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Among the three active aldehyde oxidases in Arabidopsis thaliana leaves (AAO1-3), AAO3, which catalyzes the oxidation of abscisic-aldehyde to abscisic-acid, was shown recently to function as a reactive aldehyde detoxifier. Notably, aao2KO mutants exhibited less senescence symptoms and lower aldehyde accumulation, such as acrolein, benzaldehyde, and 4-hydroxyl-2-nonenal (HNE) than in wild-type leaves exposed to UV-C or Rose-Bengal. The effect of AAO2 expression absence on aldehyde detoxification by AAO3 and/or AAO1 was studied by comparing the response of wild-type plants to the response of single-functioning aao1 mutant (aao1S), aao2KO mutants, and single-functioning aao3 mutants (aao3Ss). Notably, aao3Ss exhibited similar aldehyde accumulation and chlorophyll content to aao2KO treated with UV-C or Rose-Bengal. In contrast, wild-type and aao1S exhibited higher aldehyde accumulation that resulted in lower remaining chlorophyll than in aao2KO leaves, indicating that the absence of active AAO2 enhanced AAO3 detoxification activity in aao2KO mutants. In support of this notion, employing abscisic-aldehyde as a specific substrate marker for AAO3 activity revealed enhanced AAO3 activity in aao2KO and aao3Ss leaves compared to wild-type treated with UV-C or Rose-Bengal. The similar abscisic-acid level accumulated in leaves of unstressed or stressed genotypes indicates that aldehyde detoxification by AAO3 is the cause for better stress resistance in aao2KO mutants. Employing the sulfuration process (known to activate aldehyde oxidases) in wild-type, aao2KO, and molybdenum-cofactor sulfurase (aba3-1) mutant plants revealed that the active AAO2 in WT employs sulfuration processes essential for AAO3 activity level, resulting in the lower AAO3 activity in WT than AAO3 activity in aao2KO., (© 2024 The Author(s). The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

Ureides, the degraded products of purine catabolism in Arabidopsis, have been shown to act as antioxidant and nitrogen sources. Herein we elucidate purine degraded metabolites as a carbon source using the Arabidopsis Atxdh1, Ataln, and Ataah knockout (KO) mutants vis-à-vis wild-type (WT) plants. Plants were grown under short-day conditions on agar plates containing half-strength MS medium with or without 1% sucrose. Notably, the absence of sucrose led to diminished biomass accumulation in both shoot and root tissues of the Atxdh1, Ataln, and Ataah mutants, while no such effect was observed in WT plants. Moreover, the application of sucrose resulted in a reduction of purine degradation metabolite levels, specifically xanthine and allantoin, predominantly within the roots of WT plants. Remarkably, an increase in proteins associated with the purine degradation pathway was observed in WT plants in the presence of sucrose. Lower glyoxylate levels in the roots but not in the shoot of the Atxdh1 mutant in comparison to WT, were observed under sucrose limitation, and improved by sucrose application in root, indicating that purine degradation provided glyoxylate in the root. Furthermore, the deficit of purine-degraded metabolites in the roots of mutants subjected to carbon starvation was partially mitigated through allantoin application. Collectively, these findings signify that under conditions of sucrose limitation and short-day growth, purines are primarily remobilized within the root system to augment the availability of ureides, serving as an additional carbon (as well as nitrogen) source to support plant growth., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Advanced epithelial ovarian cancer (EOC) survival rates are dishearteningly low, with ~25% surviving beyond 5 years. Evidence suggests that cancer stem cells contribute to acquired chemoresistance and tumor recurrence. Here, we show that IRAK1 is upregulated in EOC tissues, and enhanced expression correlates with poorer overall survival. Moreover, low molecular weight hyaluronic acid, which is abundant in malignant ascites from patients with advanced EOC, induced IRAK1 phosphorylation leading to STAT3 activation and enhanced spheroid formation. Knockdown of IRAK1 impaired tumor growth in peritoneal disease models, and impaired HA-induced spheroid growth and STAT3 phosphorylation. Finally, we determined that TCS2210, a known inducer of neuronal differentiation in mesenchymal stem cells, is a selective inhibitor of IRAK1. TCS2210 significantly inhibited EOC growth in vitro and in vivo both as monotherapy, and in combination with cisplatin. Collectively, these data demonstrate IRAK1 as a druggable target for EOC., (© 2024. The Author(s).)

Pancreatic cancer remains a serious and deadly disease, impacting people globally. There remain prominent gaps in the current understanding of the disease, specifically regarding the role of the signal transducer and activator of transcription (STAT) family of proteins in pancreatic tumors. STAT proteins, particularly STAT3, play important roles in pancreatic cancer, especially pancreatic ductal adenocarcinoma (PDAC), which is the most prevalent histotype. The role of STAT3 across a continuum of molecular processes, such as PDAC tumorigenesis and progression, immune escape, drug resistance and stemness, and modulation of the tumor microenvironment (TME), are only a tip of the iceberg. In some ways, the role of STAT3 in PDAC may hold greater importance than that of oncogenic Kirsten rat sarcoma virus (KRAS). This makes STAT3 a highly attractive target for developing targeted therapies for the treatment of pancreatic cancer. In this review, the current knowledge of STAT3 in pancreatic cancer has been summarized, particularly relating to STAT3 activation in cancer cells, cells of the TME, and the state of targeting STAT3 in pre-clinical and clinical trials of PDAC., Competing Interests: The authors declare that they have no conflicts of interest., (© The Author(s) 2024.)

This retrospective observational study explores the acceleration and deceleration demands of elite male futsal players (age: 28.8 ± 2.4 years, weight: 73.7 ± 6.2 kg, height: 175.9 ± 5.9 cm) in official matches. Utilising a local positioning system, tracking data from twelve matches involving two elite teams with nineteen players was analysed. Physical demands were assessed at various thresholds, considering standing and rolling efforts based on initial and final velocities. The most prevalent efforts were rolling accelerations (32.4%) and decelerations (31.3%), along with standing accelerations (18.7%) and decelerations (17.6%). A majority of efforts occurred within small distances (less than 10 metres), representing 27.9% to 71.1% of cases. Intensity comparisons revealed that larger distances consistently had significantly higher velocities (d = 0.67 to d = 5.91). High-intensity efforts over large distances were notably shorter than their low-intensity counterparts, both in standing (d = 1.75 to d = 1.98) and rolling (d = 0.64 to d = 0.82) effort types. In essence, elite futsal players predominantly engage in rolling accelerations and decelerations within short distances, exhibiting average speeds below 3 m·s−2. This insight into the nuanced dynamics of player movements provides valuable information for optimising training regimens and enhancing performance in elite futsal competitions. [ABSTRACT FROM AUTHOR]

New drugs for visceral leishmaniasis that are safe, low cost, and adapted to the field are urgently required. Despite concerted efforts over the last several years, the number of new chemical entities that are suitable for clinical development for the treatment of Leishmania remains low. Here, we describe the discovery and preclinical development of DNDI-6174, an inhibitor of Leishmania cytochrome bc 1 complex activity that originated from a phenotypically identified pyrrolopyrimidine series. This compound fulfills all target candidate profile criteria required for progression into preclinical development. In addition to good metabolic stability and pharmacokinetic properties, DNDI-6174 demonstrates potent in vitro activity against a variety of Leishmania species and can reduce parasite burden in animal models of infection, with the potential to approach sterile cure. No major flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 is a cytochrome bc 1 complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis.

Cardiovascular toxicity is an important cause of drug failures in the later stages of drug development, early clinical safety assessment, and even postmarket withdrawals. Early-stage in vitro assessment of potential cardiovascular liabilities in the pharmaceutical industry involves assessment of interactions with cardiac ion channels, as well as induced pluripotent stem cell-derived cardiomyocyte-based functional assays, such as calcium flux and multielectrode-array assays. These methods are appropriate for the identification of acute functional cardiotoxicity but structural cardiotoxicity, which manifests effects after chronic exposure, is often only captured in vivo. CardioMotion is a novel, label-free, high throughput, in vitro assay and analysis pipeline which records and assesses the spontaneous beating of cardiomyocytes and identifies compounds which impact beating. This is achieved through the acquisition of brightfield images at a high framerate, combined with an optical flow-based python analysis pipeline which transforms the images into waveform data which are then parameterized. Validation of this assay with a large dataset showed that cardioactive compounds with diverse known direct functional and structural mechanisms-of-action on cardiomyocytes are identified (sensitivity = 72.9%), importantly, known structural cardiotoxins also disrupt cardiomyocyte beating (sensitivity = 86%) in this method. Furthermore, the CardioMotion method presents a high specificity of 82.5%., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Groundwater salinization is a problem affecting access to water in many world regions. Though desalination by conventional reverse osmosis (RO) can upgrade groundwater quality for drinking, its disadvantages include unmanaged brine discharge and accelerated groundwater depletion. Here, we propose a new approach combining RO, forward osmosis (FO), and halophyte cultivation, in which FO optimally adjusts the concentration of the RO reject brine for irrigation of Salicornia or Sarcocornia . The FO also re-uses wastewater, thus, reducing groundwater extraction and the wastewater effluent volume. To suit different groundwater salinities in the range 1-8 g/L, three practical designs are proposed and analyzed. Results include specific groundwater consumption (SGC), specific energy consumption (SEC), wastewater volume reduction, peak RO pressure, permeate water quality, efficiency of water resource utilization, and halophyte yield. Compared to conventional brackish water RO, the results show superior performance in almost all aspects. For example, SGC is reduced from 1.25 to 0.9 m 3 per m 3 of drinking water output and SEC is reduced from 0.79 to 0.70 kW h/m 3 by a FO-RO-FO system treating groundwater of salinity 8 g/L. This system can produce 1.1 m 3 of high-quality drinking water and up to 4.9 kg of edible halophyte per m 3 of groundwater withdrawn.

Ovarian cancer (OvCa) is a deadly gynecologic malignancy that presents many clinical challenges due to late-stage diagnoses and the development of acquired resistance to standard-of-care treatment protocols. There is an increasing body of evidence suggesting that STATs may play a critical role in OvCa progression, resistance, and disease recurrence, and thus we sought to compile a comprehensive review to summarize the current state of knowledge on the topic. We have examined peer reviewed literature to delineate the role of STATs in both cancer cells and cells within the tumor microenvironment. In addition to summarizing the current knowledge of STAT biology in OvCa, we have also examined the capacity of small molecule inhibitor development to target specific STATs and progress toward clinical applications. From our research, the best studied and targeted factors are STAT3 and STAT5, which has resulted in the development of several inhibitors that are under current evaluation in clinical trials. There remain gaps in understanding the role of STAT1, STAT2, STAT4, and STAT6, due to limited reports in the current literature; as such, further studies to establish their implications in OvCa are necessitated. Moreover, due to the deficiency in our understanding of these STATs, selective inhibitors also remain elusive, and therefore present opportunities for discovery.

Doublecortin like kinase 1 (DCLK1) plays a crucial role in several cancers including colon and pancreatic adenocarcinomas. However, its role in squamous cell carcinoma (SCC) remains unknown. To this end, we examined DCLK1 expression in head and neck SCC (HNSCC) and anal SCC (ASCC). We found that DCLK1 is elevated in patient SCC tissue, which correlated with cancer progression and poorer overall survival. Furthermore, DCLK1 expression is significantly elevated in human papilloma virus negative HNSCC, which are typically aggressive with poor responses to therapy. To understand the role of DCLK1 in tumorigenesis, we used specific shRNA to suppress DCLK1 expression. This significantly reduced tumor growth, spheroid formation, and migration of HNSCC cancer cells. To further the translational relevance of our studies, we sought to identify a selective DCLK1 inhibitor. Current attempts to target DCLK1 using pharmacologic approaches have relied on nonspecific suppression of DCLK1 kinase activity. Here, we demonstrate that DiFiD (3,5-bis [2,4-difluorobenzylidene]-4-piperidone) binds to DCLK1 with high selectivity. Moreover, DiFiD mediated suppression of DCLK1 led to G2/M arrest and apoptosis and significantly suppressed tumor growth of HNSCC xenografts and ASCC patient derived xenografts, supporting that DCLK1 is critical for SCC growth., (© 2022 Wiley Periodicals LLC.)

Prolactin (PRL) is a peptide hormone mainly secreted from the anterior pituitary gland. PRL is reported to play a role in pregnancy, mammary gland development, immune modulation, reproduction, and differentiation of islet cells. PRL binds to its receptor PRLR, which belongs to a superfamily of the class I cytokine receptor that has no intrinsic kinase activity. In canonical signaling, PRL binding to PRLR induces downstream signaling including JAK-STAT, AKT and MAPK pathways. This leads to increased cell proliferation, stemness, migration, apoptosis inhibition, and resistance to chemotherapy. PRL-signaling is upregulated in numerous hormone-dependent cancers including breast, prostate, ovarian, and endometrial cancer. However, more recently, the pathway has been reported to play a tumor-promoting role in other cancer types such as colon, pancreas, and hepatocellular cancers. Hence, the signaling pathway is an attractive target for drug development with blockade of the receptor being a potential therapeutic approach. Different strategies have been developed to target this receptor including modification of PRL peptides (Del1-9-G129R-hPRL, G129R-Prl), growth hormone receptor/prolactin receptor bispecific antibody antagonist, neutralizing antibody LFA102, an antibody-drug conjugate (ABBV-176) of the humanized antibody h16f (PR-1594804) and pyrrolobenzodiazepine dimer, a bispecific antibody targeting both PRLR and CD3, an in vivo half-life extended fusion protein containing PRLR antagonist PrlRA and albumin binding domain. There have also been attempts to discover and develop small molecular inhibitors targeting PRLR. Recently, using structure-based virtual screening, we identified a few antipsychotic drugs including penfluridol as a molecule that inhibits PRL-signaling to inhibit PDAC tumor progression. In this review, we will summarize the recent advances in the biology of this receptor in cancer and give an account of PRLR antagonist development for the treatment of cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Standing, Dandawate and Anant.)

Aim: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide with a survival rate below fifty percent. Addressing meager therapeutic options, a series of small molecule inhibitors were screened for antitumor efficacy. The most potent analog, acryl-3,5-bis(2,4-difluorobenzylidene)-4-piperidone (DiFiD; A-DiFiD), demonstrated strong cellular JUN proto-oncogene, activator protein 1 (AP-1) transcription factor subunit (JUN, c-Jun) antagonism. c-Jun, an oncogenic transcription factor, promotes cancer progression, invasion, and adhesion; high ( JUN ) mRNA expression correlates with poorer HNSCC survival., Methods: Four new small molecules were generated for cytotoxicity screening in HNSCC cell lines. A-DiFiD-treated HNSCC cells were assessed for cytotoxicity, colony formation, invasion, migration, and adhesion. Dot blot array was used to identify targets. Phospho-c-Jun (p-c-Jun) expression was analyzed using immunoblotting. The Cancer Genome Atlas (TCGA) head and neck cancer datasets were utilized to determine overall patient survival. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) datasets interfaced with University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) were analyzed to determine protein levels of c-Jun in HNSCC patients and correlate levels with patient., Results: Of the small molecules tested, A-DiFiD was the most potent in HNSCC lines, while demonstrating low half-maximal drug inhibitory concentration (IC 50 ) in non-malignant Het-1A cells. Additionally, A-DiFiD abrogated cell invasion, migration, and colony formation. Phospho-kinase in vitro array demonstrated A-DiFiD reduced p-c-Jun. Likewise, a time dependent reduction in p-c-Jun was observed starting at 3 min post A-DiFiD treatment. TCGA Firehose Legacy vs. recurrent and metastatic head and neck cancer reveal a nearly 3% DNA amplification in recurrent/metastatic tumor compared to below 1% in primary tumors that had no lymph node metastasis. CPTAC analysis show higher tumor c-Jun levels compared to normal. Patients with high JUN expression had significantly reduced 3-year survival., Conclusions: A-DiFiD targets c-Jun, a clinical HNSCC driver, with potent anti-tumor effects., Competing Interests: The authors declare they have no conflicts of interest., (© The Author(s) 2023.)

The Arabidopsis thaliana aldehyde oxidase 3 (AAO3) catalyzes the oxidation of abscisic aldehyde (ABal) to abscisic acid (ABA). Besides ABal, plants generate other aldehydes that can be toxic above a certain threshold. AAO3 knockout mutants (aao3) exhibited earlier senescence but equivalent relative water content compared with wild-type (WT) during normal growth or upon application of UV-C irradiation. Aldehyde profiling in leaves of 24-day-old plants revealed higher accumulation of acrolein, crotonaldehyde, 3Z-hexenal, hexanal and acetaldehyde in aao3 mutants compared with WT leaves. Similarly, higher levels of acrolein, benzaldehyde, crotonaldehyde, propionaldehyde, trans-2-hexenal and acetaldehyde were accumulated in aao3 mutants upon UV-C irradiation. Aldehydes application to plants hastened profuse senescence symptoms and higher accumulation of aldehydes, such as acrolein, benzaldehyde and 4-hydroxy-2-nonenal, in aao3 mutant leaves as compared with WT. The senescence symptoms included greater decrease in chlorophyll content and increase in transcript expression of the early senescence marker genes, Senescence-Related-Gene1, Stay-Green-Protein2 as well as NAC-LIKE, ACTIVATED-BY AP3/P1. Notably, although aao3 had lower ABA content than WT, members of the ABA-responding genes SnRKs were expressed at similar levels in aao3 and WT. Moreover, the other ABA-deficient mutants [aba2 and 9-cis-poxycarotenoid dioxygenase3-2 (nced3-2), that has functional AAO3] exhibited similar aldehydes accumulation and chlorophyll content like WT under normal growth conditions or UV-C irradiation. These results indicate that the absence of AAO3 oxidation activity and not the lower ABA and its associated function is responsible for the earlier senescence symptoms in aao3 mutant., (© 2021 Society for Experimental Biology and John Wiley & Sons Ltd.)

Purine degradation products have been shown to play roles in plant response to stresses such as drought, salinity, extended dark, nitrogen deficiency, and pathogen infection. In this study, we used Arabidopsis wild-type (WT) and an Atxdh1-knockout mutant defective in xanthine dehydrogenase1 (XDH1) to examine the role of degraded purine metabolites in the responses to wounding or UV-C stress applied to the middle leaves of the plant. Wounding or UV-C stress in the mutant resulted in lower fresh-weight, increased senescence symptoms, and increased cell death compared to WT plants. In addition, WT plants exhibited lower levels of oxidative stress indicators, reactive oxygen species, and malondialdehyde in their leaves than the mutant. Notably, transcripts and proteins functioning in the purine degradation pathway were regulated in such a way that it led to enhanced ureide levels in WT leaves 24h after applying the UV-C or wound stress. However, different remobilization of the accumulated ureides was observed after 72h of stress. In plants treated with UV-C, the concentration of allantoin was highest in young leaves, whereas in wounded plants it was lowest in these leaves and instead accumulated mainly in the middle leaves that had been wounded. These results indicated that in WT plants treated with UV-C, ureides were remobilized from the lower older and damaged leaves to support young leaf growth during the recovery period from stress. After wounding, however, whilst some ureides were remobilized to the young leaves, more remained in the wounded middle leaves to function as antioxidants and/or healing agents., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Sarcocornia A. J. Scott is a halophytic edible succulent plant belonging to the Amaranthaceae family. To date, the genus includes 28 species distributed worldwide in saline environments, usually salt marshes. Sarcocornia (Scott) is similar to Salicornia (L.), which has a recognized commercial value in morphological and taxonomical traits. Species of both genera are commonly named samphire or glassworts in Europe, and their fleshy shoots are commercialized under their traditional names. Due to their nutritional, organoleptic and medicinal properties, Sarcocornia species have a high economic potential in various biotechnology sectors. Being highly tolerant to salt, they can be cultivated in saline conditions, and dissimilar to Salicornia , they are perennial, i.e., they can be harvested year-round. Therefore, Sarcocornia species are considered promising gourmet vegetables to be explored in the context of climate change, soil and water salinization and eco-sustainability. We hereby put together and reviewed the most relevant information on Sarcocornia taxonomy, morphology, nutritional and pharmacological properties, uses in ethnomedicine, potential applications in biotechnology, and propagation strategies.

Molybdenum cofactor containing sulfite oxidase (SO) enzyme is an important player in protecting plants against exogenous toxic sulfite. It was also demonstrated that SO activity is essential to cope with rising dark-induced endogenous sulfite levels and maintain optimal carbon and sulfur metabolism in tomato plants exposed to extended dark stress. The response of SO and sulfite reductase to direct exposure of low and high levels of sulfate and carbon was rarely shown. By employing Arabidopsis wild-type, sulfite reductase, and SO-modulated plants supplied with excess or limited carbon or sulfur supply, the current study demonstrates the important role of SO in carbon and sulfur metabolism. Application of low and excess sucrose, or sulfate levels, led to lower biomass accumulation rates, followed by enhanced sulfite accumulation in SO impaired mutant compared with wild-type. SO-impairment resulted in the channeling of sulfite to the sulfate reduction pathway, resulting in an overflow of organic S accumulation. In addition, sulfite enhancement was followed by oxidative stress contributing as well to the lower biomass accumulation in SO-modulated plants. These results indicate that the role of SO is not limited to protection against elevated sulfite toxicity but to maintaining optimal carbon and sulfur metabolism in Arabidopsis plants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Oshanova, Kurmanbayeva, Bekturova, Soltabayeva, Nurbekova, Standing, Dubey and Sagi.)

Ciclopirox (CPX) is an FDA-approved topical antifungal agent that has demonstrated preclinical anticancer activity in a number of solid and hematologic malignancies. Its clinical utility as an oral anticancer agent, however, is limited by poor oral bioavailability and gastrointestinal toxicity. Fosciclopirox, the phosphoryloxymethyl ester of CPX (Ciclopirox Prodrug, CPX-POM), selectively delivers the active metabolite, CPX, to the entire urinary tract following parenteral administration. We characterized the activity of CPX-POM and its major metabolites in in vitro and in vivo preclinical models of high-grade urothelial cancer. CPX inhibited cell proliferation, clonogenicity and spheroid formation, and increased cell cycle arrest at S and G0/G1 phases. Mechanistically, CPX suppressed activation of Notch signaling. Molecular modeling and cellular thermal shift assays demonstrated CPX binding to γ-secretase complex proteins Presenilin 1 and Nicastrin, which are essential for Notch activation. To establish in vivo preclinical proof of principle, we tested fosciclopirox in the validated N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) mouse bladder cancer model. Once-daily intraperitoneal administration of CPX-POM for four weeks at doses of 235 mg/kg and 470 mg/kg significantly decreased bladder weight, a surrogate for tumor volume, and resulted in a migration to lower stage tumors in CPX-POM treated animals. This was coupled with a reduction in the proliferation index. Additionally, there was a reduction in Presenilin 1 and Hes-1 expression in the bladder tissues of CPX-POM treated animals. Following the completion of the first-in-human Phase 1 trial (NCT03348514), the pharmacologic activity of fosciclopirox is currently being characterized in a Phase 1 expansion cohort study of muscle-invasive bladder cancer patients scheduled for cystectomy (NCT04608045) as well as a Phase 2 trial of newly diagnosed and recurrent urothelial cancer patients scheduled for transurethral resection of bladder tumors (NCT04525131).

Background & Aims: Prolactin (PRL) signaling is up-regulated in hormone-responsive cancers. The PRL receptor (PRLR) is a class I cytokine receptor that signals via the Janus kinase (JAK)-signal transducer and activator of transcription and mitogen-activated protein kinase pathways to regulate cell proliferation, migration, stem cell features, and apoptosis. Patients with pancreatic ductal adenocarcinoma (PDAC) have high plasma levels of PRL. We investigated whether PRLR signaling contributes to the growth of pancreatic tumors in mice., Methods: We used immunohistochemical analyses to compare levels of PRL and PRLR in multitumor tissue microarrays. We used structure-based virtual screening and fragment-based drug discovery to identify compounds likely to bind PRLR and interfere with its signaling. Human pancreatic cell lines (AsPC-1, BxPC-3, Panc-1, and MiaPaCa-2), with or without knockdown of PRLR (clustered regularly interspaced short palindromic repeats or small hairpin RNA), were incubated with PRL or penfluridol and analyzed in proliferation and spheroid formation. C57BL/6 mice were given injections of UNKC-6141 cells, with or without knockdown of PRLR, into pancreas, and tumor development was monitored for 4 weeks, with some mice receiving penfluridol treatment for 21 days. Human pancreatic tumor tissues were implanted into interscapular fat pads of NSG mice, and mice were given injections of penfluridol daily for 28 days. Nude mice were given injections of Panc-1 cells, xenograft tumors were grown for 2 weeks, and mice were then given intraperitoneal penfluridol for 35 days. Tumors were collected from mice and analyzed by histology, immunohistochemistry, and immunoblots., Results: Levels of PRLR were increased in PDAC compared with nontumor pancreatic tissues. Incubation of pancreatic cell lines with PRL activated signaling via JAK2-signal transducer and activator of transcription 3 and extracellular signal-regulated kinase, as well as formation of pancospheres and cell migration; these activities were not observed in cells with PRLR knockdown. Pancreatic cancer cells with PRLR knockdown formed significantly smaller tumors in mice. We identified several diphenylbutylpiperidine-class antipsychotic drugs as agents that decreased PRL-induced JAK2 signaling; incubation of pancreatic cancer cells with these compounds reduced their proliferation and formation of panco spheres. Injections of 1 of these compounds, penfluridol, slowed the growth of xenograft tumors in the different mouse models, reducing proliferation and inducing autophagy of the tumor cells., Conclusions: Levels of PRLR are increased in PDAC, and exposure to PRL increases proliferation and migration of pancreatic cancer cells. Antipsychotic drugs, such as penfluridol, block PRL signaling in pancreatic cancer cells to reduce their proliferation, induce autophagy, and slow the growth of xenograft tumors in mice. These drugs might be tested in patients with PDAC., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Cancer stem cells (CSCs) have the ability to self-renew and induce drug resistance and recurrence in colorectal cancer (CRC). As current chemotherapy doesn't eliminate CSCs completely, there is a need to identify novel agents to target them. We investigated the effects of cucurbitacin B (C-B) or I (C-I), a natural compound that exists in edible plants (bitter melons, cucumbers, pumpkins and zucchini), against CRC. C-B or C-I inhibited proliferation, clonogenicity, induced G 2 /M cell-cycle arrest and caspase-mediated-apoptosis of CRC cells. C-B or C-I suppressed colonosphere formation and inhibited expression of CD44, DCLK1 and LGR5. These compounds inhibited notch signaling by reducing the expression of Notch 1-4 receptors, their ligands (Jagged 1-2, DLL1,3,4), γ-secretase complex proteins (Presenilin 1, Nicastrin), and downstream target Hes-1. Molecular docking showed that C-B or C-I binds to the ankyrin domain of Notch receptor, which was confirmed using the cellular thermal shift assay. Finally, C-B or C-I inhibited tumor xenograft growth in nude mice and decreased the expression of CSC-markers and notch signaling proteins in tumor tissues. Together, our study suggests that C-B and C-I inhibit colon cancer growth by inhibiting Notch signaling pathway.

Background & Aims: The histone lysine demethylase 3A (KDM3A) demethylates H3K9me1 and H3K9Me2 to increase gene transcription and is upregulated in tumors, including pancreatic tumors. We investigated its activities in pancreatic cancer cell lines and its regulation of the gene encoding doublecortin calmodulin-like kinase 1 (DCLK1), a marker of cancer stem cells., Methods: We knocked down KDM3A in MiaPaCa-2 and S2-007 pancreatic cancer cell lines and overexpressed KDM3A in HPNE cells (human noncancerous pancreatic ductal cell line); we evaluated cell migration, invasion, and spheroid formation under hypoxic and normoxic conditions. Nude mice were given orthotopic injections of S2-007 cells, with or without (control) knockdown of KDM3A, and HPNE cells, with or without (control) overexpression of KDM3A; tumor growth was assessed. We analyzed pancreatic tumor tissues from mice and pancreatic cancer cell lines by immunohistochemistry and immunoblotting. We performed RNA-sequencing analysis of MiaPaCa-2 and S2-007 cells with knockdown of KDM3A and evaluated localization of DCLK1 and KDM3A by immunofluorescence. We analyzed the cancer genome atlas for levels of KDM3A and DCLK1 messenger RNA in human pancreatic ductal adenocarcinoma (PDAC) tissues and association with patient survival time., Results: Levels of KDM3A were increased in human pancreatic tumor tissues and cell lines, compared with adjacent nontumor pancreatic tissues, such as islet and acinar cells. Knockdown of KDM3A in S2-007 cells significantly reduced colony formation, invasion, migration, and spheroid formation, compared with control cells, and slowed growth of orthotopic tumors in mice. We identified KDM3A-binding sites in the DCLK1 promoter; S2-007 cells with knockdown of KDM3A had reduced levels of DCLK1. HPNE cells that overexpressed KDM3A formed foci and spheres in culture and formed tumors and metastases in mice, whereas control HPNE cells did not. Hypoxia induced sphere formation and increased levels of KDM3A in S2-007 cells and in HPNE cells that overexpressed DCLK1, but not control HPNE cells. Levels of KDM3A and DCLK1 messenger RNA were higher in human PDAC than nontumor pancreatic tissues and correlated with shorter survival times of patients., Conclusions: We found human PDAC samples and pancreatic cancer cell lines to overexpress KDM3A. KDM3A increases expression of DCLK1, and levels of both proteins are increased in human PDAC samples. Knockdown of KDM3A in pancreatic cancer cell lines reduced their invasive and sphere-forming activities in culture and formation of orthotopic tumors in mice. Hypoxia increased expression of KDM3A in pancreatic cancer cells. Strategies to disrupt this pathway might be developed for treatment of pancreatic cancer., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

We previously reported that ionizing radiation (IR) mediates cell death through the induction of CUGBP elav-like family member 2 (CELF2), a tumor suppressor. CELF2 is an RNA binding protein that modulates mRNA stability and translation. Since IR induces autophagy, we hypothesized that CELF2 regulates autophagy-mediated colorectal cancer (CRC) cell death. For clinical relevance, we determined CELF2 levels in The Cancer Genome Atlas (TCGA). Role of CELF2 in radiation response was carried out in CRC cell lines by immunoblotting, immunofluorescence, autophagic vacuole analyses, RNA stability assay, quantitative polymerase chain reaction and electron microscopy. In vivo studies were performed in a xenograft tumor model. TCGA analyses demonstrated that compared to normal tissue, CELF2 is expressed at significantly lower levels in CRC, and is associated with better overall 5-year survival in patients receiving radiation. Mechanistically, CELF2 increased levels of critical components of the autophagy cascade including Beclin-1, ATG5, and ATG12 by modulating mRNA stability. CELF2 also increased autophagic flux in CRC. IR significantly induced autophagy in CRC which correlates with increased levels of CELF2 and autophagy associated proteins. Silencing CELF2 with siRNA, mitigated IR induced autophagy. Moreover, knockdown of CELF2 in vivo conferred tumor resistance to IR. These studies elucidate an unrecognized role for CELF2 in inducing autophagy and potentiating the effects of radiotherapy in CRC., (© 2019 Wiley Periodicals, Inc.)

In this review, we untangle the physiological key functions of the essential micronutrients and link them to the deficiency responses in plants. Knowledge of these responses at the mechanistic level, and the resulting deficiency symptoms, have improved over the last decade and it appears timely to review recent insights for each of them. A proper understanding of the links between function and symptom is indispensable for an accurate and timely identification of nutritional disorders, thereby informing the design and development of sustainable fertilization strategies. Similarly, improved knowledge of the molecular and physiological functions of micronutrients will be important for breeding programmes aiming to develop new crop genotypes with improved nutrient-use efficiency and resilience in the face of changing soil and climate conditions., (© 2024 The Authors. New Phytologist © 2024 New Phytologist Foundation.)

In response to oxidative stress the biosynthesis of the ROS scavenger, glutathione is induced. This requires the induction of the sulfate reduction pathway for an adequate supply of cysteine, the precursor for glutathione. Cysteine also acts as the sulfur donor for the sulfuration of the molybdenum cofactor, crucial for the last step of ABA biosynthesis. Sulfate and sulfite are, respectively, the precursor and intermediate for cysteine biosynthesis and there is evidence for stress-induced sulfate uptake and further downstream, enhanced sulfite generation by 5'-phosphosulfate (APS) reductase (APR, EC 1.8.99.2) activity. Sulfite reductase (SiR, E.C.1.8.7.1) protects the chloroplast against toxic levels of sulfite by reducing it to sulfide. In case of sulfite accumulation as a result of air pollution or stress-induced premature senescence, such as in extended darkness, sulfite can be oxidized to sulfate by sulfite oxidase. Additionally sulfite can be catalyzed to thiosulfate by sulfurtransferases or to UDP-sulfoquinovose by SQD1, being the first step toward sulfolipid biosynthesis.Determination of total sulfur in plants can be accomplished using many techniques such as ICP-AES, high-frequency induction furnace, high performance ion chromatography, sulfur combustion analysis, and colorimetric titration. Here we describe a total sulfur detection method in plants by elemental analyzer (EA). The used EA method is simple, sensitive, and accurate, and can be applied for the determination of total S content in plants.Sulfate anions in the soil are the main source of sulfur, required for normal growth and development, of plants. Plants take up sulfate ions from the soil, which are then reduced and incorporated into organic matter. Plant sulfate content can be determined by ion chromatography with carbonate eluents.Sulfite is an intermediate in the reductive assimilation of sulfate to the essential amino acids cysteine and methionine, and is cytotoxic above a certain threshold if not rapidly metabolized and can wreak havoc at the cellular and whole plant levels. Plant sulfite content affects carbon and nitrogen homeostasis Therefore, methods capable of determining sulfite levels in plants are of major importance. Here we present two robust laboratory protocols which can be used for sulfite detection in plants.Thiosulfate is an essential sulfur intermediate less toxic than sulfite which is accumulating in plants in response to sulfite accumulation. The complexity of thiosulfate detection is linked to its chemical properties. Here we present a rapid, sensitive, and accurate colorimetric method based on the enzymatic conversion of thiosulfate to thiocyanate.The plant sulfolipid sulfoquinovosyldiacylglycerol (SQDG) accounts for a large fraction of organic sulfur in the biosphere. Aside from sulfur amino acids, SQDG represents a considerable sink for sulfate in plants and is the only sulfur-containing anionic glycerolipid that is found in the photosynthetic membranes of plastids. We present the separation of sulfolipids from other fatty acids in two simple ways: by one- and two-dimensional thin-layer chromatography.

The amino acid cysteine plays a major role in plant response to abiotic stress by being the donor of elemental sulfur for the sulfuration of the molybdenum cofactor, otherwise the last step of ABA biosynthesis, the oxidation of abscisic aldehyde, is inactivated. Additionally, cysteine serves as a precursor for the biosynthesis of glutathione, the reactive oxygen species scavenger essential for redox status homeostasis during stress. Cysteine is generated by the sulfate reductive pathway where sulfite oxidase (SO; EC 1.8.3.1) is an important enzyme in the homeostasis of sulfite levels (present either as a toxic intermediate in the pathway or as a toxic air pollutant that has penetrated the plant tissue via the stomata). SO is localized to the peroxisomes and detoxifies excess sulfite by catalyzing its oxidation to sulfate. Here we show a kinetic assay that relies on fuchsin colorimetric detection of sulfite, a substrate of SO activity. This SO assay is highly specific, technically simple, and readily performed in any laboratory.5'-adenylylsulfate (APS) reductase (APR, E.C. 1.8.4.9) enzyme regulates a crucial step of sulfate assimilation in plants, algae and some human pathogens. The enzyme is upregulated in response to oxidative stress induced by abiotic stresses, such as salinity and hydrogen peroxide, to generate sulfite an intermediate for cysteine generation essential for the biosynthesis of glutathione, the hydrogen peroxide scavenger. Here we present two robust, sensitive, and simple colorimetric methods of APR activity based on sulfite determination by fuchsin.Sulfite reductase (SiR) is one of the key enzymes in the primary sulfur assimilation pathway. It has been shown that SiR is an important plant enzyme for protection plant against sulfite toxicity and premature senescence. Here we describe two methods for SiR activity determination: a kinetic assay using desalted extract and an in-gel assay using crude extract.Due to the energetically favorable equilibrium, sulfurtransferase (ST) activity measured as sulfite generation or consumption. Sulfite-generating ST activity is determined by colorimetric detection of SCN - formation at 460 nm as the red Fe(SCN) 3 complex from cyanide and thiosulfate using acidic iron reagent. Sulfite-consuming (MST) activity is detected as sulfite disappearance in the presence of thiocyanate (SCN - ) or as SCN - disappearance. To abrogate interfering SO activity, total ST activities is detected by inhibiting SO activity with tungstate.

Purpose The purpose of this study was to assess the information literacy proficiency of transfer students. This assessment of skills was undertaken to improve the services provided to transfer students in academic libraries, with a particular focus on information literacy instruction.Design/methodology/approach The Project Standardized Assessment of Information Literacy Skills (SAILS) test was administered to assess the information literacy proficiency of a cohort of undergraduate students taking courses on two regional campuses of a four-year institution. In total, 114 students participated, and SAILS test scores were compared to several demographic characteristics using one-way and two-way analysis of variance (ANOVA).Findings Results showed that undergraduate students generally lack information literacy skills, even at the junior and senior levels. Previous library instruction had a positive impact on scores for two of the Association of College and Research Libraries information literacy standards, suggesting that library instruction programs can be effective at improving these skills. When examining performance across the board on the various information literacy skills, there was no significant difference between transfer and native students in this result set.Research limitations/implications This study had a limited sample size, and only tested students taking courses from two regional campus locations. Follow-up studies could broaden the scope to include main campus transfer students to form a larger sample size.Originality/value It was difficult to find original research within the library literature that directly addressed information literacy skills in a mixed population of transfer and native students. Further research in this area can serve to improve the services offered to all students within academic libraries. [ABSTRACT FROM AUTHOR]

PURPOSE: To investigate the effects of robot-assisted gait training (RAGT) alongside conventional therapy on the standing and walking abilities of children with cerebral palsy (CP). METHODS: The study sample consisted of children (aged 4–18 years) with CP whose gross motor function classification system (GMFCS) was at levels I–V. In total, 75 children with CP were evaluated and 38 patients completed the study. Patients were divided into two groups as GMFCS levels I–III (Group 1) and levels IV–V (Group 2). RAGT (30 min/session) and conventional physiotherapy (30 min/session) were applied together in the treatment. The treatment duration was 60 min per session, 3 or 4 sessions per week, for a total of 30 sessions over 8–10 weeks. 10-meter walk test (10MWT), 6-min walk test (6MinWT), gross motor functional measurement 66 (GMFM66) -D, and -E tests were performed. RESULTS: We showed that in both groups of CP patients (mild-moderate and severe), meaningful improvements were seen in the standing (D) and walking (E) sections of GMFM-66 after treatment. When we compared the post-treatment changes in 10-m walk test, 6-min walk test, GMFM66-D, and -E between Groups 1 and 2, we noted that the improvements were statistically significant in favor of Group 1 (p < 0.01). CONCLUSION: RAGT in combination with a conventional treatment program was significantly associated with improvements in the standing and walking abilities of children with mild to moderate CP (GMFCS levels I–III). [ABSTRACT FROM AUTHOR]

Measurement of intracellular calcium release following agonist challenge within cells expressing the relevant membrane protein is a commonly used format to derive structure-activity relationship (SAR) data within a compound profiling assay. The Fluorometric Imaging Plate Reader (FLIPR) has become the gold standard for this purpose. FLIPR traditionally uses cells that are maintained in continuous culture for compound profiling of iterative chemistry campaigns. This supply dictates that assays can only be run on 4 of 5 weekdays, or alternative cell culture machinery is required such that plating can occur remotely at the weekend. The data reported here demonstrate that high-quality compound profiling data can be generated from the use of cryopreserved cells and that these cells can also be plated at various densities to generate equivalent data between 24 and 72 h post-plating. Hence, the authors report a method that allows data generation throughout the week and without the requirement of highly automated cell culture or continuous culture. [ABSTRACT FROM AUTHOR]

Abstract: Hippocampal α-Ca2+/calmodulin-dependent protein kinase II (α-CaMKII) has been implicated in spatial learning, neuronal plasticity, epilepsy, and cerebral ischemia. In the present study, an adeno-associated virus (AAV) vector was designed to express green fluorescent protein (GFP) from the CBA promoter and a small hairpin RNA targeting α-CaMKII (AAV-shCAM) driven from the U6 promoter. The AAV-shCAM or control vector was microinfused into the rat hippocampus and behavioral testing conducted 19–26 days following surgery. Expression of the marker gene and α-CaMKII was evaluated 31 days following AAV infusion. GFP expression was localized to the hippocampus and extended ±2 mm rostral and caudal from the injection site. Hippocampal α-CaMKII was significantly reduced following AAV-shCAM treatment as demonstrated using immunohistochemical and Western analysis. This suppression of α-CaMKII was associated with changes in exploratory behavior (open field task) and impaired place learning (water maze task). These results demonstrate the efficacy of a viral-based delivered shRNA to produce gene suppression in a specific circuit of the brain. [Copyright &y& Elsevier]

Melanoma is an aggressive disease with limited therapeutic options. Here, we determined the effects of honokiol (HNK), a biphenolic natural compound on melanoma cells and stemness. HNK significantly inhibited melanoma cell proliferation, viability, clonogenicity and induced autophagy. In addition, HNK significantly inhibited melanosphere formation in a dose dependent manner. Western blot analyses also demonstrated reduction in stem cell markers CD271, CD166, Jarid1b, and ABCB5. We next examined the effect of HNK on Notch signaling, a pathway involved in stem cell self-renewal. Four different Notch receptors exist in cells, which when cleaved by a series of enzymatic reactions catalyzed by Tumor Necrosis Factor-α-Converting Enzyme (TACE) and γ-secretase protein complex, results in the release of the Notch intracellular domain (NICD), which then translocates to the nucleus and induces target gene expression. Western blot analyses demonstrated that in HNK treated cells there is a significant reduction in the expression of cleaved Notch-2. In addition, there was a reduction in the expression of downstream target proteins, Hes-1 and cyclin D1. Moreover, HNK treatment suppressed the expression of TACE and γ-secretase complex proteins in melanoma cells. To confirm that suppression of Notch-2 activation is critical for HNK activity, we overexpressed NICD1, NICD2, and performed HNK treatment. NICD2, but not NICD1, partially restored the expression of Hes-1 and cyclin D1, and increased melanosphere formation. Taken together, these data suggest that HNK is a potent inhibitor of melanoma cells, in part, through the targeting of melanoma stem cells by suppressing Notch-2 signaling., (© 2014 Wiley Periodicals, Inc.)

More than half of patients with lower-limb amputation who use socket prostheses experience at least one fall annually. These falls are primarily attributed to reduced proprioception which negatively affects balance. A promising alternative to socket prostheses are osseointegrated prostheses that involve direct fixation of the prosthetic limb to the residual limb through a bone-anchored implant, yet its effect on balance remains unknown. Do osseointegrated prostheses change static and dynamic balance, as well as patient reported measures of balance confidence, compared to a socket prosthesis? A sample of 10 patients with unilateral transfemoral amputation scheduled to undergo prosthesis osseointegration were enrolled (6 F/4 M, BMI: 26.7 ± 2.9 kg/m2, Age: 46.1 ± 6.3 years). Motion capture data during quiet standing (eyes opened and eyes closed) and overground walking at a self-selected speed, and the Activities-Specific Balance Confidence (ABC) scale, were collected before (with socket prosthesis) and 12-months following osseointegration. Postural sway via the center of pressure (COP), variability of spatiotemporal parameters, and ABC scores were compared using a repeated measures design before and after osseointegration. Following prosthesis osseointegration, COP path length and 95 % confidence ellipse area were reduced during quiet standing (d = 0.75, P = 0.09; d = 0.52, P = 0.29, respectively) and the variability of step width and length were reduced during overground walking (d = 0.50, P = 0.06; d = 0.72, P = 0.06, respectively). Furthermore, patients reported significantly improved ABC scores with an osseointegrated prosthesis compared to a socket prosthesis (d = −1.36, P = 0.01). Improvements in postural sway, reductions in gait variability, and greater balance confidence indicate that osseointegrated prostheses improve balance for people with unilateral transfemoral amputation. • Osseointegrated prostheses directly attach prosthesis to residual limb. • Osseointegrated prostheses improve static/dynamic balance and balance confidence. • Balance improvements may indicate osseointegrated prostheses reduce fall risk. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) involves complex pathological mechanisms. Secretases include membrane protein extracellular structural domain proteases and intramembrane proteases that cleave the topology to type I or type II. Secretases can effectively regulate the activation of Notch and amyloid precursor protein (APP), key factors in the progression of AD and cancer. This article systematically summarizes the intracellular localization, cleavage sites and products, and biological functions of six subtypes of secretases (α-secretase, β-secretase, γ-secretase, δ-secretase, ε-secretase, and η-secretase), and for the first time, elucidates the commonalities and differences between these subtypes of secretases. We found that each subtype of secretase primarily cleaves APP and Notch as substrates, regulating Aβ levels through APP cleavage to impact the progression of AD, while also cleaving Notch receptors to affect cancer progression. Finally, we review the chemical structures, indications, and research stages of various secretase inhibitors, emphasizing the promising development of secretase inhibitors in the fields of cancer and AD. [ABSTRACT FROM AUTHOR]

This paper presents the field monitoring during construction of the Green Heart Tunnel driven by a slurry tunnel boring machine (TBM) in a semiconfined aquifer in which a sand layer was overlaid by a peat layer. Data analyses of the pore-water pressures, slurry pressures, tail-void grout pressures, and ground movements surrounding the tunnel are presented. It was found that the slurry infiltration controls the variation of pore-water pressure only close to the tunnel face. The excess pore-water pressure far from the tunnel face was induced by the elastic storage of the aquifer. It was found that the grouting had little influence on the pore-pressure distribution. Furthermore, because the excess pore-water pressure generated by slurry infiltration might contribute to the grout pressure, the measured value of grout pressure can be smaller than the actual value. Consequently, to obtain the actual value of grout pressure, grout-pressure gauges combined with the pore-pressure transducers should be installed. In the semiconfined aquifer, suction in the overlying peat layer could be induced when the TBM passed through the sand layer. For this condition, the ground movement proportionally increased with the decreasing water pressure. [ABSTRACT FROM AUTHOR]

Background: Recent research has found that strengthening hip joint stability can considerably affect foot mechanics. The purpose of this study was to determine the effect of short foot exercises (SFEs), combined exercises (CEs), and SFEs with isometric hip abduction (IHA) on navicular drop (ND), static parameters (SP), and postural sway in women with flat foot (FF). Methods: This study recruited 45 women with flexible FF. The participants were divided into three groups: the CEs group, who performed a series of strengthening, stretching, and balancing exercises, the SFEs group, and the SFEs with IHA group. The groups carried out their assigned regimens daily for six weeks. ND, SP, and postural sway (center of pressure (CoP) parameters) were measured using the ND test and pedoscan device. The data was analysed using a repeated-measures ANOVA statistical test (p≤0.05). Results: The results showed that all three groups decreased in ND, surface, and foot rotation in the post-test compared to the pre-test (P < 0.05). No difference was observed in the maximum pressure (P = 0.616) and anteroposterior fluctuations (P = 0.065) of the CEs group. Both SFEs and SFEs with IHA groups showed a reduction in all CoP parameters. When comparing the ND (P = 0.22) and mediolateral sway (P = 0.035) of the SFEs with IHA group, a significant difference was observed compared to the CEs group. Additionally, the SFEs with IHA group had a higher percentage of changes in all variables compared to the other two groups. Conclusions: SFEs with IHA appear more effective than other training methods in reducing ND and decreasing CoP oscillations and stance parameters. Future studies should investigate the long-term effect of this exercise protocol. Trial registration: Name of the registry: Iranian Registry of Clinical Trials. Trial registration number: IRCT20220409054456N. Date of registration: 28/09/2022. URL of trial registry record: https://fa.irct.ir/trial/63065. [ABSTRACT FROM AUTHOR]

Plants cultivated on the Qinghai-Tibet Plateau (QTP) are exposed to high ultraviolet radiation intensities, so they require effective mechanisms to adapt to these stress conditions. UV-B radiation is an abiotic stress factor that affects plant growth, development, and environmental adaptation. Elymus sibiricus is a common species in the alpine meadows of the QTP, with high-stress resistance, large biomass, and high nutritional value. This species plays an important role in establishing artificial grasslands and improving degraded grasslands. In this study, UV-B radiation-tolerant and UV-B radiation-sensitive E. sibiricus genotypes were subjected to simulated short-term (5 days, 10 days) and long-term (15 days, 20 days) UV-B radiation stress and the metabolite profiles evaluated to explore the mechanism underlying UV-B radiation resistance in E. sibiricus. A total of 699 metabolites were identified, including 11 primary metabolites such as lipids and lipid-like molecules, phenylpropanoids and polyketides, organic acids and their derivatives, and organic oxygen compounds. Principal component analysis distinctly clustered the samples according to the cultivar, indicating that the two genotypes exhibit distinct response mechanisms to UV-B radiation stress. The results showed that 14 metabolites, including linoleic acid, LPC 18:2, xanthosine, and 23 metabolites, including 2-one heptamethoxyflavone, glycyrrhizin, and caffeic acid were differentially expressed under short-term and long-term UV-B radiation stress, respectively. Therefore, these compounds are potential biomarkers for evaluating E. sibiricus response to UV-B radiation stress. Allantoin specific and consistent expression was up-regulated in the UV-B radiation-tolerant genotype, thereby it can be used to identify varieties resistant to UV-B radiation. Different metabolic profiles and UV-B radiation response mechanisms were observed between the UV-B radiation-tolerant and UV-B radiation-sensitive E. sibiricus genotypes. A model for the metabolic pathways and metabolic profiles was constructed for the two genotypes. This metabolomic study on the E. sibiricus response to UV-B radiation stress provides a reference for the breeding of new UV-B radiation-tolerant E. sibiricus cultivars. [ABSTRACT FROM AUTHOR]

Nitrous oxide (N2O) ranks as the third most significant greenhouse gas, capable of depleting the ozone layer and posing threats to terrestrial ecosystems. Climate change alters precipitation variability, notably in terms of frequency and magnitude. However, the implications of precipitation variability on N2O emissions and the underlying mechanisms remain inadequately understood. In this study, employing laboratory incubation methods on three representative sandy soil types (sandy soil, shrub soil, and crust soil), we examined the impacts of diverse precipitation levels (5 mm and 10 mm) and frequencies (7 days and 14 days) on N2O emissions from these soil types. This study aims to clarify the complex connections between soil N2O emission fluxes and soil physicochemical properties in the soil environment. Our findings reveal that the N2O emission flux exhibits heightened responsiveness to 5 mm precipitation events and a 14-day precipitation frequency, and compared to other treatments, the 5 mm precipitation and 14-day precipitation frequency treatment resulted in a 20% increase in cumulative nitrous oxide emissions. Consequently, cumulative N2O emissions were notably elevated under the 5 mm precipitation and 14-day precipitation frequency treatments compared to the other experimental conditions. The N2O emission flux in sandy soil displayed a positive correlation with available phosphorus (AP) and a negative correlation with pH, primarily attributed to the exceedingly low AP content in sandy soil. In shrub soil, the soil N2O emission flux exhibited a significant positive correlation with NH4+-N and a negative correlation with NO3−-N. Conversely, no significant correlations were observed between soil N2O emission flux and soil physicochemical properties in crust soil, underscoring the importance of considering plant–soil microbial interactions. Our findings suggest that soil nitrous oxide emissions in arid and semi-arid regions will be particularly responsive to small and frequent rainfall events as precipitation patterns change in the future, primarily due to their soil physicochemical characteristics. [ABSTRACT FROM AUTHOR]

The success of immunotherapy for cancer treatment is limited by the presence of an immunosuppressive tumor microenvironment (TME); Therefore, identifying novel targets to that can reverse this immunosuppressive TME and enhance immunotherapy efficacy is essential. In this study, enrichment analysis based on publicly available single‐cell and bulk RNA sequencing data from gastric cancer patients are conducted, and found that tumor‐intrinsic interferon (IFN) plays a central role in TME regulation. The results shows that KDM3A over‐expression suppresses the tumor‐intrinsic IFN response and inhibits KDM3A, either genomically or pharmacologically, which effectively promotes IFN responses by activating endogenous retroviruses (ERVs). KDM3A ablation reconfigures the dsRNA‐MAVS‐IFN axis by modulating H3K4me2, enhancing the infiltration and function of CD8 T cells, and simultaneously reducing the presence of regulatory T cells, resulting in a reshaped TME in vivo. In addition, combining anti‐PD1 therapy with KDM3A inhibition effectively inhibited tumor growth. In conclusions, this study highlights KDM3A as a potential target for TME remodeling and the enhancement of antitumor immunity in gastric cancer through the regulation of the ERV‐MAVS‐IFN axis. [ABSTRACT FROM AUTHOR]

Halophytes, such as Salicornia species, are promising new foods and are consumed for their pleasant salty taste and nutritional value. Since Salicornia is perishable, modified atmospheric packaging (MAP) can be a useful tool, in combination with proper temperature, to halt further quality degradation in this type of product. The purpose of this study was to investigate the effect of MAP, with or without refrigeration, to extend the shelf life of glasswort (Salicornia europaea L.) grown hydroponically (floating raft system) in a greenhouse with a nutrient solution containing 0 g/L (C) or 12.5 g/L of NaCl (T). The dry matter content, weight loss, respiration rate, biochemical composition, color, antioxidant capacity, and sensorial attributes were determined in shoots after harvest and during storage in plastic bags filled with technical air or with MAP at 4 or 20 °C for 120 h. At harvest, plants supplied with salt-enriched solution (T) showed a significant improvement in nutritional value and sensory profile. Storage in air at room temperature (20 °C) accelerated weight loss and diminished color stability, particularly in non-salinity samples (C), while MAP extended the shelf life of all the samples regardless of the storage temperature adopted. Optimal storage conditions were observed when MAP was combined with refrigeration, which allowed to effectively preserve shoots sensory acceptability for a period of about seven days. Future research could further explore the long-term effects on the nutritional value and sensory quality of S. europaea under various combinations of MAP and different storage temperatures ranging between 4 °C and 20 °C. [ABSTRACT FROM AUTHOR]