Small molecule inhibition of RNA binding proteins in haematologic cancer.

In recent years, advances in biomedicine have revealed an important role for post-transcriptional mechanisms of gene expression regulation in pathologic conditions. In cancer in general and leukaemia specifically, RNA binding proteins have emerged as important regulator of RNA homoeostasis that are often dysregulated in the disease state. Having established the importance of these pathogenetic mechanisms, there have been a number of efforts to target RNA binding proteins using oligonucleotide-based strategies, as well as with small organic molecules. The field is at an exciting inflection point with the convergence of biomedical knowledge, small molecule screening strategies and improved chemical methods for synthesis and construction of sophisticated small molecules. Here, we review the mechanisms of post-transcriptional gene regulation, specifically in leukaemia, current small-molecule based efforts to target RNA binding proteins, and future prospects.

The Rise of Structurally Anisotropic Plasmonic Janus Gold Nanostars.

Nanostructures intrinsically possessing two different structural or functional features, often called Janus nanoparticles, are emerging as a potential material for sensing, catalysis, and biomedical applications. Herein, we report the synthesis of plasmonic gold Janus nanostars (NSs) possessing a smooth concave pentagonal morphology with sharp tips and edges on one side and, contrastingly, a crumbled morphology on the other. The methodology reported herein for their synthesis - a single-step growth reaction - is different from any other Janus nanoparticle preparation involving either template-assisted growth or a masking technique. Interestingly, the coexistence of lower- and higher-index facets was found in these Janus NSs. The general paradigm for synthesizing gold Janus NSs was investigated by understanding the kinetic control mechanism with the combinatorial effect of all the reagents responsible for the structure. The optical properties of the Janus NSs were realized by corelating their extinction spectra with the simulated data. The size-dependent surface-enhanced Raman scattering (SERS) activity of these Janus NSs was studied with 1,4-BDT as the model analyte. Finite-difference time-domain simulations for differently sized particles revealed the distribution of electromagnetic hot-spots over the particles resulting in enhancement of the SERS signal in a size-dependent manner.

Scaffold-based spheroid models of glioblastoma multiforme and its use in drug screening.

Among several types of brain cancers, glioblastoma multiforme (GBM) is a terminal and aggressive disease with a median survival of 15 months despite the most intensive surgery and chemotherapy. Preclinical models that accurately reproduce the tumor microenvironment are vital for developing new therapeutic alternatives. Understanding the complicated interactions between cells and their surroundings is essential to comprehend the tumor's microenvironment, however the monolayer cell culture approach falls short. Numerous approaches are used to develop GBM cells into tumor spheroids, while scaffold-based spheroids provides the opportunity to investigate the synergies between cells as well as cells and the matrix. This review summarizes the development of various scaffold-based GBM spheroid models and the prospective for their use as drug testing systems.

Unraveling the connection between calreticulin and myeloproliferative neoplasms via calcium signaling.

Mutations in the form of insertions and deletions (INDEL) in the calreticulin gene lead to essential thrombocythemia (ET) which is characterized by the formation of thrombosis. However, the connection between calreticulin INDEL and ET remains largely elusive. Through combined molecular dynamics simulation, clustered regularly interspaced short palindromic repeats (CRISPR) and calcium imaging studies on the wild type and mutated isoforms of calreticulin, the mechanism underlying the calreticulin INDEL induced ET was investigated at the molecular level. Our results demonstrate that mutations in exon-9 could lead to significant conformational variations of calreticulin structure and thereby reducing its interaction with calcium ions due to decreased electrostatic contributions. The consequence of mutations on calreticulin's structural integrity was revealed by identifying the key residues and their roles in calcium binding. Furthermore, mutations implemented by CRISPR-Cas9 in exon-9 showed diminished calcium signaling in HEK-293T cells, which agree well with our in-silico findings. The current study might help in understanding the variations of molecular interactions between calreticulin's exon-9 and calcium ions during physiological and pathological conditions. The results might also provide useful information for designing novel therapeutic approaches targeting ET.

Plasmonic 3-D wrinkled polymeric shrink film-based SERS substrates for pesticide detection on real-world surfaces.

The continuous and excessive use of agrochemicals for crop improvement and protection has raised widespread concern, as they exert adverse effects on human health and the local environment. Surface Enhanced Raman Spectroscopy (SERS) provides a method for the quick identification and detection of such hazardous substances in a short amount of time due to its properties of being robust, accurate, sensitive and non-destructive. Despite the fact that several SERS substrates have been developed, the bulk of them are ineffective in terms of sample collection or providing reproducible results. In this study, we showed that a 3-D wrinkled polymeric heat-shrink film coated with Au bead@Ag nanorods (silver nanorods) serves as a potential SERS substrate for trace analysis. The surface of the heat-shrink film became wrinkled after heating, and this, along with the spatial arrangement of nanoparticles, significantly enhances the Raman signal of the analytes. The fabricated SERS substrate was able to sense two model analytes 1,4-benzenedithiol (BDT) and 2-naphthalenethiol (NT) up to 10-13 M and 10-11 M concentrations. The fabricated substrate was also effective in sensing thiram down to 10-13 M concentration. Additionally, the SERS substrate was applied in a real-world setting for the detection of the pesticide thiram spiked onto apple skin surfaces. To collect the thiram residues, the substrate was simply swabbed across the surface of the apple. This allowed for the detection of thiram at concentrations as low as 10-9 M (1 ppb). The fabricated SERS substrate can thus detect analytes in an efficient, sensitive, dependable and accurate manner, allowing for the sensing of trace analytes like pesticides in a real-world environment.

Plasmonic gold dogbone nanorattles sniff out trace molecules through surface enhanced Raman scattering.

In this study, a highly sensitive and efficient surface-enhanced Raman spectroscopy (SERS) substrate was developed using Au dogbone nanorattles (Au-DBNRTs) deposited on a 3D wrinkled polymeric heat shrink film. The plasmonic structures of Au-DBNRTs, which possess a solid gold dogbone-shaped core and a thin, porous gold shell, and Au nanorod nanorattles (Au-NRNRTs), which have a rod-shaped core, were synthesized and their SERS performance was evaluated. Au-DBNRTs exhibited better Raman signal enhancement. The substrate was used to detect the pesticide thiabendazole with a limit of detection of up to 10-8 M. The unique optical properties and geometry of the Au-DBNRT nanoparticles, which have portruding corners in the vicinity of the metal shell, along with the shrinkage of the film after heat treatment, led to the creation of a 3D surface morphology, resulting in the generation of plasmonic electromagnetic hot spots. The fabricated substrate achieved an enhancement factor of 2.77 × 1010 for BDT, and the detection limit was 10-13 M. The current work offers a simple, cost-effective, and sensitive SERS substrate design that has great potential for sensing and detecting trace analytes.

Superior Peroxidase-Like Activity of Gold Nanorattles in Ultrasensitive H2 O2 Sensing and Antioxidant Screening.

Nanozymes are artificial enzyme systems which are easy to produce, highly stable and cost-effective in comparison to natural enzymes. Herein, we evaluated the peroxidase-like activity of gold nanorattles (Au NRTs) having a solid gold octahedron core and thin, porous cubic gold shell. We also prepared solid gold nanocubes and nanospheres of similar sizes and surface charge as that of Au NRTs and compared their activity with standard horse radish peroxidase (HRP). All the prepared nanostructures followed Michaelis-Menten kinetics as observed from their substrate concentration vs. initial reaction velocity plot using 3,3',5,5'-tetramethylbenzidine (TMB) as a substrate. The kinetic parameters and the catalytic efficiency for the peroxidase-like activity of the nanostructures and HRP were calculated, and it was observed that Au NRTs possess the best nanozymatic activity with lowest KM and highest catalytic efficiency (kcat /KM ). The better activity of Au NRTs compared with other nanostructures and HRP could be attributed to the hollow porous structure with a solid core where different surfaces are available for reaction. Au NRTs, being the best amongst the tested nanozymes were further used for the sensing of hydrogen peroxide (H2 O2 ) and were found to sense H2 O2 down to 0.5 µM. Further, two naturally occurring antioxidants, tannic acid and ascorbic acid showed inhibitory effect on the peroxidase-like activity of Au NRTs in a concentration dependent manner which can be further used for screening of antioxidants or for determining the antioxidant potential.

Anionic Lipid Clustering-Mediated Bactericidal Activity and Selective Toxicity of Quaternary Ammonium-Substituted Polycationic Pullulan against the Staphylococcus aureus Bacterial Membrane.

Non-amphiphilic polycations have recently been recognized to hold excellent antimicrobial potential with great mammalian cell compatibility. In a recent study, the excellent broad-spectrum bactericidal efficacy of a quaternary ammonium-substituted cationic pullulan (CP4) was demonstrated. Their selective toxicity and nominal probability to induce the acquisition of resistance among pathogens fulfill the fundamental requirements of new-generation antibacterials. However, there have been exiguous attempts in the literature to understand the antimicrobial activity of polycations against Gram-positive bacterial membranes. Here, for the first time, we have scrutinized the molecular level interactions of CP4 tetramers with a model Staphylococcus aureus membrane to understand their probable antibacterial function using molecular dynamics simulations. Our analysis reveals that the hydrophilic CP4 molecules are spontaneously adsorbed onto the membrane outer leaflet surface by virtue of strong electrostatic interactions and do not penetrate into the lipid tail hydrophobic region. This surface binding of CP4 is strengthened by the formation of anionic lipid-rich domains in their vicinity, causing lateral compositional heterogeneity. The major outcomes of the asymmetric accumulation of bulky polycationic CP4 on one leaflet are (i) anionic lipid segregation at the interaction site and (ii) a decrease in the cationic lipid acyl tail ordering and ease of water translocation across the lipid hydrophobic barrier. The membrane-CP4 interactions are strongly monitored by the ionic strength; a higher salt concentration weakens the binding of CP4 on the membrane surface. In addition, our study also substantiates the non-interacting behavior of CP4 oligomers with biomimetic 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membrane, indicating their cell selectivity and specificity against pathogenic membranes.

MoS2 nanosheets effectively bind to the receptor binding domain of the SARS-CoV-2 spike protein and destabilize the spike-human ACE2 receptor interactions.

The use of nanotechnology is becoming increasingly significant as a tool that can provide a range of options for the identification, inactivation, and therapy of coronavirus disease 2019 (COVID-19). The potential of nanoparticles as an alternative therapeutic agent to inactivate SARS-CoV-2 is continually being investigated. Herein, we have explored the interaction of 2D molybdenum disulfide (MoS2) nanosheets with the SARS-CoV-2 spike protein, human ACE2 receptor and the complex formed between them through molecular docking and atomistic simulations. The results indicated that MoS2 nanosheets can effectively bind to the receptor binding domain (RBD) of the spike protein with good docking energies. It is interesting to note that this also applied to the extensively glycosylated spike protein and its variations, Kappa and Delta. A significant loss of secondary structures was observed when MoS2 nanosheets interacted with the RBD of the spike protein. The nanosheets interacted strongly with the proteins through a number of hydrogen bonds and van der Waals interactions. Moreover, the binding of the MoS2 nanosheets at different locations of the RBD or ACE2 in the spike-RBD/ACE2 complex resulted in significant conformational changes. Detailed energetics and solvent accessibility calculations revealed that, when present at the interface, MoS2 nanosheets can be a potential inhibitory agent. The findings were supported by de-wetting calculations, indicating strong adherence of the RBD of spike protein on the MoS2 nanosheet and de-stability of the spike-ACE2 interaction. Thus, the findings clearly demonstrate the antiviral potential of 2D MoS2 nanosheets, prompting its further exploration for combating COVID-19.

Evolution, structure and emerging roles of C1ORF112 in DNA replication, DNA damage responses, and cancer.

The C1ORF112 gene initially drew attention when it was found to be strongly co-expressed with several genes previously associated with cancer and implicated in DNA repair and cell cycle regulation, such as RAD51 and the BRCA genes. The molecular functions of C1ORF112 remain poorly understood, yet several studies have uncovered clues as to its potential functions. Here, we review the current knowledge on C1ORF112 biology, its evolutionary history, possible functions, and its potential relevance to cancer. C1ORF112 is conserved throughout eukaryotes, from plants to humans, and is very highly conserved in primates. Protein models suggest that C1ORF112 is an alpha-helical protein. Interestingly, homozygous knockout mice are not viable, suggesting an essential role for C1ORF112 in mammalian development. Gene expression data show that, among human tissues, C1ORF112 is highly expressed in the testes and overexpressed in various cancers when compared to healthy tissues. C1ORF112 has also been shown to have altered levels of expression in some tumours with mutant TP53. Recent screens associate C1ORF112 with DNA replication and reveal possible links to DNA damage repair pathways, including the Fanconi anaemia pathway and homologous recombination. These insights provide important avenues for future research in our efforts to understand the functions and potential disease relevance of C1ORF112.

Visualization of Plasmonic Couplings Using Ultrafast Electron Microscopy.

Hybrids of graphene and metal plasmonic nanostructures are promising building blocks for applications in optoelectronics, surface-enhanced scattering, biosensing, and quantum information. An understanding of the coupling mechanism in these hybrid systems is of vital importance to its applications. Previous efforts in this field mainly focused on spectroscopic studies of strong coupling within the hybrids with no spatial resolution. Here we report direct imaging of the local plasmonic coupling between single Au nanocapsules and graphene step edges at the nanometer scale by photon-induced near-field electron microscopy in an ultrafast electron microscope for the first time. The proximity of a step in the graphene to the nanocapsule causes asymmetric surface charge density at the ends of the nanocapsules. Computational electromagnetic simulations confirm the experimental observations. The results reported here indicate that this hybrid system could be used to manipulate the localized electromagnetic field on the nanoscale, enabling promising future plasmonic devices.

Fabrication techniques of biomimetic scaffolds in three-dimensional cell culture: A review.

In the last four decades, several researchers worldwide have routinely and meticulously exercised cell culture experiments in two-dimensional (2D) platforms. Using traditionally existing 2D models, the therapeutic efficacy of drugs has been inappropriately validated due to the failure in generating the precise therapeutic response. Fortunately, a 3D model addresses the foregoing limitations by recapitulating the in vivo environment. In this context, one has to contemplate the design of an appropriate scaffold for favoring the organization of cell microenvironment. Instituting pertinent model on the platter will pave way for a precise mimicking of in vivo conditions. It is because animal cells in scaffolds oblige spontaneous formation of 3D colonies that molecularly, phenotypically, and histologically resemble the native environment. The 3D culture provides insight into the biochemical aspects of cell-cell communication, plasticity, cell division, cytoskeletal reorganization, signaling mechanisms, differentiation, and cell death. Focusing on these criteria, this paper discusses in detail, the diversification of polymeric scaffolds based on their available resources. The paper also reviews the well-founded and latest techniques of scaffold fabrication, and their applications pertaining to tissue engineering, drug screening, and tumor model development.

VO2 Nanostructures for Batteries and Supercapacitors: A Review.

Vanadium dioxide (VO2 ) received tremendous interest lately due to its unique structural, electronic, and optoelectronic properties. VO2 has been extensively used in electrochromic displays and memristors and its VO2 (B) polymorph is extensively utilized as electrode material in energy storage applications. More studies are focused on VO2 (B) nanostructures which displayed different energy storage behavior than the bulk VO2 . The present review provides a systematic overview of the progress in VO2 nanostructures syntheses and its application in energy storage devices. Herein, a general introduction, discussion about crystal structure, and syntheses of a variety of nanostructures such as nanowires, nanorods, nanobelts, nanotubes, carambola shaped, etc. are summarized. The energy storage application of VO2 nanostructure and its composites are also described in detail and categorically, e.g. Li-ion battery, Na-ion battery, and supercapacitors. The current status and challenges associated with VO2 nanostructures are reported. Finally, light has been shed for the overall performance improvement of VO2 nanostructure as potential electrode material for future application.

Super-Resolution Microscopy Revealed the Lysosomal Expansion During Epigallocatechin Gallate-Mediated Apoptosis.

Direct visualization of the dynamic events in lysosomes during drug-mediated programmed cell death (apoptosis) is a great challenge. This is due to the lack of resolving power of a conventional microscope and also the unavailability of a suitable multimodal probe that simultaneously can carry the drug with high loading capacity and ensure its specific internalization into lysosomes. In this work, using super-resolution microscopy, we observed the lysosomal expansion during apoptosis that was treated with epigallocatechin gallate (EGCG) conjugated to bovine serum albumin (BSA). Albumin protein is known to internalize into lysosomes via endocytosis, thus helping in the specific delivery of EGCG to the lysosomal compartment. The conjugation of EGCG to BSA not only helped in increasing the killing efficiency of cancer cells but it also reduces the side effects and produces minimal reactive oxygen species. The decrease in local viscosity helped in lysosomal expansion during apoptosis.

Evaluation of Ultrasound, Microwave, Ultrasound-Microwave, Hydrothermal and High Pressure Assisted Extraction Technologies for the Recovery of Phytochemicals and Antioxidants from Brown Macroalgae.

This study aims to explore novel extraction technologies (ultrasound-assisted extraction (UAE), microwave-assisted extraction (MAE), ultrasound-microwave-assisted extraction (UMAE), hydrothermal-assisted extraction (HAE) and high-pressure-assisted extraction (HPAE)) and extraction time post-treatment (0 and 24 h) for the recovery of phytochemicals and associated antioxidant properties from Fucus vesiculosus and Pelvetia canaliculata. When using fixed extraction conditions (solvent: 50% ethanol; extraction time: 10 min; algae/solvent ratio: 1/10) for all the novel technologies, UAE generated extracts with the highest phytochemical contents from both macroalgae. The highest yields of compounds extracted from F. vesiculosus using UAE were: total phenolic content (445.0 ± 4.6 mg gallic acid equivalents/g), total phlorotannin content (362.9 ± 3.7 mg phloroglucinol equivalents/g), total flavonoid content (286.3 ± 7.8 mg quercetin equivalents/g) and total tannin content (189.1 ± 4.4 mg catechin equivalents/g). In the case of the antioxidant activities, the highest DPPH activities were achieved by UAE and UMAE from both macroalgae, while no clear pattern was recorded in the case of FRAP activities. The highest DPPH scavenging activities (112.5 ± 0.7 mg trolox equivalents/g) and FRAP activities (284.8 ± 2.2 mg trolox equivalents/g) were achieved from F. vesiculosus. Following the extraction treatment, an additional storage post-extraction (24 h) did not improve the yields of phytochemicals or antioxidant properties of the extracts.

Comparison of beamformer implementations for MEG source localization.

Beamformers are applied for estimating spatiotemporal characteristics of neuronal sources underlying measured MEG/EEG signals. Several MEG analysis toolboxes include an implementation of a linearly constrained minimum-variance (LCMV) beamformer. However, differences in implementations and in their results complicate the selection and application of beamformers and may hinder their wider adoption in research and clinical use. Additionally, combinations of different MEG sensor types (such as magnetometers and planar gradiometers) and application of preprocessing methods for interference suppression, such as signal space separation (SSS), can affect the results in different ways for different implementations. So far, a systematic evaluation of the different implementations has not been performed. Here, we compared the localization performance of the LCMV beamformer pipelines in four widely used open-source toolboxes (MNE-Python, FieldTrip, DAiSS (SPM12), and Brainstorm) using datasets both with and without SSS interference suppression. We analyzed MEG data that were i) simulated, ii) recorded from a static and moving phantom, and iii) recorded from a healthy volunteer receiving auditory, visual, and somatosensory stimulation. We also investigated the effects of SSS and the combination of the magnetometer and gradiometer signals. We quantified how localization error and point-spread volume vary with the signal-to-noise ratio (SNR) in all four toolboxes. When applied carefully to MEG data with a typical SNR (3-15 â€‹dB), all four toolboxes localized the sources reliably; however, they differed in their sensitivity to preprocessing parameters. As expected, localizations were highly unreliable at very low SNR, but we found high localization error also at very high SNRs for the first three toolboxes while Brainstorm showed greater robustness but with lower spatial resolution. We also found that the SNR improvement offered by SSS led to more accurate localization.

Frustrated Lewis-Pair-Meditated Selective Single Fluoride Substitution in Trifluoromethyl Groups.

Single fluoride substitution in trifluoromethylarenes is an ongoing synthetic challenge that often leads to "over-reaction", where multiple fluorides are replaced. Development of this reaction would allow simple access to a vast range of difluoromethyl derivatives of current interest to pharmaceutical, agrochemistry, and materials sciences. Using a catalytic frustrated Lewis pair approach, we have developed a generic protocol that allows a single substitution of one fluoride in trifluoromethyl groups with neutral phosphine and pyridine bases. The resulting phosphonium and pyridinium salts can be further functionalized via nucleophilic substitution, photoredox coupling, and electrophilic transfer reactions allowing the generation of a vast array of difluoromethyl products.

Optimisation of Ultrasound Frequency, Extraction Time and Solvent for the Recovery of Polyphenols, Phlorotannins and Associated Antioxidant Activity from Brown Seaweeds.

This study investigates ultrasound assisted extraction (UAE) process parameters (time, frequency and solvent) to obtain high yields of phlorotannins, flavonoids, total phenolics and associated antioxidant activities from 11 brown seaweed species. Optimised UAE conditions (35 kHz, 30 min and 50% ethanol) significantly improved the extraction yield from 1.5-fold to 2.2-fold in all seaweeds investigated compared to solvent extraction. Using ultrasound, the highest recovery of total phenolics (TPC: 572.3 ± 3.2 mg gallic acid equivalent/g), total phlorotannins (TPhC: 476.3 ± 2.2 mg phloroglucinol equivalent/g) and total flavonoids (TFC: 281.0 ± 1.7 mg quercetin equivalent/g) was obtained from Fucus vesiculosus seaweed. While the lowest recovery of TPC (72.6 ± 2.9 mg GAE/g), TPhC (50.3 ± 2.0 mg PGE/g) and TFC (15.2 ± 3.3 mg QE/g) was obtained from Laminaria digitata seaweed. However, extracts from Fucus serratus obtained by UAE exhibited the strongest 1,1-diphenyl-2-picryl-hydrazyl (DPPH) scavenging activity (29.1 ± 0.25 mg trolox equivalent/g) and ferric reducing antioxidant power (FRAP) value (63.9 ± 0.74 mg trolox equivalent/g). UAE under optimised conditions was an effective, low-cost and eco-friendly technique to recover biologically active polyphenols from 11 brown seaweed species.

Biopolymers for hydrogels in cosmetics: review.

Hydrogels are cross-linked networks of macromolecular compounds characterized by high water absorption capacity. Such materials find a wide range of biomedical applications. Several polymeric hydrogels can also be used in cosmetics. Herein, the structure, properties and selected applications of hydrogels in cosmetics are discussed in general. Detailed examples from scientific literature are also shown. In this review paper, most common biopolymers used in cosmetics are presented in detail together with issues related to skin treatment and hair conditioning. Hydrogels based on collagen, chitosan, hyaluronic acid, and other polysaccharides have been characterized. New trends in the preparation of hydrogels based on biopolymer blends as well as bigels have been shown. Moreover, biopolymer hydrogels employment in encapsulation has been mentioned.

2D MoS2 -Based Nanomaterials for Therapeutic, Bioimaging, and Biosensing Applications.

Molybdenum disulfide (MoS2 ), a typical layered 2D transition metal dichalcogenide, has received colossal interest in the past few years due to its unique structural, physicochemical, optical, and biological properties. While MoS2 is mostly applied in traditional industries such as dry lubricants, intercalation agents, and negative electrode material in lithium-ion batteries, its 2D and 0D forms have led to diverse applications in sensing, catalysis, therapy, and imaging. Herein, a systematic overview of the progress that is made in the field of MoS2 research with an emphasis on its different biomedical applications is presented. This article provides a general discussion on the basic structure and property of MoS2 and gives a detailed description of its different morphologies that are synthesized so far, namely, nanosheets, nanotubes, and quantum dots along with synthesis strategies. The biomedical applications of MoS2 -based nanocomposites are also described in detail and categorically, such as in varied therapeutic and diagnostic modalities like drug delivery, gene delivery, phototherapy, combined therapy, bioimaging, theranostics, and biosensing. Finally, a brief commentary on the current challenges and limitations being faced is provided, along with a discussion of some future perspectives for the overall improvement of MoS2 -based nanocomposites as a potential nanomedicine.