4'-C-Acetamidomethyl-2'-O-methoxyethyl Nucleic Acid Modifications Improve Thermal Stability, Nuclease Resistance, Potency, and hAgo2 Binding of Small Interfering RNAs.

In this study, we designed the 4'-C-acetamidomethyl-2'-O-methoxyethyl (4'-C-ACM-2'-O-MOE) uridine and thymidine modifications, aiming to test them into small interfering RNAs. Thermal melting studies revealed that incorporating a single 4'-C-ACM-2'-O-MOE modification in the DNA duplex reduced thermal stability. In contrast, an increase in thermal stability was observed when the modification was introduced in DNA:RNA hybrid and in siRNAs. Thermal destabilization in DNA duplex was attributed to unfavorable entropy, which was mainly compensated by the enthalpy factor to some extent. A single 4'-C-ACM-2'-O-MOE thymidine modification at the penultimate position of the 3'-end of dT20 oligonucleotides in the presence of 3'-specific exonucleases, snake venom phosphodiesterase (SVPD), demonstrated significant stability as compared to monomer modifications including 2'-O-Me, 2'-O-MOE, and 2'-F. In gene silencing studies, we found that the 4'-C-ACM-2'-O-MOE uridine or thymidine modifications at the 3'-overhang in the passenger strand in combination with two 2'-F modifications exhibited superior RNAi activity. The results suggest that the dual modification is well tolerated at the 3'-end of the passenger strand, which reflects better siRNA stability and silencing activity. Interestingly, 4'-C-ACM-2'-O-MOE-modified siRNAs showed considerable gene silencing even after 96 h posttransfection; it showed that our modification could induce prolonged gene silencing due to improved metabolic stability. Molecular modeling studies revealed that the introduction of the 4'-C-ACM-2'-O-MOE modification at the 3'-end of the siRNA guide strand helps to anchor the strand within the PAZ domain of the hAgo2 protein. The overall results indicate that the 4'-C-ACM-2'-O-MOE uridine and thymidine modifications are promising modifications to improve the stability, potency, and hAgo2 binding of siRNAs.

N-terminal ectodomain of BTNL2 inhibits T cell activation via a non-canonical interaction with its putative receptor that results in a delayed progression of DSS-induced ulcerative colitis.

Butyrophilin-like 2 (BTNL2) is a T cell inhibitory molecule that interacts with unknown binding partners to modulate the immune response in a number of inflammatory and autoimmune diseases. In this study, we found that the inhibitory effects of BTNL2 on T cell activation and effector functions can be executed by its N-terminal IgV domain (BTNL2 IgV1) alone. Structure-guided mutation of key residues on BTNL2 IgV1 based on known receptor-ligand interfaces involving immunoglobulin superfamily members revealed that BTNL2 uses a non-canonical binding interface with its putative receptor. A high avidity BTNL2 IgV1 probe revealed that in an inducible model of ulcerative colitis, severe colitis was accompanied by a selective enrichment of BTNL2-receptor expressing effector-memory CD4+ and CD8+ T cells in the Peyer's patches. Intraperitoneal administration of BTNL2 IgV1 resulted in a significant delay in the progression of DSS-induced colitis and also showed reduced activation of the BTNL2-receptor-expressing T cells in the Peyer's patches. Thus, this study demonstrates that the BTNL2-receptor-expressing T cells in the Peyer's patches participate in the disease pathogenesis and can serve as a novel therapeutic target in ulcerative colitis, which can be modulated by BTNL2 IgV1.

Liquid marbles: review of recent progress in physical properties, formation techniques, and lab-in-a-marble applications in microreactors and biosensors.

Liquid marbles (LMs) are nonsticking droplets whose surfaces are covered with low-wettability particles. Owing to their high mobility, shape reconfigurability, and widely accessible liquid/particle possibilities, the research on LMs has flourished since 2001. Their physical properties, fabrication mechanisms, and functionalisation capabilities indicate their potential for various applications. This review summarises the fundamental properties of LMs, the recent advances (mainly works published in 2020-2023) in the concept of LMs, physical properties, formation methods, LM-templated material design, and biochemical applications. Finally, the potential development and variations of LMs are discussed.

Apple-like Shape of Freezing Paraffin Wax Droplets and Its Origin.

Paraffin wax stores energy in the form of latent heat at a nearly constant temperature during melting and releases this energy during solidification. This effect is used in industrial energy storage. At the same time, the possible deformation of even small volumes of material as a result of phase change is insufficiently studied. In this paper, the physical nature of such deformation, probably for the first time, is studied on the example of a droplet of paraffin wax. An unusual change in the shape of a melted droplet of paraffin wax placed on a relatively cold glass plate was observed in the laboratory experiments. As the droplet solidifies, its upper surface becomes nearly flat, and a dimple is formed in the center of this surface, making the droplet look like a fruit (pumpkins are more commonly shaped like this, but the authors prefer apples). A series of experiments, as well as physical and numerical modeling of the droplet's thermal state, taking into account the formation of a mushy zone between liquidus and solidus, made it possible to understand the role of gravity and gradual increase in viscosity and density of paraffin wax on changing the droplet shape and, in particular, to clarify the mechanism of formation of the dimple on its upper. It was shown that the mushy zone between the liquidus and solidus of the paraffin wax is responsible for the dimple formation.

In-silico identification of novel DDI2 inhibitor in glioblastoma via repurposing FDA approved drugs using molecular docking and MD simulation study.

Glioblastoma, the most severe form of brain tumor and a leading cause of death within a year of diagnosis, is characterized by excessive protein synthesis and folding in the lumen of the endoplasmic reticulum (ER), leading to increased ER stress in the cells of GBM tissues. To mitigate this stress the cancer cells have intelligently adopted a plethora of response mechanisms and Unfolded Protein Response (UPR) is one of those. To bear with this exhaustive situation cells upregulate a strong protein degradation system in form of 26S proteasome and blocking of proteasomal gene synthesis may be a potential therapeutic action against GBM. Proteasomal gene synthesis is exclusively dependent on the transcription factor Nuclear respiratory factor 1 (NRF1) and its activating enzyme DNA damage inducible 1 homolog 2 (DDI2). Here in this study, we performed molecular docking against DDI2 with the 20 FDA-approved drugs and identified Alvimopan and Levocabastine as the top two compounds with the best binding score along with the standard drug Nelfinavir. MD simulation (100 ns) of these protein-ligand docked complexes reveals that the stability and compactness of Alvimopan are high in comparison with Nelfinavir. Our in-silico (Molecular docking and Molecular dynamics simulation) studies pointed out that Alvimopan may be repurposed as a DDI2 inhibitor and can be used as a potential anticancer agent for the treatment of brain tumors.Communicated by Ramaswamy H. Sarma.

Innovative nanotheranostics: Smart nanoparticles based approach to overcome breast cancer stem cells mediated chemo- and radioresistances.

The alarming increase in the number of breast cancer patients worldwide and the increasing death rate indicate that the traditional and current medicines are insufficient to fight against it. The onset of chemo- and radioresistances and cancer stem cell-based recurrence make this problem harder, and this hour needs a novel treatment approach. Competent nanoparticle-based accurate drug delivery and cancer nanotheranostics like photothermal therapy, photodynamic therapy, chemodynamic therapy, and sonodynamic therapy can be the key to solving this problem due to their unique characteristics. These innovative formulations can be a better cargo with fewer side effects than the standard chemotherapy and can eliminate the stability problems associated with cancer immunotherapy. The nanotheranostic systems can kill the tumor cells and the resistant breast cancer stem cells by novel mechanisms like local hyperthermia and reactive oxygen species and prevent tumor recurrence. These theranostic systems can also combine with chemotherapy or immunotherapy approaches. These combining approaches can be the future of anticancer therapy, especially to overcome the breast cancer stem cells mediated chemo- and radioresistances. This review paper discusses several novel theranostic systems and smart nanoparticles, their mechanism of action, and their modifications with time. It explains their relevance and market scope in the current era. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Interfacial crystallization in the polyhedral liquid marbles.

HYPOTHESIS: We hypothesized that interfacial crystallization occurring within evaporated polyhedral liquid marbles may be controlled by hydrophilization of the polymer plates coating the marbles. The hypothesis was tested with polyhedral marbles coated with hydrophobized and cold plasma-hydrophilized PET (Polyethylene terephthalate) plates. EXPERIMENTS: Interfacial crystallization within polyhedral liquid marbles was investigated experimentally. Two types of polyhedral marbles filled with saturated saline were prepared: i) liquid marbles coated with hydrophobized PET plates (Marbles A); ii) liquid marbles coated with Janus PET plates, one facet of which was plasma hydrophilized and the other hydrophobized (Marbles B). The hydrophobized side of the PET plate was in contact with the saline solution, whereas, the hydrophilized facet contacted air. Crystallization occurring within the marbles under their evaporation was monitored in situ. FINDINGS: It was established that for both kinds of marbles, NaCl crystallization was initiated at the edges of the plates. NaCl crystallization on the hydrophobized PET surfaces was not registered. When Marbles B were evaporated, the outer hydrophilic side of the PET plates was coated by the saline creep process. For both kinds of marbles the process resulted in the formation of hollow shells built of PET plates and NaCl crystals. The thermodynamic explanation of the observed phenomena is suggested.

An overview of kinin mediated events in cancer progression and therapeutic applications.

Kinins are bioactive peptides generated in the inflammatory milieu of the tissue microenvironment, which is involved in cancer progression and inflammatory response. Kinins signals through activation of two G-protein coupled receptors; inducible Bradykinin Receptor B1 (B1R) and constitutive receptor B2 (B2R). Activation of kinin receptors and its cross-talk with receptor tyrosine kinases activates multiple signaling pathways, including ERK/MAPK, PI3K, PKC, and p38 pathways regulating cancer hallmarks. Perturbations of the kinin-mediated events are implicated in various aspects of cancer invasion, matrix remodeling, and metastasis. In the tumor microenvironment, kinins initiate fibroblast activation, mesenchymal stem cell interactions, and recruitment of immune cells. Albeit the precise nature of kinin function in the metastasis and tumor microenvironment are not completely clear yet, several kinin receptor antagonists show anti-metastatic potential. Here, we showcase an overview of the complex biology of kinins and their role in cancer pathogenesis and therapeutic aspects.

TGF-ß1 induced autophagy in cancer associated fibroblasts during hypoxia contributes EMT and glycolysis via MCT4 upregulation.

The Transforming growth factor-ß1 (TGF- ß1) in the tumor microenvironment (TME) is the major cytokine that acts as a mediator of tumor-stroma crosstalk, which in fact has a dual role in either promoting or suppressing tumor development. The cancer-associated fibroblasts (CAFs) are the major cell types in the TME, and the interaction with most of the epithelial cancers is the prime reason for cancer survival. However, the molecular mechanisms, associated with the TGF- ß1 induced tumor promotion through tumor-CAF crosstalk are not well understood. In the Reverse Warburg effect, CAFs feed the adjacent cancer cells by lactate produced during the aerobic glycolysis. We hypothesized that the monocarboxylate transporter, MCT4 which is implicated in lactate efflux from the CAFs, must be overexpressed in the CAFs. Contextually, to explore the role of TGF- ß1 in the hypoxia-induced autophagy in CAFs, we treated CoCl2 and external TGF- ß1 to the human dermal fibroblasts and L929 murine fibroblasts. We demonstrated that hypoxia accelerated the TGF- ß1 signaling and subsequent transformation of normal fibroblasts to CAFs. Moreover, we elucidated that synergistic induction of autophagy by hypoxia and TGF- ß1 upregulate the aerobic glycolysis and MCT4 expression in CAFs. Furthermore, we showed a positive correlation between glucose consumption and MCT4 expression in the CAFs. Autophagy was also found to be involved in the EMT in hypoxic CAFs. Collectively, these findings reveal the unappreciated role of autophagy in TME, which enhances the CAF transformation and that promotes tumor migration and metastasis via the reverse Warburg effect.

An insight into the ubiquitin-proteasomal axis and related therapeutic approaches towards central nervous system malignancies.

The Ubiquitin-Protease system (UPS) is a major destruction system responsible for eliminating dysfunctional/misfolded proteins, thus acting as a pivotal regulator of protein homeostasis in eukaryotic cells. In this review, the UPS system and its various functions in the cell and their detailed impact such as cell cycle control, DNA damage response, apoptosis, and cellular stress regulations have been elucidated with a focus on the central nervous system. Since the Ubiquitin-Protease pathway(UPP) plays a prominent role in the sculpting of the CNS cells and their maintenance, it is naturally deeply involved in many malignancies that develop due to dysregulation of the UPS. Understanding the major disruptive players of the UPS in the development of these malignancies, for example, insoluble protein aggregates or inclusion bodies deposits due to malfunctioning of the UPS has paved the pathway for the development of new therapeutics. Here, the de-regulation of the UPS at various checkpoints in CNS malignancies has been detailed, thus facilitating an easy comprehension of the different targets that remain to be explored yet. The present therapeutic advancements in the field of CNS malignancies management through UPS targeting have also been included thus broadening the scope of drug development. Thus, this review while shedding sufficient light on the details of the UPS system and its connection to CNS malignancies, also opens new avenues for therapeutic advancements in the form of novel targetable UPP proteins and their interactions.

Comparative Study of Nitro- and Azide-Functionalized ZnII -Based Coordination Polymers (CPs) as Fluorescent Turn-On Probes for Rapid and Selective Detection of H2 S in Living Cells.

Selective detection of H2 S in the cellular systems using fluorescent CPs/MOFs is of great scientific interest due to their outstanding aqueous stability, biocompatibility and real-time detection ability. Fabrication of such materials using complete biologically essential elements and applying them as an efficient biosensor is still quite challenging. In this context, two newly synthesized CPs containing biologically essential metal ion (Zn) and nitro/azido functional groups into the framework to sense extracellular and intracellular H2 S by reducing into respective amines are presented. The CP-1 containing the azide group acted as an efficient fluorescent turn-on probe with the lowest detection limit (7.2 µM) and shortest response time (30 s) among the Zn-based probes reported till date. Moreover, CP-1 exhibited green luminescence in live cells after imaging a very low concentration of H2 S, whereas the nitro analogue CP-2 could not detect the target analyte due to its framework disruption.

Prevalence of intestinal parasitic infection and its associated factors among children in Puducherry, South India: a community-based study.

There is paucity of studies at community level on prevalence of intestinal parasitic infection among under 18 years age group. This cross-sectional community-based research aimed to determine the prevalence of intestinal worm infections and its associated risk factors among 1 to 18 years age group in Puducherry, India. Sociodemographic, behavioral and other associated factors were collected using a structured questionnaire. One stool sample was collected from each participant and examined using direct (saline/iodine wet mount) and concentration (floatation/sedimentation) microscopic techniques. Log binomial regression analysis was used to find the factors independently associated with intestinal parasitic infection. Of 187 participants who provided the stool sample, 25 (13.4%) had at least one of the parasitic infections and among them 12 (6.4%) had Soil Transmitted Helminth infection (STH) and 13 (6.9%) had intestinal protozoan parasites. Parasitic infection is marginally higher among 1 to 7 years age group (14.4%) compared to 8 to 18 years age group (12.1%). After adjusting for confounding, urban residence (APR = 3.3, 95% CI 1.4-8.0) and open-air defecation (APR = 3.3, 95% CI 1.4-7.5) were significantly associated with intestinal parasitic infections. One out of eight children had any of the parasitic infection and nearly 50% of parasitic infections were caused by STH. Those children residing in urban areas and practice of open-air defecation had higher prevalence of parasitic infection.

Therapeutic targeting of membrane-associated proteins in central nervous system tumors.

The activity of the most complex system, the central nervous system (CNS) is profoundly regulated by a huge number of membrane-associated proteins (MAP). A minor change stimulates immense chemical changes and the elicited response is organized by MAP, which acts as a receptor of that chemical or channel enabling the flow of ions. Slight changes in the activity or expression of these MAPs lead to severe consequences such as cognitive disorders, memory loss, or cancer. CNS tumors are heterogeneous in nature and hard-to-treat due to random mutations in MAPs; like as overexpression of EGFRvIII/TGFßR/VEGFR, change in adhesion molecules α5ß3 integrin/SEMA3A, imbalance in ion channel proteins, etc. Extensive research is under process for developing new therapeutic approaches using these proteins such as targeted cytotoxic radiotherapy, drug-delivery, and prodrug activation, blocking of receptors like GluA1, developing viral vector against cell surface receptor. The combinatorial approach of these strategies along with the conventional one might be more potential. Henceforth, our review focuses on in-depth analysis regarding MAPs aiming for a better understanding for developing an efficient therapeutic approach for targeting CNS tumors.

Prevalence and association of depressive symptoms with spiritual intelligence among older adults: A community-based study in rural Puducherry, South India.

INTRODUCTION: Depression is more common among older adults, but there is a paucity of information about its association with spiritual intelligence. This study aimed to determine the prevalence and association of depressive symptoms with spiritual intelligence among older adults. MATERIALS AND METHODS: This community-based cross-sectional analytical study was conducted among 292 older adults in a rural area of Puducherry, India. A structured questionnaire was used to collect each participant's socio-demographic and behavioral factors; the presence of depressive symptoms was assessed by using Geriatric Depression Scale (short form), spiritual intelligence by the Spiritual Intelligence Self-Report Inventory-24 questionnaire and activities of daily living by Katz Index of Independence scale. Proportion for prevalence estimate, bivariate and multivariable log binomial regression analysis were done. RESULTS: The prevalence of depressive symptoms was 64.1 % (187/292; 95 % CI 58.3-69.3). Of total, 103 (35.3 %) had low, 92 (31.55 %) had moderate and 97 (33.2 %) had high spiritual intelligence. About 11 % (32/292) were partially or fully dependent. Depressive symptoms showed a significant association with marital status, education, sleep pattern, relationship with family members and spiritual intelligence in bivariate analysis. Depressive symptoms were high among those with low spiritual intelligence and disturbed sleep pattern with Adjusted Prevalence Ratio of 1.33 (95 %CI 1.26-1.4) and 1.06 (95 %CI 1.0-1.14) respectively. CONCLUSION: Majority of the older adults had depressive symptoms and significantly more among those with low spiritual intelligence and disturbed sleep. This study gives new evidence on spiritual intelligence among older adults in a community setting and the magnitude of association of depressive symptoms with spiritual intelligence.

Study of wetting of the animal retinas by Water and organic liquids and its Implications for ophthalmology.

Interfacial properties of the animal retinas are reported. Wetting of the retina-retinal pigment epithelium-choroid-sclera tissues of cow, sheep, and pig eyes by water, silicone and castor oil was explored experimentally. Both water and silicone oils demonstrated complete wetting of the retina, regardless of the viscosity of the silicone oil, whereas the castor oil demonstrated a partial wetting regime. Similar wetting regimes were observed for sheep, cow and pig retinas. The intact surface of animal retina was found to be both hydrophilic and oleophilic. Wetting experiments with double sandwich oil/water layers were performed. Water demonstrated stronger affinity to the retina than silicone and castor oils, and eventually replaced the oils at the liquid/retina interface. We conclude that aqueous solutions continuously secreted in the living eye may displace silicone oil from the retinal surface and contribute to retinal re-detachment. Study of dynamics of wetting of the animal retina by water and organic oils is reported. The exponent describing the dynamics of spreading of the castor oil is lower than that predicted by the Tanner law. Castor oil may provide more effective tamponade than silicone oil.

Composite Liquid Marbles as a Macroscopic Model System Representing Shedding of Enveloped Viruses.

A model macroscopic system imitating the entry of viruses into living cells is suggested. The system represents the contact of a composite (core-shell) liquid marble with hydrophobic/hydrophilic particles. Composite liquid marbles are water droplets coated with silicone oil armored with nanometer-sized hydrophobic particles serving as an interfacial model of a living cell. Composite marbles absorbed hydrophilic polymer particles but prevented hydrophobic particles from entering their core. Swallowing of hydrophilic particles by composite marbles resembles the penetration of viruses into living cells. The interfacial mechanism of absorption is suggested.

Manufacture and properties of composite liquid marbles.

HYPOTHESIS: Liquid marbles are non-stick droplets coated with colloidal usually hydrophobic particles. We suggest that "composite" liquid marbles, i.e. bi-liquid droplets, may be prepared with water droplets coated by a thin silicone oil layer containing hydrophobic, colloidal particles. EXPERIMENTS: The process enabling manufacturing water marbles coated with silicone oil containing fumed fluorosilica particles is reported. The marbles remained stable when placed on solid and liquid supports. Bouncing and coalescence of the composite marbles was explored. FINDINGS: Non-coalescence prolonged (ca. 20 min) jumping of composite marbles above a vibrating water bath was observed. Composite marbles withstand coalescence better than colloidal particle-stabilized liquid marbles. The effective surface tension of the composite marbles is markedly lower than that of water marbles coated with fumed fluorosilica particles. The coefficient of restitution of the composite marbles bouncing on a hydrophobic solid substrate is lower than that established for water marbles. This observation is related to the viscous dissipation occurring within the silicone layer making up the composite marbles.

Evaporation dynamics of pure and binary mixture drops on dry and lubricant coated slippery surfaces.

HYPOTHESIS: Lubricating fluid coated slippery (LCS) surfaces offer a new scope to study the evaporation of sessile drops due to pinning free motion of the three-phase contact line (TPCL). This work aims to experimentally demonstrate the different evaporation behavior of water and binary mixture drops on dry and LCS surfaces. EXPERIMENTS: Evaporation study on dry and LCS surfaces is performed by capturing top and side views of evaporating drops to extract various parameters which are subsequently used to distinguish between different evaporation modes. FINDINGS: Formation of a wetting ridge and cloaking of water drops on LCS surfaces affect the overall evaporation process and make it different compared to that on dry surfaces. Evaporation dynamics on LCS surfaces reveal that wetting ridge height of an evaporating drop varies non-monotonically compared to the drop height. Diffusion based theoretical model is used to predict the role of various system parameters on the evaporation process. In contrast to dry solid surfaces, where coffee ring effects are commonly observed towards the end of the evaporation process, LCS surfaces show the formation of a wrinkle like pattern of the lubricating fluid which disappears at long times.

Mobility of Aqueous and Binary Mixture Drops on Lubricating Fluid-Coated Slippery Surfaces.

The mobility of liquid drops on lubricant-infused slippery surfaces depends strongly on various system parameters, for example, surface energy and roughness of the underlying solid surface and surface tension and viscosity of the test and the lubricating fluids. Here, we investigate lubricant-coated slippery surfaces fabricated on smooth hydrophobic solid surfaces and examine the influence of thickness and viscosity of the lubricating oil on the velocity of aqueous drops. We also investigate the effect of surface tension of the test liquid using a binary mixture of water and ethanol, on the apparent contact angle, which further affects their slip velocity. A theoretical model, based on various dissipative forces acting in different regions of the lubricating oil and a test drop, is also presented, which elucidates the dependence of drop velocity on lubricating oil viscosity and base radius of drops of test liquids.

Tunable superoleophobicity via harnessing the surface chemistry of UV responsive titania coatings.

Superoleophobic surfaces exhibiting tunable wettability are prepared by the combination of simple spray coating of Ultra Violet (UV) responsive titania nanoparticles and a low surface energy coating of a self-assembled monolayer (SAM) of 1H,1H,2H,2H-perflurodecyltrichlorosilane (PFDTS). Spray coating creates random micron-sized roughness with reentrant geometry, a necessary requirement for the superoleophobic surface, and a porous network at the nanometer size level, confirmed by the field emission scanning electron microscope (FE-SEM) images. By employing the rough surface and a low surface energy monolayer, the substrates possess superhydrophobicity with a water (γ = 72 mN m-1) contact angle of 163° and superoleophobicity with a decane (γ = 23 mN m-1) contact angle of 144°. Wettability of these surfaces is completely reversed to the superoleophilic state upon 6 h of UV irradiation. A quantitative X-ray photoelectron spectroscopy (XPS) analysis has confirmed the mechanism of decomposition of PFDTS molecules on the superoleophilic surfaces via interaction with the defect Ti3+ states of titania upon UV exposure. Furthermore, the superoleophobicity is restored to complete the transition cycle by changing the surface chemistry of the UV exposed surface via annealing and regrafting of the PFDTS monolayer.