Unique regulatory network of dragon fruit simultaneously mitigates the effect of vanadium pollutant and environmental factors.

Under changing climatic conditions, plants are simultaneously facing conflicting stresses in nature. Plants can sense different stresses, induce systematic ROS signals, and regulate transcriptomic, hormonal, and stomatal responses. We performed transcriptome analysis to reveal the integrative stress response regulatory mechanism underlying heavy metal stress alone or in combination with heat and drought conditions in pitaya (dragon fruit). A total of 70 genes were identified from 31,130 transcripts with conserved differential expression. Furthermore, weighted gene co-expression network analysis (WGCNA) identified trait-associated modules. By integrating information from three modules and protein-protein interaction (PPI) networks, we identified 10 interconnected genes associated with the multifaceted defense mechanism employed by pitaya against co-occurring stresses. To further confirm the reliability of the results, we performed a comparative analysis of 350 genes identified by three trait modules and 70 conserved genes exhibiting their dynamic expression under all treatments. Differential expression pattern of genes and comparative analysis, have proven instrumental in identifying ten putative structural genes. These ten genes were annotated as PLAT/LH2, CAT, MLP, HSP, PB1, PLA, NAC, HMA, and CER1 transcription factors involved in antioxidant activity, defense response, MAPK signaling, detoxification of metals and regulating the crosstalk between the complex pathways. Predictive analysis of putative candidate genes, potentially governing single, double, and multifactorial stress response, by several signaling systems and molecular patterns. These findings represent a valuable resource for pitaya breeding programs, offering the potential to develop resilient "super pitaya" plants.

Syncope and Brugada-Like ECG Pattern in a Patient with Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH).

Syncope is a brief loss of consciousness caused by reduced blood flow to the brain, characterised by sudden onset, short duration and full recovery without intervention. Anamnesis, physical examination and other diagnostic tests such as laboratory analysis and electrocardiogram (ECG) can be conducted to identify the underlying cause of syncope. A Brugada pattern on an ECG in individuals with syndrome of inappropriate antidiuretic hormone secretion (SIADH) who have syncope symptoms may indicate cardiac issues. A 69-year-old man with hypertension and a history of smoking presented with syncope. His vital signs were within normal limits, with no signs of a neurological deficit. The patient met the diagnostic criteria for SIADH, as evidenced by the presence of hyponatraemia (Na 118 mmol/l), a hyperosmolar condition and euvolemia. Upon arrival, a twelve-lead ECG showed ST-segment anomalies that reflected a Brugada ECG pattern. No ventricular arrhythmias were detected during the 24-hour Holter monitoring. Coronary angiography revealed no abnormalities in the coronary arteries. The ECG demonstrated the normalisation of ST elevations and the disappearance of the Brugada ECG pattern after the correction of hyponatraemia. After three months of follow-up the patient, with a normal sodium level, had no episodes of syncope. LEARNING POINTS: Syncope in elderly patients with Brugada-like ECG patterns can arise from cardiac causes, thus necessitating more examinations.Severe hyponatraemia in patients with SIADH can cause syncope and a Brugada-like ECG pattern.Correction of hyponatraemia, after ruling out cardiac causes, can improve syncope and normalise the Brugada-like ECG pattern.

Fabrication of photo-induced molecular superoxide radical generator for highly efficient therapy against bacterial wound infection.

The pressing need for highly efficient antibacterial strategies arises from the prevalence of microbial biofilm infections and the emergence of rapidly evolving antibiotic-resistant strains of pathogenic bacteria. Photodynamic therapy represents a highly efficient and compelling antibacterial approach, offering promising prospects for effective control of the development of bacterial resistance. However, the effectiveness of many photosensitizers is limited due to the reduced generation of reactive oxygen species (ROS) in hypoxic microenvironment, which commonly occur in pathological conditions such as inflammatory and bacteria-infected wounds. Herein, we designed and prepared two phenothiazine-derived photosensitizers (NB-1 and NB-2), which can effectively generate superoxide anion radicals (O2●-) through the type I process. Both photosensitizers demonstrate significant efficacy in vitro for the eradication of broad-spectrum bacteria. Moreover, NB-2 possesses distinct advantages including strong membrane binding and strong generation of O2●-, rendering it an exceptionally efficient antibacterial agent against mature biofilms. In addition, laser activated NB-2 could be applied to treat MRSA-infected wound in vivo, which offers new opportunities for potential practical applications.

Corrigendum: Sesquiterpene lactones attenuate paclitaxel resistance via inhibiting MALAT1/STAT3/ FUT4 axis and P-Glycoprotein transporters in lung cancer cells.

[This corrects the article DOI: 10.3389/fphar.2022.795613.].

Mechanistic approach of tannery wastewater and sulfadiazine mutual toxicity in wheat (Triticum aestivum L.) and mitigation through exogenous application of gallic acid.

Excessive release of chromium (Cr) from the tanning industry and antibiotics from livestock caused severe hazards to humans. Gallic acid (GA 10 mM) alleviated alone/combined SDZ 30 mg kg-1 and TWW 40, 60, and 100% stress in wheat. GA (10 mM) decreased the TSP 12 and 13%, TFAA 8 and 10%, TSS 14 and 16%, RS 18 and 16%, and NRS 11 and 9% in shoots and grains under SDZ + TWW (30 mg kg-1+100%), compared without foliar. GA (10 mM) declined the MDA 20 and 31, EL 13 and 36%, H2O2 17 and 15%, O2•- 10 and 11% in leaves and roots, under combined SDZ + TWW (30 mg kg-1+100%), compared without foliar. GA (10 mM) improved the POD 106 and 30%, SOD 145 and 31%, CAT 78, and 35%, APX 100 and 25% in leaves and roots under combined SDZ + TWW (30 mg kg-1+100%), compared without foliar application. Considerably GA (10 mM) reduced total Cr 18, CrIII 20, and CrVI 50% in roots and shoots 19, 41, and 48%, and grains 15, 27, and 29% respectively, under combined SDZ + TWW (30 mg kg-1+100%) stress, compared without foliar. Overall, GA boosted the wheat growth, physiology, and defence system by inhibiting the combined SDZ + Cr toxicity.

Applicability of SCoT markers in unraveling genetic variation and population structure among sugar beet (Beta vulgaris L.) germplasm.

BACKGROUND: Sugar beet (Beta vulgaris L.) holds significant importance as a crop globally cultivated for sugar production. The genetic diversity present in sugar beet accessions plays a crucial role in crop improvement programs. METHODS AND RESULTS: During the present study, we collected 96 sugar beet accessions from different regions and extracted DNA from their leaves. Genomic DNA was amplified using SCoT primers, and the resulting fragments were separated by gel electrophoresis. The data were analyzed using various genetic diversity indices, and constructed a population STRUCTURE, applied the unweighted pair-group method with arithmetic mean (UPGMA), and conducted Principle Coordinate Analysis (PCoA). The results revealed a high level of genetic diversity among the sugar beet accessions, with 265 bands produced by the 10 SCoT primers used. The percentage of polymorphic bands was 97.60%, indicating substantial genetic variation. The study uncovered significant genetic variation, leading to higher values for overall gene diversity (0.21), genetic distance (0.517), number of effective alleles (1.36), Shannon's information index (0.33), and polymorphism information contents (0.239). The analysis of molecular variance suggested a considerable amount of genetic variation, with 89% existing within the population. Using STRUCTURE and UPGMA analysis, the sugar beet germplasm was divided into two major populations. Structure analysis partitioned the germplasm based on the origin and domestication history of sugar beet, resulting in neighboring countries clustering together. CONCLUSION: The utilization of SCoT markers unveiled a noteworthy degree of genetic variation within the sugar beet germplasm in this study. These findings can be used in future breeding programs with the objective of enhancing both sugar beet yield and quality.

Adaptation of Research Project Requirement at Pharmacy Undergraduate Studies: Students' Perception, Attitude, and Experiences.

Objective: To determine the final year pharmacy undergraduate students' attitudes toward research after completing a research project. Methods: A research project was introduced in the final year of the PharmD program in January 2022. After a period of one year, in Janurary 2023, students submitted their final research to the faculty members. The survey was conducted from 1st March to 30st April 2023 using a study tool that contained items asking students' demographic, their research perceptions, attitude and experience, and also motivation/barriers faced during the research project. Descriptive and t-test statistics were utilized to compare the means of subgroups at a level of significance, i.e., p < 0.05. The data were also analyzed using Goodman and Kruskal's gamma and Mann-Whitney U test. Results: Majority of the students (93.8%) agreed regarding the significance of research in the pharmacy profession. Students were found to have their projects a worthwhile learning opportunity (94.2%). Students' motivation to execute research project stems from mandatory curriculum courses, improving clinical or hospital pharmacist training and fulfilling research skills (90%). Barriers hindered include lack of training, time, and patient follow-up (approximately 70%). Conclusion: The current study's finding was concluded with the fact that research is a valuable component of a well-rounded education and can enhance a pharmacist's skills. However, they need a combination of formal education and practical experience to pursue a profession in pharmacy.

Ferroptosis and the ubiquitin-proteasome system: exploring treatment targets in cancer.

Ferroptosis is an emerging mode of programmed cell death fueled by iron buildup and lipid peroxidation. Recent evidence points to the function of ferroptosis in the aetiology and development of cancer and other disorders. Consequently, harnessing iron death for disease treatment has diverted the interest of the researchers in the field of basic and clinical research. The ubiquitin-proteasome system (UPS) represents a primary protein degradation pathway in eukaryotes. It involves labelling proteins to be degraded by ubiquitin (Ub), followed by recognition and degradation by the proteasome. Dysfunction of the UPS can contribute to diverse pathological processes, emphasizing the importance of maintaining organismal homeostasis. The regulation of protein stability is a critical component of the intricate molecular mechanism underlying iron death. Moreover, the intricate involvement of the UPS in regulating iron death-related molecules and signaling pathways, providing valuable insights for targeted treatment strategies. Besides, it highlights the potential of ferroptosis as a promising target for cancer therapy, emphasizing the combination between ferroptosis and the UPS. The molecular mechanisms underlying ferroptosis, including key regulators such as glutathione peroxidase 4 (GPX4), cysteine/glutamate transporter (system XC-), and iron metabolism, are thoroughly examined, alongside the role of the UPS in modulating the abundance and activity of crucial proteins for ferroptotic cell death, such as GPX4, and nuclear factor erythroid 2-related factor 2 (NRF2). As a pivotal regulatory system for macromolecular homeostasis, the UPS substantially impacts ferroptosis by directly or indirectly modulating iron death-related molecules or associated signaling pathways. This review explores the involvement of the UPS in regulating iron death-related molecules and signaling pathways, providing valuable insights for the targeted treatment of diseases associated with ferroptosis.

Artificial intelligence models for validating and predicting the impact of chemical priming of hydrogen peroxide (H2O2) and light emitting diodes on in vitro grown industrial hemp (Cannabis sativa L.).

Industrial hemp (Cannabis sativa L.) is a highly recalcitrant plant under in vitro conditions that can be overcome by employing external stimuli. Hemp seeds were primed with 2.0-3.0% hydrogen peroxide (H2O2) followed by culture under different Light Emitting Diodes (LEDs) sources. Priming seeds with 2.0% yielded relatively high germination rate, growth, and other biochemical and enzymatic activities. The LED lights exerted a variable impact on Cannabis germination and enzymatic activities. Similarly, variable responses were observed for H2O2 × Blue-LEDs combination. The results were also analyzed by multiple regression analysis, followed by an investigation of the impact of both factors by Pareto chart and normal plots. The results were optimized by contour and surface plots for all parameters. Response surface optimizer optimized 2.0% H2O2 × 918 LUX LEDs for maximum scores of all output parameters. The results were predicted by employing Multilayer Perceptron (MLP), Random Forest (RF), and eXtreme Gradient Boosting (XGBoost) algorithms. Moreover, the validity of these models was assessed by using six different performance metrics. MLP performed better than RF and XGBoost models, considering all six-performance metrics. Despite the differences in scores, the performance indicators for all examined models were quite close to each other. It can easily be concluded that all three models are capable of predicting and validating data for cannabis seeds primed with H2O2 and grown under different LED lights.

Novel Solid-State Electrolyte Na3La5Cl18 with High Stability and Fast Ionic Conduction.

Motivated by the recent experimental synthesis of a LaCl3-based lithium superionic conductor [Yin, Y.-C. Nature 2023, 616, 77-83], we explore the potential of a LaCl3-based system for a sodium superionic conductor in this work. Using density functional theory combined with molecular dynamics simulation and a grand potential phase diagram analysis, we find that the resulting Na3La5Cl18 exhibits high energetic stability with a small energy-above-hull of 18 meV per atom, a large band gap of 5.58 eV, a wide electrochemical window of 0.41-3.76 V from the cathodic to the anodic limit, and a high Na+ conductivity of 1.3 mS/cm at 300 K. Furthermore, Na3La5Cl18 shows high chemical interface stability with the reported high-potential cathode materials such as NaCoO2, NaCrO2, Na2FePO4F, Na3V2(PO4)3, and Na3V2(PO4)2F3. These findings clearly suggest that the LaCl3-based framework can be used as a building block not only for Li-ion but also for Na-ion batteries.

Hybrid Rice Production: A Worldwide Review of Floral Traits and Breeding Technology, with Special Emphasis on China.

Rice is an important diet source for the majority of the world's population, and meeting the growing need for rice requires significant improvements at the production level. Hybrid rice production has been a significant breakthrough in this regard, and the floral traits play a major role in the development of hybrid rice. In grass species, rice has structural units called florets and spikelets and contains different floret organs such as lemma, palea, style length, anther, and stigma exsertion. These floral organs are crucial in enhancing rice production and uplifting rice cultivation at a broader level. Recent advances in breeding techniques also provide knowledge about different floral organs and how they can be improved by using biotechnological techniques for better production of rice. The rice flower holds immense significance and is the primary focal point for researchers working on rice molecular biology. Furthermore, the unique genetics of rice play a significant role in maintaining its floral structure. However, to improve rice varieties further, we need to identify the genomic regions through mapping of QTLs (quantitative trait loci) or by using GWAS (genome-wide association studies) and their validation should be performed by developing user-friendly molecular markers, such as Kompetitive allele-specific PCR (KASP). This review outlines the role of different floral traits and the benefits of using modern biotechnological approaches to improve hybrid rice production. It focuses on how floral traits are interrelated and their possible contribution to hybrid rice production to satisfy future rice demand. We discuss the significance of different floral traits, techniques, and breeding approaches in hybrid rice production. We provide a historical perspective of hybrid rice production and its current status and outline the challenges and opportunities in this field.

Development and characterization of non-proprietary ultra high performance concrete.

This paper presents the developmental process of ultra-high performance concrete (UHPC), the most advanced form of concrete. The entire process exclusively utilized locally available materials. The mixes were prepared without using any specialized mixer or treatments, such as elevated pressure, etc. The primary objective of the research was to develop low-cost non-proprietary version of UHPC by optimizing both cementitious and non-cementitious materials to attain the highest levels of workability, compressive strength, flexural strength and durability. The research utilizes a trial-and-error approach, subjecting specimens to curing in both regular and heated water. The findings validate the viability of producing self-compacting UHPC with compressive strength ranging from 120 to 160 MPa, employing local materials and manufacturing methods. Raw materials and mixing sequence had a significant influence on the fresh and hardened properties of UHPC. The inclusion of steel fibers and the application of heat treatment remarkably enhanced the compressive strength. Furthermore, cost analysis revealed that this particular UHPC is only slightly over four times more expensive than conventional concrete, in contrast to commercially available UHPC, which is approximately 10 times expensive than traditional concrete.

Remediation of organic pollutant from the aqueous environment using in-house fabricated polyaniline-based hybrid composite (PANI-MnPBA/NiCoMnS) materials.

Polyaniline-based hybrid material (PANI-MnPBA/NiCoMnS) was prepared by hydrothermal-solvothermal approach. Synthesized hybrid material was characterized through FTIR-spectroscopy, p-XRD, SEM, EDX, BET, and Zetasizer techniques. Hybrid material as adsorbent for removal of Congo red (CR) from water system showed excellent results such as 98 % removal efficiency and 254 mg/g adsorption capacity. Furthermore, various studies like adsorption isothermal, kinetic, thermodynamic, and statistical analysis were performed to understand the adsorption phenomenon. From various kinetic models, pseudo-first and second-order kinetic models, intra-particle and liquid film diffusion kinetic models, pseudo-first-order kinetic model, and liquid-film diffusion kinetic model both are most suitable for explaining the adsorption phenomenon due to the greater value of R2 (0.955) for CR. According to these kinetic models, physio-sorption and diffusion play a basic role in the adsorption of CR. Moreover, ΔG (-1779.508 kJ mol-1) and ΔH (61,760.889 kJ mol-1) values explained the spontaneous and exothermic nature of the adsorption process, respectively. Furthermore, for support of the adsorption mechanism via electrostatic attractions before and after the adsorption process FTIR results of as-synthesized adsorbent were measured (NH peaks before 3668.88, after 3541.41 cm-1). These results confirm electrostatic attraction for the adsorption process. Finally, the statistical model was added (n < 1), according to this model, adsorption follows a multi-anchorage approach and adsorbent contains enough sites for adsorption of CR.

Hemophilia Healing with AAV: Navigating the Frontier of Gene Therapy.

Gene therapy for hemophilia has advanced tremendously after thirty years of continual study and development. Advancements in medical science have facilitated attaining normal levels of Factor VIII (FVIII) or Factor IX (FIX) in individuals with haemophilia, thereby offering the potential for their complete recovery. Despite the notable advancements in various countries, there is significant scope for further enhancement in haemophilia gene therapy. Adeno-associated virus (AAV) currently serves as the primary vehicle for gene therapy in clinical trials targeting haemophilia. Subsequent investigations will prioritize enhancing viral capsid structures, transgene compositions, and promoters to achieve heightened transduction efficacy, diminished immunogenicity, and more predictable therapeutic results. The present study indicates that whereas animal models have transduction efficiency that is over 100% high, human hepatocytes are unable to express clotting factors and transduction efficiency to comparable levels. According to the current study, achieving high transduction efficiency and high levels of clotting factor expression in human hepatocytes is still insufficient. It is also crucial to reduce the risk of cellular stress caused by protein overload. Despite encountering various hurdles, the field of haemophilia gene therapy holds promise for the future. As technology continues to advance and mature, it is anticipated that a personalized therapeutic approach will be developed to cure haemophilia effectively.

The Multifunctional TRPC6 Protein: Significance in the Field of Cardiovascular Studies.

Cardiovascular disease is the leading cause of death, medical complications, and healthcare costs. Although recent advances have been in treating cardiovascular disorders linked with a reduced ejection fraction, acutely decompensate cardiac failure remains a significant medical problem. The transient receptor potential cation channel (TRPC6) family responds to neurohormonal and mechanical stress, playing critical roles in cardiovascular diseases. Therefore, TRP C6 channels have great promise as therapeutic targets. Numerous studies have investigated the roles of TRP C6 channels in pain neurons, highlighting their significance in cardiovascular research. The TRPC6 protein exhibits a broad distribution in various organs and tissues, including the brain, nerves, heart, blood vessels, lungs, kidneys, gastrointestinal tract, and other bodily structures. Its activation can be triggered by alterations in osmotic pressure, mechanical stimulation, and diacylglycerol. Consequently, TRPC6 plays a significant role in the pathophysiological mechanisms underlying diverse diseases within living organisms. A recent study has indicated a strong correlation between the disorder known as TRPC6 and the development of cardiovascular diseases. Consequently, investigations into the association between TRPC6 and cardiovascular diseases have gained significant attention in the scientific community. This review explores the most recent developments in the recognition and characterization of TRPC6. Additionally, it considers the field's prospects while examining how TRPC6 might be altered and its clinical applications.

Elevated 2-oxoglutarate antagonizes DNA damage responses in cholangiocarcinoma chemotherapy through regulating aspartate beta-hydroxylase.

Cholangiocarcinoma (CCA) is resistant to systemic chemotherapies that kill malignant cells mainly through DNA damage responses (DDRs). Recent studies suggest that the involvement of 2-oxoglutarate (2-OG) dependent dioxygenases in DDRs may be associated with chemoresistance in malignancy, but how 2-OG impacts DDRs in CCA chemotherapy remains elusive. We examined serum 2-OG levels in CCA patients before receiving chemotherapy. CCA patients are classified as progressive disease (PD), partial response (PR), and stable disease (SD) after receiving chemotherapy. CCA patients classified as PD showed significantly higher serum 2-OG levels than those defined as SD and PR. Treating CCA cells with 2-OG reduced DDRs. Overexpression of full-length aspartate beta-hydroxylase (ASPH) could mimic the effects of 2-OG on DDRs, suggesting the important role of ASPH in chemoresistance. Indeed, the knockdown of ASPH improved chemotherapy in CCA cells. Targeting ASPH with a specific small molecule inhibitor also enhanced the effects of chemotherapy. Mechanistically, ASPH modulates DDRs by affecting ATM and ATR, two of the major regulators finely controlling DDRs. More importantly, targeting ASPH improved the therapeutic potential of chemotherapy in two preclinical CCA models. Our data suggested the impacts of elevated 2-OG and ASPH on chemoresistance through antagonizing DDRs. Targeting ASPH may enhance DDRs, improving chemotherapy in CCA patients.

Clinical Outcomes With Nurse-Coordinated Multidisciplinary Care in Patients With Heart Failure: A Systematic Review and Meta-analysis.

The American Heart Association (AHA) and the European Society of Cardiology (ESC) recommend nurse-inclusive multidisciplinary care for patients with heart failure (HF). However, there is no meta-analysis that focuses specifically on the impact of nurse-coordinated multidisciplinary care. Considering this literature gap, we conducted this review that seeks to systematically synthesize the current evidence available regarding the impact of nurse-coordinated multidisciplinary care on clinical outcomes in patients with HF. A comprehensive search was done using PubMed/Medline, Cochrane Library, and EMBASE from inception till July 2023 for randomized controlled trials (RCTs) comparing nurse-coordinated multidisciplinary care with usual care in adult patients (>18 years) with acute or chronic HF. Data about all-cause mortality, HF-related hospitalizations, and all-cause hospitalizations was extracted, pooled, and analyzed. Forrest plots were generated using the random effects model. A total of 30 RCTs were included in the analysis with a total of 7950 HF patients. Our pooled analysis demonstrated a significant reduction in all-cause mortality in HF patients who received nurse-coordinated multidisciplinary care (RR = 0.80, 95% CI: 0.72-0.88, P = 0.0001). Similarly, there was a significantly lesser risk of HF-related hospitalizations (RR = 0.56, 95% CI: 0.45-0.71, P = 0.00001) and all-cause hospitalizations (RR = 0.78, 95% CI: 0.70-0.87, P = 0.0001) among HF patients with nurse-coordinated multidisciplinary care as compared to the usual care. Nurse-coordinated multidisciplinary care significantly reduces the risk of all-cause mortality, HF-related hospitalizations, and all-cause hospitalizations in HF patients' posthospital discharge.

Neurotoxicity, antipsychotic and antidepressant screening of the fruit of Rosa moschata in mice.

Extract of Rosa moschata (RM) fruits was evaluated for the anti-schizophrenic and antidepressant activities. We first determined the neurotoxic effect of hydro-methanolic extract of RM using inverted-screen test. Further, the extract was tested in the ketamine-induced schizophrenia model and its antidepressant effect was assessed by tail suspension and forced swim test in mice. Different doses of extract were administered once/day to the animals for 14 consecutive days. Behavioral parameters were investigated 24h after last administration of drug/extract by performing Y-maze test, forced swim test and open field test. Results showed that TD50 of the extract was ~1000mg/Kg. Moreover, extract significantly increased % alternations in YMT, reduced immobility time in FST and enhanced locomotion in OFT compared to saline group. Similarly, RM extract decreased time of immobility in FST and TST significantly showed antidepressant effect. Thus, it was concluded that extract of RM has antipsychotic and antidepressant properties.

Molecular profiling reveals potential targets in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is a devastating malignancy and has a very poor prognosis if tumors spread outside the liver. Understanding the molecular mechanisms underlying the CCA progression will likely yield therapeutic approaches toward treating this deadly disease. AIM: To determine the molecular pathogenesis in CCA progression. METHODS: In silico analysis, in vitro cell culture, CCA transgenic animals, histological, and molecular assays were adopted to determine the molecular pathogenesis. RESULTS: The transcriptomic data of human CCA samples were retrieved from The Cancer Genome Atlas (TGCA, CHOL), European Bioinformatics Institute (EBI, GAD00001001076), and Gene Expression Omnibus (GEO, GSE107943) databases. Using Gene set enrichment analysis, the cell cycle and Notch related pathways were demonstrated to be significantly activated in CCA in TCGA and GEO datasets. We, through differentially expressed genes, found several cell cycle and notch associated genes were significantly up-regulated in cancer tissues when compared with the non-cancerous control samples. The associated genes, via quantitative real-time PCR and western blotting assays, were further examined in normal human cholangiocytes, CCA cell lines, mouse normal bile ducts, and mouse CCA tumors established by specifically depleting P53 and expressing KrasG12D mutation in the liver. Consistently, we validated that the cell cycle and Notch pathways are up-regulated in CCA cell lines and mouse CCA tumors. Interestingly, targeting cell cycle and notch pathways using small molecules also exhibited significant beneficial effects in controlling tumor malignancy. More importantly, we demonstrated that several cell cycle and Notch associated genes are significantly associated with poor overall survival and disease-free survival using the Log-Rank test. CONCLUSION: In summary, our study comprehensively analyzed the gene expression pattern of CCA samples using publicly available datasets and identified the cell cycle and Notch pathways are potential therapeutic targets in this deadly disease.

Shifts in the Distribution Range and Niche Dynamics of the Globally Threatened Western Tragopan (Tragopan melanocephalus) Due to Climate Change and Human Population Pressure.

The impact of a changing climate, particularly global warming, often harms the distribution of pheasants, particularly those with limited endemic ranges. To effectively create plans of action aimed at conserving species facing threats such as the Western Tragopan, (Tragopan melanocephalus; Gray, 1829; Galliformes, found in the western Himalayas), it is crucial to understand how future distributions may be affected by anticipated climate change. This study utilized MaxEnt modeling to assess how suitable the habitat of the targeted species is likely to be under different climate scenarios. While similar studies have been conducted regionally, there has been no research on this particular endemic animal species found in the western Himalayas throughout the entire distribution range. The study utilized a total of 200 occurrence points; 19 bioclimatic, four anthropogenic, three topographic, and a vegetation variable were also used. To determine the most fitting model, species distribution modeling (SDM) was employed, and the MaxEnt calibration and optimization techniques were utilized. Data for projected climate scenarios of the 2050s and 2070s were obtained from SSPs 245 and SSPs 585. Among all the variables analyzed; aspect, precipitation of coldest quarter, mean diurnal range, enhanced vegetation index, precipitation of driest month, temperature seasonality, annual precipitation, human footprint, precipitation of driest quarter, and temperature annual range were recognized as the most influential drivers, in that order. The predicted scenarios had high accuracy values (AUC-ROC > 0.9). Based on the feedback provided by the inhabitants, it was observed that the livability of the selected species could potentially rise (between 3.7 to 13%) in all projected scenarios of climate change, because this species is relocating towards the northern regions of the elevation gradient, which is farther from the residential areas, and their habitats are shrinking. The suitable habitats of the Tragopan melanocephalus in the Himalayan region will move significantly by 725 m upwards, because of predicted climate change. However, the fact that the species is considered extinct in most areas and only found in small patches suggests that further research is required to avert a further population decline and delineate the reasons leading to the regional extinction of the species. The results of this study can serve as a foundation for devising conservation strategies for Tragopan melanocephalus under the changing climate and provide a framework for subsequent surveillance efforts aimed at protecting the species.