The sulfatase family of enzymes catalyzes hydrolysis of sulfate ester bonds of a wide variety of substrates. Seventeen genes have been identified in this class of sulfatases, many of which are ...associated with genetic disorders leading to reduction or loss of function of the corresponding enzymes. Amino acid sequence homology suggests that the enzymes have similar overall folds, mechanisms of action, and bivalent metal ion-binding sites. A catalytic cysteine residue, strictly conserved in prokaryotic and eukaryotic sulfatases, is post-translationally modified into a formylglycine. Hydroxylation of the formylglycine residue by a water molecule forming the activated hydroxylformylglycine (a formylglycine hydrate or a gem-diol) is a necessary step for the enzyme's sulfatase activity. Crystal structures of three human sulfatases, arylsulfatases A and B(ARSA and ARSB), and estrone/dehydroepiandrosterone sulfatase or steroid sulfatase (STS), also known as arylsulfatase C, have been determined. While ARSA and ARSB are water-soluble enzymes, STS has a hydrophobic domain and is an integral membrane protein of the endoplasmic reticulum. In this article, we compare and contrast sulfatase structures and revisit the proposed catalytic mechanism in light of available structural and functional data. Examination of the STS active site reveals substrate-specific interactions previously identified as the estrogen-recognition motif. Because of the proximity of the catalytic cleft of STS to the membrane surface, the lipid bilayer has a critical role in the constitution of the active site, unlike other sulfatases.
Abstract
The animal model deals with the species other than the human, as it can imitate the disease progression, its’ diagnosis as well as a treatment similar to human. Discovery of a drug and/or ...component, equipment, their toxicological studies, dose, side effects are in vivo studied for future use in humans considering its’ ethical issues. Here lies the importance of the animal model for its enormous use in biomedical research. Animal models have many facets that mimic various disease conditions in humans like systemic autoimmune diseases, rheumatoid arthritis, epilepsy, Alzheimer’s disease, cardiovascular diseases, Atherosclerosis, diabetes, etc., and many more. Besides, the model has tremendous importance in drug development, development of medical devices, tissue engineering, wound healing, and bone and cartilage regeneration studies, as a model in vascular surgeries as well as the model for vertebral disc regeneration surgery. Though, all the models have some advantages as well as challenges, but, present review has emphasized the importance of various small and large animal models in pharmaceutical drug development, transgenic animal models, models for medical device developments, studies for various human diseases, bone and cartilage regeneration model, diabetic and burn wound model as well as surgical models like vascular surgeries and surgeries for intervertebral disc degeneration considering all the ethical issues of that specific animal model. Despite, the process of using the animal model has facilitated researchers to carry out the researches that would have been impossible to accomplish in human considering the ethical prohibitions.
Non orthogonal multiple access (NOMA) is expected to be the most significant and viable solution for fifth generation (5 G) communication system due to its incredible advantage of spectral ...efficiency. This paper proposes joint channel allocation and power optimization for downlink NOMA system, so as to maximize the system throughput while preserving the minimum data rate of every user equipment necessary to maintain quality of service and successive interference cancellation constraint. The optimization problem so formulated is a joint mixed integer nonlinear programming problem. Hence, two stage solution is proposed that uses mosek solver for channel assignment followed by power allocation across assigned channels. We use the difference between two convex functions (DC) programming technique for modifying the nonconvex optimization problem into a convex subproblem. Thus, we achieve efficient and fair power allocation coefficients across channels by solving the convex subproblem iteratively. Simulation results demonstrate better efficiency of our proposed scheme for resource allocation compared to some of the existing baseline schemes.
The contribution of platelets is well recognized in thrombosis and hemostasis. However, platelets also promote tumor progression and metastasis through their crosstalk with various cells of the tumor ...microenvironment (TME). For example, several cancer models continue to show that platelet functions are readily altered by cancer cells upon activation leading to the formation of platelet-tumor aggregates, triggering release of soluble factors from platelet granules and altering platelet turnover. Further, activated platelets protect tumor cells from shear forces in circulation and assault of cytotoxic natural killer (NK) cells. Platelet-secreted factors promote proliferation of malignant cells, metastasis, and chemoresistance. Much of our knowledge of platelet biology in cancer has been achieved with animal models, particularly murine. However, this preclinical understanding of the complex pathophysiology is yet to be fully realized and translated to clinical trials in terms of new approaches to treat cancer via controlling the platelet function. In this review, we summarize the current state of knowledge of platelet physiology obtained through existing in vivo and in vitro cancer models, the complex interactions of platelets with cancer cells in TME and the pathways by which platelets may confer chemoresistance. Since the FDA Modernization Act recently passed by the US government has made animal models optional in drug approvals, we critically examine the existing and futuristic value of employing bioengineered microphysiological systems and organ-chips to understand the mechanistic role of platelets in cancer metastasis and exploring novel therapeutic targets for cancer prevention and treatment.
We study the prospects of searches for exotic long-lived particles with the MoEDAL detector at the LHC, assuming the integrated luminosity of 30 fb
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1
that is expected at the end of Run 3. MoEDAL ...incorporates nuclear track detectors deployed a few metres away from the interaction point, which are sensitive to any highly-ionizing particles. Hence MoEDAL is able to detect singly- or doubly-charged particles with low velocities
β
<
0.15
or
<
0.3
, respectively, and lifetimes larger than
O
(
1
)
m
/
c
. We examine the MoEDAL sensitivity to various singly-charged supersymmetric particles with long lifetimes and to several types of doubly-charged long-lived particles with different spins and SU(2) charges. We compare the prospective MoEDAL mass reaches to current limits from ATLAS and CMS, which involve auxiliary analysis assumptions. MoEDAL searches for doubly-charged fermions are particularly competitive.
Little is known about how animals integrate multiple sensory inputs in natural environments to balance avoidance of danger with approach to things of value. Furthermore, the mechanistic link between ...internal physiological state and threat-reward decision making remains poorly understood. Here we confronted C. elegans worms with the decision whether to cross a hyperosmotic barrier presenting the threat of desiccation to reach a source of food odor. We identified a specific interneuron that controls this decision via top-down extrasynaptic aminergic potentiation of the primary osmosensory neurons to increase their sensitivity to the barrier. We also establish that food deprivation increases the worm’s willingness to cross the dangerous barrier by suppressing this pathway. These studies reveal a potentially general neural circuit architecture for internal state control of threat-reward decision making.
•Autocrine neuropeptide signaling motif regulates a C. elegans multisensory decision•Multisensory decision is also modulated by top-down extrasynaptic aminergic signal•Computational modeling reveals neuronal network dynamics underlying decision•Food deprivation suppresses aminergic feedback pathway to increase threat tolerance
Ghosh et al. characterize a neural circuit in C. elegans by which hunger state regulates threat tolerance in a multisensory risk-reward decision by suppressing an interneuron-derived extrasynaptic top-down aminergic feedback signal to a primary sensory neuron.
Abstract Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease with heightened disease severity in children. The incomplete understanding of the precise cellular and molecular ...events that drive disease activity pose a significant hurdle to the development of targeted therapeutic agents. Here, we performed single-cell phenotypic and functional characterization of pediatric SLE patients and healthy controls blood via mass cytometry. We identified a distinct CD14hi monocyte cytokine signature, with increased levels of monocyte chemoattractant protein-1 (MCP1), macrophage inflammatory protein-1β (Mip1β), and interleukin-1 receptor antagonist (IL-1RA). This signature was shared by every clinically heterogeneous patient, and reproduced in healthy donors' blood upon ex-vivo exposure to plasma from clinically active patients only. This SLE-plasma induced signature was abrogated by JAK1/JAK2 selective inhibition. This study demonstrates the utility of mass cytometry to evaluate immune dysregulation in pediatric autoimmunity, by identification of a multi-parametric immune signature that can be further dissected to delineate the events that drive disease pathogenesis.
The present study was undertaken to determine the mechanism of antibacterial activity of a polyphenolic fraction, composed of mainly catechin and isorhamnetin, previously isolated from Kombucha, a ...14‐day fermented beverage of sugared black tea, against the enteropathogen Vibrio cholerae N16961. Bacterial growth was found to be seriously impaired by the polyphenolic fraction in a dose‐dependent manner. Scanning Electron Microscopy demonstrated morphological alterations in bacterial cells when exposed to the polyphenolic fraction in a concentration‐dependent manner. Permeabilization assays confirmed that the fraction disrupted bacterial membrane integrity in both time‐ and dose‐dependent manners, which were proportional to the production of intracellular reactive oxygen species (ROS). Furthermore, each of the polyphenols catechin and isorhamnetin showed the ability to permeate bacterial cell membranes by generating oxidative stress, thereby suggesting their role in the antibacterial potential of Kombucha. Thus, the basic mechanism of antibacterial activity of the Kombucha polyphenolic fraction against V. cholerae involved bacterial membrane permeabilization and morphological changes, which might be due to the generation of intracellular ROS. To the best of our knowledge, this is the first report on the investigation of antibacterial mechanism of Kombucha, which is mostly attributed to its polyphenolic content.
Significance and Impact of the Study
The emergence of multidrug‐resistant Vibrio cholerae strains has hindered an efficient anti‐Vibrio therapy. This study has demonstrated the membrane damage‐mediated antibacterial mechanism of Kombucha, a popular fermented beverage of sugared tea, which is mostly attributed to its polyphenolic content. This study also implies the exploitation of Kombucha as a potential new source of bioactive polyphenols against V. cholerae.
Significance and Impact of the Study: The emergence of multidrug‐resistant Vibrio cholerae strains has hindered an efficient anti‐Vibrio therapy. This study has demonstrated the membrane damage‐mediated antibacterial mechanism of Kombucha, a popular fermented beverage of sugared tea, which is mostly attributed to its polyphenolic content. This study also implies the exploitation of Kombucha as a potential new source of bioactive polyphenols against V. cholerae.
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