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Phonon linewidths in twisted bilayer graphene near the magic angle
No full textWe present a computational study of the phonon linewidths in twisted bilayer graphene arising from electron-phonon and phonon-phonon interactions. The electronic structure is calculated using distance-dependent transfer integrals based on the atomistic Slater-Koster tight-binding formalism including electron-electron interactions treated at the Hartree level, and the phonons are calculated using classical force fields. These ingredients are used to calculate the phonon linewidths arising from electron-phonon interactions. Furthermore, effects of the phonon-phonon interactions on the linewidths are computed using the mode-projected velocity autocorrelation function obtained from classical molecular dynamics. We predict a moiré potential induced splitting of the Raman-active mode, near the magic angle, which arises due to contributions from high-symmetry stacking regions. Our findings show that both electron-phonon and anharmonic effects have a significant impact on the linewidth of this mode near the magic angle
Hydrogen bonding-driven self-coacervation of nonionic homopolymers for stimuli-triggered therapeutic release.
No full textInspired by the unique functionalities of biomolecular membraneless organelles (MLOs) formed via liquid–liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs) and nucleic acids, a great deal of effort has been devoted to devising phase-separated artificial subcellular dynamic compartments. These endeavors aim to unravel the molecular mechanism underlying the formation and intracellular delivery of susceptible macromolecular therapeutics. We report herein pyroglutamic acid (PGA)-based well-defined homopolymers featuring stimuli-tunable reversible self-coacervation ability. The polymer exhibits an upper critical solution temperature (UCST) transition in aqueous solutions and has the propensity to undergo cooling-induced LLPS, producing micrometer-sized liquid droplets. This phase separation phenomenon could be modulated by various factors, including polymer concentration, chain length, solution pH, and types and concentrations of different additives. These micrometer droplets are thermally reversible and encapsulate a wide variety of cargoes, including small hydrophobic fluorescent molecules, hydrophilic anticancer drugs, and fluorophore-labeled macromolecular proteins (bovine serum albumin and lysozyme). The payloads were released by exploiting the thermo/pH-mediated disassembly behavior of the coacervates, preserving the bioactivity of the sensitive therapeutics. This environmentally responsive, simple yet versatile artificial MLO model system will provide insights into the biomolecular nonionic condensates and pave the way for the de novo design of dynamic biomolecule depots
SMART-ESAS: Smartphone Monitoring and Assessment in Real Time of Edmonton Symptom Assessment System Scores for Patients With Cancer
No full textPurpose
Serial patient-reported outcome (PRO) measurements in clinical practice are associated with a better quality of life and survival. Recording electronic PROs using smartphones is an efficient way to implement this. We aimed to assess the feasibility of the electronically filled Edmonton Symptom Assessment System (e-ESAS) scale in the lower-middle–income country (LMIC) setting.
Methods
Baseline clinical features and conventional paper-based ESAS (p-ESAS) were collected in newly diagnosed patients with solid organ tumors. Text message link was sent to these patients for filling e-ESAS. ESAS was categorized into physical, psychological, and total symptom domains. Scores were divided into none to mild (0-3) and moderate to severe (4-10). Intraclass correlation coefficients (ICCs) were used to determine the correlation between p-ESAS and e-ESAS. Multivariable logistic regression was used to identify independent factors affecting symptom burden.
Results
Of 1,160 participants who filled out p-ESAS, 595 completed both e-ESAS and p-ESAS questionnaires and were included in the final analysis. Moderate to severe physical, psychological, and total symptom scores were seen in 39.8%, 40%, and 39% of participants. Tiredness and anxiety were the most common physical and psychological symptoms, respectively. ICCs between the p-ESAS and e-ESAS varied between 0.75 and 0.9. Total symptom scores were independently predicted by metastatic disease (odds ratio [OR], 1.83; 95% CI, 1.26 to 2.67; P = .001) and a higher level of education (OR, 0.42; 95% CI, 0.25 to 0.72; P = .001).
Conclusion
Paper-based and electronically filled ESASs have good intraobserver reliability across individual symptoms and domain scores in a representative cohort at a tertiary care institute in the LMIC. This may help us incorporate e-ESAS in routine clinical care in the real-world setting with financial, infrastructural, and manpower limitations
AML-749 Regulation of Autophagy and Oxidative Phosphorylation Is Predominantly Altered at the Transcription Level in Leukemic Stem Cells (LSCs) in Relapsed AML
No full textAim
Acute myeloid leukemia (AML) is a highly aggressive malignancy of uncontrolled myeloid progenitor cell proliferation and has a dismal survival rate. Despite the availability of standard and targeted therapeutic regimens, the rate of relapse is high in patients when leukemic stem cells (LSCs) are present. LSCs can self-renew and reinitiate leukemia in patients at any time point. Altered gene expression patterns in LSCs at diagnosis and relapse might help elucidate the factors responsible for relapse in AML.
Methodology
To identify and characterize various factors responsible for tumorigenesis and chemoresistance in AML, transcriptomic profiling of LSCs was done using diagnostic and relapse samples (n=18) collected from the same patient. LSCs predominantly reside in CD34+ CD38- fractions. We sorted LSCs from bone marrow aspirate (BMA) samples obtained from all 18 patients at diagnosis and relapse based on the presence of aberrant markers using BD FACSAria™ III. Bulk RNA sequencing was performed, and the differentially expressed genes identified by DESeq2 were used for pathway enrichment analysis via ShinyGO. Additionally, we employed the rMATS tool to identify altered splicing patterns between relapse and diagnostic LSCs, along with rMAPS to pinpoint significant RNA-binding proteins instrumental in regulating alternative splicing events.
Results
The most significantly altered pathways were those involved in autophagy and oxidative phosphorylation processes. The identified genes ULK1, ATG13, GABARAPL1, ATP5F1D, UQCRC2, and UQQCR10 were significantly downregulated at relapse in AML LSCs, pointing to the altered metabolic profiles compared to diagnosis. We also identified substantial splicing aberrations in genes that play pivotal roles in autophagy.
Conclusion
Autophagy and oxidative phosphorylation pathways are significantly altered in AML patients at relapse. These alterations occur at levels of transcription and its regulation during splicing. Our study's future scope is identifying RNA-binding proteins that regulate these processes. This will help decipher the regulatory networks to better understand LSC biology and unveil novel therapeutic targets to improve patient survival outcomes
AML-014 Expression Analysis, Clinical Significance, and Potential Function of ALOX5AP in Acute Myeloid Leukemia
No full textContext
Acute myeloid leukemia (AML) presents as a heterogeneous group of hematologic malignancies characterized by dysregulated proliferation and differentiation of leukemic primitive cells. Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) has been implicated in carcinogenesis, yet its role in AML remains under-studied. This work aimed to investigate the clinical and prognostic significance of the ALOX5AP gene in AML through analysis of its expression, methylation patterns, and molecular mechanisms.
Objective
This work aimed to investigate the clinical and prognostic significance of the ALOX5AP gene in AML through analysis of its expression, methylation patterns, and molecular mechanisms.
Methods
A total of 173 AML patients and 70 control cases were assessed for ALOX5AP gene expression and DNA methylation status. Kaplan–Meier survival estimation was employed to evaluate ALOX5AP's predictive importance. Correlations between ALOX5AP expression and functional states in AML single-cell datasets were estimated. Additionally, correlation analysis identified associated genes using the Linked Omics database, while gene set enrichment analysis (GSEA) elucidated molecular mechanisms of ALOX5AP in AML.
Results
ALOX5AP was significantly overexpressed and exhibited lower methylation levels in AML cohorts compared to controls (P<0.05). Notably, SLC40A1 gene expression negatively correlated with lower ALOX5AP gene methylation (P<0.0342) and was associated with poor overall survival in AML patients (P 0.0024). ALOX5AP expression was higher in M5 subtypes, females, older AML patients, and those with FLT3-ITD mutations. Furthermore, ALOX5AP expression correlated positively with metastasis, differentiation, proliferation, inflammation, and angiogenesis in AML single-cell datasets. Correlation analysis identified positive associations with genes like NCF1, SIRPB1, and IL1RN, while negative correlations were found with UBFD1 and KDM5B (P<0.001). Gene enrichment analysis revealed ALOX5AP involvement in granulocyte activation, cytokine binding, and chemokine signaling pathways.
Conclusions
ALOX5AP emerges as a critical factor in AML development, offering potential as a prognostic biomarker and therapeutic target. Its overexpression and methylation patterns correlate with clinical outcomes and molecular subtypes, underscoring its importance in AML pathogenesis. These findings highlight ALOX5AP's multifaceted role in AML and its potential for guiding personalized treatment strategies in the future
ASO Visual Abstract: Malignant Chest Wall Tumors: Complex Defects and Their Management—A Review of 181 Cases
No full textMeasuring piezo1 and actin polarity in chemokine-stimulated jurkat cells during live-cell imaging.
No full textThe process of T-lymphocyte migration involves a complex interplay of chemical and mechanical signals. Mechanotransduction mechanisms in T lymphocytes enable them to efficiently navigate through diverse architectural and topographical features of the dynamic tissue macro- and micro-niches encountered during immune responses. Piezo1 mechanosensors are crucial for driving optimal T-cell migration by driving actin-cytoskeletal remodeling. Chemokine-stimulated T lymphocytes demonstrate significant asymmetry or polarity of Piezo1 and actin along the cell axis. The establishment and maintenance of polarity in migrating cells are paramount for facilitating coordinated and directional movements along gradients of chemokine signals. Live-cell imaging techniques are widely employed to study the trajectories of migrating cells. Our approach expands upon current methodologies by not only tracking migrating cells but also imaging fluorescently labeled cellular components. Specifically, our method enables measurement of protein enrichment in the front and rear halves of the moving cell by analyzing the temporal direction of cell trajectories, subsequently bisecting the cell into front-back halves, and measuring the intensities of the fluorescent signals in each cell half at each time frame. Our protocol also facilitates the quantification of the angular distribution of fluorescent signals, enabling visualization of the spatial distribution of signals relative to the direction of cell migration. The protocol describes the examination of polarity in chemokine-treated Jurkat cells transfected with Piezo1-mCherry and actin-GFP constructs. This approach can be extended to live-cell imaging and polarity assessment of other fluorescently labeled proteins
Hit-to-lead optimization of 2-aminoquinazolines as anti-microbial agents against Leishmania donovani.
No full textVisceral leishmaniasis is a potentially fatal disease caused by infection by the intracellular protist pathogens Leishmania donovani or Leishmania infantum. Present therapies are ineffective because of high costs, variable efficacy against different species, the requirement for hospitalization, toxicity and drug resistance. Detailed analysis of previously published hit molecules suggested a crucial role of ‘guanidine’ linkage for their efficacy against L. donovani. Here we report the design of 2-aminoquinazoline heterocycle as a basic pharmacophore-bearing guanidine linkage. The introduction of various groups and functionality at different positions of the quinazoline scaffold results in enhanced antiparasitic potency with modest host cell cytotoxicity using a physiologically relevant THP-1 transformed macrophage infection model. In terms of the ADME profile, the C7 position of quinazoline was identified as a guiding tool for designing better molecules. The good ADME profile of the compounds suggests that they merit further consideration as lead compounds for treating visceral leishmaniasis
Nitrogen doping-induced structural distortion in LaMnO<sub>3</sub> enhances oxygen reduction and oxygen evolution reactions
No full textNitrogen-doped perovskites (LaMnO3) were designed as bifunctional catalysts for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). Nitridation led to O-substitution in LaMnO3, creating distortion in the LaMnO3 structure and generating oxygen vacancies. N-doping facilitated an increase of Mn3+ content, enhancing ORR and OER activities. LaMnO3 with 4 h of nitridation exhibits 3.35 and 1.75 times higher specific and mass activities in comparison to pristine LaMnO3 (highest reported among perovskite oxides). The enhancement in catalytic activity is attributed to the increase of Mn3+ content and distorted Mn–O, leading to compressive strain. The substitution of N at the crystal lattice of perovskite stabilizes the intermediates through a combination of strain and charge modulation of the active Mn center, which causes the enhancement in ORR and OER performance. The bifunctional character of the catalyst was further evaluated for practical zinc–air battery applications in which nitrogen-doped LaMnO3 undergoes steady operation up to 500 cycles in harsh industrial conditions of 6 M KOH
Surface‐engineered Ni<sub>2</sub>P: An efficient oxygen electrocatalyst for zinc‐air battery
No full textThe surface engineering of electrocatalysts is one of the promising strategies to increase the intrinsic activity of electrocatalysts. It generates anion/cation vacancy defects and increases the electrochemically active surface area. We describe the surface engineering of Ni2P to favorably tune the bifunctional oxygen electrocatalytic activity and the development of a rechargeable zinc-air battery (ZAB). Ni2P encapsulated with N and P-dual doped carbon (Ni2P@NPC) is synthesized using a single-source precursor complex tris-(2,2′-bipyridine)nickel(II) bis(hexafluorophosphate). The surface engineering of the as-synthesized Ni2P@NPC catalyst is achieved by the controlled acid treatment at room temperature. The surface engineering removes the carbon debris and opens the pores, exfoliates the encapsulating carbon layer, increases the P-vacancy in the crystal lattice, and boosts the electrochemically active surface area. The surface-engineered catalyst exhibits enhanced bifunctional activity towards oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). The electrocatalytically active sites of engineered catalysts are highly accessible for facilitated electron transfer kinetics. P-vacancy favors the facile formation of defect-rich OER active metal oxyhydroxide species. The rechargeable ZAB based on the engineered catalyst delivers a specific capacity of 770.25 mA h gZn−1, energy density of 692 Wh kgZn−1, and excellent charge-discharge cycling performance with negligible voltaic efficiency loss (0.6%) after 100 h