9 research outputs found
Linear cyclodextrin polymer prodrugs as novel yherapeutics for Niemann-Pick type C1 disorder
No full textNiemann-Pick Type C1 disorder (NPC) is a rare lysosomal storage disease characterized by the accumulation of cholesterol in lysosomes. NPC has no FDA approved treatments yet, however 2-hydroxypropyl-β-cyclodextrin (HPβCD) has shown efficacy for treating the disease in both mouse and feline NPC models and is currently being investigated in late stage clinical trials. Despite promising results, therapeutic use of HPβCD is limited by the need for high doses, ototoxicity and intrathecal administration. These limitations can be attributed to its poor pharmacokinetic profile. In the attempt to overcome these limitations, we have designed a β-cyclodextrin (βCD) based polymer prodrugs (ORX-301) for an enhanced pharmacokinetic and biodistribution profile, which in turn can potentially provide an improved efficacy at lower doses. We demonstrated that subcutaneously injected ORX-301 extended the mean lifespan of NPC mice at a dosage 5-fold lower (800 mg/kg, body weight) the HPβCD dose proven efficacious (4000 mg/kg). We also show that ORX-301 penetrates the blood brain barrier and counteracts neurological impairment. These properties represent a substantial improvement and appear to overcome major limitations of presently available βCD-based therapy, demonstrating that this novel prodrug is a valuable alternative/complement for existing therapies
High Performance Data Traversal: Cache Aware Computing With Space Filling Curve
No full text"What Mathematics is to Physics, Data traversal is to High-performance computing." The world of Computational science has witnessed an exponential expansion of sophisticated numerical algorithms in the last few decades mainly to understand minute details and solve complex physical problems. It has established itself as the third pillar of science after theory and experimentation and has managed to gain immense popularity as a mainstream research work among academicians and scientists working in entirely different fields. The Computational Sciences has brought together Mathematicians and Computer Scientists to work in close collaboration on the variety of interdisciplinary research problems. The principal challenge to achieve high performance for computational researchers in near about every front is data traversal, data placement, and memory access pattern which mostly influences floating point performance and energy efficiency. The Data traversal is the soul of high-performance computing. Indeed it is the backbone; the way data travels to the CPU from main memory mainly influences the performance of particular computational kernel on specific machine architecture. The majority of modern computing devices are designed to deliver high performance if data traversal can utilize maximum bandwidth to main memory (DRAM) and make efficient use of hierarchical memory structure. Thus, a hardware optimal data access pattern should be designed to take advantage of the underlying hardware to scale and achieve performance, and that forms the central theme of this work. The more important point here is, expensive hardware or massive computational infrastructure does not naturally invoke high-performance computing but implementation of hardware auxiliary mathematical ideas, cache efficient data traversal strategies, sensible use of parallel programming paradigms and energy aware management of computational resources on machines ranging from very grass-root level primary NUMA system to entire million core server stack does. In this master's thesis, we will first focus on investigating the impact of data traversal patterns on the performance of several micro-benchmarks on Non-Uniform Memory Access machine, and in the second part, we will implement Morton-order Space Filling Curve to improve cache utilization for two numerical methods and analyze performance impact
Building Your Own Urban Tool Kit
No full textThe paper describes the development of a set of smart BIM components to facilitate and accelerate the creation of large-scale urban models in the early design phase in a BIM software environment. The components leverage the analytical, parametric and modelling capabilities of the BIM environment to support adaptive parameter-driven building geometry, patterning of different building types, early numerical and graphical design evaluation, various simulation methods and the exploration of design alternatives. The toolset consists of the most common building shapes, but can be extended with additional shapes and their respective area and volumetric calculations when necessary. The rapid large-scale deployment of the components has been achieved by diverting existing tools from their intended use
Asymmetric Synthesis of Bridged NHeterocycles with Tertiary Carbon Center through Barbas Dienamine-Catalysis: Scope and Applications
No full textA direct aza-Diels–Alder reaction
between 2-aryl-3H-indolin-3-ones and cyclic-enones
has been developed to
access chiral indolin-3-one fused polycyclic bridged compounds. This
method proceeds via proline-catalyzed Barbas-dienamine intermediate
formation from various cyclic-enones such as 2-cyclopenten-1-one,
2-cyclohexene-1-one, and 2-cycloheptene-1-one, followed by a reaction
with 2-aryl-3H-indol-3-ones. Several indolin-3-ones
fusing [2.2.2], [2.2.1], and [3.2.1] skeletons decorated with a tertiary
carbon chiral center have been prepared. Computational studies (DFT)
supported the observed stereoselectivity in the method. The synthesized
compounds have shown exciting photophysical activities and selective
sensing of Pd2+ and Fe3+ ions through the fluorescence
quenching “switch-off” mode
Enantioselective Direct Synthesis of C3-Hydroxyalkylated Pyrrole via an Amine-Catalyzed Aldol/Paal–Knorr Reaction Sequence
No full textCreating functionality with chirality at position C3
of pyrrole
is challenging. An operationally simple organocatalytic method has
been developed to generate functionality with a chiral tertiary/quaternary
stereocenter at position C3 of pyrrole. The process proceeds through
an amine-catalyzed direct aldol reaction of succinaldehyde with various
acceptor carbonyls, followed by a Paal–Knorr reaction with
a primary amine in the same pot. A series of chiral C3-hydroxyalkylated N-alkyl/Ar/H-pyrroles have been synthesized for the first
time with good to high yields and excellent enantioselectivity
Asymmetric Synthesis of Bridged <i>N</i>‑Heterocycles with Tertiary Carbon Center through Barbas Dienamine-Catalysis: Scope and Applications
No full textA direct aza-Diels–Alder reaction
between 2-aryl-3H-indolin-3-ones and cyclic-enones
has been developed to
access chiral indolin-3-one fused polycyclic bridged compounds. This
method proceeds via proline-catalyzed Barbas-dienamine intermediate
formation from various cyclic-enones such as 2-cyclopenten-1-one,
2-cyclohexene-1-one, and 2-cycloheptene-1-one, followed by a reaction
with 2-aryl-3H-indol-3-ones. Several indolin-3-ones
fusing [2.2.2], [2.2.1], and [3.2.1] skeletons decorated with a tertiary
carbon chiral center have been prepared. Computational studies (DFT)
supported the observed stereoselectivity in the method. The synthesized
compounds have shown exciting photophysical activities and selective
sensing of Pd2+ and Fe3+ ions through the fluorescence
quenching “switch-off” mode
Inhibiting Extracellular Cathepsin D Reduces Hepatic Steatosis in Sprague–Dawley Rats <sup>†</sup>
No full textDietary and lifestyle changes are leading to an increased occurrence of non-alcoholic fatty liver disease (NAFLD). Using a hyperlipidemic murine model for non-alcoholic steatohepatitis (NASH), we have previously demonstrated that the lysosomal protease cathepsin D (CTSD) is involved with lipid dysregulation and inflammation. However, despite identifying CTSD as a major player in NAFLD pathogenesis, the specific role of extracellular CTSD in NAFLD has not yet been investigated. Given that inhibition of intracellular CTSD is highly unfavorable due to its fundamental physiological function, we here investigated the impact of a highly specific and potent small-molecule inhibitor of extracellular CTSD (CTD-002) in the context of NAFLD. Treatment of bone marrow-derived macrophages with CTD-002, and incubation of hepatic HepG2 cells with a conditioned medium derived from CTD-002-treated macrophages, resulted in reduced levels of inflammation and improved cholesterol metabolism. Treatment with CTD-002 improved hepatic steatosis in high fat diet-fed rats. Additionally, plasma levels of insulin and hepatic transaminases were significantly reduced upon CTD-002 administration. Collectively, our findings demonstrate for the first time that modulation of extracellular CTSD can serve as a novel therapeutic modality for NAFLD
Electrochemical Synthesis of 2‑Aryl-3-(2-aminoaryl)quinoxalines via Oxidative Dearomatization/Ring-Opening/Cyclization Cascade Sequence of 2‑Arylindoles with 1,2-Diaminoarenes
No full textA straightforward method has been developed to synthesize
2-aryl-3-(2-aminoaryl)
quinoxalines from 2-arylindoles and 1,2-diaminoarenes under mild electrochemical
conditions. The reaction proceeds through in situ generations of 2-arylindole-3-ones
under electrochemical oxidative dearomatization of 2-arylindoles,
followed by a ring opening-cyclization sequence with 1,2-diaminoarenes.
A series of 2-aryl-3-(2-aminoaryl) quinoxalines have been prepared
with moderate to good yields (up to 75%)
In Search of Other Worlds: The Dalit in De Facto Statelessness in Avinash Dolas’s "The Refugee"
No full textThis article is reproduced here with permission from the author and may be found online at http://www.mcrg.ac.in/rw%20files/RW57/RW57.pdf.In this article, I discuss the position of the dalit citizen of India as one of de facto statelessness. To embark on my discussion, I delineate the dalit body as primally marked by the absence of the materiality of intimate touch from the caste-Hindu. This absence of touch allows me to locate the dalit body within social distance, that is, in empty space as the site facilitating the pure existence of humiliation. The humiliation, I allude to stems from the habitation of the dalit body in a perpetual state of alterity, given the absence of the warm touch of the other encasing it. This framework of humiliation stains the body in corporal lowness— a lowness in which the ruins of the consciousness inhabiting the body are trapped. Such a state of entrapment may lead these ruins of consciousness to go to great lengths to do violence to their bondage in social distance, as I demonstrate through my reading of the suicide letter written by dalit doctoral student and activist Rohith Vemula (1988-2016). Seeming to drift as the dalit body does in the perennial liminality of social distance, Marathi dalit writer and activist Avinash Dolas portrays the figure of the dalit as akin to that of a refugee in the Indian nation-state. Through a reading of Dolas’s short story “The Refugee,” I aver the untenability of this portrayal. Indeed, the dalit can, I suggest, perhaps be said to occupy a position which is closer to that of an internally displaced person— a person disowned by Brahminical touch and recognised in her internal displacement as a figure that the United Nations would term an ‘invisible citizen’ of India. This state of invisible citizenship, I argue, situates the dalit in de facto statelessness within an international juridical regime of human rights. Though the dalit’s claim to these human rights will not ensure that her body is liberated from the humiliation of social distance, her voicing of such a claim will set a tussle against caste privilege in motion. This tussle, as I show in broad strokes, bears the possibility of ending with the dalit being able to articulate her human rights as political rights
