scholarly journals σ2 Receptor and Its Role in Cancer with Focus on a MultiTarget Directed Ligand (MTDL) Approach

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3743
Author(s):  
Francesca Serena Abatematteo ◽  
Mauro Niso ◽  
Enza Lacivita ◽  
Carmen Abate
Keyword(s):  
Targeted Delivery ◽  
Transmembrane Protein ◽  
Simultaneous Administration ◽  
Cancer Disease ◽  
Pharmacological Targets ◽  
Multiple Cell ◽  
Diverse Groups ◽  
Multiple Molecules ◽  
Shed Light ◽  
Cancer Diseases

Sigma-2 (σ2) is an endoplasmic receptor identified as the Endoplasmic Reticulum (ER) transmembrane protein TMEM97. Despite its controversial identity, which was only recently solved, this protein has gained scientific interest because of its role in the proliferative status of cells; many tumor cells from different organs overexpress the σ2 receptor, and many σ2 ligands display cytotoxic actions in (resistant) cancer cells. These properties have shed light on the σ2 receptor as a potential druggable target to be bound/activated for the diagnosis or therapy of tumors. Additionally, diverse groups have shown how the σ2 receptor can be exploited for the targeted delivery of the anticancer drugs to tumors. As the cancer disease is a multifactorial pathology with multiple cell populations, a polypharmacological approach is very often needed. Instead of the simultaneous administration of different classes of drugs, the use of one molecule that interacts with diverse pharmacological targets, namely MultiTarget Directed Ligand (MTDL), is a promising and currently pursued strategy, that may overcome the pharmacokinetic problems associated with the administration of multiple molecules. This review aims to point out the progress regarding the σ2 ligands in the oncology field, with a focus on MTDLs directed towards σ2 receptors as promising weapons against (resistant) cancer diseases.

scholarly journals The Impact of Race on Speech Perception and Accentedness Judgments in Racially Diverse and Non-Diverse Groups

2020 ◽  
Author(s):  
Ethan Kutlu ◽  
Mehrgol Tiv ◽  
Stefanie Wulff ◽  
Debra Titone
Keyword(s):  
Social Network ◽  
South Asian ◽  
Racially Diverse ◽  
Indian English ◽  
Linguistic Ideologies ◽  
Negative Stereotypes ◽  
Diverse Groups ◽  
The Impact ◽  
Asian Face ◽  
Shed Light

Linguistic ideologies are informed by social stereotyping (Fiske et al. 2007) to maintain the standard variety, which is often interpreted as morally superior to nonstandard varieties (Hill 2008). Consequently, these ideologies racialize nonstandard varieties (Rosa 2016), leading to even more negative stereotypes (Giles & Watson 2013). One outlet of such stereotypes can be observed with accentism. This study examines whether seeing a White or a South Asian face impacts listeners’ perception of American, British, Indian English and to what extent listeners’ social network diversity plays a role in predicting their perception of speech. Results showed that intelligibility scores decreased and accentedness judgments increased for all varieties when speech was paired with South Asian faces. However, listeners who have racially less diverse social network have the highest accentedness judgments. Currently, there is a pressing question to understand how to account for the emergence of different English varieties and their differing pronunciations. Results here shed light on to how these varieties are perceived. The implications will be discussed in light of language teaching and linguistic practices.

scholarly journals Meta-Omics Reveals Genetic Flexibility of Diatom Nitrogen Transporters in Response to Environmental Changes

2019 ◽  
Vol 36 (11) ◽  
pp. 2522-2535 ◽  
Author(s):  
Greta Busseni ◽  
Fabio Rocha Jimenez Vieira ◽  
Alberto Amato ◽  
Eric Pelletier ◽  
Juan J Pierella Karlusich ◽  
...  
Keyword(s):  
Environmental Changes ◽  
Seawater Temperature ◽  
Holistic Approach ◽  
Gene Families ◽  
Functional Trait ◽  
Marine Phytoplankton ◽  
Functional Biology ◽  
Key Events ◽  
Diverse Groups ◽  
Shed Light

Abstract Diatoms (Bacillariophyta), one of the most abundant and diverse groups of marine phytoplankton, respond rapidly to the supply of new nutrients, often out-competing other phytoplankton. Herein, we integrated analyses of the evolution, distribution, and expression modulation of two gene families involved in diatom nitrogen uptake (DiAMT1 and DiNRT2), in order to infer the main drivers of divergence in a key functional trait of phytoplankton. Our results suggest that major steps in the evolution of the two gene families reflected key events triggering diatom radiation and diversification. Their expression is modulated in the contemporary ocean by seawater temperature, nitrate, and iron concentrations. Moreover, the differences in diversity and expression of these gene families throughout the water column hint at a possible link with bacterial activity. This study represents a proof-of-concept of how a holistic approach may shed light on the functional biology of organisms in their natural environment.

Waiting in organisations

2018 ◽  
Vol 28 (2) ◽  
pp. 587-612 ◽  
Author(s):  
Catherine Bailey
Keyword(s):  
Social Sciences ◽  
Lived Experience ◽  
Consumer Behaviour ◽  
Future Research ◽  
The Individual ◽  
Employee Experience ◽  
Diverse Groups ◽  
Shed Light

Waiting is a pervasive feature of organisational life and, as such, is likely to be important for a range of individual and organisational outcomes. Although extant research has shed light on the waiting experiences of diverse groups such as those suffering from illness, waiting in detention centres or queuing, there have been no previous attempts to theorise waiting specifically from the perspective of the employee. To address this gap, we draw on theories of temporality and waiting in fields such as consumer behaviour as well as the wider social sciences to develop the notion of ‘situated waiting’ which uncovers the complexity of the lived experience of waiting from the perspective of the employee. This experience is associated with factors at the level of the individual, the wait itself, and the broader waiting context. We outline the implications for future research on this hitherto hidden domain of the employee experience.

scholarly journals MS4A3 Promotes Differentiation in Chronic Myeloid Leukemia by Enhancing Common β Chain Cytokine Receptor Endocytosis

Blood ◽  
2021 ◽  
Author(s):  
Helong Zhao ◽  
Anthony D Pomicter ◽  
Anna M Eiring ◽  
Anca Franzini ◽  
Jonathan Ahmann ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Targeted Delivery ◽  
Myeloid Leukemia ◽  
Ex Vivo ◽  
Transmembrane Protein ◽  
Chronic Phase ◽  
Aberrant Methylation ◽  
Blast Phase ◽  
Β Chain

The chronic phase of chronic myeloid leukemia (CP-CML) is characterized by excessive production of maturating myeloid cells. As CML stem/progenitor cells (LSPCs) are poised to cycle and differentiate, LSPCs must balance conservation and differentiation to avoid exhaustion, similar to normal hematopoiesis under stress. Since BCR-ABL1 tyrosine kinase inhibitors (TKIs) eliminate differentiating cells, but spare BCR-ABL1-independent LSPCs, understanding the mechanisms that regulate LSPC differentiation may inform strategies to eliminate LSPCs. Upon performing a meta-analysis of published CML transcriptomes, we discovered that low expression of the MS4A3 transmembrane protein is a universal characteristic of LSPC quiescence, BCR-ABL1 independence, and transformation to blast phase. Several mechanisms are involved in suppressing MS4A3, including aberrant methylation and a MECOM-C/EBPε axis. Contrary to previous reports, we find that MS4A3 does not function as a G1/S phase inhibitor, but promotes endocytosis of common β chain (βc) cytokine receptors upon GM-CSF/IL-3 stimulation, enhancing downstream signaling and cellular differentiation. This suggests that LSPCs downregulate MS4A3 to evade βc cytokine-induced differentiation and maintain a more primitive, TKI-insensitive state. Accordingly, knockdown or deletion of MS4A3/Ms4a3 promotes TKI resistance and survival of CML cells ex vivo and enhance leukemogenesis in vivo, while targeted delivery of exogenous MS4A3 protein promotes differentiation. These data support a model in which MS4A3 governs response to differentiating myeloid cytokines, providing a unifying mechanism for the differentiation block characteristic of CML quiescence and blast phase CML. Promoting MS4A3 re-expression or delivery of ectopic MS4A3 may help eliminating LSPCs in vivo.

scholarly journals The yeast protein Gdt1p transports Mn2+ ions and thereby regulates manganese homeostasis in the Golgi

2018 ◽  
Vol 293 (21) ◽  
pp. 8048-8055 ◽  
Author(s):  
Louise Thines ◽  
Antoine Deschamps ◽  
Palanivelu Sengottaiyan ◽  
Oksana Savel ◽  
Jiri Stribny ◽  
...  
Keyword(s):  
Calcium Homeostasis ◽  
Transmembrane Protein ◽  
Protein Glycosylation ◽  
Yeast Cells ◽  
Yeast Protein ◽  
Bacterial Host ◽  
Uncharacterized Protein ◽  
Suggested Link ◽  
Secondary Ion ◽  
Shed Light

The uncharacterized protein family 0016 (UPF0016) is a family of secondary ion transporters implicated in calcium homeostasis and some diseases. More precisely, genetic variants of the human UPF0016 ortholog transmembrane protein 165 (TMEM165) have been linked to congenital disorders of glycosylation (CDG). The Saccharomyces cerevisiae ortholog Gdt1p has been shown to be involved in calcium homeostasis and protein glycosylation. Moreover, plant and bacterial UPF0016 members appear to have putative roles in Mn2+ homeostasis. Here, we produced the yeast UPF0016 member Gdt1p in the bacterial host Lactococcus lactis. Using Mn2+-induced quenching of Fura-2–emitted fluorescence, we observed that Gdt1p mediates Mn2+ influx, in addition to its previously reported regulation of Ca2+ influx. The estimated Km values of Gdt1p of 15.6 ± 2.6 μm for Ca2+ and 83.2 ± 9.8 μm for Mn2+ indicated that Gdt1p has a higher affinity for Ca2+ than for Mn2+. In yeast cells, we found that Gdt1p is involved in the resistance to high Mn2+ concentration and controls total Mn2+ stores. Lastly, we demonstrated that GDT1 deletion affects the activity of the yeast Mn2+-dependent Sod2p superoxide dismutase, most likely by modulating cytosolic Mn2+ concentrations. Taken together, we obtained first evidence that Gdt1p from yeast directly transports manganese, which strongly reinforces the suggested link between the UPF0016 family and Mn2+ homeostasis and provides new insights into the molecular causes of human TMEM165-associated CDGs. Our results also shed light on how yeast cells may regulate Golgi intraluminal concentrations of manganese, a key cofactor of many enzymes involved in protein glycosylation.

scholarly journals PHRED-1 is a divergent neurexin-1 homolog that organizes muscle fibers and patterns organs during regeneration

2017 ◽  
Author(s):  
Carolyn E. Adler ◽  
Alejandro Sánchez Alvarado
Keyword(s):  
Body Wall ◽  
Structural Integrity ◽  
Transmembrane Protein ◽  
Muscle Fibers ◽  
Cell Types ◽  
Bhlh Transcription Factor ◽  
Body Parts ◽  
Normal Muscle ◽  
Complex Process ◽  
Multiple Cell

AbstractRegeneration of body parts requires the replacement of multiple cell types. To dissect this complex process, we utilized planarian flatworms that are capable of regenerating any tissue after amputation. An RNAi screen for genes involved in regeneration of the pharynx identified a novel gene, Pharynx regeneration defective-1 (PHRED-1) as essential for normal pharynx regeneration. PHRED-1 is a predicted transmembrane protein containing EGF, Laminin G, and WD40 domains, is expressed in muscle, and has predicted homologs restricted to other lophotrochozoan species. Knockdown of PHRED-1 causes abnormal regeneration of muscle fibers in both the pharynx and body wall muscle. In addition to defects in muscle regeneration, knockdown of PHRED-1 or the bHLH transcription factor MyoD also causes defects in muscle and intestinal regeneration. Together, our data demonstrate that muscle plays a key role in restoring the structural integrity of closely associated organs, and in planarians it may form a scaffold that facilitates normal intestinal branching.Graphical AbstractHighlights-PHRED-1 is a predicted transmembrane protein that contains Laminin G, EGF and WD40 domains-PHRED-1 is required for normal muscle patterning during regeneration-phred-1 is expressed in muscle cells-Muscle forms an essential scaffold for regeneration

scholarly journals MicroRNA-7a2 Regulates Prolactin in Developing Lactotrophs and Prolactinoma Cells

Endocrinology ◽  
2020 ◽  
Vol 162 (2) ◽  
Author(s):  
Mary P LaPierre ◽  
Svenja Godbersen ◽  
Mònica Torres Esteban ◽  
Anaïs Nura Schad ◽  
Mathias Treier ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mirna Family ◽  
Dynamic Network ◽  
Loss Of Function ◽  
Gradual Loss ◽  
Prolactin Gene ◽  
Multiple Cell ◽  
Complex Regulation ◽  
Mouse Pituitary ◽  
Shed Light

Abstract Prolactin production is controlled by a complex and temporally dynamic network of factors. Despite this tightly coordinated system, pathological hyperprolactinemia is a common endocrine disorder that is often not understood, thereby highlighting the need to expand our molecular understanding of lactotroph cell regulation. MicroRNA-7 (miR-7) is the most highly expressed miRNA family in the pituitary gland and the loss of the miR-7 family member, miR-7a2, is sufficient to reduce prolactin gene expression in mice. Here, we used conditional loss-of-function and gain-of-function mouse models to characterize the function of miR-7a2 in lactotroph cells. We found that pituitary miR-7a2 expression undergoes developmental and sex hormone–dependent regulation. Unexpectedly, the loss of mir-7a2 induces a premature increase in prolactin expression and lactotroph abundance during embryonic development, followed by a gradual loss of prolactin into adulthood. On the other hand, lactotroph development is delayed in mice overexpressing miR-7a2. This regulation of lactotroph function by miR-7a2 involves complementary mechanisms in multiple cell populations. In mouse pituitary and rat prolactinoma cells, miR-7a2 represses its target Raf1, which promotes prolactin gene expression. These findings shed light on the complex regulation of prolactin production and may have implications for the physiological and pathological mechanisms underlying hyperprolactinemia.

scholarly journals Klotho inhibits neuronal senescence in human brain organoids

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Mohammed R. Shaker ◽  
Julio Aguado ◽  
Harman Kaur Chaggar ◽  
Ernst J. Wolvetang
Keyword(s):  
Human Brain ◽  
Cortical Neurons ◽  
Brain Aging ◽  
Transmembrane Protein ◽  
Cell Types ◽  
The Body ◽  
Aging Effects ◽  
Multiple Cell ◽  
Senescence Associated Genes

AbstractAging is a major risk factor for many neurodegenerative diseases. Klotho (KL) is a glycosylated transmembrane protein that is expressed in the choroid plexus and neurons of the brain. KL exerts potent anti-aging effects on multiple cell types in the body but its role in human brain cells remains largely unclear. Here we show that human cortical neurons, derived from human pluripotent stem cells in 2D cultures or in cortical organoids, develop the typical hallmarks of senescent cells when maintained in vitro for prolonged periods of time, and that moderate upregulation or repression of endogenous KL expression in cortical organoids inhibits and accelerates senescence, respectively. We further demonstrate that KL expression alters the expression of senescence-associated genes including, extracellular matrix genes, and proteoglycans, and can act in a paracrine fashion to inhibit neuronal senescence. In summary, our results establish an important role for KL in the regulation of human neuronal senescence and offer new mechanistic insight into its role in human brain aging.

Nanotechonology for Drug Targeting

2010 ◽  
Vol 76 ◽  
pp. 177-183
Author(s):  
Barbara Ruozi ◽  
Giovanni Tosi ◽  
Flavio Forni ◽  
Maria Angela Vandelli
Keyword(s):  
Flow Cytometry ◽  
Targeted Delivery ◽  
Drug Targeting ◽  
Drug Delivery Systems ◽  
Polymeric Nanoparticles ◽  
Primary Effusion Lymphoma ◽  
Preliminary Study ◽  
The Brain ◽  
Cancer Diseases

Nanoparticles (Np) and liposomes (L) were engineered obtaining selective drug delivery systems able to cross BBB and to treat cancer diseases, respectively. The first goal was achieved conjugating a specific epta-glucopeptide (g7) to polymeric nanoparticles (Np). The data related the nociceptive activity showed the ability of g7-Np to cross the BBB and to release loperamide in the brain. To reach the second goal we have recently proposed the immunoliposomes (ILp) for tumor-targeted delivery of gene material (particularly SiRNAs), which are selected in vitro for the specific antineoplastic activity against herpesvirus-associated B-cell lymphomas, particularly HHV8+ Primary Effusion Lymphoma (PEL). In the preliminary study we have prepared and characterized the ILp direct to PEL cells (BCBL-1 cell line). The cellular trafficking of the encapsulated model FITC-ODN obtained by flow cytometry and confocal microscopy was evaluated by the ability of the new carriers to selectively interact with cells. The data were compared with the different behaviour of these liposomes respect to the un-targeted cationic and pegylated liposomes.

scholarly journals Analysis of Dynamics Targeting CNT-Based Drug Delivery through Lung Cancer Cells: Design, Simulation, and Computational Approach

Membranes ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 283
Author(s):  
Nafiseh Sohrabi ◽  
Afshar Alihosseini ◽  
Vahid Pirouzfar ◽  
Maysam Zamani Pedram
Keyword(s):  
Drug Delivery ◽  
Cell Membrane ◽  
Delivery System ◽  
Targeted Delivery ◽  
Specific Area ◽  
Systemic Delivery ◽  
Cancer Disease ◽  
Magnetic Field Profile ◽  
Human Lung Cells ◽  
Analysis Of Dynamics

Nowadays, carbon nano (CN) structures and specifically carbon nanotubes (CNTs), because of the nanotube’s nanoscale shape, are widely used in carrier and separation applications. The conjugation of CNTs with polysaccharide, proteins, drugs, and magnetic nanoparticles provides a chance for smart targeting and trajectory manipulation, which are used in the crucial field of life science applications, including for cancer disease diagnostics and treatments. Providing an optimal procedure for delivering a drug to a specific area based on mathematical criteria is key in systemic delivery design. Trajectory guidance and applied force control are the main parameters affected by systemic delivery. Moreover, a better understanding of the tissue parameters and cell membrane molecular behaviour are other factors that can be indirectly affected by the targeted delivery. Both sides are an essential part of successful targeting. The lung is one of the challenging organs for drug delivery inside the human body. It has a large surface area with a thin epithelium layer. A few severe diseases directly involve human lung cells, and optimal and successful drug delivery to the lung for the treatment procedure is vital. In this paper, we studied functionalized CNTs’ targeted delivery via crossing through the lung cell membrane. Molecular dynamics (MD) software simulated all the interaction forces. Mathematical modelling of the cell membrane and proposed delivery system based on the relation of velocity and force has been considered. Dynamics equations for CNTs were defined in the time and frequency domain using control theory methods. The proposed delivery system consists of two main parts: crossing through the cell membrane and targeting inside the cell. For both steps, a mathematical model and a proper magnetic field profile have been proposed. The designed system provides criteria for crossing through the cell membrane within 30 s to 5 min and a translocation profile of 1 to 100 Å.

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