Search

Safe, effective, and low-cost oral antiviral therapies are needed to treat those at high risk for developing severe COVID-19. To that end, we performed a high-throughput screen to identify non-peptidic, non-covalent inhibitors of the SARS-CoV-2 main protease (Mpro), an essential enzyme in viral replication. NZ-804 was developed from a screening hit through iterative rounds of structure-guided medicinal chemistry. NZ-804 potently inhibits SARS-CoV-2 Mpro (0.009 μM IC 50 ) as well as SARS-CoV-2 replication in human lung cell lines (0.008 μM EC 50 ) and primary human airway epithelial cell cultures. Antiviral activity is maintained against distantly related sarbecoviruses and endemic human CoV OC43. In SARS-CoV-2 mouse and hamster disease models, NZ-804 therapy given once or twice daily significantly diminished SARS-CoV-2 replication and pathogenesis. NZ-804 synthesis is low cost and uncomplicated, simplifying global production and access. These data support the exploration of NZ-804 as a therapy for COVID-19 and future emerging sarbecovirus infections., Competing Interests: Declaration of interests J.C.S., S.T., X.B., I.V.K., J.L.W., N.E.Z., M.K.P., A.A., P.K.J., R.B., A.F., and Z.S. are listed as inventors on a patent for NZ-804. R.S.B. is a member of the advisory boards of VaxArt and Invivyd and has collaborations with Takeda, Pfizer, Moderna, Ridgeback Biosciences, Gilead, and Eli Lily. Y.K. has received unrelated funding support from Daiichi Sankyo Pharmaceutical, Toyama Chemical, Tauns Laboratories, Inc., Shionogi & Co., Ltd., Otsuka Pharmaceutical, KM Biologics, Kyoritsu Seiyaku, Shinya Corporation, and Fuji Rebio., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

We present results from the molecular dynamics simulation of surface-directed spinodal decomposition in binary fluid mixtures (A + B) with off-critical compositions. The aim is to elucidate the role of composition ratio in the early time wetting kinetics under the influence of long-range surface potential. In our simulations, the attractive part of surface potential varies as V(z) = -ϵa/zn, with ϵa being the surface-potential strength. The surface prefers the "A" species to form the wetting layer. Its thickness [R1(t)] for the majority wetting (number of A-type particles [NA] > number of B-type particles [NB]) grows as a power-law with an exponent of 1/(n + 2). This is consistent with the early time kinetics in the form of potential-dependent growth present in the Puri-Binder model. However, for minority wetting (NA < NB), the growth exponent in R1(t) is less than 1/(n + 2). Furthermore, on decreasing the field strength ϵa, we recover 1/(n + 2) for a minority wetting case. We provide phenomenological arguments to explain the early time wetting kinetics for both cases., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Breast cancer is one of the leading causes of death among women globally, making its diagnosis and treatment challenging. The use of nanotechnology for cancer diagnosis and treatment is an emerging area of research. To address this issue, multiwalled carbon nanotubes (MWCNTs) were ligand exchanged with butyric acid (BA) to gain hydrophilic character. The successful functionalization was confirmed by FTIR spectroscopy. Surface morphology changes were observed using SEM, while TEM confirmed the structural integrity of the MWCNTs after functionalization. Particle size, zeta potential, and UV spectroscopy were also performed to further characterize the nanoparticles. The breast cancer aptamer specific to Mucin-1 (MUC-1) was then conjugated with the functionalized MWCNTs. These MWCNTs successfully targeted breast cancer cells (MDA-MB-231) as examined by cellular uptake studies and exhibited a reduction in cancer-induced inflammation, as evidenced by gene transcription (qPCR) and protein expression (immunoblotting) levels. Immunoblot and confocal-based immunofluorescence assay (IFA) indicated the ability of CNTs to induce photothermal cell death of MDA-MB-231 cells. Upon imaging, cancer cells were effectively visualized due to the MWCNTs' ability to act as magnetic resonance imaging (MRI) contrast agents. Additionally, MWCNTs demonstrated photothermal capabilities to eliminate bound cancer cells. Collectively, our findings pave the way for developing aptamer-labeled MWCNTs as viable "theranostic alternatives" for breast cancer treatment., (© 2024. The Author(s).)

Purpose: Total hip arthroplasty (THA) is a common and successful operation. However, dislocation remains a significant cause of implant failure in fixed-bearing designs. This study investigated the effect of dual-mobility implants (DM) compared to fixed-bearing (FB) implants on all-cause revisions, revisions due to dislocation, post-operative complications and functional scores in patients undergoing primary and revision THA., Methods: A systematic review was performed including studies that compared DM with FB implants in primary or revision THA according to PRISMA guidelines, and was registered in PROSPERO (ID CRD42023403736). The Cochrane Library, Embase, MEDLINE, Web of Science, and Scopus were searched from the time of database inception to March 12, 2023. Eligible studies underwent meta-analysis and risk of bias assessment using the ROBINS-I tool. Treatment effects were assessed using odds ratios and data were pooled using a random-effects maximum-likelihood, where appropriate., Results: Eight comparative, non-randomised studies involving 2810 DM implants and 3188 FB implants were included. In primary THA, there was an imprecise estimate of the difference in all-cause revision (OR 0.82, 95 % CI 0.25-2.72) and a significant benefit for the DM cohort in revision due to dislocation (OR 0.08, 95 % CI 0.02-0.28). In revision THA, the DM cohort showed benefit in all-cause revision (OR 0.57, 95 % CI 0.31-1.05) and revision due to dislocation (OR 0.14, 95 % CI 0.04-0.53). DM implants were associated with a lower incidence of implant dislocation and infection. The analysis of functional outcomes was limited due to reporting limitations. No intraprosthetic dislocations were observed., Conclusion: The results suggest that contemporary DM designs may be advantageous in reducing the risk of all-cause revision, revision due to dislocation, and post-operative complication incidence at mid-term follow-up. Further high-quality prospective studies are needed to evaluate the long-term risk profile of this design, especially in the revision context., (© 2024 The Authors.)

In castration-resistant prostate cancer (CRPC), increased glucocorticoid receptor (GR) expression and ensuing transcriptional activity have been proposed as an oncogenic "bypass" mechanism in response to androgen receptor (AR) signaling inhibition (ARSi). Here, we report that GR transcriptional activity acquired following ARSi is associated with the upregulation of cyclic adenosine monophosphate (cAMP)-associated gene expression pathways in both model systems and metastatic prostate cancer patient samples. In the context of ARSi, the expression of GR-mediated genes encoding cAMP signaling pathway-associated proteins can be inhibited by treatment with selective GR modulators (SGRMs). For example, in the context of ARSi, we found that GR activation resulted in upregulation of protein kinase inhibitor beta (PKIB) mRNA and protein levels, leading to nuclear accumulation of the cAMP-dependent protein kinase A catalytic subunit (PKA-c). Increased PKA-c, in turn, is associated with increased cAMP response element-binding protein phosphorylation and activity. Furthermore, enzalutamide and SGRM combination therapy in mice bearing CRPC xenografts delayed CRPC progression compared with enzalutamide therapy alone, and reduced tumor PKIB mRNA expression. Supporting the clinical importance of GR/PKA signaling activation in CRPC, we found a significant enrichment of both cAMP pathway signaling-associated gene expression and high NR3C1 (GR) activity in patient-derived xenograft models and metastatic human CRPC samples. These findings suggest a novel mechanism linking CRPC-induced GR transcriptional activity with increased cAMP signaling in AR-antagonized CRPC. Furthermore, our findings suggest that GR-specific modulation in addition to AR antagonism may delay GR+ CRPC time to recurrence, at least in part, by inhibiting tumor cAMP/PKA pathways., (©2023 The Authors; Published by the American Association for Cancer Research.)

Respiratory diseases (RD) are a group of common ailments with a rapidly increasing global prevalence, posing a significant threat to humanity, especially the elderly population, and imposing a substantial burden on society and the economy. RD represents an unmet medical need that requires the development of viable pharmacotherapies. While various promising strategies have been devised to advance potential treatments for RD, their implementation has been hindered by difficulties in drug delivery, particularly in critically ill patients. Nanotechnology offers innovative solutions for delivering medications to the inflamed organ sites, such as the lungs. Although this approach is enticing, delivering nanomedicine to the lungs presents complex challenges that require sophisticated techniques. In this context, we review the potential of novel nanomedicine-based immunomodulatory strategies that could offer therapeutic benefits in managing this pressing health condition.

Using all-atom molecular dynamics simulations, we report the structure and ion transport characteristics of a new class of solid polymer electrolytes that contain the biodegradable and mechanically stable biopolymer pectin. We used highly conducting ethylene carbonate (EC) as a solvent for simulating lithium-trifluoromethanesulfonimide (LiTFSI) salt containing different weight percentages of pectin. Our simulations reveal that the pectin chains reduce the coordination number of lithium ions around their counterions (and vice versa ) because of stronger lithium-pectin interactions compared to lithium-TFSI interactions. Furthermore, the pectin is found to promote smaller ionic aggregates over larger ones, in contrast to the results typically reported for liquid and polymer electrolytes. We observed that the loading of pectin in EC-LiTFSI electrolytes increases their viscosity ( η ) and relaxation timescales ( τ c ), indicating higher mechanical stability, and, consequently, a decrease of the mean squared displacement, diffusion coefficient ( D ), and Nernst-Einstein conductivity ( σ NE ). Interestingly, while the lithium diffusivities are related to the ion-pair relaxation timescales as D + ∼ τ c -3.1 , the TFSI - diffusivities exhibit excellent correlations with ion-pair relaxation timescales as D - ∼ τ c -0.95 . On the other hand, the NE conductivities are dictated by distinct transport mechanisms and scales with ion-pair relaxation timescales as σ NE ∼ τ c -1.85 .

Pharmaceutical development of cancer therapeutics is a dynamic area of research. Even after decades of intensive work, cancer continues to be a dreadful disease with an ever-increasing global incidence. The progress of nanotechnology in cancer research has overcome inherent limitations in conventional cancer chemotherapy and fulfilled the need for target-specific drug carriers. Nanotechnology uses the altered patho-physiological microenvironment of malignant cells and offers various advantages like improved solubility, reduced toxicity, prolonged drug circulation with controlled release, circumventing multidrug resistance, and enhanced biodistribution. Early cancer detection has a crucial role in selecting the best drug regime, thus, diagnosis and therapeutics go hand in hand. Furthermore, nanobots are an amazing possibility and promising innovation with numerous significant applications, particularly in fighting cancer and cleaning out blood vessels. Nanobots are tiny robots, ranging in size from 1 to 100 nm. Moreover, the nanobots would work similarly to white blood cells, watching the bloodstream and searching for indications of distress. This review articulates the evolution of various organic and inorganic nanoparticles and nanobots used as therapeutics, along with their pros and cons. It also highlights the shift in diagnostics from conventional methods to more advanced techniques. This rapidly growing domain is providing more space for engineering desired nanoparticles that can show miraculous results in therapeutic and diagnostic trials.

Background: Coronaviruses such as Severe Acute Respiratory Syndrome coronavirus (SARS), Middle Eastern Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are associated with critical illnesses, including severe respiratory disorders. SARS-CoV-2 is the causative agent of the deadly COVID-19 illness, which has spread globally as a pandemic. SARS-CoV-2 may enter the human body through olfactory lobes and interact with the angiotensin-converting enzyme2 (ACE2) receptor, further facilitating cell binding and entry into the cells. Reports have shown that the virus can pass through the blood-brain barrier (BBB) and enter the central nervous system (CNS), resulting in various disorders. Cell entry by SARS-CoV-2 largely relies on TMPRSS2 and cathepsin L, which activate S protein. TMPRSS2 is found on the cell surface of respiratory, gastrointestinal and urogenital epithelium, while cathepsin-L is a part of endosomes., Aim: The current review aims to provide information on how SARS-CoV-2 infection affects brain function.. Furthermore, CNS disorders associated with SARS-CoV-2 infection, including ischemic stroke, cerebral venous thrombosis, Guillain-Barré syndrome, multiple sclerosis, meningitis, and encephalitis, are discussed. The many probable mechanisms and paths involved in developing cerebrovascular problems in COVID patients are thoroughly detailed., Main Body: There have been reports that the SARS-CoV-2 virus can cross the blood-brain barrier (BBB) and enter the central nervous system (CNS), where it could cause a various illnesses. Patients suffering from COVID-19 experience a range of neurological complications, including sleep disorders, viral encephalitis, headaches, dysgeusia, and cognitive impairment. The presence of SARS-CoV-2 in the cerebrospinal fluid (CSF) of COVID-19 patients has been reported. Health experts also reported its presence in cortical neurons and human brain organoids. The possible mechanism of virus infiltration into the brain can be neurotropic, direct infiltration and cytokine storm-based pathways. The olfactory lobes could also be the primary pathway for the entrance of SARS-CoV-2 into the brain., Conclusions: SARS-CoV-2 can lead to neurological complications, such as cerebrovascular manifestations, motor movement complications, and cognitive decline. COVID-19 infection can result in cerebrovascular symptoms and diseases, such as strokes and thrombosis. The virus can affect the neural system, disrupt cognitive function and cause neurological disorders. To combat the epidemic, it is crucial to repurpose drugs currently in use quickly and develop novel therapeutics., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The development of early non-invasive diagnosis methods and identification of novel biomarkers are necessary for managing Alzheimer's disease (AD) and facilitating effective prognosis and treatment. AD has multi-factorial nature and involves complex molecular mechanism, which causes neuronal degeneration. The primary challenges in early AD detection include patient heterogeneity and lack of precise diagnosis at the preclinical stage. Several cerebrospinal fluid (CSF) and blood biomarkers have been proposed to show excellent diagnosis ability by identifying tau pathology and cerebral amyloid beta (Aβ) for AD. Intense research endeavors are being made to develop ultrasensitive detection techniques and find potent biomarkers for early AD diagnosis. To mitigate AD worldwide, understanding various CSF biomarkers, blood biomarkers, and techniques that can be used for early diagnosis is imperative. This review attempts to provide information regarding AD pathophysiology, genetic and non-genetic factors associated with AD, several potential blood and CSF biomarkers, like neurofilament light, neurogranin, Aβ, and tau, along with biomarkers under development for AD detection. Besides, numerous techniques, such as neuroimaging, spectroscopic techniques, biosensors, and neuroproteomics, which are being explored to aid early AD detection, have been discussed. The insights thus gained would help in finding potential biomarkers and suitable techniques for the accurate diagnosis of early AD before cognitive dysfunction., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Machine learning has proven exceptionally competent in numerous applications of studying dynamical systems. In this article, we demonstrate the effectiveness of reservoir computing, a famous machine learning architecture, in learning a high-dimensional spatiotemporal pattern. We employ an echo-state network to predict the phase ordering dynamics of 2D binary systems-Ising magnet and binary alloys. Importantly, we emphasize that a single reservoir can be competent enough to process the information from a large number of state variables involved in the specific task at minimal computational training cost. Two significant equations of phase ordering kinetics, the time-dependent Ginzburg-Landau and Cahn-Hilliard-Cook equations, are used to depict the result of numerical simulations. Consideration of systems with both conserved and non-conserved order parameters portrays the scalability of our employed scheme., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

A few protein kinases and phosphatases regulate tau protein phosphorylation and an imbalance in their enzyme activity results in tau hyper-phosphorylation. Aberrant tau phosphorylation causes tau to dissociate from the microtubules and clump together in the cytosol to form neurofibrillary tangles (NFTs), which lead to the progression of neurodegenerative disorders including Alzheimer's disease (AD) and other tauopathies. Hence, targeting hyperphosphorylated tau protein is a restorative approach for treating neurodegenerative tauopathies. The cyclin-dependent kinase (Cdk5) and the glycogen synthase kinase (GSK3β) have both been implicated in aberrant tau hyperphosphorylation. The limited transport of drugs through the blood-brain barrier (BBB) for reaching the central nervous system (CNS) thus represents a significant problem in the development of drugs. Drug delivery systems based on nanocarriers help solve this problem. In this review, we discuss the tau protein, regulation of tau phosphorylation and abnormal hyperphosphorylation, drugs in use or under clinical trials, and treatment strategies for tauopathies based on the critical role of tau hyperphosphorylation in the pathogenesis of the disease. Pathology of neurodegenerative disease due to hyperphosphorylation and various therapeutic approaches including nanotechnology for its treatment., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Favipiravir (FAV) has become a promising antiviral agent for the treatment of COVID-19. Herein, a green, fast, high-sample-throughput, non-instrumental, and affordable analytical method is proposed based on surfactant-assisted dispersive liquid-liquid microextraction (SA-DLLME) combined with thin-layer chromatography-digital image colourimetry (TLC-DIC) for determining favipiravir in biological and pharmaceutical samples. Triton X-100 and dichloromethane (DCM) were used as the disperser and extraction solvents, respectively. The extract obtained after DLLME procedure was spotted on a TLC plate and allowed to develop with a mobile phase of chloroform:methanol (8:2, v / v ). The developed plate was photographed using a smartphone under UV irradiation at 254 nm. The quantification of FAV was performed by analysing the digital images' spots with open-source ImageJ software. Multivariate optimisation using Plackett-Burman design (PBD) and central composite design (CCD) was performed for the screening and optimisation of significant factors. Under the optimised conditions, the method was found to be linear, ranging from 5 to 100 µg/spot, with a correlation coefficient (R 2 ) ranging from 0.991 to 0.994. The limit of detection (LOD) and limit of quantification (LOQ) were in the ranges of 1.2-1.5 µg/spot and 3.96-4.29 µg/spot, respectively. The developed approach was successfully applied for the determination of FAV in biological (i.e., human urine and plasma) and pharmaceutical samples. The results obtained using the proposed methodology were compared to those obtained using HPLC-UV analysis and found to be in close agreement with one another. Additionally, the green character of the developed method with previously reported protocols was evaluated using the ComplexGAPI, AGREE, and Eco-Scale greenness assessment tools. The proposed method is green in nature and does not require any sophisticated high-end analytical instruments, and it can therefore be routinely applied for the analysis of FAV in various resource-limited laboratories during the COVID-19 pandemic.

We present simulation results from a comprehensive molecular dynamics (MD) study of surface-directed spinodal decomposition (SDSD) in unstable symmetric binary mixtures at wetting surfaces. We consider long-ranged and short-ranged surface fields to investigate the early stage wetting kinetics. The attractive part of the long-ranged potential is of the form V(z)∼z^{-n}, where z is the distance from the surface and n is the power-law exponent. We find that the wetting-layer thickness R&#95;{1}(t) at very early times exhibits a power-law growth with an exponent α=1/(n+2). It then crosses over to a universal fast-mode regime with α=3/2. In contrast, for the short-ranged surface potential, a logarithmic behavior in R&#95;{1}(t) is observed at initial times. Remarkably, similar rapid growth is seen in this case too. We provide phenomenological arguments to understand these growth laws. Our MD results firmly establish the existence of universal fast-mode kinetics and settle the related controversy.

Antimicrobial peptides (AMPs) attracted attention as potential source of novel antimicrobials. Multi-drug resistant (MDR) infections have emerged as a global threat to public health in recent years. Furthermore, due to rapid emergence of new diseases, there is pressing need for development of efficient antimicrobials. AMPs are essential part of the innate immunity in most living organisms, acting as the primary line of defense against foreign invasions. AMPs kill a wide range of microorganisms by primarily targeting cell membranes or intracellular components through a variety of ways. AMPs can be broadly categorized based on their physico-chemical properties, structure, function, target and source of origin. The synthetic analogues produced either with suitable chemical modifications or with the use of suitable delivery systems are projected to eliminate the constraints of toxicity and poor stability commonly linked with natural AMPs. The concept of peptidomimetics is gaining ground around the world nowadays. Among the delivery systems, nanoparticles are emerging as potential delivery tools for AMPs, amplifying their utility against a variety of pathogens. In the present review, the broad classification of various AMPs, their mechanism of action (MOA), challenges associated with AMPs, current applications, and novel strategies to overcome the limitations have been discussed., Competing Interests: Declaration of competing interest None., (Copyright © 2022. Published by Elsevier B.V.)

The integrity of the blood-brain barrier (BBB) is essential for normal central nervous system (CNS) functioning. Considering the significance of BBB in maintaining homeostasis and the neural environment, we aim to provide an overview of significant aspects of BBB. Worldwide, the treatment of neurological diseases caused by BBB disruption has been a major challenge. BBB also restricts entry of neuro-therapeutic drugs and hinders treatment modalities. Hence, currently nanotechnology-based approaches are being explored on large scale as alternatives to conventional methodologies. It is necessary to investigate the in-depth characteristic features of BBB to facilitate the discovery of novel drugs that can successfully cross the barrier and target the disease effectively. It is imperative to discover novel strategies to treat life-threatening CNS diseases in humans. Therefore, insights regarding building blocks of BBB, activation of immune response on breach of this barrier, and various autoimmune neurological disorders caused due to BBB dysfunction are discussed. Further, special emphasis is given on delineating BBB disruption leading to CNS disorders. Moreover, various mechanisms of transport pathways across BBB, several novel strategies, and alternative routes by which drugs can be properly delivered into CNS are also discussed., (© 2022. The Author(s).)

Hippo pathway is a master regulator of development, cell proliferation, stem cell function, tissue regeneration, homeostasis, and organ size control. Hippo pathway relays signals from different extracellular and intracellular events to regulate cell behavior and functions. Hippo pathway is conserved from Protista to eukaryotes. Deregulation of the Hippo pathway is associated with numerous cancers. Alteration of the Hippo pathway results in cell invasion, migration, disease progression, and therapy resistance in cancers. However, the function of the various components of the mammalian Hippo pathway is yet to be elucidated in detail especially concerning tumor biology. In the present review, we focused on the Hippo pathway in different model organisms, its regulation and deregulation, and possible therapeutic targets for cancer treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This paper is the second in a two-part exposition on surface-directed spinodal decomposition (SDSD), i.e., the interplay of kinetics of wetting and phase separation at a surface which is wetted by one of the components of a binary mixture. In our first paper [P. Das, P. K. Jaiswal, and S. Puri, Phys. Rev. E 102, 012803 (2020)2470-004510.1103/PhysRevE.102.012803], we studied SDSD on chemically heterogeneous and physically flat substrates. In this paper, we study SDSD on a chemically homogeneous but morphologically patterned substrate. Such substrates arise in a vast variety of technological applications. Our goal is to provide a theoretical understanding of SDSD in this context. We present detailed numerical results for domain growth both inside and above the grooves in the substrate. The morphological evolution can be understood in terms of the interference of SDSD waves originating from the different surfaces comprising the substrate.

Surface-directed spinodal decomposition (SDSD) is the kinetic interplay of phase separation and wetting at a surface. This process is of great scientific and technological importance. In this paper, we report results from a numerical study of SDSD on a chemically patterned substrate. We consider simple surface patterns for our simulations, but most of the results apply for arbitrary patterns. In layers near the surface, we observe a dynamical crossover from a surface-registry regime to a phase-separation regime. We study this crossover using layerwise correlation functions and structure factors and domain length scales.

The key to the survival of a species lies in understanding its evolution in an ever-changing environment. We report a theoretical model that integrates frequency-dependent selection, mutation, and asexual reproduction for understanding the biological evolution of a host species in the presence of parasites. We study the host-parasite coevolution in a one-dimensional genotypic space by considering a dynamic and heterogeneous environment modeled using a fitness landscape. It is observed that the presence of parasites facilitates a faster evolution of the host population toward its fitness maximum. We also find that the time required to reach the maximum fitness (optimization time) decreases with increased infection from the parasites. However, the overall fitness of the host population declines due to the parasitic infection. In the limit where parasites are considered to evolve much faster than the hosts, the optimization time reduces even further. Our findings indicate that parasites can play a crucial role in the survival of its host in a rapidly changing environment.

Snorc (Small NOvel Rich in Cartilage) has been identified as a chondrocyte-specific gene in the mouse. Yet little is known about the SNORC protein biochemical properties, and mechanistically how the gene is regulated transcriptionally in a tissue-specific manner. The goals of the present study were to shed light on those important aspects. The chondrocyte nature of Snorc expression was confirmed in mouse and rat tissues, in differentiated (day 7) ATDC5, and in RCS cells where it was constitutive. Topological mapping and biochemical analysis brought experimental evidences that SNORC is a type I protein carrying a chondroitin sulfate (CS) attached to serine 44. The anomalous migration of SNORC on SDS-PAGE was due to its primary polypeptide features, suggesting no additional post-translational modifications apart from the CS glycosaminoglycan. A highly conserved SOX9-binding enhancer located in intron 1 was necessary to drive transcription of Snorc in the mouse, rat, and human. The enhancer was active independently of orientation and whether located in a heterologous promoter or intron. Crispr-mediated inactivation of the enhancer in RCS cells caused reduction of Snorc. Transgenic mice carrying the intronic multimerized enhancer drove high expression of a βGeo reporter in chondrocytes, but not in the hypertrophic zone. Altogether these data confirmed the chondrocyte-specific nature of Snorc and revealed dependency on the intronic enhancer binding of SOX9 for transcription.

This work discloses an electrochemical oxidative cross-coupling of amines with aryl and aliphatic isocyanides. In an undivided cell, the reaction proceeds without involving any transition-metal catalyst, oxidant, or toxic reagents providing carbodiimides in good yields, thereby circumventing stoichiometric chemical oxidants, with H 2 as the only byproduct. Moreover, carbodiimides were in situ converted into unsymmetrical ureas in moderate to good yields using an electricity ON-OFF strategy.

PDEF (prostate-derived ETS factor, also known as SAM-pointed domain containing ETS transcription factor (SPDEF)) is expressed in luminal epithelial cells of the prostate gland and associates with luminal phenotype. The Hippo pathway regulates cell growth/proliferation, cellular homeostasis, and organ development by modulating phosphorylation of its downstream effectors. In previous studies, we observed decreased levels of PDEF during prostate cancer progression. In the present study, we evaluated the effects of the expression of PDEF on total/phosphoprotein levels of YAP1 (a downstream effector of the Hippo pathway). We observed that the PC3 and DU145 cells transfected with PDEF (PDEF-PC3 and PDEF-DU145) showed an increased phospho-YAP1 (Ser127) and total YAP1 levels as compared to the respective PC3 vector control (VC-PC3) and DU145 vector control cells (VC-DU145). We also observed an increased cytoplasmic YAP1 levels in PDEF-PC3 cells as compared to VC-PC3 cells. Moreover, our gene set enrichment analysis (GSEA) of mRNA expression in PDEF-PC3 and VC-PC3 cells revealed that PDEF resulted in inhibition of YAP1 target genes, directly demonstrating that PDEF plays a critical role in modulating YAP1 activity, and by extension in the regulation of the Hippo pathway. We also observed a decrease in YAP1 mRNA levels in prostate cancer tissues as compared to normal prostate tissues. Our analysis of multiple publicly available clinical cohorts revealed a gradual decrease in YAP1 mRNA expression during prostate cancer progression and metastasis. This decrease was similar to the decrease in PDEF levels, which we had reported earlier, and we observed a direct correlation between PDEF and YAP1 expression in CRPC data set. To the best of our knowledge, these results provide the first demonstration of inhibiting YAP1 activity by PDEF in any system and suggest a cross-talk between PDEF and the Hippo signaling pathway.

A metal-free diastereo-/regioselective modular synthetic approach for the synthesis of highly constrained tetrahydroquinoline-fused tetracyclic heterocycles from easily available substrates has been developed. This two-step strategy utilizes an Ugi four-component reaction, followed by the intramolecular spirocarbocyclization and iodination reactions in a single operation. The transformation is mild and operationally simple, which provides architecturally complex polycyclic heterocycles with high diastereoselectivity. Furthermore, the preliminary cytotoxicity screening of selected compounds displayed promising anticancer activity against human cancer cell lines.

Background: Cap-dependent mRNA translation is essential for the translation of key oncogenic proteins at optimal levels and is highly regulated by the rate limiting, initiation step in protein synthesis. Eukaryotic Translation Initiation Factor 4 Gamma 1 (EIF4G1) serves as a scaffold for assembly of cap-dependent translation components in EIF4F complex formation. In the current study, we analyzed the role and expression of EIF4G1 in Pan human cancer panels through various approaches., Methods: Immunohistochemistry analysis of EIF4G1 protein was done on high-density multi-organ Human Cancer tissue microarray (TMA) derived from the patient samples from different cancers. We used multiple clinical cohorts to analyze the EIF4G1 mRNA expression across human cancers. TCGA data analysis of EIF4G1 was done through Ualcan and c-bioportal web servers. Western blots for EIF4G1 protein was done for different cell lines in representing the multiple cancer types. Dependency score was calculated through Cancer Dependency Map. Clonogenic, tumorosphere assay and cell invasion assay were done with EIF4G complex inhibitor. Association of EIF4G1 mRNA and Kaplan-Meier survival analysis was done on available TCGA datasets., Results: We observed an increase in EIF4G1 protein levels in tissue sections from different cancers as compared to their respective normal tissue. Our analysis of the TCGA data revealed that EIF4G1 mRNA expression is significantly increased in tumor tissues compared to respective control tissues across human cancers and variable expression was observed among different datasets. We discovered that alteration frequency in EIF4G1 is prevalent in human cancers e.g. prostate cancer (~ 25%), ovarian cancer (~ 15%), Head and Neck cancer (~ 13%) and cervical cancer (~ 12.5%). EIF4G1 mRNA and protein levels were high across cancer cell lines from multiple organs. Our analysis of DepMap datasets utilizing depletion assays revealed that EIF4G1 is critical for cancer cell survival. Treatment with EIF4G complex inhibitor impaired clonogenic, tumorosphere formation potential and inhibited cell invasion. Moreover, higher EIF4G1 mRNA level was associated with a lower median survival of patients in multiple tumor types., Conclusions: These studies show that EIF4G1 is amplified/over-expressed in multiple cancers and plays an essential role in cancer cell survival, as such EIF4G1 could serve as a novel potential target for therapeutic intervention across many cancers., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Standard therapy for advanced Prostate Cancer (PCa) consists of antiandrogens, which provide respite from disease progression, but ultimately fail resulting in the incurable phase of the disease: mCRPC. Targeting PCa cells before their progression to mCRPC would greatly improve the outcome. Combination therapy targeting the DNA Damage Response (DDR) has been limited by general toxicity, and a goal of clinical trials is how to target the DDR more specifically. We now show that androgen deprivation therapy (ADT) of LNCaP cells results in increased expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DDR that typically results in a temporary cell cycle arrest of androgen responsive PCa cells. Following DNA damage, addition of the TLK specific inhibitor, thioridazine (THD), impairs ATR and Chk1 activation, establishing the existence of a ADT > TLK1 > NEK1 > ATR > Chk1, DDR pathway, while its abrogation leads to apoptosis. Treatment with THD suppressed the outgrowth of androgen-independent (AI) colonies of LNCaP and TRAMP-C2 cells cultured with bicalutamide. Moreover, THD significantly inhibited the growth of several PCa cells in vitro (including AI lines). Administration of THD or bicalutamide was not effective at inhibiting long-term tumor growth of LNCaP xenografts. In contrast, combination therapy remarkably inhibited tumor growth via bypass of the DDR. Moreover, xenografts of LNCaP cells overexpressing a NEK1-T141A mutant were durably suppressed with bicalutamide. Collectively, these results suggest that targeting the TLK1/NEK1 axis might be a novel therapy for PCa in combination with standard of care (ADT)., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

An environmentally benign highly atom-economic protocol for the construction of the C-C bond has been developed under catalyst- and solvent-free conditions. This protocol involves the efficient coupling of 2-methyl quinazolinones with isatin for the highly diastereoselective access of schizocommunin derivatives in excellent yields (up to 97%). Furthermore, the preliminary cytotoxicity screening of selected schizocommunin analogues displayed promising anticancer activity against human cancer cell lines, and the cytotoxic potential of active compound 12ac was also validated by in silico molecular docking simulation studies., Competing Interests: The authors declare no competing financial interest.

We recently uncovered the critical TLK1>NEK1>ATR > Chk1 axis in mediating the DDR and cell cycle checkpoint while transiting from Androgen Sensitive to Insensitive growth for LNCaP and TRAMP-C2 cells. However, we did not know the generality of this pathway in PCa progression since there are few cell lines where the transition has been studied. Furthermore, the identification of Nek1, and more importantly the TLK-mediated phosphorylation of T141, has never been studied in PCa biopsies. We now report the first study of a PCa TMA of p-Nek1-T141 and correlation to the Gleason score. In addition we found that TRAMP mice treated with the TLK inhibitor, thioridazine (THD), following castration did not recover cancerous growth of their prostates. Moreover, we recapitulated the process of translational increase in TLK1B expression in a naïve PDX model that was established from an AR + adenocarcinoma. Therefore, we believe that this TLK1-Nek1 mediated DDR axis is likely to be a common adaptive response during the transition of PCa cells toward androgen-insensitive growth, and hence CRPC progression, which has the potential to be targeted with THD and other TLK or Nek1 inhibitors., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Delays to surgery after hip fracture have been associated with mortality Uncertainty remains as to what timing benchmark should be utilized as a marker of quality of care and how other patient factors might also influence the impact of time to surgery on mortality. The goal of this study was to determine how time to surgery affects 30- and 90-day mortality by age and to explore the impact of preoperative comorbid burden and sex., Participants: We used population-based administrative data from a Canadian province collected from 01April2008 to 31March2015. Of 12,713 Albertans 50-years and older who experienced a hip fracture and underwent surgery within 100 h of admission, 11,996 (94.8%) provided data., Methods: Time to surgery was analyzed in hours from admission to surgery. Age and the interaction between age and time to surgery were evaluated using logistic regression. Charlson co-morbidity score and sex were also considered in the analysis. Survival was evaluated at 30-and 90-days post hip fracture using a provincial registry., Results: The average age of the cohort was 79.6 ± 11.2 years and 8,412 (70.1%) were female. Overall, 586 (4.9%) patients died within 30-days and 1,023 (8.5%) died within 90-days of hip fracture. Mortality increased significantly with increasing time to surgery (30-day mortality odds ratio [OR] = 1.03; 95%CI 1.01-1.05: 90-day mortality OR = 1.03; 95% CI 1.01-1.04). Mortality also increased substantially with increasing age; those ≥85 years were 19.63 (95% CI 6.83-67.33) and 15.66 (95%CI 7.20-37.16) times the odds more likely to die relative to those between 50-64 years of age at 30-days and 90-days postoperatively respectively. Further, those who were ≥85 years were more significantly affected by increasing time to surgery than those who were 50-64 years of age at both 30-days (p = 0.04) and 90-days (p = 0.025) post-fracture. Males and those with a higher comorbid burden also had higher odds of dying after controlling for time to surgery (p < 0.001) CONCLUSION: Time to surgery following hip fracture may have a differential effect on 30- and 90-day survival dependent on age. Older patients appear to be at higher risk of dying with surgical delays than younger patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

GEMIN4 is a member of the GEMIN gene family which is involved in multiple pathologies including cancer. It is located on Chr17p13.3, the most notorious chromosome and a hotspot for various carcinomas. We therefore intend to find genetic variants of GEMIN4 gene associated with renal cell carcinoma risk (RCC). This study comprised 100 patients and 225 controls. Genotyping of GEMIN4 gene variants was done using Taqman ® assay. The association of GEMIN4 variants and risk prediction of RCC was done by statistical analysis. Haplotype analysis was done to see the combined effect of variants on RCC. Patients carrying variant genotype, CC of GEMIN4 T/C rs7813 showed significant association whereas in case of GEMIN4 G/C rs910925 variant genotype, CC significant risk was found. GEMIN4 rs7813 T/C variant genotype, CC showed risk with smoking ( p  = 0.034). Our study gives a substantive support for the association between the GEMIN4 gene variants and RCC risk., Competing Interests: Compliance with Ethical StandardsThe authors declare that they have no conflict of interest.

An unprecedented organocatalytic, regioselective, modified Guareschi-Thorpe type protocol toward the modular synthesis of 5,6,7,8-tetrahydroquinolines 22a-g and other alicyclic[ b]-fused pyridines 23-28 via the identification of Chitosan as a heterogeneous catalyst is reported. This novel strategy is operationally simple and showed a wide range of functional group tolerance and substrate compatibility. The proposed mechanistic pathway involves an imine-enamine cascade approach for the synthesis of structurally diverse alicyclic[ b]-fused pyridine heterocycles. The gram scale synthesis and identification of a new class of antifungal molecules 29-31 emphasize the practicality of this method.

To explore the potential of aporphine alkaloids, a novel series of functionalized aporphine analogues with alkoxy (OCH 3 , OC 2 H 5 , OC 3 H 7 ) functional groups at C1/C2 of ring A and an acyl (COCH 3 and COPh) or phenylsulfonyl (SO 2 Ph and SO 2 C 6 H 4 -3-CH 3 ) functionality at the N6 position of ring B of the aporphine scaffold were synthesized and evaluated for their arachidonic acid (AA)-induced antiplatelet aggregation inhibitory activity and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical-scavenging antioxidant activity, with acetylsalicylic acid and ascorbic acid as standard references, respectively. The preliminary structure-activity relationship related to AA-induced platelet aggregation inhibitory activity results showed that the aporphine analogues 1-[1,2,9,10-tetramethoxy-6a,7-dihydro-4H-dibenzo[de,g]quinolin-6(5H)-yl]ethanone and 1-[2-(benzyloxy)-1,9,10-trimethoxy-6a,7-dihydro-4H-dibenzo[de,g]quinolin-6(5H)-yl]ethanone to be the best compounds of the series. Moreover, the DPPH free-radical-scavenging antioxidant activity results demonstrated that the aporphine analogues 1,2,9,10-tetramethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, 2-ethoxy-1,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, 1-ethoxy-2,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, 2,9,10-trimethoxy-6-(methylsulfonyl)-1-propoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, and 1-(benzyloxy)-2,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline were the best compounds of the series. Moreover, in silico molecular docking simulation studies of the active analogues were also performed., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cephalandole A 2, a small indole alkaloid isolated from the Taiwanese orchid Cephalanceropsis gracilis (Orchidaceae), exhibits anticancer activity. Surprisingly, this natural product has not been evaluated for any other biological activity so far. To discover other novel potential of Cephalandole A 2, an efficient and economic synthetic protocol for novel Cephalandole A analogues 21a-o has been developed, in only 3 steps from using indole, and applied for their biological activity. Biological testing showed that Cephalandole A 2 and its novel analogues 21a-o exhibited potential antimicrobial and antiplatelet activity in preliminary assay. To the best of our knowledge, this is the first report of Cephalandole A 2 and its novel synthetic analogues 21a-o as a new class of antimicrobial and antiplatelet agents. In this study, 2 and other analogues i.e., 21b, 21d, 21i and 21o showed promising antimicrobial activity against the phytopathogenic bacteria and fungi. Cephalandole A 2, 21c, 21f and 21i, also showed potent antiplatelet activity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

eIF4G1, a critical component of the eIF4F complex, is required for cap-dependent mRNA translation, a process necessary for tumor growth and survival. However, the role of eIF4G1 has not been evaluated in Prostate Cancer (PCa). We observed an increased eIF4G1 protein levels in PCa tissues as compared to normal tissues. Analysis of the TCGA data revealed that eIF4G1 gene expression positively correlated with higher tumor grade and stage. Furthermore, eIF4G1 was over-expressed and or amplified, in 16% patients with metastatic PCa (SU2C/PCF Dream Team dataset) and in 59% of castration-resistant prostate cancer (CRPC) patients (Trento/Cornell/Broad dataset). We showed for the first time that eIF4G1 expression was increased in PCa and that increased eIF4G1 expression associated with tumor progression and metastasis. We also observed high protein levels of eIF4G1 in PCa cell lines and prostate tissues from the TRAMP model of PCa as compared to normal prostate cell line and prostate tissues from the wild type mice. Knockdown of eIF4G1 in PCa cells resulted in decreased Cyclin D1 and p-Rb protein level, cell cycle delay, reduced cell viability and proliferation, impaired clonogenic activity, reduced cell migration and decreased mRNA loading to polysomes. Treatment with eIF4G complex inhibitor also impaired prostasphere formation. eIF4G1 knockdown or treatment with eIF4G complex inhibitor sensitized CRPC cells to Enzalutamide and Bicalutamide. Our results showed that eIF4G1 plays an important role in PCa growth and therapeutic resistance. These data suggested that eIF4G1 functions as an oncoprotein and may serve as a novel target for intervention in PCa and CRPC.

A series of 2-oxo-2-phenylethylidene linked 2-oxo-benzo[1,4]oxazine analogues 17a-x and 18a-o, incorporated with a variety of electron-withdrawing as well as electron-donating groups at ring A and ring C, were synthesized under greener conditions in excellent yields (up to 98%). These analogues 17a-x and 18a-o were evaluated for their arachidonic acid (AA)-induced platelet aggregation inhibitory activities in comparison with the standard reference aspirin (IC 50  = 21.34 ± 1.09 µg/mL). Among all the screened compounds, eight analogues, 17i, 17x, 18f, 18g, 18h, 18i, 18l, and 18o, were identified as promising platelet aggregation inhibitors as compared to aspirin. In addition, cytotoxic studies in 3T 3 fibroblast cell lines by MTT assay of the promising compounds (17i, 17x, 18f-18i, 18l, and 18o) were also performed and the compounds were found to be non-toxic in nature. Furthermore, the results on the AA-induced platelet aggregation inhibitory activities of these compounds (17i, 17x, 18f-18i, 18l, and 18o) were validated via in silico molecular docking simulation studies. To the best of our knowledge, this is the first report of the identification of non-peptide-based functionalized 2-oxo-benzo[1,4]oxazines as platelet aggregation inhibitors., (© 2018 Deutsche Pharmazeutische Gesellschaft.)

The discovery of C-3 tethered 2-oxo-benzo[1,4]oxazines as potent antioxidants is disclosed. All the analogs 20a-20ab have been synthesized via "on water" ultrasound-assisted irradiation conditions in excellent yields (upto 98%). All the compounds have been evaluated for their in vitro antioxidant activities using DPPH free radical scavenging assay as well as FRAP assay. The result showed promising antioxidant activities having IC 50 values in the range of 4.74 ± 0.08 to 92.20 ± 1.54 μg/mL taking ascorbic acid (IC 50 = 4.57 μg/mL) as standard reference. In this study, compounds 20b and 20t , the most active compound of the series, showed IC 50 values of 6.89 ± 0.07 μg/mL and 4.74 ± 0.08 μg/mL, respectively in comparison with ascorbic acid. In addition, the detailed SAR study shows that electron-withdrawing group increases antioxidant activity and vice versa. Furthermore, in the FRAP assay, eight compounds ( 20c , 20j , 20m , 20n , 20r , 20u , 20z , and 20aa ) were found more potent than standard reference BHT (C 0.5FRAP = 546.0 ± 13.6 μM). The preliminary cytotoxic study reveals the non-toxic nature of active compounds 20b and 20t in non-cancerous 3T 3 fibroblast cell lines in MTT assay up to 250 μg/mL concentration. The results were validated via carrying out in silico molecular docking studies of promising compounds 20a , 20b , and 20t in comparison with standard reference. To the best of our knowledge, this is the first detailed study of C-3 tethered 2-oxo-benzo[1,4]oxazines as potential antioxidant agents.

Background: Poor viability and retention of transplanted bone marrow mesenchymal stem cells (BM-MSC) remains an obstacle in promoting healing after myocardial infarction (MI). This study aimed to understand the migratory, angiogenic, and cardioprotective effects induced by tumor necrosis factor (TNF)-α and hypoxia through rat BM-MSC (rBM-MSC) paracrine secretions, collectively referred to as secretome, after MI., Methods: Secretome from rBM-MSC cultures treated with various combinations of H9c2 cardiomyoblast-conditioned medium, TNF-α, and hypoxia was initially collected. Immunocytochemistry, Western blot analyses, and transwell cell migration assays were conducted. In vivo, echocardiography was performed on rats with induced MI after their treatment with TNF-α and hypoxia-induced secretome., Results: Immunocytochemistry confirmed the presence of TNF receptors 1 and 2 on rBM-MSCs. Western blot analyses of rBM-MSCs treated with TNF-α and hypoxia showed an overall increasing trend in the expression of antiinflammatory proteins and angiogenic and migratory cytokines (transforming growth factor-β, fibroblast growth factor-2, angiopoietin-2, vascular endothelial growth factor-1). In addition, the TNF-α and hypoxia-induced secretome significantly increased the in vitro rBM-MSCs migration. In the rat MI model, the rats treated with the TNF-α and hypoxia-induced secretome had a significantly higher left ventricular fractional shortening than the control group., Conclusions: Our data suggest that after MI, rBM-MSCs secrete paracrine factors in response to TNF-α and hypoxia that work together to manipulate the microenvironment and decrease inflammation. In addition, these signaling factors trigger angiogenic and migratory effects at the site of the infarct to promote myocardial healing and improve the cardiac function., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

A microwave-assisted, environmentally benign green protocol for the synthesis of functionalized (Z)-3-(2-oxo-2-phenylethylidene)-3, 4-dihydro-2H-benzo[b][1,4]oxazin-2-ones (11a-n) in excellent yields (upto 97%) and (Z)-3-(2-oxo-2-phenylethylidene)-3,4-dihydroquinoxalin-2(1H)-ones (14a-h) (upto 96% yield) are reported. The practical applicability of developed methodology were also confirmed by the gram scale synthesis of 11a, 14c and 14e; synthesis of anticancer alkaloid Cephalandole A 16 (89% yield). All the synthesized compounds 11a-n, 14a-h and 16 were assessed for their in vitro antioxidant activities in DPPH radical scavenging and FRAP assay. In DPPH assay, compounds 11a, 14c and 14e, the most active compounds of the series, were found to show IC50 value of 10.20 ± 0.08 μg/mL, 9.89 ± 0.15 μg/mL and 8.97 ± 0.13 μg/mL, respectively in comparison with standard reference (ascorbic acid, IC50 = 4.57 μg/mL). Whereas, in FRAP antioxidant assay seven compounds (11c, 11e, 11i, 11k, 11l, 14d and 14h) displayed higher antioxidant activity in comparison to the reference standard BHT (C0.5FRAP = 546.2 μM). Moreover, the cytotoxic studies of the compounds 11a, 14c, 14e and 14h were found to be non-toxic in nature in 3T3 fibroblast cell lines using MTT assay.

A new series of functionalized (Z)-3-(2-oxo-2-substituted ethylidene)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-ones 23-26, incorporating pharmaceutically privileged substructures such as cyclopropyl, naphthyl, biphenyl and cyclohexylphenyl were synthesized in excellent yields. All the synthesized compounds were screened for their in vitro antibacterial activity against gram-(+)ve and gram-(-)ve bacterial species i.e. S. griseus, S. aureus, B. subtillis and E. coli as well as in vitro antifungal activity against fungal species i.e. F. oxysporium, A. niger, P. funiculosum and T. reesei, respectively. In this study, compounds containing cyclopropyl and cyclohexylphenyl substructures were identified as promising antimicrobial agents than standard drugs, ampicillin and chloramphenicol as well as ketoconazole. SAR study illustrates that electron-withdrawing groups increases the antibacterial as well as antifungal activity of 2-oxo-benzo[1,4]oxazines and vice versa. Compounds 23e and 26e, the most active compounds of the series, displayed promising antibacterial activity than Ampicillin and Chloramphenicol. Moreover, compound 26d showed promising antifungal potency as compared to Ketoconazole. Cytotoxic studies of the active compounds i.e. 23c-e, 24e, 25d and 26d-e found to be non-toxic in nature in 3T 3 fibroblast cell lines using MTT assay., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

This study reports the simultaneous delivery of EGFP siRNA and the chemotherapeutic drug, doxorubicin by means of the composition that results from the electrostatic interaction between positively charged siRNA-complexes of gold nanoparticles (AuNPs) capped with PEI, 25kDa (P25-AuNPs) and negatively charged carboxymethyl cellulose formulated PLGA nanoparticles loaded with doxorubicin. The nanoparticles and their facile interaction were studied by means of dynamic light scattering (DLS), zeta potential, transmission electron microscopic (TEM) measurements. The flow cytometric and confocal microscopic analysis evidenced the simultaneous internalization of both labelled siRNA and doxorubin into around 55% of the HeLa cancer cell population. Fluorescence microscopic studies enabled the visual analysis of EGFP expressing HeLa cells which suggested that the composition mediated codelivery resulted in a substantial downregulation of EGFP expression and intracellular accumulation of doxorubicin. Interestingly, codelivery treatment resulted in an increased cellular delivery of doxorubicin when compared to PLGA-DOX alone treatment. On the other hand, the activity of siRNA complexes of PEI-AuNPs was completely retained even when they were part of composition. The results suggest that this formulation can serve as promising tool for delivery applications in combinatorial anticancer therapy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: For more than a decade, stem cells isolated from different tissues have been evaluated in cell therapy. Among them, the human bone marrow-derived mesenchymal stem cells (hBM-MSCs) were investigated extensively in the treatment of myocardial infarction. Recently, the human placenta-derived mesenchymal stem cells (hPD-MSCs), which are readily available from a biological waste, appear to be a viable alternative to hBM-MSCs., Methods: C-X-C chemokine receptor type 4 (CXCR4) gene expression and localization were detected and validated in hPD-MSCs and hBM-MSCs via polymerase chain reaction and immunofluorescence. Subsequently, cell culture conditions for CXCR4 expression were optimized in stromal-derived factor-1 alpha (SDF1-α), glucose, and cobalt chloride (CoCl 2 ) by the use of cell viability, proliferation, and migration assays. To elucidate the cell signaling pathway, protein expression of CXCR4, hypoxia-inducible factor-1α, interleukin-6, Akt, and extracellular signal-regulated kinase were analyzed by Western blot. CXCR4-positive cells were sorted and analyzed by florescence-activated cell sorting., Results: CXCR4 was expressed on both hPD-MSCs and hBM-MSCs at the basal level. HPD-MSCs were shown to have a greater sensitivity to SDF-1α-dependent cell migration compared with hBM-MSCs. In addition, CXCR4 expression was significantly greater in both hPD-MSCs and hBM-MSCs with SDF-1α or CoCl 2 -induced hypoxia treatment. However, CXCR4 + hPD-MSCs population increased by 10-fold in CoCl 2 -induced hypoxia. In contrast, only a 2-fold increase was observed in the CXCR4 + hBM-MSCs population in similar conditions. After CoCl 2 -induced hypoxia, the CXCR4/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathway was activated prominently in hPD-MSCs, whereas in hBM-MSCs, the CXCR4/phosphatidylinositol 3-kinase/Akt pathway was triggered., Conclusions: Our current results suggest that hPD-MSCs could represent a viable and effective alternative to hBM-MSCs for translational studies in cardiocellular repair., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

We revisit the problem of the stress distribution in a frictional sandpile with both normal and tangential (frictional) inter-granular forces, under gravity, equipped with a new numerical method of generating such assemblies. Numerical simulations allow a determination of the spatial dependence of all the components of the stress field, principle stress axis, angle of repose, as a function of systems size, the coefficient of static friction and the frictional interaction with the bottom surface. We compare these results with the predictions of a theory based on continuum equilibrium mechanics. Basic to the theory of sandpiles are assumptions about the form of scaling solutions and constitutive relations for cohesive-less hard grains for which no typical scale is available. We find that these constitutive relations must be modified; moreover for smaller friction coefficients and smaller piles these scaling assumptions break down in the bulk of the sandpile due to the presence of length scales that must be carefully identified. Fortunately, for larger friction coefficient and for larger piles the breaking of scaling is weak in the bulk, allowing an approximate analytic theory which agrees well with the observations. After identifying the crucial scale, triggering the breaking of scaling, we provide a predictive theory to when scaling solutions are expected to break down. At the bottom of the pile the scaling assumption breaks always, due to the different interactions with the bottom surface. The consequences for measurable quantities like the pressure distribution and shear stress at the bottom of the pile are discussed. For example one can have a transition from no dip in the base-pressure to a dip at the center of the pile as friction increases.

A mechanical study investigating the use of two different methods (grub and bolt screws) to secure external fixation half pins to circular frames. A four part experiment: (1) Grub and bolt screws were used to secure half pins in Taylor Spatial frames. Loosening torques were measured using a calibrated torque wrench. (2) Using universal testing machine (UTM), axial loading was applied to establish thresholds for loosening in grub and bolt screw constructs. (3) We established the application torque to produce failure at the head-driver interface using these two methods. (4) Grub and bolt screw constructs were created controlling torque. Using UTM, axial loading was applied to establish thresholds for loosening. Statistical analysis was conducted using SPSS v20.0.0. (1) Higher torque is employed when bolt rather than grub screws is used to secure half pins on Rancho cubes (p < 0.05). (2) Loading threshold for loosening is higher in bolt screw constructs when the torque applied to secure the constructs is not controlled (p < 0.05). (3) Torque required for failure at the head-driver interface was 5.3 Nm for grub screws and 9.9 Nm for bolts. (4) Loading threshold for loosening is higher in grub screw constructs when the same torque was applied to secure them (p < 0.05). Bolt screws can be employed to secure the half pin-frame interface. They offer good stability and reduce failure at the head-driver interface. Further research is needed to determine the mechanical properties of such constructs in vivo., Competing Interests: The authors declare that they have no conflict of interest. Statement of human and animal rights This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent For this type of study formal consent is not required.