Ineffective esophageal motility: Characterization and outcomes across pediatric neurogastroenterology and motility centers in the United States.

OBJECTIVES: Ineffective esophageal motility (IEM) on high-resolution manometry (HRM) is not consistently associated with specific clinical syndromes or outcomes. We evaluated the prevalence, clinical features, management, and outcomes of pediatric IEM patients across the United States. METHODS: Clinical and manometric characteristics of children undergoing esophageal HRM during 2021-2022 were collected from 12 pediatric motility centers. Clinical presentation, test results, management strategies, and outcomes were compared between children with IEM and normal HRM. RESULTS: Of 236 children (median age 15 years, 63.6% female, 79.2% Caucasian), 62 (23.6%) patients had IEM, and 174 (73.7%) patients had normal HRM, with similar demographics, medical history, clinical presentation, and median symptom duration. Reflux monitoring was performed more often for IEM patients (25.8% vs. 8.6%, p = 0.002), but other adjunctive testing was similar. Among 101 patients with follow-up, symptomatic cohorts declined in both groups in relation to the initial presentation (p > 0.107 for each comparison) with management targeting symptoms, particularly acid suppression. Though prokinetics were used more often and behavioral therapy less often in IEM (p ≤ 0.015 for each comparison), symptom outcomes were similar between IEM and normal HRM. Despite a higher proportion with residual dysphagia on follow-up in IEM (64.0% vs. 39.1%, p = 0.043), an alternate mechanism for dysphagia was identified more often in IEM (68.8%) compared to normal HRM (27.8%, p = 0.017). CONCLUSIONS: IEM is a descriptive manometric pattern rather than a clinical diagnosis requiring specific intervention in children. Management based on clinical presentation provides consistent symptom outcomes.

Canonical WNT/ß-catenin signaling upregulates aerobic glycolysis in diverse cancer types.

Despite many efforts, a comprehensive understanding and clarification of the intricate connections within cancer cell metabolism remain elusive. This might pertain to intracellular dynamics and the complex interplay between cancer cells, and cells with the tumor stroma. Almost a century ago, Otto Warburg found that cancer cells exhibit a glycolytic phenotype, which continues to be a subject of thorough investigation. Past and ongoing investigations have demonstrated intricate mechanisms by which tumors modulate their functionality by utilizing extracellular glucose as a substrate, thereby sustaining the essential proliferation of cancer cells. This concept of "aerobic glycolysis," where cancer cells (even in the presence of enough oxygen) metabolize glucose to produce lactate plays a critical role in cancer progression and is regulated by various signaling pathways. Recent research has revealed that the canonical wingless-related integrated site (WNT) pathway promotes aerobic glycolysis, directly and indirectly, thereby influencing cancer development and progression. The present review seeks to gather knowledge about how the WNT/ß-catenin pathway influences aerobic glycolysis, referring to relevant studies in different types of cancer. Furthermore, we propose the concept of impeding the glycolytic phenotype of tumors by employing specific inhibitors that target WNT/ß-catenin signaling.

7-amino carboxycoumarin 2 inhibits lactate induced epithelial-to-mesenchymal transition via MPC1 in oral and breast cancer cells.

Lactate is an oncometabolite that play important role in tumor aggressiveness. Lactate from the tumor microenvironment (TME) is taken up by cancer cells as an energy resource via mitochondrial oxidative phosphorylation (or OXPHOS). In the present study, by using an online meta-analysis tool we demonstrated that in oral squamous cancer cells (OSCCs) glycolytic and OXPHOS governing genes are overexpressed, like in breast cancer. For experimental demonstration, we treated the OSCC cell line (SCC4) and breast cancer cells (MDA-MB-231) with sodium L-lactate and analyzed its effects on changes in EMT and migration. For the therapeutic intervention of lactate metabolism, we used AZD3965 (an MCT1 inhibitor), and 7ACC2 (an MPC inhibitor). Like breast cancer, oral cancer tissues showed increased transcripts of 12 genes that were previously shown to be associated with glycolysis and OXPHOS. We experimentally demonstrated that L-lactate treatment induced mesenchymal markers and migration of cancer cells, which was significantly neutralized by MPC inhibitor that is, 7ACC2. Such an effect on EMT status was not observed with AZD3965. Furthermore, we showed that lactate treatment increases the MPC1 expression in both cancer cells, and this might be the reason why cancer cells in the high lactate environment are more sensitive to 7ACC2. Overall, our present findings demonstrate that extracellular lactate positively regulates the MPC1 protein expression in cancer cells, thereby putting forward the notion of using 7ACC2 as a potential therapeutic alternative to inhibit malignant oxidative cancers. Future preclinical studies are warranted to validate the present findings.

Combating anoikis resistance: bioactive compounds transforming prostate cancer therapy.

The study aims to discuss the challenges associated with treating prostate cancer (PCa), which is known for its complexity and drug resistance. It attempts to find differentially expressed genes (DEGs), such as those linked to anoikis resistance and circulating tumor cells, in PCa samples. This study involves analyzing the functional roles of these DEGs using gene enrichment analysis, and then screening of 102 bioactive compounds to identify a combination that can control the expression of the identified DEGs. In this study, 53 DEGs were identified from PCa samples including anoikis-resistant PCa cells and circulating tumor cells in PCa. Gene enrichment analysis with regards to functional enrichment of DEGs was performed. An inclusive screening process was carried out among 102 bioactive compounds to identify a combination capable of affecting and regulating the expression of selected DEGs. Eventually, gastrodin, nitidine chloride, chenodeoxycholic acid, and bilobalide were selected, as their combination demonstrated ability to modulate expression of 50 out of the 53 genes targeted. The subsequent analysis focused on investigating the biological pathways and processes influenced by this combination. The findings revealed a multifaceted and multidimensional approach to tumor regression. The combination of bioactive compounds exhibited effects on various genes including those related to production of inflammatory cytokines, cell proliferation, autophagy, apoptosis, angiogenesis, and metastasis. The current study has made a valuable contribution to the development of a combination of bioactive natural compounds that can significantly impede the development of treatment resistance in prostate tumor while countering the tumors' evasion of the immune system. The implications of this study are highly significant as it suggests the creation of an enhanced immunotherapeutic, natural therapeutic concoction with combinatorial potential.

Species discrimination from hair using ATR-FTIR spectroscopy: Application in wildlife forensics.

Hair is a commonly encountered trace evidence in wildlife crimes involving mammals and can be used for species identification which is essential for subsequent judicial proceedings. This proof of concept study aims, to distinguish the black guard hair of three wild cat species belonging to the genus Panthera i.e. Royal Bengal Tiger (Panthera tigris tigris), Indian Leopard (Panthera pardus fusca), and Snow Leopard (Panthera uncia) using a rapid and non-destructive ATR-FTIR spectroscopic technique in combination with chemometrics. A training dataset including 72 black guard hair samples of three species (24 samples from each species) was used to construct chemometric models. A PLS2-DA model successfully classified these three species into distinct classes with R-Square values of 0.9985 (calibration) and 0.8989 (validation). VIP score was also computed, and a new PLS2DA-V model was constructed using variables with a VIP score ≥ 1. External validation was performed using a validation dataset including 18 black guard hair samples (6 samples per species) to validate the constructed PLS2-DA model. It was observed that PLS2-DA model provides greater accuracy and precision compared to the PLS2DA-V model during cross-validation and external validation. The developed PLS2-DA model was also successful in differentiating human and non-human hair with R-Square values of 0.99 and 0.91 for calibration and validation, respectively. Apart from this, a blind test was also carried out using 10 unknown hair samples which were correctly classified into their respective classes providing 100 % accuracy. This study highlights the advantages of ATR-FTIR spectroscopy associated with PLS-DA for differentiation and identification of the Royal Bengal Tiger, Indian Leopard, and Snow Leopard hairs in a rapid, accurate, eco-friendly, and non-destructive way.

ToTE: A global database on trees of the treeline ecotone.

Globally, treelines form a transition zone between tree-dominated forest downslope and treeless alpine vegetation upslope. Treelines represent the highest boundary of "tree" life form in high-elevation mountains and at high latitudes. Recently, treelines have been shifting upslope in response to climate warming, so it has become important to understand global tree diversity and treeline distributions. However, to the best of our knowledge, no global database on tree flora of treelines exists, which limits our capacity to undertake macroecological analyses. Here, for the first time, we present a global data set on the trees of the treeline ecotone, supported by an online ToTE database. We synthesized the database from 1202 studies published over the last 60 years (1962 to 2022) following the Preferred Reporting Items in Systematic Reviews and Meta-Analysis (PRISMA) protocol. We classified the tree species in the database into three categories: treeline tree (TL) species, near to treeline (NTL) tree species, and tree species with an upper montane range limit (TUMR). The ToTE Version-1 presents a total of 208 tree taxa, including 189 species, five subspecies, and 14 varieties, belonging to 54 genera and 26 families distributed across 34 mountain regions worldwide that either grow exactly at the treeline or have a range limit below the treeline. Of the total taxa, 155, 14, and 39 belong to TL, NTL, and TUMR, respectively. Genera such as Abies, Picea, Pinus, Larix, and Juniperus are more represented in the treeline tree category. On the other hand, Acer, Prunus, Populus, and Quercus have more representatives in the near to treeline category, whereas Erica, Nothofagus, and Polylepis contribute more tree species with an upper montane range limit. Furthermore, families such as Rosaceae and Pinaceae include trees that occur both at the treeline and with an upper montane range limit, whereas Sapindaceae includes trees that occur exclusively near to treeline. Our database also includes information on the global distribution patterns of treeline tree species richness across mountains and biomes. The mountains with the highest number of tree species are the Andes (39) followed by the Himalaya (37). Close to 67% of tree species show restricted distributions in different mountains, with the highest endemism in the Andes and the Himalaya. In terms of tree species distribution, Pinus sylvestris was widespread, with a distribution across nine mountain regions, followed by Picea glauca and Fagus sylvatica, both distributed across five mountain regions. In terms of species' distribution across biomes, the temperate biome harbors the highest treeline tree species richness (152 species), which may reflect the fact that the majority of studies are available from the temperate regions of the world. The remaining 56 species are distributed within five other biomes, with the least in dry tropical and subarctic (four species each). Furthermore, currently 40 treeline tree species fall under different International Union for Conservation of Nature threat categories. We anticipate that our database will help advance research on macroecological, biogeographic, evolutionary, climate-change, and conservation aspects of the treeline on a global scale. The data are released under a Creative Commons Attribution 4.0 international license. Please cite this data paper when the data are reused.

Preliminary study on cranial measurements and sexual dimorphism in skull bones of gaur (Bos gaurus gaurus, Smith 1827).

Cranial measurements have been widely used in various studies in wildlife sciences, ranging from understanding predator ecology to wildlife forensics. However, detailed description of morphometry and sexual dimorphism of the skull of gaur Bos gaurus gaurus is lacking. The present study was undertaken to determine the sexual dimorphism based on the cranial measurements of gaur. A total of 12 individual gaur skulls of male (n = 6) and female (n = 6) were studied in the field from the naturally deceased animals between January 2018 and December 2021 in different ranges of Bandhavgarh tiger reserve (BTR), Madhya Pradesh, India. The skull measurements were analysed using univariate and multivariate statistics to determine whether cranial dimensions could be used to differentiate male and female skulls reliably. A total of 43 morphometrical parameters grouped into nine indices were calculated. Select morphometrical parameters viz PL, GFL, AKI, LBB, LFB, GBEE, GBAN, BPOP and GTCH were significantly different (p < 0.05) between sexes, whereas GBAN were significantly higher in female skulls. The measurements demonstrated that the skull of the gaur was dolichocephalic as the profile length and the otion to otion breath in both male and female were <75% of the length. Overall, 28 linear measurements of both the sexes were statistically significant (p < 0.05; <0.01). The calculated indices revealed that the foramen magnum index in the female gaur were significantly higher. In calculated cranial indices the facial index (a) was higher in female and facial index (b) were higher in males. The two important parameters, facial breadth in facial index (a) and the greatest breadth in facial index (b) were positively correlated, though facial index (a) was statistically not significant between the sexes. The greater inner length of the foramen magnum in female skull resulted in foramen being oval whereas it was circular in males. These parameters were decisive for sexual dimorphism, skull comparison and craniological studies. This study ascertained that the frontal index and skull index had no significant influence and were not good indices for discriminating skulls between male and female. Based on the Principal Component Analysis, it was found that skull of male and female gaurs exhibits differences in cranial morphology viz. cranial profile length or total length (PL) and the least inner height of the temporal groove (LIHT). The findings of the present study provide baseline information on various craniometrical measurements of skull of gaur, indices and parameters for sex identification that can be effectively used in understanding sex biased predation ecology, provide base line information to describe variation across its geographic range, and in identifying skulls recovered in wildlife offence cases.

International Variation in Severe Exacerbation Rates in Patients With Severe Asthma.

BACKGROUND: Exacerbation frequency strongly influences treatment choices in patients with severe asthma. RESEARCH QUESTION: What is the extent of the variability of exacerbation rate across countries and its implications in disease management? STUDY DESIGN AND METHODS: We retrieved data from the International Severe Asthma Registry, an international observational cohort of patients with a clinical diagnosis of severe asthma. We identified patients aged ≥ 18 years who did not initiate any biologics prior to baseline visit. A severe exacerbation was defined as the use of oral corticosteroids for ≥ 3 days or asthma-related hospitalization/ED visit. A series of negative binomial models were applied to estimate country-specific severe exacerbation rates during 365 days of follow-up, starting from a naive model with country as the only variable to an adjusted model with country as a random-effect term and patient and disease characteristics as independent variables. RESULTS: The final sample included 7,510 patients from 17 countries (56% from the United States), contributing to 1,939 severe exacerbations (0.27/person-year). There was large between-country variation in observed severe exacerbation rate (minimum, 0.04 [Argentina]; maximum, 0.88 [Saudi Arabia]; interquartile range, 0.13-0.54), which remained substantial after adjusting for patient characteristics and sampling variability (interquartile range, 0.16-0.39). INTERPRETATION: Individuals with similar patient characteristics but coming from different jurisdictions have varied severe exacerbation risks, even after controlling for patient and disease characteristics. This suggests unknown patient factors or system-level variations at play. Disease management guidelines should recognize such between-country variability. Risk prediction models that are calibrated for each jurisdiction will be needed to optimize treatment strategies.

Autophagy: a necessary evil in cancer and inflammation.

Autophagy, a highly regulated cellular process, assumes a dual role in the context of cancer. On the one hand, it functions as a crucial homeostatic pathway, responsible for degrading malfunctioning molecules and organelles, thereby maintaining cellular health. On the other hand, its involvement in cancer development and regression is multifaceted, contingent upon a myriad of factors. This review meticulously examines the intricacies of autophagy, from its molecular machinery orchestrated by Autophagy-Related Genes (ATG) initially discovered in yeast to the various modes of autophagy operative within cells. Beyond its foundational role in cellular maintenance, autophagy reveals context-specific functions in processes like angiogenesis and inflammation. Our analysis delves into how autophagy-related factors directly impact inflammation, underscoring their profound implications for cancer dynamics. Additionally, we extend our inquiry to explore autophagy's associations with cardiovascular conditions, neurodegenerative disorders, and autoimmune diseases, illuminating the broader medical relevance of this process. Furthermore, this review elucidates how autophagy contributes to sustaining hallmark cancer features, including stem cell maintenance, proliferation, angiogenesis, metastasis, and metabolic reprogramming. Autophagy emerges as a pivotal process that necessitates careful consideration in cancer treatment strategies. To this end, we investigate innovative approaches, ranging from enzyme-based therapies to MTOR inhibitors, lysosomal blockers, and nanoparticle-enabled interventions, all aimed at optimizing cancer treatment outcomes by targeting autophagy pathways. In summary, this comprehensive review provides a nuanced perspective on the intricate and context-dependent role of autophagy in cancer biology. Our exploration not only deepens our understanding of this fundamental process but also highlights its potential as a therapeutic target. By unraveling the complex interplay between autophagy and cancer, we pave the way for more precise and effective cancer treatments, promising better outcomes for patients.

Benchmarking signal quality and spatiotemporal distribution of interictal spikes in prolonged human iEEG recordings using CorTec wireless brain interchange.

Neuromodulation through implantable pulse generators (IPGs) represents an important treatment approach for neurological disorders. While the field has observed the success of state-of-the-art interventions, such as deep brain stimulation (DBS) or responsive neurostimulation (RNS), implantable systems face various technical challenges, including the restriction of recording from a limited number of brain sites, power management, and limited external access to the assessed neural data in a continuous fashion. To the best of our knowledge, for the first time in this study, we investigated the feasibility of recording human intracranial EEG (iEEG) using a benchtop version of the Brain Interchange (BIC) unit of CorTec, which is a portable, wireless, and externally powered implant with sensing and stimulation capabilities. We developed a MATLAB/SIMULINK-based rapid prototyping environment and a graphical user interface (GUI) to acquire and visualize the iEEG captured from all 32 channels of the BIC unit. We recorded prolonged iEEG (~ 24 h) from three human subjects with externalized depth leads using the BIC and commercially available clinical amplifiers simultaneously in the epilepsy monitoring unit (EMU). The iEEG signal quality of both streams was compared, and the results demonstrated a comparable power spectral density (PSD) in all the systems in the low-frequency band (< 80 Hz). However, notable differences were primarily observed above 100 Hz, where the clinical amplifiers were associated with lower noise floor (BIC-17 dB vs. clinical amplifiers < - 25 dB). We employed an established spike detector to assess and compare the spike rates in each iEEG stream. We observed over 90% conformity between the spikes rates and their spatial distribution captured with BIC and clinical systems. Additionally, we quantified the packet loss characteristic in the iEEG signal during the wireless data transfer and conducted a series of simulations to compare the performance of different interpolation methods for recovering the missing packets in signals at different frequency bands. We noted that simple linear interpolation has the potential to recover the signal and reduce the noise floor with modest packet loss levels reaching up to 10%. Overall, our results indicate that while tethered clinical amplifiers exhibited noticeably better noise floor above 80 Hz, epileptic spikes can still be detected successfully in the iEEG recorded with the externally powered wireless BIC unit opening the road for future closed-loop neuromodulation applications with continuous access to brain activity.

Unveiling HPV's hidden link: Cardiovascular diseases and the viral intrigue.

Cardiovascular diseases (CVD) remain a major global health challenge, with an escalating impact on mortality despite advancements in managing conventional risk factors. This review investigates the intricate relationship between human papillomavirus (HPV) and CVD, shedding light on a novel aspect of cardiovascular health. Despite significant progress in understanding and managing traditional CVD risk factors, a substantial proportion of CVD cases lack these conventional markers. Recent research has unveiled HPV, a prevalent sexually transmitted infection, as a potential unconventional risk factor for CVD. This review delves into the underlying mechanisms linking HPV to CVD pathogenesis. HPV's influence on vascular endothelium and induction of systemic inflammation are key contributors. Additionally, HPV disrupts host lipid metabolism, further exacerbating the development of atherosclerosis. The link between HPV and CAD is not merely correlative; it encompasses a complex interplay of virological, immunological, and metabolic factors. Understanding the connection between HPV and CVD holds transformative potential. Insights from this review not only underscore the significance of considering HPV as a crucial risk factor but also advocate for targeted HPV screening and vaccination strategies to mitigate CVD risks. This multidisciplinary exploration bridges the gap between infectious diseases and cardiovascular health, emphasizing the need for a comprehensive approach to combating the global burden of cardiovascular disease. Further research and clinical guidelines in this realm are essential to harness the full scope of preventive and therapeutic interventions, ultimately shaping a healthier cardiovascular landscape.

Topical Diclofenac for Prevention of Capecitabine-Associated Hand-Foot Syndrome: A Double-Blind Randomized Controlled Trial.

PURPOSE: Hand-foot syndrome (HFS) is a dose-limiting side effect of capecitabine. Celecoxib prevents HFS by inhibiting cyclooxygenase-2 (COX-2) that is upregulated because of the underlying associated inflammation. However, systemic side effects of celecoxib have limited routine prescription. Topical diclofenac inhibits COX-2 locally with minimal risk of systemic adverse events. Therefore, we conducted this study to assess the efficacy of topical diclofenac in the prevention of capecitabine-induced HFS. METHODS: In this single-site phase III randomized double-blind trial, we enrolled patients with breast or GI cancer who were planned to receive capecitabine-based treatment. Participants were randomly assigned in a 1:1 ratio to receive topical diclofenac or placebo gel for 12 weeks or until the development of HFS, whichever occurred earlier. The primary end point was the incidence of grade 2 or 3 HFS (Common Terminology Criteria for Adverse Events version 5), which was compared between the two groups using simple logistic regression. RESULTS: In total, 264 patients were randomly assigned to receive topical diclofenac gel (n = 131) or placebo (n = 133). Grade 2 or 3 HFS was observed in 3.8% of participants in the diclofenac group compared with 15.0% in the placebo group (absolute difference, 11.2%; 95% CI, 4.3 to 18.1; P = .003). Grade 1-3 HFS was lower in the diclofenac group than in the placebo group (6.1% v 18.1%; absolute risk difference, 11.9%; 95% CI, 4.1 to 19.6). Capecitabine dose reductions because of HFS were less frequent in the diclofenac group (3.8%) than in the placebo group (13.5%; absolute risk difference, 9.7%; 95% CI, 3.0 to 16.4). CONCLUSION: Topical diclofenac prevented HFS in patients receiving capecitabine. This trial supports the use of topical diclofenac to prevent capecitabine-associated HFS.

Natural Compound Dioscin Targeting Multiple Cancer Pathways through its High Affinity Binding to B Cell Lymphoma-2.

OBJECTIVE: The study aimed to explore the crucial genes involved in cancer-related biological processes, including EMT, autophagy, apoptosis, anoikis, and metastasis. It also sought to identify common genes among the pathways linked to these biological processes, determine the level of Bcl-2 expression in various types of cancers, and find a potent inhibitor of Bcl-2 among natural compounds. METHODS: Common genes involved in the pathways related to EMT, autophagy, apoptosis, anoikis, and metastasis were explored, and the level of the most frequently overexpressed gene that was Bcl-2, in various types of cancers was analyzed by gene expression analysis. A set of 102 natural compounds was sorted according to their docking scores using molecular docking and filtering. The top-ranked molecule was chosen for additional molecular dynamics (MD) simulation for 100 ns. Differential gene expression analysis was performed for Dioscin using GEO2R. RESULTS: The study identified four common genes, Bcl-2, Bax, BIRC3, and CHUK, among the pathways linked to EMT, autophagy, apoptosis, anoikis, and metastasis. Bcl-2 was highly overexpressed in many cancers, including Acute Myeloid Leukemia, Diffuse large B cell lymphoma, and Thymoma. The Dioscin structure in the Bcl-2 binding site received the highest docking score and the most relevant interactions. Dioscin's determined binding free energy by MM/GBSA was -52.21 kcal/mol, while the same calculated by MM/PBSA was -9.18 kcal/mol. A p-value of less than 0.05 was used to determine the statistical significance of the analysis performed using GEO2R. It was observed that Dioscin downregulates Bcl-2, BIRC3, and CHUK and upregulates the pro-apoptotic protein Bax. CONCLUSION: The study concluded that Dioscin has the potential to act as a protein inhibitor, with a noteworthy value of binding free energy and relevant interactions with the Bcl-2 binding site. Dioscin might be a good alternative for targeting multiple cancer pathways through a single target.

Application of Pathfinding Algorithms in Partial Discharge Localization in Power Transformers.

The introduction of artificial intelligence (AI) to ultra-high-frequency (UHF) partial discharge (PD) monitoring systems in power transformers for the localization of PD sources can help create a robust and reliable system with high usability and precision. However, training the AI with experimental data or data from electromagnetic simulation is costly and time-consuming. Furthermore, electromagnetic simulations often calculate more data than needed, whereas, for localization, the signal time-of-flight information is the most important. A tailored pathfinding algorithm can bypass the time-consuming and computationally expensive process of simulating or collecting data from experiments and be used to create the necessary training data for an AI-based monitoring system of partial discharges in power transformers. In this contribution, Dijkstra's algorithm is used with additional line-of-sight propagation algorithms to determine the paths of the electromagnetic waves generated by PD sources in a three-dimensional (3D) computer-aided design (CAD) model of a 300 MVA power transformer. The time-of-flight information is compared with results from experiments and electromagnetic simulations, and it is found that the algorithm maintains accuracy similar to that of the electromagnetic simulation software, with some under/overestimations in specific scenarios, while being much faster at calculations.

Cloning, expression, and characterization of a novel thermo-acidophilic l-asparaginase of Pseudomonas aeruginosa CSPS4.

In the present investigation, a soil isolate Pseudomonas aeruginosa CSPS4 was used for retrieving the l-asparaginase encoding gene (Asn_PA) of size 1089 bp. The gene was successfully cloned into the pET28a (+) vector and expressed into E. coli BL21(DE3) for characterization of the protein. The recombinant rAsn_PA enzyme was purified by affinity chromatography using Ni-NTA2+ resins. Molecular weight analysis using SDS-PAGE unveiled rAsn_PA as a monomeric protein of molecular weight ~ 35 kDa. On characterization, the recombinant rAsn_PA showed optimum pH and temperature of 6.0 and 60 °C, respectively, along with significant stability at 50-70 °C, along with 50% residual activity at 80 °C after 3 h of incubation. Similarly, the rAsn_PA exhibited asparaginase activity over a broad pH range between 4 and 8. The enzyme was not significantly inhibited in the presence of detergents. The rAsn_PA was grouped into the asparaginase-glutaminase family II due to the glutaminase activity. The purified rAsn_PA showed antitumor activity by exhibiting a cytotoxic effect on three different cell lines, where IC50 of purified rAsn_PA was 2.3 IU, 3.7 IU, and 20.5 IU for HL-60, MOLM-13, and K-562 cell lines, respectively. Thus, recombinant rAsn_PA of P. aeruginosa CSPS4 may also be explored as an antitumor agent after reducing or minimizing the glutaminase activity. Thermo-acidophilic properties of rAsn_PA make it a novel enzyme that needs to be further investigated.

Elevated senescence in the bone marrow mesenchymal stem cells of acquired aplastic anemia patients: A possible implication of DNA damage responses and telomere attrition.

BACKGROUND: Bone marrow mesenchymal stem cells (BM-MSC) are an integral part of the BM niche that is essential to maintain hematopoietic homeostasis. In aplastic anemia (AA), a few studies have reported phenotypic defects in the BM-MSC, such as reduced proliferation, imbalanced differentiation, and apoptosis; however, the alterations at the molecular level need to be better characterized. Therefore, the current study aims to identify the causative factors underlying the compromised functions of AA BM-MSC that might eventually be contributing to the AA pathobiology. METHODS: We performed RNA sequencing (RNA-Seq) using the Illumina platform to comprehend the distinction between the transcriptional landscape of AA and control BM-MSC. Further, we validated the alterations observed in senescence by Senescence- associated beta-galactosidase (SA -ß-gal) assay, DNA damage by γH2AX staining, and telomere attrition by relative telomere length assessment and telomerase activity assay. We used qRT-PCR to analyze changes in some of the genes associated with these molecular mechanisms. RESULTS: The transcriptome profiling revealed enrichment of senescence-associated genes and pathways in AA BM-MSC. The senescent phenotype of AA BM-MSC was accompanied by enhanced SA -ß-gal activity and elevated expression of senescence associated genes TP53, PARP1, and CDKN1A. Further, we observed increased γH2AX foci indicating DNA damage, reduced telomere length, and diminished telomerase activity in the AA BM-MSC. CONCLUSION: Our results highlight that AA BM-MSC have a senescent phenotype accompanied by other cellular defects like DNA damage and telomere attrition, which are most likely driving the senescent phenotype of AA BM-MSC thus hampering their hematopoiesis supporting properties as observed in AA.

Modern pollen dispersal in relation to present vegetation distribution and land use in the Baspa valley, Kinnaur, western Himalayas.

Interpretation of a fossil pollen data for the vegetation and climate reconstruction of any region needs a modern pollen-vegetation analogue for its calibration. We analyzed the surface sediments and moss polsters for the pollen and microcharcoal records to understand the modern pollen-vegetation relationship and human activities in the Baspa Valley, Kinnaur, Himachal Pradesh. Presently, valley is occupied by the arboreal and non-arboreal vegetation of temperate to subalpine habitats and land use activities. The recovered pollen assemblages showed variability in the dispersal behavior of pollen of taxa growing along the valley transect and also captured the signals of human activities over land use. The overall dominance of arboreal pollen in the recovered pollen assemblage corresponds with the dominant growth of conifers and broadleaf tree taxa and represents the valley vegetation at a regional scale. However, the profuse pollen production of a few arboreal taxa and long distance pollen transport from one vegetation zone to other by the strong upthermic valley winds could bias the pollen representation of in-situ vegetation. The high pollen frequency of non-arboreal taxa in the open meadows represents the near vicinity to their plant source. Human activities like fire burning and cultivation by the local population are evident by the recovery of microcharcoal particles and pollen of plants belonging to Cerealia Poaceae, Asteraceae, Amaranthaceae, Polygonaceae, Rosaceae, Juglandaceae, etc. The dataset taken as modern pollen-vegetation analogue is useful to assess past changes in the vegetation and land cover in relation to climate and human factors for future sustenance.

Synthesis and Biological Evaluation of Oxindole Sulfonamide Derivatives as Bruton's Tyrosine Kinase Inhibitors.

Bruton's tyrosine kinase (BTK) is a promising molecular target for several human B-cell-related autoimmune disorders, inflammation, and haematological malignancies. The pathogenic alterations in various cancer tissues depend on mutant BTK for cell proliferation and survival, and BTK is also overexpressed in a range of hematopoietic cells. Due to this, BTK is emerging as a potential drug target to treat various human diseases, and several reversible and irreversible inhibitors have been developed and are being developed. As a result, BTK inhibition, clinically validated as an anticancer treatment, is finding great interest in B-cell malignancies and solid tumours. This study focuses on the design and synthesis of new oxindole sulfonamide derivatives as promising inhibitors of BTK with negligible off-target effects. The most cytotoxic compounds with greater basicity were PID-4 (2.29±0.52 µM), PID-6 (9.37±2.47 µM), and PID-19 (2.64±0.88 µM). These compounds caused a selective inhibition of Burkitt's lymphoma RAMOS cells without significant cytotoxicity in non-BTK cancerous and non-cancerous cell lines. Further, PID-4 showed promising activity in inhibiting BTK and downstream signalling cascades. As a potent inhibitor of Burkitt's lymphoma cells, PID-4 is a promising lead for developing novel chemotherapeutics.

Biogenic synthesis of dopamine/carboxymethyl cellulose/TiO2 nanoparticles using Psidium guajava leaf extract with enhanced antimicrobial and anticancer activities.

The green synthesis of metal oxide nanoparticles (NPs) has garnered considerable attention from researchers due to its utilization of eco-friendly solvents during synthesis and cost-effective approaches. This study focuses on the synthesis of titanium oxide (TiO2) and dopamine (DA) carboxymethyl cellulose (CMC)-doped TiO2 (DA/CMC/TiO2) NP using Psidium guajava leaf extract, while also investigating the structural, optical, and morphological and biocidal potential of the prepared NPs. Significantly larger zones of inhibition were observed for DA/CMC/TiO2 NPs compared to TiO2 against various pathogens. Moreover, the MTT assay was carried out to evaluate the anticancer activity of the prepared samples against MG-63 cells, and the results revealed that DA/CMC/TiO2 NPs exhibited significantly higher level of anticancer activity compared to TiO2. The experimental results demonstrated that DA/CMC/TiO2 NPs exhibited enhanced anticancer activity in a dose-dependent manner when compared to TiO2 NPs.

Exploring digital narratives: A comprehensive dataset of household energy app reviews.

This paper presents an anonymous dataset of 7999 user reviews covering five household energy mobile applications used in Norwegian households. Such reviews are usually available through the Google Play Store and Apple App Store platforms. They were collected using Python-based Google-Play-Scraper and App Store Scraper. To the best of our knowledge, this dataset represents a unique and valuable resource for investigating sustainable household energy behaviour within the specific context of Norway, where a considerable proportion of households already use these applications. Given the recent rise of mobile applications and the ongoing development of technological infrastructure worldwide, this dataset holds a potential for empirical research. It can provide valuable insights into daily energy practices, user sentiments, perceptions, and motivations for adopting digital solutions. Further, it can shed light on the potential of these solutions to drive sustainable behavioural change. Moreover, conducting the empirical analysis of this dataset can provide valuable insights to stakeholders involved in policy formulation, utility improvement, emissions reduction, and promotion of technology-driven behavioural change.