Novel FOXM1 inhibitor STL001 sensitizes human cancers to a broad-spectrum of cancer therapies.

Forkhead box protein M1 (FOXM1) is often overexpressed in human cancers and strongly associated with therapy resistance and less good patient survival. The chemotherapy options for patients with the most aggressive types of solid cancers remain very limited because of the acquired drug resistance, making the therapy less effective. NPM1 mutation through the inactivation of FOXM1 via FOXM1 relocalization to the cytoplasm confers more favorable treatment outcomes for AML patients, confirming FOXM1 as a crucial target to overcome drug resistance. Pharmacological inhibition of FOXM1 could be a promising approach to sensitize therapy-resistant cancers. Here, we explore a novel FOXM1 inhibitor STL001, a first-generation modification drug of our previously reported FOXM1 inhibitor STL427944. STL001 preserves the mode of action of the STL427944; however, STL001 is up to 50 times more efficient in reducing FOXM1 activity in a variety of solid cancers. The most conventional cancer therapies studied here induce FOXM1 overexpression in solid cancers. The therapy-induced FOXM1 overexpression may explain the failure or reduced efficacy of these drugs in cancer patients. Interestingly, STL001 increased the sensitivity of cancer cells to conventional cancer therapies by suppressing both the high-endogenous and drug-induced FOXM1. Notably, STL001 does not provide further sensitization to FOXM1-KD cancer cells, suggesting that the sensitization effect is conveyed specifically through FOXM1 suppression. RNA-seq and gene set enrichment studies revealed prominent suppression of FOXM1-dependent pathways and gene ontologies. Also, gene regulation by STL001 showed extensive overlap with FOXM1-KD, suggesting a high selectivity of STL001 toward the FOXM1 regulatory network. A completely new activity of FOXM1, mediated through steroid/cholesterol biosynthetic process and protein secretion in cancer cells was also detected. Collectively, STL001 offers intriguing translational opportunities as combination therapies targeting FOXM1 activity in a variety of human cancers driven by FOXM1.

Analysis of Tapered Fibre Optic Surface Plasmon Resonance Bio-Sensor Chip with highly Perturbed Taper Profiles.

A numerical model based on the Transfer matrix method (TMM) is proposed for the first time to study the gold coated tapered fibre optic surface plasmon resonance (SPR) with eight different types of taper profiles namely linear, exponential-linear, Gaussian, quadratic, sinusoidal, error function type and highly perturbed taper profile so-called chirp type of profile. The performance in terms of sensitivity, full width at half maximum (FWHM), detection accuracy (D.A.), amplitude dip, and half power points are estimated with respect to tapering ratio and choices of taper profile. It is found that sensitivity increased almost linearly with the taper ratio of each taper choice for the account of the reduction of detection accuracy. It has been found that sensitivity is highest for the case of chirp taper profile and lowest for the case of quadratic taper profile at low taper ratio. In this study, the aqueous solution is considered for sensor development which is adulterated by biomolecules species like DNA, blood samples, etc.

Small-molecule inhibitors targeting FOXM1: Current challenges and future perspectives in cancer treatments.

Forkhead box (FOX) protein M1 (FOXM1) is a critical proliferation-associated transcription factor (TF) that is aberrantly overexpressed in the majority of human cancers and has also been implicated in poor prognosis. A comprehensive understanding of various aspects of this molecule has revealed its role in, cell proliferation, cell migration, invasion, angiogenesis and metastasis. The FOXM1 as a TF directly or indirectly regulates the expression of several target genes whose dysregulation is associated with almost all hallmarks of cancer. Moreover, FOXM1 expression is associated with chemoresistance to different anti-cancer drugs. Several studies have confirmed that suppression of FOXM1 enhanced the drug sensitivity of various types of cancer cells. Current data suggest that small molecule inhibitors targeting FOXM1 in combination with anticancer drugs may represent a novel therapeutic strategy for chemo-resistant cancers. In this review, we discuss the clinical utility of FOXM1, further, we summarize and discuss small-molecule inhibitors targeting FOXM1 and categorize them according to their mechanisms of targeting FOXM1. Despite great progress, small-molecule inhibitors targeting FOXM1 face many challenges, and we present here all small-molecule FOXM1 inhibitors in different stages of development. We discuss the current challenges and provide insights on the future application of FOXM1 inhibition to the clinic.

High sensitivity detection of different pH ranges with rGO-nanocomposite coated eFBG sensor.

In the proposed work, a highly sensitive reduced graphene oxide (rGO) coated etched fiber Bragg grating (eFBG) pH sensor is developed and characterized. To create the sensing probe, a nanocomposite layer of rGO is coated over the unclad area of the eFBG. The analysis of rGO material has been done using different characterization tools such as UV-VIS-NIR spectroscopy, x-ray diffraction (XRD), and field emission scanning electron microscopy (FESEM). Experiments are performed using pH samples ranging from pH 2 to pH 12 to validate the operational sensing range of the proposed sensor. The effectiveness of the proposed sensor is evaluated with various pH values by monitoring the shift in the resonance peak of the sensor's reflection spectrum in a real-time interrogation system. The sensor performs well in both low and high pH ranges, with a maximum sensitivity of 0.232 nm/pH at pH 12. Due to a shift in the rGO's optical band-gap at both low and high pH values in the samples, the sensor can detect minimal changes in concentration. In the reflected spectrum, the Bragg wavelength (λ B) shifts as a result of the change in the refractive index. The λ B is observed to change as the pH of the aqueous solution is changed experimentally. Its performance is shown to be minimally affected by the ambient temperature (in the range of 19-21∘ C). The sensor also has the capacity for remote sensing, a quick response time, a small size, a low cost, a miniaturized probe, and the ability to reuse the probe.

Recent Advancement in Fiber-Optic-Based SPR Biosensor for Food Adulteration Detection-A Review.

Food safety is a scientific discipline that requires sophisticated handling, production, and storage. Food is common for microbial development; it acts as a source for growth and contamination. The traditional procedures for food analysis are time-consuming and labor-intensive, but optical sensors overcome these constraints. Biosensors have replaced rigorous lab procedures like chromatography and immunoassays with more precise and quick sensing. It offers quick, nondestructive, and cost-effective food adulteration detection. Over the last few decades, the significant spike in interest in developing surface plasmon resonance (SPR) sensors for the detection and monitoring of pesticides, pathogens, allergens, and other toxic chemicals in foods. This review focuses on fiber-optic SPR (FO-SPR) biosensors for detecting various adulterants in food matrix while also discussing the future perspective and the key challenges encountered by SPR based sensors.

A Numerical Study of Different Metal and Prism Choices in the Surface Plasmon Resonance Biosensor Chip for Human Blood Group Identification.

Optimized design of Surface plasmon resonance (SPR) based biosensor in terms of different metal choices and prisms are presented to the first time for the high precision detection of human blood group in near infrared wavelength range. The results are well compared with the earlier published gold coated silicon biosensor chip while discussing the pros and cons of various prism/metal choices. In this study buffer layer onto SPR active metal has been deployed to avoid the oxidation problem and contamination issue related with blood samples. Refractive index of blood samples has been considered in theoretical model based on the experimental data. Si prism has been found to be the best choice as a substrate material with combination of Al as a SPR active metal for blood group identification analysis. SPR dip slope (S), detection accuracy (D.A.) and blood group discrimination factor ( δθSPR ) have been studied with respect to different metal choices with their suitability to the next generation biosensor applications.

Role of Long Non-Coding RNAs in Human-Induced Pluripotent Stem Cells Derived Megakaryocytes: A p53, HOX Antisense Intergenic RNA Myeloid 1, and miR-125b Interaction Study.

Megakaryocytes (MKs) are rare polyploid cells found in the bone marrow and produce platelets. Platelets are small cell fragments that are essential during wound healing and vascular hemostasis. In vitro differentiation of MKs from human-induced pluripotent stem cell-derived CD34+ hematopoietic stem cells (hiPSC-HSCs) could provide an alternative treatment option for thrombocytopenic patients as a platelet source. In this approach, we developed a method to produce functional MKs from hiPSC-HSCs using a xeno-free and feeder-free condition and minimize the variation and risk from animal-derived products in cell culture. We have also investigated the genome-wide expression as well as functional significance of long noncoding RNAs (lncRNAs) in hiPSC-HSC-derived MKs to get insight into MK biology. We have performed lncRNAs expression profiling by using the Human LncProfilers qPCR Array Kit and identified 26 differentially regulated lncRNAs in hiPSC-HSC-derived MKs as compared with those in hiPSC-HSCs. HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) was the most highly upregulated lncRNA in hiPSC-HSC-derived MKs and phorbol 12-myristate 13-acetate (PMA)-induced megakaryocytic-differentiating K562 cells. Furthermore, we have studied the potential mechanism of HOTAIRM1 based on the interactions between HOTAIRM1, p53, and miR-125b in PMA-induced K562 cells. Our results demonstrated that during MK maturation, HOTAIRM1 might be associated with the transcriptional regulation of p53 via acting as a decoy for miR-125b. Thus, the interaction between HOTAIRM1, p53, and miR-125b is likely involved in controlling cell cycling (cyclin D1), reactive oxygen species production, and apoptosis to support terminal maturation of MKs. SIGNIFICANCE STATEMENT: In vitro generation of megakaryocytes (MKs) from human-induced pluripotent stem cell-derived hematopoietic stem cells (hiPSC-HSCs) could provide an alternative source of platelets for treating thrombocytopenic patients. This study has investigated the functional significance of long non-coding RNAs in hiPSC-HSC-derived MKs, which remains unclear. This study's findings suggest that the regulatory role of HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) in p53-mediated regulation of cyclin D1 during megakaryocytopoiesis is to promote MK maturation by decoying miR-125b.

SPR Based Biosensing Chip for COVID-19 Diagnosis-A Review.

Surface Plasmon Resonance (SPR) techniques are highly accurate in detecting biomolecular like blood group measurement, food adulteration, milk adulteration and recently developing as a rapid detection for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. In order to validate the clinical diagnosis, Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) of nasopharyngeal swabs has been utilized, which is time consuming and expensive. For fast and accurate detection of the SARS-CoV-2 virus, SPR based biosensing chips are described in this review article. SPR sensors have the potential to be employed for fast, accurate, and portable SARS-CoV-2 virus diagnosis. To combat the SARS-CoV-2 pandemic, there is considerable interest in creating innovative biosensors that are quick, reliable, and sensitive for COVID-19 diagnosis.

Numerical analysis of a grating embedded bidirectional integrated optical coupler pressure sensor.

A numerical analysis of a grating embedded bidirectional optical coupled waveguide structure is presented for the first time, to our knowledge. A finite difference method (FDM) based scheme is devised to extract the allowed eigen TE and TM modes of the structure. Sensing characteristics of the grating employed between two high refractive index couplers are then explored. The influence of strain on the composite structure is numerically analyzed for better understanding of guiding phenomena. A numerical method based on a three-point central finite difference scheme with proper boundary conditions at the point of discontinuity is developed. For an accurate sensitivity analysis, a large number of mesh points (N=1000) are used in the FDM algorithm, while the whole analysis is done on MATLAB software. To the best of the authors' knowledge, Bragg grating sensitivities of individual TE and TM modes have been estimated for the first time. It is found that higher order TE and TM modes show improved sensitivity performance. The physics behind the improved sensitivity of the proposed structure is correlated with existing cases. The proposed technique is based on effective refractive index theory, and hence it is easy to implement. This work can be easily extended to obtain temperature, humidity, and vibration sensitivities of other novel structures.

Megakaryoblastic leukemia: a study on novel role of clinically significant long non-coding RNA signatures in megakaryocyte development during treatment with phorbol ester.

Acute megakaryocytic leukemia (AMKL) is one of the rarest sub-types of acute myeloid leukemia (AML). AMKL is characterized by high proliferation of megakaryoblasts and myelofibrosis of bone marrow, this disease is also associated with poor prognosis. Previous analyses have reported that the human megakaryoblastic cells can be differentiated into cells with megakaryocyte (MK)-like characteristics by phorbol 12-myristate 13-acetate (PMA). However, little is known about the mechanism responsible for regulating this differentiation process. We performed long non-coding RNA (lncRNA) profiling to investigate the differently expressed lncRNAs in megakaryocyte blast cells treated with and without PMA and examined those that may be responsible for the PMA-induced differentiation of megakaryoblasts into MKs. We found 30 out of 90 lncRNA signatures to be differentially expressed after PMA treatment of megakaryoblast cells, including the highly expressed JPX lncRNA. Further, in silico lncRNA-miRNA and miRNA-mRNA interaction analysis revealed that the JPX is likely involved in unblocking the expression of TGF-ß receptor (TGF-ßR) by sponging oncogenic miRNAs (miR-9-5p, miR-17-5p, and miR-106-5p) during MK differentiation. Further, we report the activation of TGF-ßR-induced non-canonical ERK1/2 and PI3K/AKT pathways during PMA-induced MK differentiation and ploidy development. The present study demonstrates that TGF-ßR-induced non-canonical ERK1/2 and PI3K/AKT pathways are associated with PMA-induced MK differentiation and ploidy development; in this molecular mechanism, JPX lncRNA could act as a decoy for miR-9-5p, miR-17-5p, and miR-106-5p, titrating them away from TGF-ßR mRNAs. Importantly, this study reveals the activation of ERK1/2 and PI3K/AKT pathway in PMA-induced Dami cell differentiation into MK. The identified differentially expressed lncRNA signatures may facilitate further study of the detailed molecular mechanisms associated with MK development. Thus, our data provide numerous targets with therapeutic potential for the modulation of the differentiation of megakaryoblastic cells in AMKL.

Endocannabinoid system: Role in blood cell development, neuroimmune interactions and associated disorders.

The endocannabinoid system (ECS) is a complex physiological network involved in creating homeostasis and maintaining human health. Studies of the last 40 years have shown that endocannabinoids (ECs), a group of bioactive lipids, together with their set of receptors, function as one of the most important physiologic systems in human body. ECs and cannabinoid receptors (CBRs) are found throughout the body: in the brain tissues, immune cells, and in the peripheral organs and tissues as well. In recent years, ECs have emerged as key modulators of affect, neurotransmitter release, immune function, and several other physiological functions. This modulatory homoeostatic system operates in the regulation of brain activity and states of physical health and disease. In several research studies and patents the ECS has been recognised with neuro-protective properties thus it might be a target in neurodegenerative diseases. Most immune cells express these bioactive lipids and their receptors, recent data also highlight the immunomodulatory effects of endocannabinoids. Interplay of immune and nervous system has been recognized in past, recent studies suggest that ECS function as a bridge between neuronal and immune system. In several ongoing clinical trial studies, the ECS has also been placed in the anti-cancer drugs spotlight. This review summarizes the literature of cannabinoid ligands and their biosynthesis, cannabinoid receptors and their distribution, and the signaling pathways initiated by the binding of cannabinoid ligands to cannabinoid receptors. Further, this review highlights the functional role of cannabinoids and ECS in blood cell development, neuroimmune interactions and associated disorders. Moreover, we highlight the current state of knowledge of cannabinoid ligands as the mediators of neuroimmune interactions, which can be therapeutically effective for neuro-immune disorders and several diseases associated with neuroinflammation.

Co-stimulatory effect of TLR2 and TLR4 stimulation on megakaryocytic development is mediated through PI3K/NF-ĸB and XBP-1 loop.

Toll-like receptors (TLRs) are a class of proteins (patterns recognition receptors-PRRs) capable of recognizing molecules frequently found in pathogens (that are so-called pathogen-associated molecular patterns-PAMPs), they play a key role in the initiation of innate immune response by detecting PAMPs. Our findings show that the functional effects of TLRs co-stimulation on megakaryocytopoiesis. A single cell may receive multiple signal inputs and we consider that multiple TLRs are likely triggered during infection by multiple PAMPs that, in turn, might be involved in infection driven megakaryocytopoiesis, and the present study provide the evidence for the megakaryocytic effects of TLRs co-stimulation.

Virodhamine, an endocannabinoid, induces megakaryocyte differentiation by regulating MAPK activity and function of mitochondria.

Endocannabinoids are well-known regulators of neurotransmission by activating the cannabinoid (CB) receptors. Endocannabinoids are being used extensively for the treatment of various neurological disorders such as Alzheimer's and Parkinson's diseases. Although endocannabinoids are well studied in cell survival, proliferation, and differentiation in various neurological disorders and several cancers, the functional role in the regulation of blood cell development is less examined. In the present study, virodhamine, which is an agonist of CB receptor-2, was used to examine its effect on megakaryocytic development from a megakaryoblastic cell. We observed that virodhamine increases cell adherence, cell size, and cytoplasmic protrusions. Interestingly, we have also observed large nucleus and increased expression of megakaryocytic marker (CD61), which are the typical hallmarks of megakaryocytic differentiation. Furthermore, the increased expression of CB2 receptor was noticed in virodhamine-induced megakaryocytic cells. The effect of virodhamine on megakaryocytic differentiation could be mediated through CB2 receptor. Therefore, we have studied virodhamine induced molecular regulation of megakaryocytic differentiation; mitogen-activated protein kinase (MAPK) activity, mitochondrial function, and reactive oxygen species (ROS) production were majorly affected. The altered mitochondrial functions and ROS production is the crucial event associated with megakaryocytic differentiation and maturation. In the present study, we report that virodhamine induces megakaryocytic differentiation by triggering MAPK signaling and ROS production either through MAPK effects on ROS-generating enzymes or by the target vanilloid receptor 1-mediated regulation of mitochondrial function.

Real-time interrogation of fiber optic biosensor using TiO2 coated etched long-period grating.

In this work, a TiO2 coated etched long-period grating (e-LPG) fiber optic biosensor is developed for the detection of Escherichia coli (E. coli) bacteria in food items. Label-free Escherichia coli bacteria monitoring is done over the detection range of 0 cfu/ml-50 cfu/ml using an advanced spectral interrogation mechanism. The thin film deposition of 40 nm TiO2 over the e-LPG is confirmed by the microscopy method, such as scanning electron microscopy. In our proposed biosensor design, T4-bacteriophage is covalently immobilized over the TiO2 coated fiber surface. This biosensor system has reached sensitivity at 2.55 nm/RIU. Our experiments confirm the resolution and the limit of detection (3σ/S) of 0.0039 RIU and 10.05 ppm, respectively. The proposed biosensor with enhanced sensitivity is suitable for monitoring harmful pathogens/infectious agents in various food products.

Photonic generation of a parabolic-shaped microwave signal and dual-linear-chirp microwave waveform.

Based on an external modulation technique through a dual-polarized dual-parallel Mach-Zehnder modulator, a photonic technique is proposed for the generation of a microwave signal with a parabolic shape. An optically modulated waveform from the modulator is passed through an optical bandpass filter, which results in parabolic signals of 1 GHz and 9 GHz frequencies at the photo detector. A peak power spectral component of -30dBm power is obtained at 1 GHz and 9 GHz frequencies of the parabolic signal. Based on the present methodology, a parabolic signal of the desired frequency band can be obtained. The obtained signal is processed to generate a dual-linear-chirp signal by passing through the phase modulator. Here, a dual-linear-chirp microwave waveform with a chirp rate of 1.53Π×1019Hz/s is achieved at 6 GHz center frequency. The results are obtained through MATLAB simulation and verified by experimental results. A fair agreement is found between the result obtained through MATLAB simulation and the result obtained by experimental verification.

Photonic-technique-based highly steerable beamforming system incorporating a prism of super Gaussian apodized tunable chirped fiber Bragg grating for X-band applications.

Conventional phased arrays operate over bandwidths that are inversely proportional to the array size. The use of true-time delays (TTDs) instead of phase shifts would eliminate the bandwidth restrictions due to beam squint. Photonic techniques for dynamically controlling the delay at the input of a phased array antenna opens an area of new powerful methods for remarkably precisely increasing the speed of beamsteering of an antenna in a desired direction. In this paper, we demonstrate a photonic-based wideband TTD beamforming network employing super-Gaussian apodized chirped fiber Bragg gratings (SGFBGs) of different lengths such as 1.5 cm, 2 cm, 2.5 cm, and many more, as well as different chirp rates, which can be used as variable TTD lines for controlling the radiation angle of the phased array antenna (the main lobe radiated by the phased array antenna can be steered squint-free between 0° and ±49.63∘), suitable for continuous beamforming at microwave frequencies in the X-band (8-12 GHz). The main purpose of using SGFBGs in a TTD module is the reduction of ripples in delay with respect to wavelength, which results in reduction in ambiguity while tuning the laser wavelength to any particular value within spectral width of FBG. To the best of the authors' knowledge, this is the first experimental demonstration that shows the impact of tuning wavelength on delay change due to SGFBGs in the RF signal fed to the respective element of the antenna array.

RUNX1 and TGF-ß signaling cross talk regulates Ca2+ ion channels expression and activity during megakaryocyte development.

Thrombocytopenia is characterized by low platelet count and is typically observed among all preterm and low birthweight neonates admitted to the neonatal intensive care unit. Although the underlying cause for this predisposition is unclear, recent studies have proposed that the intrinsic inability of neonatal hematopoietic stem/progenitor cells to produce mature polyploid megakaryocytes (MKs) may result in delayed platelet engraftment. The developmental and molecular differences between neonatal and adult MKs are not yet fully understood. Previously, we had reported that the key MK transcription factor RUNX1, which is crucial for the regulation of MK specification and maturation, is down-regulated in neonatal MKs when compared with adult MKs. In humans, loss-of-function mutations in RUNX1 cause familial platelet disorder, which is characterized by thrombocytopenia, indicating its crucial role in MK development. However, information about its cross talk with developmentally regulated signaling pathways in MKs is lacking. In this study, we performed a differential gene expression analysis in MKs derived from human cord blood (CB) and adult peripheral blood (PB) CD34+ cells. Further, validation and correlation studies between RUNX1 and transforming growth factor beta (TGF-ß) were performed in a differentiating megakaryocytic cell line model. The analysis revealed that TGF-ß pathway was the main pathway affected between CB- and PB-MKs. RUNX1 is reported to be a modulator of TGF-ß signaling in several studies. The correlation between RUNX1 and TGF-ß pathway was analyzed in the PMA-induced megakaryocytic differentiating K562 cells, which exhibit mature megakaryocytic features. The RT2 profiler PCR array analysis revealed that TGF-ß pathway components were up-regulated in the PMA-induced megakaryocytic differentiating cells. Furthermore, our study indicated that human TGF-ß1 promotes cytosolic calcium (Ca2+ ) activity and MK maturation. We noticed that TGF-ß1 increased intracellular free Ca2+ ([Ca2+ ]i) via reactive oxygen species-mediated activation of transient receptor potential (TRP) ion channels. Moreover, we observed that decreased cytosolic Ca2+ activity in the siRUNX1-transfected cells was associated with down-regulation of TRP ion channel expression. Finally, we demonstrated that TGF-ß/SMAD signaling augments the development of MKs derived from CB-CD34+ . Present data suggest that RUNX1/TGF-ß pathway cross talk is crucial for MK maturation.

Endoplasmic reticulum stress induced apoptosis and caspase activation is mediated through mitochondria during megakaryocyte differentiation.

Megakaryocytopoiesis involves the process of the development of hematopoietic stem cells into megakaryocytes (MKs), which are the specialized cells responsible for the production of blood platelets. Platelets are one of the crucial factors for hemostasis and thrombosis. In terminally differentiated MKs, many molecular process such as caspase activation and a massive cytoskeletal rearrangement drive the formation of cytoplasmic extensions called proplatelets. These cytoplasmic extensions packed with granules and organelles are then released from the bone marrow into the blood circulation as platelets. Classically, caspase activation is associated with apoptosis and recent reports suggest their involvement in cell differentiation and maturation. There is no clear evidence about the stimulus for caspase activation during megakaryocyte development. In the current study, we attempted to understand the importance of endoplasmic reticulum stress in the caspase activation during megakaryocyte maturation. We used human megakaryoblstic cell line (Dami cells) as an experimental model. We used PMA (Phorbol 12-myristate 13 acetate) to induce megakaryocytic differentiation to understand the involvement of ER stress and caspase activation during MK maturation. Further, we used Thapsigargin, a non-competitive inhibitor of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) as a positive control to induce ER stress. We observed larger and adherent cells with the increased expression of megakaryocytic markers (CD41 and CD61) and UPR markers in PMA or Thapsigargin treated cells as compared to control. Also, Thapsigargin treatment induced increased caspase activity and PARP cleavage. The increased expression of megakaryocyte maturation markers alongside with ER stress and caspase activation suggests the importance of ER stress in caspase activation during MK maturation.

Long non-coding RNA: Classification, biogenesis and functions in blood cells.

While there exist some long non-coding RNAs (lncRNAs) that are structurally similar to mRNAs (capped, spliced, poly a tail), not all of the lncRNAs exhibit these features. Structurally, lncRNAs are classified under the regulatory non-coding RNAs category these lncRNA molecules operate as signals, decoys, guides, and scaffolds. In eukaryotes, lncRNAs are transcribed by RNA Polymerase II and RNA Polymerase III at several loci of the genome. Unlike other protein-coding mRNAs, lncRNAs exhibit functional uniqueness by participating in and modulating the various cellular processes such as, histone modification, DNA methylation, and cellular transcription (Wei et al., 2017). LncRNA alters chromatin structure and DNA accessibility, thereby regulating patterns of gene expression (Wang et al., 2011b). Disordered lncRNA with quantitative or qualitative alterations lead to the progression of numerous diseases including blood associated diseases. LncRNAs not only regulate lineage commitment such as cardiovascular lineage but also contribute for the hematopoietic stem cell development with a significant role in myeloid and lymphoid lineage commitment. However, the key molecular functions of lncRNAs in hematopoiesis are still unclear, particularly, their functional role during megakaryocyte development from hematopoietic stem cells (HSCs) is largely unexplored. This review summarizes the current status of knowledge on lncRNAs classification, biogenesis and its role in blood cells.

Exosome mediated differentiation of megakaryocytes: a study on TLR mediated effects.

Megakaryocytes are large polyploid bone marrow cells whose function is to produce circulatory platelets. Megakaryocytes are also known to release extracellular vesicles (EVs) of varying sizes. Toll like receptors (TLRs), present on the sentinel cells are essential components of the innate immune response, these receptors are also expressed by platelets and megakaryocytes. Our data provide the evidence that TLR-2 induced MKEVs are able to recapitulate TLR-2 signalling in megakaryocytic cell line (Dami cells) and that likely induces megakaryocytic maturation by increasing the production of cytokines involved in MK maturation. TLR-2 induced MKEVs may be involved in replenishment of the immune effector platelets in circulation and its progenitor megakaryocyte in bone marrow for the physiological need of the platelets by inducing the maturation of megakaryocyte.