130553 research outputs found
Sort by
Next-generation membrane-active glycopeptide antibiotics that also inhibit bacterial cell division
No full textResistance to vancomycin, a life-saving drug against Gram-positive bacterial infections necessitates developing alternative therapeutics. Herein, we report vancomycin derivatives that assimilate mechanisms beyond D-Ala–D-Ala binding. The role of hydrophobicity towards the structure and function of the membrane-active vancomycin showed that alkyl-cationic substitutions favored broad-spectrum activity. The lead molecule, VanQAmC10 delocalized the cell division protein MinD in Bacillus subtilis, implying an impact on bacterial cell division. Further examination of wild-type, GFP-FtsZ, or GFP-FtsI producing- and ΔamiAC mutants of Escherichia coli revealed filamentous phenotypes and delocalization of the FtsI protein. The findings indicate that VanQAmC10 also inhibits bacterial cell division, a property previously unknown for glycopeptide antibiotics. The conjunction of multiple mechanisms contributes to its superior efficacy against metabolically active and inactive bacteria, wherein vancomycin is ineffective. Additionally, VanQAmC10 exhibits high efficacy against methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii in mouse models of infection
Induced Flow Inside a Droplet by Static Electrical Charge
No full textIntroducing controlled fluid motion in a droplet turns out to be of outstanding scientific importance, hallmarked by a plethora of applications ranging from engineering to biology. While internal mechanisms such as interfacial tension or buoyancy-driven dynamics may trigger fascinating flow structures inside a droplet, controllability of the same without external forcing remains questionable. On the other hand, in an electrically forced environment, complex fabrication steps and special choices of the ionic liquid are often demanded. Circumventing these limits, here we bring out a new method of flow manipulation inside a sessile droplet by simply deploying a static charge produced by the triboelectric effect. This is physically actuated by charge transfer between the two lateral electrodes within which the droplet is entrained, triggering a strong ionized air current. The flow inside the droplet is generated due to the shear exerted at the interface by the charged-induced ionized airflow around the droplet, a paradigm that has hitherto remained unexplored. The strength of the fluid flow can be controlled by adjusting the supplied charge. Such unique controllability without sacrificing the physical simplicity opens up new possibilities for flow manipulation in a multitude of applications ranging from droplet microreactors to digital microfluidics
Indian National Association for Study of the Liver (INASL) Guidance Paper on Nomenclature, Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease (NAFLD)
No full textNonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease globally and in India. The already high burden of NAFLD in India is expected to further increase in the future in parallel with the ongoing epidemics of obesity and type 2 diabetes mellitus. Given the high prevalence of NAFLD in the community, it is crucial to identify those at risk of progressive liver disease to streamline referral and guide proper management. Existing guidelines on NAFLD by various international societies fail to capture the entire landscape of NAFLD in India and are often difficult to incorporate in clinical practice due to fundamental differences in sociocultural aspects and health infrastructure available in India. A lot of progress has been made in the field of NAFLD in the 7 years since the initial position paper by the Indian National Association for the Study of Liver on NAFLD in 2015. Further, the ongoing debate on the nomenclature of NAFLD is creating undue confusion among clinical practitioners. The ensuing comprehensive review provides consensus-based, guidance statements on the nomenclature, diagnosis, and treatment of NAFLD that are practically implementable in the Indian setting
Metavalent Bonding-Mediated Dual 6s2 Lone Pair Expression Leads to Intrinsic Lattice Shearing in n-Type TlBiSe<sub>2</sub>
No full textMetavalent bonding has attracted immense interest owing to its capacity to impart a distinct property portfolio to materials for advanced functionality. Coupling metavalent bonding to lone pair expression can be an innovative way to propagate lattice anharmonicity from lone pair-induced local symmetry-breaking via the soft p-bonding electrons to achieve long-range phonon dampening in crystalline solids. Motivated by the shared chemical design pool for topological quantum materials and thermoelectrics, we based our studies on a three-dimensional (3D) topological insulator TlBiSe2 that held prospects for 6s2 dual-cation lone pair expression and metavalent bonding to investigate if the proposed hypothesis can deliver a novel thermoelectric material. Herein, we trace the inherent phononic origin of low thermal conductivity in n-type TlBiSe2 to dual 6s2 lone pair-induced intrinsic lattice shearing that strongly suppresses the lattice thermal conductivity to a low value of 1.1-0.4 Wm-1 K-1 between 300 and 715 K. Through synchrotron X-ray pair distribution function and first-principles studies, we have established that TlBiSe2 exists not in a monomorphous R-3m structure but as a distribution of distorted configurations. Via a cooperative movement of the constituent atoms akin to a transverse shearing mode facilitated by metavalent bonding in TlBiSe2, the structure shuttles between various energetically accessible low-symmetry structures. The orbital interactions and ensuing multicentric bonding visualized through Wannier functions augment the long-range transmission of atomic displacement effects in TlBiSe2. With additional point-defect scattering, a κlatt of 0.3 Wm-1 K-1 was achieved in TlBiSeS with a maximum n-type thermoelectric figure of merit (zT) of ∼0.8 at 715 K
Metavalent Bonding Origins of Unusual Properties of Group IV Chalcogenides
No full textA distinct type of metavalent bonding (MVB) is recently proposed to explain an unusual combination of anomalous functional properties of group IV chalcogenide crystals, whose electronic mechanisms and origin remain controversial. Through theoretical analysis of evolution of bonding along continuous paths in structural and chemical composition space, emergence of MVB in rocksalt chalcogenides is demonstrated as a consequence of weakly broken symmetry of parent simple-cubic crystals of Group V metalloids. High electronic degeneracy at the nested Fermi surface of parent metal drives spontaneous breaking of its translational symmetry with structural and chemical fields, which open up a small energy gap and mediate strong coupling between conduction and valence bands making metavalent crystals highly polarizable, conductive, and sensitive to bond-lengths. Stronger symmetry-breaking structural and chemical fields, however, transform them discontinuously to covalent and ionic semiconducting states. MVB involves bonding-antibonding pairwise interactions alternating along linear chains of at least five atoms, which facilitate long-range electron transfer in response to polar fields causing unusual properties. The precise picture of MVB predicts anomalous second-order Raman scattering as an addition to set off their unusual properties, and will guide in design of new metavalent materials with improved thermoelectric, ferroelectric and nontrivial electronic topological properties
Intermediate-range order governs dynamics in dense colloidal liquids
No full textThe conventional wisdom is that liquids are completely disordered and lack nontrivial structure beyond nearest-neighbor distances. Recent observations have upended this view and demonstrated that the microstructure in liquids is surprisingly rich and plays a critical role in numerous physical, biological, and industrial processes. However, approaches to uncover this structure are either system-specific or yield results that are not physically intuitive. Here, through single-particle resolved three-dimensional confocal microscope imaging and the use of a recently introduced four-point correlation function, we show that bidisperse colloidal liquids have a highly nontrivial structure comprising alternating layers with icosahedral and dodecahedral order, which extends well beyond nearest-neighbor distances and grows with supercooling. By quantifying the dynamics of the system on the particle level, we establish that it is this intermediate-range order, and not the short-range order, which has a one-to-one correlation with dynamical heterogeneities, a property directly related to the relaxation dynamics of glassy liquids. Our experimental findings provide a direct and much sought-after link between the structure and dynamics of liquids and pave the way for probing the consequences of this intermediate-range order in other liquid state processes
Photostimulated extended nitric oxide (no) release from water-soluble block copolymer to enhance antibacterial activity.
No full textN-Nitrosamines are well established motifs to release nitric oxide (NO) under photoirradiation. Herein, a series of amphiphilic N-nitrosamine-based block copolymers (BCPx-NO) are developed to attain controlled NO release under photoirradiation (365 nm, 3.71 mW/cm2). The water-soluble BCPx-NO forms micellar architecture in aqueous medium and exhibits a sustained NO release of 92–160 μM within 11.5 h, which is 36.8–64.0% of the calculated value. To understand the NO release mechanism, a small molecular NO donor (NOD) resembling the NO releasing functional motif of BCPx-NO is synthesized, which displays a burst NO release in DMSO within 2.5 h. The radical nature of the released NO is confirmed by electron paramagnetic resonance (EPR) spectroscopy. The gradual NO release from micellar BCPx-NO enhances antibacterial activity over NOD and exhibits a superior bactericidal effect on Gram-positive Staphylococcus aureus. In relation to biomedical applications, this work offers a comprehensive insight into tuning light-triggered NO release to improve antibacterial activity
Zwitterionic polysulfobetaine inhibits cancer cell migration owing to actin cytoskeleton dynamics.
No full textCell migration is an essential dynamic process for most living cells, mainly driven by the reorganization of actin cytoskeleton. To control actin dynamics, a molecular architecture that can serve as a nucleator has been designed by polymerizing sulfobetaine methacrylate. The synthesized zwitterionic polymer, poly(sulfobetaine methacrylate) (PZI), effectively nucleates the polymerization process of G-actin and substantially accelerates the rate of polymerization. Isothermal titration calorimetry (ITC) and bioinformatics analysis indicated binding between PZI and monomeric G-actin. Thus, in vitro actin dynamics was studied by dynamic light scattering (DLS), pyrene-actin polymerization assay, and total internal reflection fluorescence microscopy (TIRFM). Furthermore, a 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophore-containing monomeric unit was incorporated into the sulfobetaine zwitterionic architecture to visualize the effect of polymer in the cellular environment. The BODIPY-containing zwitterionic sulfobetaine polymer (PZI-F) successfully penetrated the cell and remained in the lysosome with minimal cytotoxicity. Confocal microscopy revealed the influence of this polymer on the cellular actin cytoskeleton dynamics. The PZI-F polymer was successfully able to inhibit the collective migration of the human cervical cancer cell line (HeLa cell) and breast cancer cell line (MDA-MB-231 cell), as confirmed by a wound healing assay. Therefore, polyzwitterionic sulfobetaine could be explored as an inhibitor of cancer cell migration
Rodent model preclinical assessment of pegylated block copolymer targeting cognition and oxidative stress insults of alzheimer’s disease.
No full textMisfolded peptide amyloid beta (Aβ42), neurofibrillary tangles of hyper-phosphorylated tau, oxidative damage to the brain, and neuroinflammation are distinguished determinants of Alzheimer’s disease (AD) responsible for disease progression. This multifaceted neurodegenerative disease is challenging to cure under a single treatment regime until the key disease determinants are traced for their sequential occurrence in disease progression. In an early report, a novel side-chain tripeptide containing PEGylated block copolymer has been tested thoroughly in vitro and in silico for the early inhibition of Aβ42 aggregation as well as degradation of preformed Aβ42 fibril deposits. The present study demonstrates a preclinical assessment of the PEGylated block copolymer in colchicine-induced AD-mimicking rodent model. The colchicine-induced Wistar rats receiving an intranasal delivery of the block copolymer at a daily dosage of 100 µg/kg and 200 µg/kg body weights, respectively, for 14 days manifested a notable attenuation of behavioral deficit pattern, oxidative stress, and neurotransmitters’ deficiency as compared to the untreated ones. The current study also reports the ameliorative property of the PEGylated compound for progressive neuroinflammation and decreased mitochondrial bioenergetics in astrocytoma cell line, viz., U87. A closer look into the drug mechanism of action of a compact 3D PEGylated block copolymer confirmed its disintegrative interaction with Aβ42 fibril via in silico simulation. The results obtained from this study signify the potential of the novel PEGylated block copolymer to ameliorate the cognitive decline and progressive oxidative insults in AD and may envision a successful clinical phase trial
RNA binding protein IGF2BP1 synergizes with ETV6-RUNX1 to drive oncogenic signaling in B-cell Acute Lymphoblastic Leukemia
No full textBackground
Acute lymphoblastic leukemia (ALL) is the most common pediatric hematological malignancy, with ETV6::RUNX1 being the most prevalent translocation whose exact pathogenesis remains unclear. IGF2BP1 (Insulin-like Growth Factor 2 Binding Protein 1) is an oncofetal RNA binding protein seen to be specifically overexpressed in ETV6::RUNX1 positive B-ALL. In this study, we have studied the mechanistic role of IGF2BP1 in leukemogenesis and its synergism with the ETV6::RUNX1 fusion protein.
Methods
Gene expression was analyzed from patient bone marrow RNA using Real Time RT-qPCR. Knockout cell lines were created using CRISPR-Cas9 based lentiviral vectors. RNA-Seq and RNA Immunoprecipitation sequencing (RIP-Seq) after IGF2BP1 pulldown were performed using the Illumina platform. Mouse experiments were done by retroviral overexpression of donor HSCs followed by lethal irradiation of recipients using a bone marrow transplant model.
Results
We observed specific overexpression of IGF2BP1 in ETV6::RUNX1 positive patients in an Indian cohort of pediatric ALL (n=167) with a positive correlation with prednisolone resistance.
IGF2BP1 expression was essential for tumor cell survival in multiple ETV6::RUNX1 positive B-ALL cell lines. Integrated analysis of transcriptome sequencing after IGF2BP1 knockout and RIP-Seq after IGF2BP1 pulldown in Reh cell line revealed that IGF2BP1 targets encompass multiple pro-oncogenic signalling pathways including TNFα/NFκB and PI3K-Akt pathways. These pathways were also dysregulated in primary ETV6::RUNX1 positive B-ALL patient samples from our center as well as in public B-ALL patient datasets. IGF2BP1 showed binding and stabilization of the ETV6::RUNX1 fusion transcript itself. This positive feedback loop led to constitutive dysregulation of several oncogenic pathways.
Enforced co-expression of ETV6::RUNX1 and IGF2BP1 in mouse bone marrow resulted in marrow hypercellularity which was characterized by multi-lineage progenitor expansion and strong Ki67 positivity. This pre-leukemic phenotype confirmed their synergism in-vivo. Clonal expansion of cells overexpressing both ETV6::RUNX1 and IGF2BP1 was clearly observed. These mice also developed splenomegaly indicating extramedullary hematopoiesis.
Conclusion
Our data suggest a combined impact of the ETV6::RUNX1 fusion protein and RNA binding protein, IGF2BP1 in activating multiple oncogenic pathways in B-ALL which makes IGF2BP1 and these pathways as attractive therapeutic targets and biomarkers