phosphorylated cAMP-response element binding (pCREB)]. In SIM-A9 cells stimulated with lipopolysaccharides (LPS), markers of inflammation were measured when cells were treated with or without CYR119. In rats, microinjections of QA and vehicle were administered into the right and left hemispheres of striatum, respectively, and then rats were dosed daily with either CYR119 (10 mg/kg) or vehicle for 7 days. The activation of microglia [ionized calcium binding adaptor molecule 1 (Iba1)] and astrocytes [glial fibrillary acidic protein (GFAP)] was measured by immunohistochemistry. Diet-induced obese (DIO) mice were treated daily with CYR119 (10 mg/kg) for 6 weeks, after which inflammatory genetic markers were analyzed in the prefrontal cortex. Results In vitro, CYR119 synergized with exogenous NO to increase the production of cGMP in HEK cells and in primary rat neuronal cell cultures. In primary neurons, CYR119 stimulated sGC, resulting in accumulation of cGMP and phosphorylation of CREB, likely through the activation of protein kinase G (PKG). CYR119 attenuated LPS-induced elevation of interleukin 6 (IL-6) and tumor necrosis factor (TNF) in mouse microglial cells. Following oral dosing in rats, CYR119 crossed the blood–brain barrier (BBB) and stimulated an increase in cGMP levels in the cerebral spinal fluid (CSF). In addition, levels of proinflammatory markers associated with QA administration or high-fat diet feeding were lower in rodents treated with CYR119 than in those treated with vehicle. Conclusions These data suggest that sGC stimulation could provide neuroprotective effects by attenuating inflammatory responses in nonclinical models of neuroinflammation.

Peptides can recognize and selectively bind to a wide variety of materials dependent on both their surface properties and the environment. Biopanning with phage or cell peptide display libraries can identify material-specific binding peptides. However, the limitations with sequence diversity of traditional bacteriophage (phage) display libraries and loss of unique phage clones during the amplification cycles results in a smaller pool of peptide sequences identified. False positive sequences tend to emerge during the biopanning process due to highly proliferating, yet nonspecific, phages. In order to overcome this limitation of traditional biopanning methodology, a modified method using high-throughput next generation sequencing (HTS) was tested to select for unique peptides specific to two types of single wall carbon nanotube (SWNTs) sources with varying diameter distribution and chirality. Here, the process, analysis, and characterization of peptide sequences identified using the modified method is further described and compared to a peptide identified in literature using the traditional method. Selected sequences from this study were incorporated in a SWNT dispersion experiment to probe their selectivity to the nanotube diameter. We show that NHTS can uncover unique binding sequences that might have otherwise been lost during the traditional biopanning method.

Protein ionic liquids (PIL) are a new class of biologic stabilizers designed to protect the functionality and extend the shelf-life of biotechnological and therapeutic agents making them more readily available, and resistant to austere environments. Protein biorecognition elements such as monoclonal antibodies are commonly utilized therapeutics that require the robust stabilization offered by PILs, but biocompatibility remains an important issue. This study has focused on characterizing the biocompatibility of an antibody based PIL by exposing multiple cells types to a cationized immunoglobulin suspended in an anionic liquid (IgG-IL). The IgG-IL caused no significant alterations in cellular health for all three cell types with treatments

Novel methods that enable sensitive, accurate and rapid detection of RNA would not only benefit fundamental biological studies but also serve as diagnostic tools for various pathological conditions, including bacterial and viral infections and cancer. Although highly sensitive, existing methods for RNA detection involve long turn-around time and extensive capital equipment. Here, an ultrasensitive and amplification-free RNA quantification method is demonstrated by integrating CRISPR-Cas13a system with an ultrabright fluorescent nanolabel, plasmonic fluor. This plasmonically enhanced CRISPR-powered assay exhibits nearly 1000-fold lower limit-of-detection compared to conventional assay relying on enzymatic reporters. Using a xenograft tumor mouse model, it is demonstrated that this novel bioassay can be used for ultrasensitive and quantitative monitoring of cancer biomarker (lncRNA H19). The novel biodetection approach described here provides a rapid, ultrasensitive, and amplification-free strategy that can be broadly employed for detection of various RNA biomarkers, even in resource-limited settings.

This paper presents a study on peptide-functionalized carbon nanotube (CNT) chemiresistors, where the effect of CNT density is investigated to optimize their gas sensing performances. While previous CNT density studies mostly focused on sensor performance and its reliability testing from a handful of devices, we systemically control CNT density and investigate more than 30 devices in terms of sensitivity, noise, and signal-to-noise ratio (SNR). The results exhibit that the higher CNT resistance results in 1) higher sensitivity, 2) higher noise, and 3) lower SNR. These results indicate that careful control of CNT density is crucial for optimizing CNT-based gas sensors.

Effective treatments for neurodegenerative diseases remain elusive and are critically needed since the burden of these diseases increases across an aging global population. Nitric oxide (NO) is a gasotransmitter that binds to soluble guanylate cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP). Impairment of this pathway has been demonstrated in neurodegenerative diseases. Normalizing deficient NO-cGMP signaling could address multiple pathophysiological features of neurodegenerative diseases. sGC stimulators are small molecules that synergize with NO, activate sGC, and increase cGMP production. Many systemic sGC stimulators have been characterized and advanced into clinical development for a variety of non-central nervous system (CNS) pathologies. Here, we disclose the discovery of CY6463, the first brain-penetrant sGC stimulator in clinical development for the treatment of neurodegenerative diseases, and demonstrate its ability to improve neuronal activity, mediate neuroprotection, and increase cognitive performance in preclinical models. In several cellular assays, CY6463 was demonstrated to be a potent stimulator of sGC. In agreement with the known effects of sGC stimulation in the vasculature, CY6463 elicits decreases in blood pressure in both rats and mice. Relative to a non-CNS penetrant sGC stimulator, rodents treated with CY6463 had higher cGMP levels in cerebrospinal fluid (CSF), functional-magnetic-resonance-imaging-blood-oxygen-level-dependent (fMRI-BOLD) signals, and cortical electroencephalographic (EEG) gamma-band oscillatory power. Additionally, CY6463 improved cognitive performance in a model of cognitive disruption induced by the administration of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. In models of neurodegeneration, CY6463 treatment increased long-term potentiation (LTP) in hippocampal slices from a Huntington’s disease mouse model and decreased the loss of dendritic spines in aged and Alzheimer’s disease mouse models. In a model of diet-induced obesity, CY6463 reduced markers of inflammation in the plasma. Furthermore, CY6463 elicited an additive increase in cortical gamma-band oscillatory power when co-administered with donepezil: the standard of care in Alzheimer’s disease. Together, these data support the clinical development of CY6463 as a novel treatment for neurodegenerative disorders.

This study provides an improved statistical modelling framework for understanding historical variability and trends in water constituent fluxes in subarctic western Canada. We evaluated total phosphorus (TP) and dissolved organic carbon (DOC) fluxes for the Hay, Liard and Peel tributaries of the Mackenzie River. The TP and DOC concentrations primarily exhibit chemodynamic relationships with discharge, with the exception of the chemostatic relationship between DOC and discharge for the Hay River. With this understanding, we explored a number of enhancements in the load estimation model that included the use of (i) linear regression and logarithmic models, (ii) air-temperature as an alternate input variable and (iii) quantile mapping for bias-correction. Further, we evaluated uncertainties in the simulation of fluxes and trends by using a bootstrapping method. The modelled TP and DOC fluxes show considerable seasonal and interannual variability that generally follow the runoff dynamics. The annual and seasonal trends are mostly small and insignificant, with the largest significant increases occurring in the winter months. These trends are amplified compared with discharge, suggesting the possibility of pronounced changes with large changes in discharge. Additionally, the results provide evidence that directly using limited water constituent samples for trend analysis can be problematic.

MitoNEET (gene cisd1) is a mitochondrial outer membrane [2Fe-2S] protein and is a potential drug target in several metabolic diseases. Previous studies have demonstrated that mitoNEET functions as a redox-active and pH-sensing protein that regulates mitochondrial metabolism, although the structural basis of the potential drug binding site(s) remains elusive. Here we report the crystal structure of the soluble domain of human mitoNEET with a sulfonamide ligand, furosemide. Exploration of the high-resolution crystal structure is used to design mitoNEET binding molecules in a pilot study of molecular probes for use in future development of mitochondrial targeted therapies for a wide variety of metabolic diseases, including obesity, diabetes and neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. MitoNEET is an iron-sulfur protein found in the outer mitochondrial membrane and implicated in several metabolic disorders. Here the crystal structure of mitoNEET with a bound sulfonamide ligand is reported and used to design new mitoNEET ligands.

The aim of this editorial is to evaluate the evidence for using pimavanserin for the treatment of Parkinson's disease psychosis (PDP) from randomized controlled trials (RCTs). We only identified two published trials that evaluated the use of pimavanserin among individuals with PDP. Both studies found that pimavanserin improved psychotic symptoms among individuals with PDP when compared to placebo. Pimavanserin was fairly well tolerated in both studies and did not appear to cause significant sedation or worsen motor symptoms among individuals with PDP. However, given the limited data, additional confirmatory studies are required before pimavanserin can be considered as a first line agent for the treatment of psychotic symptoms among individuals with PD.

Disease relapse in B-cell acute lymphoblastic leukemia (ALL), either due to development of acquired resistance after therapy or because of de novo resistance, remains a therapeutic challenge. In the present study, we have developed a cytarabine (Ara-C)-resistant REH cell line (REH/Ara-C) as a chemoresistance model. REH/Ara-C 1) was not crossresistant to vincristine or methotrexate; 2) showed a similar proliferation rate and cell surface marker expression as parental REH; 3) demonstrated decreased chemotaxis toward bone marrow stromal cells; and 4) expressed higher transcript levels of cytidine deaminase (CDA) and mitoNEET (CISD1) than the parental REH cell line. Based on these findings, we tested NL-1, a mitoNEET inhibitor, which induced a concentration-dependent decrease in cell viability with a comparable IC(50) value in REH and REH/Ara-C. Furthermore, NL-1 decreased cell viability in six different ALL cell lines and showed inhibitory activity in a hemosphere assay. NL-1 also impaired the migratory ability of leukemic cells, irrespective of the chemoattractant used, in a chemotaxis assay. More importantly, NL-1 showed specific activity in inducing death in a drug-resistant population of leukemic cells within a coculture model that mimicked the acquired resistance and de novo resistance observed in the bone marrow of relapsed patients. Subsequent studies indicated that NL-1 mediates autophagy, and inhibition of autophagy partially decreased NL-1–induced tumor cell death. Finally, NL-1 showed antileukemic activity in an in vivo mouse ALL model. Taken together, our study demonstrates that mitoNEET has potential as a novel antileukemic drug target in treatment refractory or relapsed ALL.

The main objective of the present study is to investigate potential effects of PCA in OBX induced depressive-like behavior in rat model. PCA was administered at a dose of 100 mg/kg and 200 mg/kg, by per oral in OBX and sham operated rats. Behavioral (ambulatory and rearing activity and immobility time), neurochemical [serotonin (5-HT), dopamine (DA), norepinephrine (NE) and brain derived neurotrophic factor (BDNF) expression], biochemical (MDA formation, IL-6, TNF-α and antioxidants) changes in hippocampus and cerebral cortex along with serum corticosterone were investigated. Experimental findings reveals that OBX subjected rats showed alteration in behaviors like, increase in immobility time, ambulatory and rearing behaviors significantly, reduced BDNF level, 5-HT, DA,NE and antioxidant parameters along with increased serum corticosterone, MDA formation, IL-6, and TNF-α in hippocampus and cerebral cortex compared to sham operated rats. Administration of PCA significantly attenuated behavioral and neurobiochemical alterations, thus, its antidepressant-like activity is largely mediated through modulation of neurotransmitter, endocrine and immunologic systems, mainly by improvements of BDNF, 5-HT, DA, NE, reduced MDA, IL-6, and TNF-α in hippocampus and cerebral cortex.

Here we present the use of a well-known materials binding peptide for the generation of highly catalytically reactive Rh nanoplates. To this end, the A3 peptide, originally isolated with affinity f...

The multiple effect of pristine graphene (pG) toxicity on cardiovascular developmental defects was assessed using zebrafish as a model. Recently, the nanotoxicity is emerging as a critical issue, and it is more significant in embryogenesis. Especially, graphene and its derivatives have attracted a lot of interest in biomedical applications. However, very little is known about the toxic effects of pG which has been widely used carbon nanomaterial according to concentration and its effects on biological and cardiovascular development. In the present study, we examined the development of zebrafish embryos by exposing to pG (5, 10, 15, 20 and 25 μg/L) under different developmental toxicity end-points such as cardiotoxicity, cardiovascular defect, retardation of cardiac looping, apoptosis and globin expression analysis. For this, the developmental cardiotoxicity of pG at different concentrations and the specific cardiovascular defects thereof were elucidated for the first time. As a result, the exposure to pG was found to be a potential risk factor to cardiovascular system of zebrafish embryos. However, a further study on the variations of physical, molecular properties and mechanisms of nanotoxicity which vary depending on production method and surface functionalization is required. In addition, the potential risks of pG flakes to aquatic organisms and human health should be considered or checked before releasing them to the environment.

Several agents may be useful for treating mild to moderate withdrawal symptoms.

The use of biomolecules has been invaluable at generating and controlling optical chirality in nanomaterials; however, the structure and properties of the chiral biotemplate are not well understood due to the complexity of peptide-nanoparticle interactions. In this study, we show that the complex interactions between d-peptides and gold nanomaterials led to a chiral restructuring of peptides as demonstrated by circular dichroism and proteolytic cleavage of d-peptides via gold-mediated inversion of peptide chirality. The gold nanoparticles synthesized using d-peptide produce a highly ordered atomic surface and restructured peptide bonds for enzyme cleavage. Differences in gold nanoparticle catalyzed reduction of 4-nitrophenol were observed on the basis of the chiral peptide used in nanoparticle synthesis. Notably, the proteolytic cleavage of d-peptides on gold provides an opportunity for designing nanoparticle based therapeutics to treat peptide venoms, access new chemistries, or modulate the catalytic activity of nanomaterials.

In this chapter, we review the important topics of biochemistry and neuropharmacology as it relates to older adults.

Structural proteins such as "suckerins" present promising avenues for fabricating functional materials. Suckerins are a family of naturally occurring block copolymer-type proteins that comprise the sucker ring teeth of cephalopods and are known to self-assemble into supramolecular networks of nanoconfined β-sheets. Here, we report the characterization and controllable, nanoscale self-assembly of suckerin-12 (S12). We characterize the impacts of salt, pH, and protein concentration on S12 solubility, secondary structure, and self-assembly. In doing so, we identify conditions for fabricating ∼100 nm nanoassemblies (NAs) with narrow size distributions. Finally, by installing a noncanonical amino acid (ncAA) into S12, we demonstrate the assembly of NAs that are covalently conjugated with a hydrophobic fluorophore and the ability to change self-assembly and β-sheet content by PEGylation. This work presents new insights into the biochemistry of suckerin-12 and demonstrates how ncAAs can be used to expedite and fine-tune the design of protein materials.

Ethanol withdrawal commonly leads to anxiety-related disorder, a central factor toward negative reinforcement leading to relapse. The lateral habenula (LHb), an epithalamic nucleus, has emerged to be critical for both reward and aversion processing. Recent studies have also implicated the hyperactivity of LHb, adding to the emergence of negative emotional states during withdrawal from addictive drugs. Herein, we have studied the effects of glutamate transporter inhibitor (PDC), GluN2B-containing NMDAR antagonist (Ro25-6981), and intracellular calcium chelator (BAPTA-AM) injection in LHb on ethanol withdrawal symptoms. We found that ethanol 4 g/kg 20 % w/v intragastric (i.g.) for 10 days followed by 24 h of withdrawal showed a significant increase in somatic signs characterized by vocalization, shaking, and scratching. It also increased locomotor activity and anxiety-like behavior, collectively showing expression of ethanol withdrawal symptoms. The intra-LHb administration of PDC (0.5 ng) worsened the effect of ethanol withdrawal, whereas Ro25-6981 (2 and 4 ng) and BAPTA-AM (6.5 and 13 ng) significantly reversed ethanol withdrawal-induced behavior evident by a decrease in somatic signs, locomotor activity, and anxiety-like behavior. Further, pretreatment of Ro25-6981 and BAPTA-AM reduced the neuronal loss, whereas PDC increased it compared to the vehicle-treated group, as evidenced by NeuN staining. Altogether, our results suggest that increased glutamate, GluN2B activation, and likely calcium increase indicative of glutamate excitotoxicity-induced neuronal loss in LHb possibly endorse the emergence of ethanol withdrawal symptoms, while their inhibition might help in alleviating the ethanol withdrawal symptoms.

Introduction Alzheimer's disease (AD) is among the most prevalent forms of dementia in the world. Approximately 25%-50% of individuals with AD develop psychotic symptoms sometime during their illness. The presence of psychosis in AD worsens outcomes. Currently, there are no FDA-approved medications for the treatment of psychosis in AD. Pimavanserin, a novel atypical antipsychotic medication, was approved by the FDA for the treatment of hallucinations and delusions associated with psychosis in Parkinson disease. Pimavanserin is also currently in clinical trials for the treatment of psychosis in AD. The purpose of this literature review is to evaluate the existing literature regarding the use of pimavanserin for treating psychosis in individuals with AD. Methods A literature review of clinical studies of pimavanserin treatment for psychosis in individuals with AD was performed using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Trials were identified by systematically searching PubMed, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus through October 2019. The 5-point JADAD scoring system was used to assess the methodologic quality of randomized placebo-controlled trials (RCT). Results A total of 499 citations were retrieved and pooled. After de-duplication, two separate screeners evaluated the titles, abstracts, and full text of the remaining 258 citations. Two publications from 1 RCT were included in the final analysis. The quality of evidence was assessed to be of good methodologic quality, scoring 4 out of 5 using the 5-point JADAD questionnaire with the JADAD Scoring calculation. This systematic review found only one RCT that evaluated the use of pimavanserin for the treatment of psychosis among individuals with AD. This phase 2 trial resulted in two publications, the second of which was a subgroup analysis from the original study. The evidence from these two publications indicated that pimavanserin improves psychotic symptoms among individuals with AD when compared to placebo at the week 6 checkpoint. Conclusions Pimavanserin may be a pharmacologic consideration for the treatment for psychosis in AD. Additional RCTs are needed to assess the evidence of effectiveness before pimavanserin is considered a standard treatment. Funding This research received no funding agency in the public, commercial, or not-for-profit sectors.

Soluble guanylate cyclase (sGC) is a clinically validated therapeutic target in the treatment of pulmonary hypertension. Modulators of sGC have the potential to treat diseases that are affected by dysregulation of the NO-sGC-cGMP signal transduction pathway. This letter describes the SAR efforts that led to the discovery of CYR715, a novel carboxylic acid-containing sGC stimulator, with an improved metabolic profile relative to our previously described stimulator, IWP-051. CYR715 addressed potential idiosyncratic drug toxicity (IDT) liabilities associated with the formation of reactive, migrating acyl glucuronides (AG) found in related carboxylic acid-containing analogs and demonstrated high oral bioavailability in rat and dose-dependent hemodynamic pharmacology in normotensive Sprague-Dawley rats.

HYD1 is an all D-amino acid linear 10-mer peptide that was discovered by one-bead-one-compound screening. HYD1 has five hydrophobic amino acids flanked by polar amino acids. Alanine scanning studies showed that alternating hydrophobic amino acid residues and N- and C-terminal lysine side chains were contributors to the biological activity of the linear 10-mer analogs. This observation led us to hypothesize that display of the hydrophobic pentapeptide sequence of HYD1 in a cyclic beta-hairpin-like scaffold could lead to better bioavailability and biological activity. An amphipathic pentapeptide sequence was used to form an antiparallel strand and those strands were linked via dipeptide-like sequences selected to promote β-turns. Early cyclic analogs were more active but otherwise mimicked the biological activity of the linear HYD1 peptide. The cyclic peptidomimetics were synthesized using standard Fmoc solid phase synthesis to form linear peptides, followed by solution phase or on-resin cyclization. SAR studies were carried out with an aim to increase the potency of these drug candidates for the killing of multiple myeloma cells

Conopeptides are neurotoxic peptides in the venom of marine cone snails and have broad therapeutic potential for managing pain and other conditions. Here, we identified the single-disulfide peptides Czon1107 and Cca1669 from the venoms of Conus zonatus and Conus caracteristicus, respectively. We observed that Czon1107 strongly inhibits the human α3β4 (IC(50) 15.7 ± 3.0 μm) and α7 (IC(50) 77.1 ± 0.05 μm) nicotinic acetylcholine receptor (nAChR) subtypes, but the activity of Cca1669 remains to be identified. Czon1107 acted at a site distinct from the orthosteric receptor site. Solution NMR experiments revealed that Czon1107 exists in equilibrium between conformational states that are the result of a key Ser(4)–Pro(5) cis-trans isomerization. Moreover, we found that the X-Pro amide bonds in the inter-cysteine loop are rigidly constrained to cis conformations. Structure-activity experiments of Czon1107 and its variants at positions P5 and P7 revealed that the conformation around the X-Pro bonds (cis-trans) plays an important role in receptor subtype selectivity. The cis conformation at the Cys(6)–Pro(7) peptide bond was essential for α3β4 nAChR subtype allosteric selectivity. In summary, we have identified a unique single-disulfide conopeptide with a noncompetitive, potentially allosteric inhibitory mechanism at the nAChRs. The small size and rigidity of the Czon1107 peptide could provide a scaffold for rational drug design strategies for allosteric nAChR modulation. This new paradigm in the “conotoxinomic” structure-function space provides an impetus to screen venom from other Conus species for similar, short bioactive peptides that allosterically modulate ligand-gated receptor function.

Highlights • Medical costs varied over time with low vs. high conformance to guidelines. • Pharmacy costs varied over time with low vs. high conformance to guidelines. • Pharmacy costs were lower in members with low conformance to guidelines. • Diabetes-related outpatient costs were higher in members with low conformance., Objectives To determine if there is a difference in the outcomes of diabetes patients managed with high, intermediate, or low conformance to diabetes guidelines. Study design Retrospective database analysis. Methods This was a retrospective database analysis of adults diagnosed with type 2 diabetes and with glycated hemoglobin (HbA1c) ≥7% (53 mmol/mol) who were commercially insured by, or receiving Medicare benefits through, Aetna. Subjects were classified as having high, intermediate, or low conformance to current guidelines. Six, 12, and 18 months later, health care resource utilization, clinical outcomes, and costs were assessed using multivariable regression analysis to determine whether differences existed between patients with high, intermediate, and low conformance. Regression models were adjusted using pre-index variables, and the results were expressed as incidence rate ratios (IRRs) with 95% confidence intervals (CIs). Results A total of 21,171 individuals were included in the analysis. In analyses of patients with low versus high conformance, pharmacy costs were significantly lower over 18 months of outcome assessment (P

PURPOSE: Pyrvinium pamoate (PP) is an anthelmintic drug that has been found to have anti-cancer activity in several cancer types. In the present study, we evaluated PP for potential anti-leukemic activity in B-cell acute lymphoblastic leukemia (ALL) cell lines, in an effort to evaluate the repurposing potential of this drug in leukemia. METHODS: ALL cells were treated with PP at various concentrations to determine its effect on cell proliferation. Metabolic function was tested by evaluating Extracellular Acidification Rate (ECAR) and Oxygen Consumption Rate (OCR). Lastly, 3D spheroids were grown, and PP was reformulated into nanoparticles to evaluate distribution effectiveness. RESULTS: PP was found to inhibit ALL proliferation, with varied selectivity to different ALL cell subtypes. We also found that PP’s cell death activity was specific for leukemic cells, as primary normal immune cells were resistant to PP-mediated cell death. Metabolic studies indicated that PP, in part, inhibits mitochondrial oxidative phosphorylation. To increase the targeting of PP to a hypoxic bone tumor microenvironment (BTME) niche, we successfully encapsulated PP in a nanoparticle drug delivery system and demonstrated that it retained its anti-leukemic activity in a hemosphere assay. CONCLUSION: We have demonstrated that PP is a novel therapeutic lead compound that counteracts the respiratory reprogramming found in refractory ALL cells and can be effectively formulated into a nanoparticle delivery system to target the BTME.

Competition-enhanced ligand screening (CompELS) was employed to rapidly screen through large DNA libraries to identify single-stranded, oligonucleotide-based ligands called aptamers that bind to a nonbiological target. This previously unreported aptamer screening approach involves the repeated introduction of unenriched random sequence populations during the biopanning process, but avoids iterative elution and polymerase chain reaction (PCR) amplification steps inherent to traditional SELEX (systematic evolution of ligands by exponential enrichment) screening. In this study, 25 aptamers were identified against a gold surface via CompELS and evaluated to identify patterns in primary structures and predicted secondary structures. Following a final one-round competition experiment with the 25 identified aptamers, one particular aptamer sequence (1N) emerged as the most competitive adsorbate species for the gold substrate. Binding analysis indicated at least an order of magnitude difference in the binding affinity of 1N ( K

Earlier, we have shown the efficacy of racemic (±) CIQ, a positive allosteric modulator of GluN2C/2D receptor against MK-801 induced impairment of prepulse inhibition as well as working memory. The present study investigated the antipsychotic-like profile of different CIQ (±, +, -) isomers against schizophrenia-like symptoms in series of behavioural animal models like apomorphine climbing, social isolation behaviour and NMDA receptor antagonist MK-801 induced cognitive deficits. Further, we also tested CIQ (±, +, -) isomers in neurodevelopmental model against MK-801induced deficits using open field test, Y-maze test and novel object recognition test. CIQ (±, +, -) isomers decreased climbing behaviour, increased social interaction and improved the MK-801 induced deficits in working memory in Y-maze. Further, CIQ (±, +) but not CIQ (-) improved the recognition memory in novel object recognition test as well as reduced hyperlocomotion and stereotyped behaviour. We conclude that CIQ (±, +) but not CIQ (-) exhibit the significant antipsychotic-like profile.

Mechanisms of biomaterial sclerotization in natural systems promise new insights into how the mechanical properties of engineered materials may be dynamically modulated. One such example involves the proteinaceous jaw of the marine sandworm, Nereis virens. Previously, the mechanical properties of the N. virens jaw were shown to be modulated by Zn binding, a property that was proposed to be enabled by the presence of the histidine-rich jaw protein, Nvjp-1. Here we demonstrate the creation of Nvjp-1-based hydrogels and show that progressive sclerotization of these hydrogels can be accomplished with hierarchical exposure to metal cations and anions. Divalent Zn cations are capable of reversibly sclerotizing the hydrogels through the formation of coordinate cross-links, an effect that is shown to be remarkably specific for Zn. Additionally, the degree of Zn-induced sclerotization is strongly influenced by the identity of the anion present in the hydrogel. Thus, the viscoelastic properties of Nvjp-1 hydrogels can be modulated through programmed, hierarchical exposure to specific cations and anions present in the sclerotizing salts. These observations have resulted in new hydrogel capabilities, such as the creation of anion-controlled shape-memory polymers, and will add to the number of control parameters that can be used to tune the properties of functional hydrogels in a dynamic manner.

Minicollagens from cnidarian nematocysts are attractive potential building blocks for the creation of strong, lightweight and tough polymeric materials with the potential for dynamic and reconfigurable crosslinking to modulate functionality. In this study, the Hydra magnipapillata minicollagen-1 isoform was recombinantly expressed in bacteria, and a high throughput purification protocol was developed to generate milligram levels of pure protein without column chromatography. The resulting minicollagen-1 preparation demonstrated spectral properties similar to those observed with collagen and polyproline sequences as well as the ability to self-assemble into oriented fibers and bundles. Photo-crosslinking with Ru(II) ( bpy ) 3 2 + was used to create robust hydrogels that were analyzed by mechanical testing. Interestingly, the minicollagen-1 hydrogels could be dissolved with reducing agents, indicating that ruthenium-mediated photo-crosslinking was able to induce disulfide metathesis to create the hydrogels. Together, this work is an important first step in creating minicollagen-based materials whose properties can be manipulated through static and reconfigurable post-translational modifications.

Graphene has been used in several fields covering from electronics to biomedicine, especially exhibiting a widespread variety of promising biological and biomedical applications. In the past decade, the biomedical applications of graphene have attracted much interest. However, the effect of pristine graphene (pG) toxicity in aquatic vertebrates has not been fully studied. Thus, in this study, the toxicity of pG was experimentally evaluated using developing zebrafish embryos as in vivo model system. To determine this, 4-hpf embryos were exposed to different concentrations of pG (1, 5, 10, 15, 20, 25, 30, 35, 40, 45, and 50 μg/L) and different early life-stage parameters were observed at 24, 48, 72, and 96 hpf. Through embryogenesis, pG was observed to induce significant embryonic mortality, delayed hatching, heartbeat, several morphological defects, pericardial toxicity, and bradycardia. Yolk sac edema and pericardial edema were induced by pG in developing embryos. These outcomes would provide new insights into the adverse effects of pG on the developing embryonic cardiac defects in vertebrates and highlight the probable natural environment and health hazards of pG flakes.

As the quest toward novel materials proceeds, improved characterization technologies are needed. In particular, the atomic thickness in graphene and other 2D materials renders some conventional technologies obsolete. Characterization technologies at wafer level are needed with enough sensitivity to detect strain in order to inform fabrication. In this work, NEXAFS spectroscopy was combined with simulations to predict lattice parameters of graphene grown on copper and further transferred to a variety of substrates. The strains associated with the predicted lattice parameters are in agreement with experimental findings. The approach presented here holds promise to effectively measure strain in graphene and other 2D systems at wafer levels to inform manufacturing environments.

In this paper a detailed investigation for corrosion behavior of magnesium substrate electrodeposited differently by nanoparticles like Reduced Graphene Oxide (r-GO synthesized through Modified Hummer’s Method), Silicon Carbide (SiC mechanically alloyed) and also r-GO/SiC nanocomposites (dispersed through ultrasonication process) as coating materials for varying time period was done. Synthesized nanocomposite was characterized through various physio-chemical techniques and confirmation of the same was carried out. Surface morphology of the developed set of specimens was scrutinized through SEM and EDAX which establishes a clean surface coating with minimal defects attainment through electro deposition technique. Electrochemical corrosion behavior for the magnesium substrates coated with r-GO, SiC, r-GO/SiC for 5 and 10 min coating time period was conceded over in 0.1 M of NaCl and Na 2 SO 4 aqueous solution using Tafel polarization and then compared with a pure magnesium substrate. r-GO/SiC nanocomposite coated magnesium substrate showcased a drastic breakthrough in corrosion resistance when compared with other set of specimens in aqueous medium. Delamination behavior for the same set of specimens was carried and the r-GO/SiC nanocomposite coated magnesium exposed a minimum delamination area accounting to the hydrophobic property of graphene and the binding effect of SiC nano particles.

Enzyme‐linked immunosorbent assay is widely utilized in serologic assays, including COVID‐19, for the detection and quantification of antibodies against SARS‐CoV‐2. However, due to the limited stability of the diagnostic reagents (e.g., antigens serving as biorecognition elements) and biospecimens, temperature‐controlled storage and handling conditions are critical. This limitation among others makes biodiagnostics in resource‐limited settings, where refrigeration and electricity are inaccessible or unreliable, particularly challenging. In this work, metal–organic framework encapsulation is demonstrated as a simple and effective method to preserve the conformational epitopes of antigens immobilized on microtiter plate under non‐refrigerated storage conditions. It is demonstrated that in situ growth of zeolitic imidazolate framework‐90 (ZIF‐90) renders excellent stability to surface‐bound SARS‐CoV‐2 antigens, thereby maintaining the assay performance under elevated temperature (40 °C) for up to 4 weeks. As a complementary method, the preservation of plasma samples from COVID‐19 patients using ZIF‐90 encapsulation is also demonstrated. The energy‐efficient approach demonstrated here will not only alleviate the financial burden associated with cold‐chain transportation, but also improve the disease surveillance in resource‐limited settings with more reliable clinical data., Using metal‐organic framework nanocrystals as protective encapsulants, surface bound SARS‐CoV‐2 antigens and antibodies in serum samples obtained from COVID‐19 patients are preserved against elevated temperature for improving the stability of serological assays.