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Assembly of serotonin on DNA tetrahedron for application in treating ?-Synucleinopathy
No full textThis study presents a comprehensive protocol for assembling and applying tetrahedral DNA nanostructures (TDNs) as carriers for neurotransmitter delivery, explicitly targeting the treatment of ?-synucleinopathies such as Parkinson�s disease. TDNs, self-assembled from four single-stranded DNA oligonucleotides, offer a stable, programmable, and biocompatible platform with enhanced nuclease resistance and the ability to traverse the blood-brain barrier (BBB) via catherin-1-mediated transcytosis. The protocol details the synthesis, characterization, and functionalization of TDNs with neurotransmitters-serotonin, epinephrine, and norepinephrine-through electrostatic and hydrogen bonding interactions, exploiting the negative charge of the DNA backbone and the positive charge of protonated neurotransmitter amines. Structural validation is achieved via electrophoretic mobility shift assays, atomic force microscopy, dynamic light scattering, and fluorescence quenching studies. Functional assays in MPTP-induced PC12 cell models demonstrate that TDN-neurotransmitter complexes (TD:NTs) are efficiently internalized, reduce ?-synuclein accumulation, and mitigate key pathological features, including oxidative stress, iron buildup, lipid peroxidation, and autophagy. In vivo zebrafish studies confirm high brain tissue accumulation and negligible neurotoxicity. Compared to conventional nanocarriers, TDNs exhibit superior biocompatibility, BBB permeability, and drug loading efficiency, while minimizing immunogenicity and off-target effects. Nonetheless, limitations such as restricted drug payload, rapid systemic clearance, and susceptibility to enzymatic degradation are acknowledged, alongside the need for further research into long-term safety and targeted delivery. This protocol establishes a robust workflow for TDN synthesis, neurotransmitter conjugation, and biological validation, underscoring the potential of TDNs as next-generation nanocarriers for targeted neurotransmitter delivery in neurodegenerative disease therapy
Unpacking Interaction Markers of Critical Thinking
No full textIn this paper, we focus on critical thinking activities conducted in an online environment and describe interaction markers based on the data collected from those activities. The work is based on the ENACT framework. We conducted an empirical study to understand the clusters of critical thinkers based on performance and interactional marker values of the participants (n=37). The paper highlights the definitions of the interaction markers and conducts an clustering analysis of the types of Critical Thinking patterns that emerged. The results show two clusters with similar critical thinking outcome performance but different action patterns. We discuss the need of further empirical evidence relating learning effect on the actions and Critical Thinking
Designer DNA nanocages modulate anti-oxidative and anti-inflammatory responses in tumor associated macrophages
No full textCancer is a complex disease, with multiple treatment modalities, but no definitive cure. The tumor microenvironment contributes to the complexity of the disease by forming a niche of multiple cell types supporting each other to carry out various cellular functions. Tumor associated macrophages are one such kind of cells which support the tumor microenvironment via immunosuppression. DNA tetrahedron (TD), a widely explored DNA nanocage, has shown a lot of potential in therapeutics. However, the role of TD still remains quite unexplored in immunology. Here, we first establish the anti-oxidative and anti-inflammatory role of TD. We then proceed with using TD as a therapeutic agent in tumor associated macrophages by modulating the response of PD-L1. The findings of this work create a base for TD in biological applications such as cancer immunotherapy
Relocating NSAIDs into the endoplasmic reticulum induces ER stress-mediated apoptosis in cancer cells
No full textThe endoplasmic reticulum (ER) is a vital subcellular organelle that orchestrates numerous essential biological processes, including protein synthesis and processing. Disruption of ER function can lead to ER stress, a condition closely associated with the progression and development of cancer. Consequently, inducing ER stress in cancer cells has emerged as an unconventional yet promising therapeutic approach. However, selectively targeting the ER within cancer cells remains a significant challenge. To address this, we have designed and synthesized a novel small-molecule library composed of non-steroidal anti-inflammatory drugs (NSAIDs), fluorescent probes, and ER-targeting moieties. Through screening the library in cancer cells, we identified a promising compound: an ibuprofen derivative conjugated with a dansyl group as a dual fluorescence tag and ER-targeting moiety. This ibuprofen derivative successfully localized into the ER of HCT-116 colon cancer cells within 3 h, induced ER stress by upregulating key stress markers such as CHOP, GRP94, IRE-1α, PERK, and Cas-12, while simultaneously inhibiting Cox-2. The resulting ER stress triggered autophagy by upregulating Beclin and LC3-II/LC3-I as autophagy markers, followed by apoptosis, culminating in significant cancer cell death, particularly when combined with bafilomycin A, 10-hydroxycamptothecin and obatoclax. This NSAID-based ER stress inducer provides a powerful tool for exploring the chemical biology of NSAIDs in the ER and holds great potential for advancing ER-targeted cancer therapies in combination with other anti-cancer drugs
Sub-seasonal prediction of compound hot and dry extremes in India
No full textIn India’s summer monsoon-dominated climate, compound hot and dry extremes (CHDEs) pose considerable challenges to agriculture and water resources. However, their drivers and predictability at sub-seasonal time scale remain largely unexplored. Using observations, reanalysis datasets, and forecast products, we examine the occurrence, drivers, and prediction skills of soil moisture based CHDEs in India from 1951 to 2020. The observed warming has resulted in a significant (p-value < 0.05) rise in the frequency of CHDEs in four (Himalayan, West Central, Central Northeast, and Northeast) out of six regions from 1951 to 2020. The area affected by CHDEs has also increased significantly during the recent (1986–2020) period compared to the previous (1951–1985). The most severe CHDEs occurred during the major summer monsoon failures in 1972, 1987, 2002, 2009, 2014, and 2015. The summer monsoon breaks are the main drivers of CHDEs, as about 98% of the events occurred during the break periods. We used sub-seasonal to seasonal (S2S) forecasts from the United Kingdom Meteorological Office (UKMO) and Extended Range Forecast Systems (ERFS) to examine the prediction skills of CHDEs at different lead times. While UKMO (from S2S) and ERFS forecasts demonstrate satisfactory skills to predict CHDEs in India at a 15-day lead, UKMO provides better skills than the ERFS, which is currently operational in India. Good prediction skills from both the models for severity and area of CHDEs demonstrate their utility for the early warning of compound extremes in India, which can assist in climate adaptation
Surface Functionalization of Graphene-Based Materials: Biological Behavior, Toxicology, and Safe-By-Design Aspects
No full textThe increasing exploitation of graphene-based materials (GBMs) is driven by their unique properties and structures, which ignite the imagination of scientists and engineers. At the same time, the very properties that make them so useful for applications lead to growing concerns regarding their potential impacts on human health and the environment. Since GBMs are inert to reaction, various attempts of surface functionalization are made to make them reactive. Herein, surface functionalization of GBMs, including those intentionally designed for specific applications, as well as those unintentionally acquired (e.g., protein corona formation) from the environment and biota, are reviewed through the lenses of nanotoxicity and design of safe materials (safe-by-design). Uptake and toxicity of functionalized GBMs and the underlying mechanisms are discussed and linked with the surface functionalization. Computational tools that can predict the interaction of GBMs behavior with their toxicity are discussed. A concise framing of current knowledge and key features of GBMs to be controlled for safe and sustainable applications are provided for the community. � 2021 Elsevier B.V., All rights reserved
Dynamics of mid-level stratiform clouds over the semi-arid regions of Western India: a post-monsoon case study
No full textStratiform clouds, which form under stable atmospheric conditions, play a crucial role in negative cloud radiative forcing. Utilizing a combination of ground-based observations, satellite data, and reanalysis datasets, the study investigates the formation of stratiform clouds over Udaipur (24.58° N, 73.71° E, 598 m a.m.s.l) compared to Ahmedabad (23.02° N, 72.57° E, 56 m a.m.s.l) in the semi-arid region of Western India during the post-monsoon period. Ground-based Lidar observations indicated consistent cloud occurrences between 2 and 4 km over Udaipur during post-monsoon. Conversely, cloud occurrence over Ahmedabad is found to be lower despite the city having higher levels of columnar water vapor during this period. During the post-monsoon period of 2022–2023, the total cloud occurrence between 2 and 4 km altitude over Udaipur (~ 4.24%) was approximately double that observed over Ahmedabad (~ 2.02%). This disparity is linked to higher relative humidity near the 750 hPa level over Udaipur, sustained by surface moisture lifted to the 2–4 km range. Vertical moisture transport is facilitated by persistent low-level convergence at ~ 950 hPa and upper-level divergence at ~ 750 hPa, creating favorable conditions for vertical air motion and mid-level cloud formation. This study explores the influence of surface water bodies, orography, and local meteorological conditions on cloud dynamics in semi-arid urban areas. The insights from this study into cloud formation and atmospheric dynamics over the semi-arid Western-Indian region can contribute to improving regional weather forecasting