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A combination of starvation therapy and ferroptosis offers a potent therapeutic strategy to treat triple-negative breast cancer (TNBC). Herein, a polymersome-based nanoreactor containing ferric ions and glucose oxidase (GOx) activates cascade reactions for multifaced and cooperative cancer treatments. The nanoreactor is constructed from a redox-responsive poly(methacrylic acid)–SS–poly(ε-caprolactone) copolymer (PCL–SS–PMAA) with a disulfide linkage located between the hydrophobic and hydrophilic junctions. The hydrophilic core of the polymersome (namely PSP) is loaded with oxidoreductase enzyme to induce starvation, and the outer shell of carboxylic groups is chelated with Fe3+ions to activate ferroptosis. The nanoreactor, FePSP@GOx, demonstrates the activation of a chain reaction that produces reactive oxygen species (ROS), thereby accelerating ferroptosis. The TNBC cell line MDA-MB-231 exposed to FePSP@GOx exhibits efficient glutathione (GSH) and glutathione peroxidase 4 (GPX4) depletion. Furthermore, the level of lipid peroxidation in MDA-MB-231 cells is significantly enhanced following the treatment with FePSP@GOx. In cytotoxicity assays, MDA-MB-231 cells treated with FePSP@GOx show pronounced enhancement in cell death. The integrated results imply that while starvation therapy coincides with the occurrence of a defensive autophagic response, the predominance of the ferroptosis mechanism over autophagy ultimately leads to cell death. FePSP@GOx, constructed from a GSH-responsive copolymer as a cascade nanoreactor, is a safe and promising nanomedicine for cooperative starvation-ferroptosis cancer therapy.

Divalent cations, especially Ca2+and Mg2+, play a vital role in the function of biomolecules and making them important to be constituents in samples for in vitro biophysical and biochemical characterizations. Although lipid nanodiscs are becoming valuable tools for structural biology studies on membrane proteins and for drug delivery, most types of nanodiscs used in these studies are unstable in the presence of divalent metal ions. To avoid the interaction of divalent metal ions with the belt of the nanodiscs, synthetic polymers have been designed and demonstrated to form stable lipid nanodiscs under such unstable conditions. Such polymer-based nanodiscs have been shown to provide an ideal platform for structural studies using both solid-state and solution NMR spectroscopies because of the near-native cell-membrane environment they provide and the unique magnetic-alignment behavior of large-size nanodiscs. In this study, we report an investigation probing the effects of Ca2+and Mg2+ions on the formation of polymer-based lipid nanodiscs and the magnetic-alignment properties using a synthetic polymer, styrene maleimide quaternary ammonium (SMA-QA), and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipids. Phosphorus-31 NMR experiments were used to evaluate the stability of the magnetic-alignment behavior of the nanodiscs for varying concentrations of Ca2+or Mg2+at different temperatures. It is remarkable that the interaction of divalent cations with lipid headgroups promotes the stacking up of nanodiscs that results in the enhanced magnetic alignment of nanodiscs. Interestingly, the reported results show that both the temperature and the concentration of divalent metal ions can be optimized to achieve the optimal alignment of nanodiscs in the presence of an applied magnetic field. We expect the reported results to be useful in the design of nanodisc-based nanoparticles for various applications in addition to atomic-resolution structural and dynamics studies using NMR and other biophysical techniques.

In an attempt to develop reversible sensors based on ionic liquid/porous silicon (IL/pSi) platforms, we introduce an approach using task-specific, alkene-terminal ILs (AT-ILs) for direct grafting to the hydrogen-passivated as prepared-pSi (ap-pSi) surface via UV-hydrosilylation to address previous shortcomings associated with IL pattern impermanence (i.e., spread). By employing photoluminescence emission (PLE) and Fourier-transform infrared (FT-IR) imaging measurements, we demonstrate that the covalent grafting of AT-ILs onto the ap-pSi surface via photochemical hydrosilylation not only mitigates such feature spreading but also greatly improves PLE pattern stability. Significantly, we have discovered that, upon hydrosilylation, the resulting contact pin printed IL features remain stable to repeated challenges by toluene vapors, demonstrating the utility of AT-IL hydrosilylation for producing high-fidelity microarray features on pSi toward robust optical sensory microarrays.

The ability of amphipathic polymers to self-assemble with lipids and form nanodiscs has been a boon for the field of functional reconstitution of membrane proteins. In a field dominated by detergent micelles, a unique feature of polymer nanodiscs is their much-desired ability to align in the presence of an external magnetic field. Magnetic alignment facilitates the application of solid-state nuclear magnetic resonance (NMR) spectroscopy and aids in the measurement of residual dipolar couplings via well-established solution NMR spectroscopy. In this study, we comprehensively investigate the magnetic alignment properties of styrene maleimide quaternary ammonium (SMA-QA) polymer-based nanodiscs by using 31P and 14N solid-state NMR experiments under static conditions. The results reported herein demonstrate the spontaneous magnetic alignment of large-sized (≥20 nm diameter) SMA-QA nanodiscs (also called as macro–nanodiscs) with the lipid bilayer normal perpendicular to the magnetic field direction. Consequently, the orientation of macro–nanodiscs is further shown to flip the alignment axis parallel to the magnetic field direction upon the addition of a paramagnetic lanthanide salt. These results demonstrate the use of SMA-QA polymer nanodiscs for solid-state NMR applications including structural studies on membrane proteins.

Lipid compositional asymmetry across the leaflets of the plasma membrane is an ubiquitous feature in eukaryotic cells. How this asymmetry is maintained is thought to be primarily controlled by active transport of lipids between leaflets. This strategy is facilitated by the fact that long-tail phospholipids and sphingolipids diffuse through the lipid bilayer slowly—taking many hours or days. However, a lipid like cholesterol—which is the most abundant lipid in the plasma membrane of animal cells—has been harder to pinpoint in terms of its favored side. In this work we show that, when a saturated lipid is added to a mix of the unsaturated lipid palmitoyl-oleoyl-phosphatidylcholine (POPC) and cholesterol, both cholesterol and the long-tail phospholipids organize asymmetrically across the membrane’s leaflets naturally. In these extruded unilamellar vesicles, most cholesterol as well as the saturated lipid—dipalmitoylphosphatidylcholine or sphingomyelin—segregated to the inner leaflet while POPC preferentially localized in the outer leaflet. This asymmetric arrangement generated a slight phospholipid number imbalance favoring the outer leaflet and thus opposite to where cholesterol and the saturated lipids preferentially partitioned. These results were obtained using magic-angle spinning nuclear magnetic resonance (MAS NMR) in combination with small-angle neutron scattering (SANS) using isotope labeling to differentiate lipid species. We suggest that sidedness in membranes can be driven by thermodynamic processes. In addition, our MAS NMR results show that the lower bound for cholesterol’s flip-flop half-time at 45°C is 10 ms, which is at least two orders of magnitude slower than current MD simulations predict. This result stands in stark contrast to previous work that suggested that cholesterol’s flip-flop half-time at 37°C has an upper bound of 10 ms.

There is a growing interest in the use of lipid bilayer nanodiscs for various biochemical and biomedical applications. Among the different types of nanodiscs, the unique features of synthetic polymer-based nanodiscs have attracted additional interest. A styrene–maleic acid (SMA) copolymer demonstrated to form lipid nanodiscs has been used for structural biology related studies on membrane proteins. However, the application of SMA polymer based lipid nanodiscs is limited because of the strong absorption of the aromatic group interfering with various experimental measurements. Thus, there is considerable interest in the development of other molecular frameworks for the formation of polymer-based lipid nanodiscs. In this study, we report the first synthesis and characterization of a library of polymethacrylate random copolymers as alternatives to SMA polymer. In addition, we experimentally demonstrate the ability of these polymers to form lipid bilayer nanodiscs through the fragmentation of lipid vesicles by means of light scattering, electron microscopy, differential scanning calorimetry, and solution and solid-state NMR experiments. We further demonstrate a unique application of the newly developed polymer for kinetics and structural characterization of the aggregation of human islet amyloid polypeptide (also known as amylin) within the lipid bilayer of the polymer nanodiscs using thioflavin-T-based fluorescence and circular dichroism experiments. Our results demonstrate that the reported new styrene-free polymers can be used in high-throughput biophysical experiments. Therefore, we expect that the new polymer nanodiscs will be valuable in the structural studies of amyloid proteins and membrane proteins by various biophysical techniques.

Nasogastric tube insertion under anaesthesia have high reported failure rate of almost 50%.Use of front of the neck manipulations and airway instrumentation are not without complications. We hypothesized that flexion of the neck assisted NGT insertion can result in more successful nasogastric intubations over the conventional technique.

Background: Phosphatidylinositol-3-kinase α (PI3Kα) is a ubiquitous intracellular enzyme, mainly involved in intracellular signaling pathways, promotes cellular growth, proliferation, and differentiation. Therefore, inhibition of PI3K can be a hotspot in molecular targeted therapy for the treatment of cancer. Methods: The present research work involves molecular docking studies performed to screen derivatives of urea and thiourea bearing thieno [3,2-d]-pyrimidines against the active site of PI3K enzyme using MOE.2008.10. The designed structures (6a-f) and (7a-j) were synthesized by the facile synthetic methods and evaluated for their anticancer activity against HT-29 and MCF-7 cell lines and inhibitory activity against PI3Kα enzyme. Results: Among the tested compounds, 4-(4-(2-(3-(pyrimidin-2-yl)thioureido)ethyl)piperazin-1-yl)thieno[3,2- d]pyrimidine-6-carboxamide (7f) showed the highest anticancer activity against HT-29 and MCF-7 cell lines with IC50 values of 2.18 μM and 4.25 μM, respectively. Further, the same compound also exhibited potent PI3Kα inhibitory activity with IC50 value of 1.26 μM. Conclusion: Docking studies supported the initial pharmacophoric hypothesis and suggested a mode of interaction at the active binding site of PI3Kα, demonstrating that the target compounds were potential inhibitory agents for cancer therapy.

An experimental investigation of compressive failure in masonry made of soft clay bricks is presented. The research attempts to address the concern of strong/stiff mortars available in the market today in combination with poor quality burnt clay bricks available in India. Masonry assemblages are tested to evaluate the influence of the relative strength of mortar on the observed damage evolution and compressive failure. Damage evolution associated with the formation and propagation of vertical splitting cracks during the compressive load response of masonry assemblages in the stack bonded arrangement are studied using a full-field optical technique based on digital image correlation. The stress state in the composite material produces tension in the mortar and confined compression in brick. Using image correlation clear evidence of the crack forming in the mortar and propagating into the brick is established. Failure is produced by vertical splitting and the number of cracks depend upon the tensile strength of the mortar relative to the brick and the number of head joints. Head joints act as stress risers, leading to high tensile stress.

Layered transition metal dichalcogenides (TMDs) have attracted increased attention due to their enhanced hydrogen evolution reaction (HER) performance. More specifically, ternary TMD nanohybrids, such as MoS2(1–x)Se2xor bimetallic sulfides, have arisen as promising electrocatalysts compared to MoS2and MoSe2due to their electronic, morphologic, and size tunabilities. Herein, we report the successful synthesis of few-layered MoS2/rGO, SnS2/rGO, and (MoS2)x(SnO2)1–x/rGO nanohybrids anchored on reduced graphene oxide (rGO) through a facile hydrothermal reaction in the presence of ionic liquids as stabilizing, delayering agents. Spectroscopic and microscopic techniques (electron microscopy, X-ray diffraction, Raman spectroscopy, neutron activation analysis, and UV–vis spectrophotometry) are used to validate the hierarchical properties, phase identity, and the smooth compositional tunability of the (MoS2)x(SnO2)1–x/rGO nanohybrids. Linear sweep voltammetry measurements reveal that incorporation of Sn into the ternary nanohybrids (as a discrete SnO2phase) greatly reduces the overpotential by 90–130 mV relative to the MoS2electrocatalyst. Significantly, the (MoS2)0.6(SnO2)0.4/rGO nanohybrid displays superior catalytic performance over MoS2alone, exhibiting a low overpotential (η10) of 263 ± 5 mV and a small Tafel slope of 50.8 mV dec–1. The hybrid catalyst shows high stability for the HER in acidic solutions, with negligible activity loss after 1000 cycles. The hierarchical structures and large surface areas possessing exposed, active edge sites make few-layered (MoS2)x(SnO2)1–x/rGO nanohybrids promising nonprecious metal electrocatalysts for the HER.

ABSTRACTTo investigate long-term antibody persistence following the administration of the 10-valent pneumococcal non-typeable Haemophilus influenzaeprotein D conjugate vaccine (PHiD-CV), we present results of 2 follow-up studies assessing antibody persistence following 2 3+1 schedules up to 4 (NCT00624819 – Study A) and 5 years (NCT00891176 – Study B) post-booster vaccination. In Study A, antibody persistence was measured one, 2 and 4 years post-booster in children previously primed and boosted with PHiD-CV, or primed with the 7-valent pneumococcal conjugate vaccine (7vCRM) and boosted with either PHiD-CV or 7vCRM. In Study B, PHiD-CV was co-administered with meningococcal vaccines, and pneumococcal antibody persistence was measured 2, 3 and 5 years post-booster. An age-matched control group, unvaccinated against Streptococcus pneumoniae, was enrolled in Study A, allowing assessment of immunologic memory by administration of one dose of PHiD-CV to both primed (4 years post-booster) and unprimed 6-year-old children. Four years post-booster (Study A), antibody concentrations and opsonophagocytic activity (OPA) titers remained higher compared to the pre-booster timepoint, with no major differences between the 3 primed groups. Antibody persistence was also observed in Study B, with minimal differences between groups. The additional PHiD-CV dose administered 4 years post-booster in Study A elicited more robust immune responses in primed children than in unprimed children. Long-term serotype-specific antibody persistence and robust immunologic memory responses observed in these 2 studies suggest induction of long-term protection against pneumococcal disease after PHiD-CV vaccination.

Studies have shown that low or high serum bicarbonate levels (reflecting metabolic acidosis or alkalosis)are associated with increased all-cause mortality rates in moderate and advanced chronic kidney disease (CKD) cases. Correction of presumed acidosis using sodium bicarbonate, targeting serum levels around 22 mmol/l, has proven beneficial in delaying the progression of the disease and provided mortality benefit. A similar prognostic association may exist between uncorrected metabolic acidosis in chronic liver disease. Correcting it with sodium-containing salts may require more interventions due to increased sodium/fluid load. In patients with liver failure, a naturally alkalotic state, where sodium load is a concern, the impact of this intervention is unclear. This study aims to generate proof of concept through a retrospective chart review in individuals with CKD-related metabolic acidosis and liver cirrhosis. We extrapolate that lowering bicarbonate targets in other clinical scenarios like liver failure, pregnancy, and cardiac failure may be prudent and will lead to a lower sodium load.

The physical verification process is a vital step in an ASIC chip design flow to enable the mask layouts manufacturable and functional. The input/output (I/O) pads which are at the peripheries of the chip operating at the multi-voltage domains are critical components to be verified during the top-level verification. The proposal made in this article uses a methodical approach towards verifying the I/O layouts by constructing pad ring based on the maximal, typical and minimal scaling factors. The need of scaling factors provides the degree of optimisation in the pad ring construction which enhances the level of verifying I/O pad layouts effectively based on the user's intent to run physical verification on the number of I/O pads in the library. The concept is developed, implemented, and verified in cadence design framework full custom environment to illustrate the effectiveness of the automation in the present industry standard. The automated physical verification is validated across several libraries and technologies to achieve significant reduction in iterative time and manual effort during the layout verification platform setup.

Background:Artificial intelligence (AI) is one of the active research fields to develop systems that mimic human intelligence and is helpful in many fields, particularly in medicine. (“Role of Artificial Intelligence Techniques ... - PubMed”) Physiotherapy is mainly involving in curing bone-related pain and injuries. The recent emergence of artificially intelligent machines has seen human cognitive capacity enhanced by computational agents that can recognize previously hidden patterns within massive data sets. (“(PDF) Artificial intelligence in clinical practice ...”) In this context, artificial intelligence in pediatric physiotherapy could be one of the most important modalities in delivering better medical and healthcare services to needy people. It is an attempt to identify the types, as well as to assess the effectiveness of interventions provided by artificial intelligence on pediatric physical therapy optimization-related outcomes.

Service members and law enforcement experience repeated blast exposures frequently due to the constant use of heavy weaponry, including large caliber rifles and explosives. Over the past five years, there has been growth in preclinical traumatic brain injury models of repeated exposure to blasts. While the literature is still limited, recent evidence is shedding light on potential cumulative effects and long-term consequences. In real-life scenarios, personnel experience low-level blasts extensively during training programs. In humans, low-level blasts are often not associated with overt symptoms; however, exposure to repeated low-level blasts can lead to cognitive impairments, attention deficits, and sleep disturbances over time. For this review, we focused on studies reproducing repeated blasts from 2015 to 2021. Overall, we found that repeated moderate blasts induce similar neurological changes as a single moderate blast, whereas repeated low-level blasts show a trend of neuropathological changes similar to a single moderate blast.

The enhanced power density, long term cycling stability, and fast rate of operation, makes supercapacitors as desirable energy storage devices. Though metal oxides play a significant part in energy storage systems, Vanadium oxides have piqued the interest of electrochemists due to their multi-valency, potential window, unique layer structure, affordability, and plentiful availability.  Vanadium pentoxide typically has relatively low specific capacitance due to its weak electrical conductivity and ionic diffusivity. However, these properties can be enhanced by encasing vanadium pentoxide in metal or carbonaceous materials, reducing it to the nanoscale, or changing its shape. On the other hand, the synthetic strategies are mostly essential in raising a compound's specific capacitance. Here, we report the synthesis of vanadium pentoxide nanoparticles using a cost effective solution combustion method. The synthesized material was characterized by X-ray diffraction analysis, UV-Vis Spectroscopy, FT-IR Spectroscopy, Scanning Electron Microscopy, Cyclic voltammetry, Galvanostatic Charge-discharge, and Electrochemical Impedance Spectroscopy. The crystallite size of obtained nanoparticles is 28 nm. The specific capacitance of Vanadium pentoxide nanoparticles is 310 F/g and is calculated at 1 A/g using Galvanostatic Charge-discharge method. The obtained specific capacitance is higher than the existing reports on V2O5 nanoparticles.

Autoclaved Aerated Concrete (AAC) flyash Blocks are light weight bricks, which is rapidly used in high rise buildings. The AAC Blocks are one of the sustainable materials manufactured using industrial waste flyash. The masonry infills made with AAC blocks contribute to light weight of structure, thermal conductivity and faster construction. The AAC block masonry needs to be studied at material level to improve its efficiency. The material level understanding of the behavior of AAC block masonry is lacking in the literatures. In this paper, Experimental investigation is presented to understand the compressive stress-strain behavior of AAC Block masonry and its constituents. The response of AAC block masonry with weak and strong mortar is obtained from compression test.

The Internet of Things (IoT) is a network of interconnected, Internet‐connected items that can gather and transmit data without the need for human interaction through a wireless network. Cryptography is a way of using codes to safeguard information and communications so that only those who are supposed to read and process it may do so. Existing system shows privacy and replication issues caused during cipher text attribute set based encryption. The technical issues in achieving secured authentication is removed by using multi‐channel attack detection based on lightweight message authentication code (LMAC) access control using IoT design in which collision attack can be removed by using secure hash algorithm based Merkle tree and to control sinkhole attacks agent navigation algorithm is proposed and long short‐term memory (LSTM) recurrent neural network (RNN) is proposed to provide the conformity of the user login password. Moreover, to identify attackers on the transmitter side by ensuring authentication, multichannel detection method is proposed. Finally, the security and privacy is improved by using LMAC and user revocation. Thus the multi‐channel attack detection based on LMAC using IoT design can be outperforming the other existing model with higher throughput and low execution time. Message authentication code access control multi‐channel attack detection model.

ABSTRACTIn this phase III, open-label, multicenter, and descriptive study in India, children primed with 3 doses (at ages 6, 10, and 14 weeks) of the 10-valent pneumococcal nontypeable Haemophilus influenzaeprotein D conjugate vaccine (PHiD-CV) were randomized (1:1) to receive a booster dose at 9 to 12 (early booster) or 15 to 18 months old (late booster) in order to evaluate impact of age at booster. We also evaluated a 2-dose catch-up vaccination plus an experimental booster dose in unprimed children age 12 to 18 months. The early booster, late booster, and catch-up vaccinations were administered to 74, 95, and 87 children, respectively; 66, 71, and 81 children, respectively, were included in the immunogenicity according-to-protocol cohort. One month postbooster, for each PHiD-CV serotype, =95.2% (early booster) and =93.8% (late booster) of the children had antibody concentrations of =0.2 µg/ml; =96.7% and =93.0%, respectively, had opsonophagocytic activity (OPA) titers of =8. The postbooster antibody geometric mean concentrations (GMCs) were in similar ranges for early and late boosters; the OPA titers appeared to be lower for most PHiD-CV serotypes (except 6B and 19F) after the early booster. After dose 2 and postbooster, for each PHiD-CV serotype, =88.6% and =96.3%, respectively, of the catch-up immunogenicity according-to-protocol cohort had antibody concentrations of =0.2 µg/ml; =71.4% and =90.6%, respectively, had OPA titers of =8. At least 1 serious adverse event was reported by 2 children in the early booster (skin infection and gastroenteritis) and 1 child in the catch-up group (febrile convulsion and urinary tract infection); all were resolved, and none were considered by the investigators to be vaccine related. PHiD-CV induced robust immune responses regardless of age at booster. Booster vaccination following 2 catch-up doses induced robust immune responses indicative of effective priming and immunological memory. (These studies have been registered at www.clinicaltrials.govunder registration no. NCT01030822 and NCT00814710; a protocol summary is available at www.gsk-clinicalstudyregister.com[study ID 112909]).