Repression Of Activity Research Articles

VvMYBA1 and VvMYB3 form an activator–repressor system to regulate anthocyanin biosynthesis in grape

Anthocyanins are important metabolites that provide a red or blue–purple hue to plants. The biosynthesis of these metabolites is mainly activated by the MYB-bHLH-WD40 (MBW) complex and repressed by a wide variety of proteins. Studies have shown that MYB activators activate MYB repressors to balance anthocyanin biosynthesis. However, there is a scarcity of studies investigating this mechanism in grapes. To explore the transcription factors involved in the regulation of anthocyanin biosynthesis, we reanalyzed the RNA-seq database for different developmental stages of ‘Muscat Hamburg’ berries, and the R2R3-MYB gene, annotated as VvMYB3, was screened. Our study revealed the anthocyanin content of the grape cultivar ‘Y73’ was higher than that of its parental cultivar MH, and the putative repressor VvMYB3 was found to be highly expressed in ‘Y73’ by qRT-PCR. The calli transgenic assays demonstrated that the repressive activity of VvMYB3 was conferred by the bHLH-binding motif, as well as by the C1 and C2 motifs. Yeast hybridization and chip-PCR assays revealed that VvMYB3 could repress anthocyanin biosynthesis by competing with VvMYBA1 to bind to VvMYC1 and promoting histone deacetylation of VvUFGT via the C2 motif. However, the expression of VvMYB3 was activated by VvMYBA1, which forms a negative feedback regulatory loop to modulate anthocyanin accumulation. In addition, we found a 408-bp repeat tandem sequence insertion in the VvMYBA1 promoter region of ‘Y73’ by sequencing. The GUS activity analysis showed that this sequence enhanced the expression of VvMYBA1 and led to an excessive accumulation of anthocyanins. Overall, our results provide insights into the anthocyanin activator–repressor system in grapes that prevents overaccumulation of anthocyanins.

Analysis of R2R3-MYB Repressor Subfamily Identifies FcMYB57 as a Negative Regulator of Anthocyanin Biosynthesis in Ficus carica L. Fruit

Dry fig is a traditional healthy snack and has important economic value in a number of Mediterranean and Middle Eastern countries. Cultivars with no anthocyanin accumulation in the fruit peel are preferred for dry fig production. R2R3-MYB transcription factors have promotive or repressive regulatory roles in plant anthocyanin biosynthesis. In this study, 113 R2R3-MYB genes were identified in Ficus carica, 3 of which were assigned to the S4 subfamily of flavonoid-biosynthesis repressors. FcMYB57 was further recruited as a candidate anthocyanin-biosynthesis repressor based on its sequence features and expression, which was significantly negatively correlated with that of anthocyanin-biosynthesis structural genes. Transient overexpression of FcMYB57 in strawberry totally inhibited fruit pigmentation and significantly increased fruit firmness. The metabolomic analysis confirmed a significant reduction in the contents of cyanidin-3-O-glucoside and pelargonidin-3-O-glucoside, as well as other flavonoids, and transmission electron microscopy revealed an increment in cell-wall thickness. Transcriptome analysis showed downregulation of anthocyanin-biosynthesis structural genes and upregulation of genes related to xylan synthesis. Yeast one-hybrid and dual luciferase assays demonstrated a negative regulatory effect of FcMYB57 on the promoter of FcUFGT3 (UDP glucose-flavonoid 3-O-glcosyl-transferase). Yeast two-hybrid assay showed that FcMYB57 does not interact with FcbHLH42, 3, 14, MYC2, or FcTTG1, all of which have a previously identified or predicted role in flavonoid biosynthesis, however, interaction was detected with FcTPL (Topless), suggesting that FcMYB57 serves as an active repressor of anthocyanin biosynthesis. This is the first identification of an anthocyanin-biosynthesis repressor in fig, with a possible role in fig fruit quality.

Integrated Dual-Channel Retrograde Signaling Directs Stress Responses by Degrading the HAT1/TPL/IMPα-9 Suppressor Complex and Activating CAMTA3.

This study uncovers how the stress-induced signaling metabolite MEcPP disrupts the HAT1/TPL/IMPα-9 suppressor complex, liberating the activator CAMTA3 and enabling Ca 2+ influx essential for CAMTA3 activation, thus orchestrating stress responses via repressor degradation and activator induction.

HOS15-mediated turnover of PRR7 enhances freezing tolerance.

Arabidopsis PSEUDORESPONSE REGULATOR7 (PRR7) is a core component of the circadian oscillator which also plays a crucial role in freezing tolerance. PRR7 undergoes proteasome-dependent degradation to discretely phase maximal expression in early evening. While its repressive activity on downstream genes is integral to cold regulation, the mechanism of the conditional regulation of the PRR7 abundance is unknown. We used mutant analysis, protein interaction and ubiquitylation assays to establish that the ubiquitin ligase adaptor, HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENE 15 (HOS15), controls the protein accumulation pattern of PRR7 through direct protein-protein interactions at low temperatures. Freezing tolerance and electrolyte leakage assays show that PRR7 enhances cold temperature sensitivity, supported by ChIP-qPCR at C-REPEAT BINDING FACTOR1 (CBF1) and COLD-REGULATED 15A (COR15A) promoters where PRR7 levels were higher in hos15 mutants. HOS15 mediates PRR7 turnover through enhanced ubiquitylation at low temperature in the dark. Under the same conditions, increased PRR7 association with the promoters of CBFs and COR15A in hos15 correlates with decreased CBF1 and COR15A transcription and enhanced freezing sensitivity. We propose a novel mechanism whereby HOS15-mediated degradation of PRR7 provides an intersection between the circadian system and other cold acclimation pathways that lead to increased freezing tolerance.

Gene network analysis combined with preclinical studies to identify and elucidate the mechanism of action of novel irreversible Keap1 inhibitor for Parkinson's disease.

The cysteine residues of Keap1 such as C151, C273, and C288 are critical for its repressor activity on Nrf2. However, to date, no molecules have been identified to covalently modify all three cysteine residues for Nrf2 activation. Hence, in this study, our goal is to discover new Keap1 covalent inhibitors that can undergo a Michael addition with all three cysteine residues. The Keap1's intervening region was modeled using Modeller v10.4. Covalent docking and binding free energy were calculated using CovDock. Molecular dynamics (MD) was performed using Desmond. Various in-vitro assays were carried out to confirm the neuroprotective effects of the hit molecule in 6-OHDA-treated SH-SY5Y cells. Further, the best hit was evaluated in vivo for its ability to improve rotenone-induced postural instability and cognitive impairment in male rats. Finally, network pharmacology was used to summarize the complete molecular mechanism of the hit molecule. Chalcone and plumbagin were found to form the necessary covalent bonds with all three cysteine residues. However, MD analysis indicated that the binding of plumbagin is more stable than chalcone. Plumbagin displayed neuroprotective effects in 6-OHDA-treated SH-SY5Y cells at concentrations 0.01 and 0.1 μM. Plumbagin at 0.1 µM had positive effects on reactive oxygen species formation and glutathione levels. Plumbagin also improved postural instability and cognitive impairment in rotenone-treated male rats. Our network analysis indicated that plumbagin could also improve dopamine signaling. Additionally, plumbagin could exhibit anti-oxidant and anti-inflammatory activity through the activation of Nrf2. Cumulatively, our study suggests that plumbagin is a novel Keap1 covalent inhibitor for Nrf2-mediated neuroprotection in PD.

Outward askew endodermal cell divisions reveal INFLORESCENCE AND ROOT APICES RECEPTOR KINASE functions in division orientation.

Oriented cell divisions establish plant tissue and organ patterning and produce different cell types; this is particularly true of the highly organized Arabidopsis (Arabidopsis thaliana) root meristem. Mutant alleles of INFLORESCENCE AND ROOT APICES RECEPTOR KINASE (IRK) exhibit excess cell divisions in the root endodermis. IRK is a transmembrane receptor kinase that localizes to the outer polar domain of these cells, suggesting that directional signal perception is necessary to repress endodermal cell division. Here, a detailed examination revealed many of the excess endodermal divisions in irk have division planes that specifically skew towards the outer lateral side. Therefore, we termed them 'outward askew' divisions. Expression of an IRK truncation lacking the kinase domain retains polar localization and prevents outward askew divisions in irk; however, the roots exhibit excess periclinal endodermal divisions. Using cell identity markers, we show that the daughters of outward askew divisions transition from endodermal to cortical identity similar to those of periclinal divisions. These results extend the requirement for IRK beyond repression of cell division activity to include cell division plane positioning. Based on its polarity, we propose that IRK at the outer lateral endodermal cell face participates in division plane positioning to ensure normal root ground tissue patterning.

Interaction between microRNA-195 and HuR regulates Paneth cell function in the intestinal epithelium by altering SOX9 translation.

Paneth cells at the bottom of small intestinal crypts secrete antimicrobial peptides, enzymes, and growth factors and contribute to pathogen clearance and maintenance of the stem cell niche. Loss of Paneth cells and their dysfunction occur commonly in various pathologies, but the mechanism underlying the control of Paneth cell function remains largely unknown. Here, we identified microRNA-195 (miR-195) as a repressor of Paneth cell development and activity by altering SOX9 translation via interaction with RNA-binding protein HuR. Tissue-specific transgenic expression of miR-195 (miR195-Tg) in the intestinal epithelium decreased the levels of mucosal SOX9 and reduced the numbers of lysozyme-positive (Paneth) cells in mice. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restored Paneth cell development ex vivo. miR-195 did not bind to Sox9 mRNA but it directly interacted with HuR and prevented HuR binding to Sox9 mRNA, thus inhibiting SOX9 translation. Intestinal mucosa from mice that harbored both Sox9 transgene and ablation of the HuR locus exhibited lower levels of SOX9 protein and Paneth cell numbers than those observed in miR-195-Tg mice. Inhibition of miR-195 activity by its specific antagomir improved Paneth cell function in HuR-deficient intestinal organoids. These results indicate that interaction of miR-195 with HuR regulates Paneth cell function by altering SOX9 translation in the small intestinal epithelium.NEW & NOTEWORTHY Our results indicate that intestinal epithelial tissue-specific transgenic miR-195 expression decreases the levels of SOX9 expression, along with reduced numbers of Paneth cells. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restores Paneth cell development ex vivo. miR-195 inhibits SOX9 translation by preventing binding of HuR to Sox9 mRNA. These findings suggest that interaction between miR-195 and HuR controls Paneth cell function via SOX9 in the intestinal epithelium.

Trajectories of Contestation: Motivational Dynamics in Repressive Regimes

Abstract This article examines four different trajectories of contestation individuals go through. We highlight how the five motivational dynamics function per trajectory, depending on how they interact within individuals’ psyche, their perceptions, and the surrounding political setting. We argue that through the citizens’ narratives about these political moments we can better understand how the motivational dynamics function per trajectory of contention. Our focal point is to disentangle how, under the same political conditions, individuals act differently, even though they might hold the same political stances. Repression is a focal point of analysis in the article showing how the individuals within the various trajectories react to regime’s repression differently. It is the context within which individuals within the four trajectories function that is affecting their behaviour. We investigate how the ways individual express dissent change by interacting with the regime whose repressive actions might push them to change their attitudes.

Tdh3 and Rom2 are functional modulators of a conserved condensate-resident RNA-binding protein, Scd6, in Saccharomyces cerevisiae.

Arginine-glycine-glycine motif proteins play a crucial role in determining mRNA fate. Suppressor of clathrin deficiency 6 (Scd6) is a conserved arginine-glycine-glycine motif containing ribonucleoprotein (RNP) condensate-resident, translation repressor, and decapping activator protein in Saccharomyces cerevisiae. Identifying protein factors that can modulate Scd6 function is critical to understanding the regulation of mRNA fate by Scd6. In this study, using an approach that combined mRNA tethering assay with flow cytometry, we screened 50 genes for their role in modulating the translation repression activity of Scd6. We identified 8 conserved modulators with human homologs. Of these, we further characterized in detail guanine nucleotide exchange factor Rho1 multicopy suppressor 2 (Rom2) and glycolytic enzyme triose phosphate dehydrogenase 3 (Tdh3), which, respectively, impede and promote translation repression activity of Scd6. Our study reveals that Rom2 negatively regulates the arginine methylation of Scd6 and antagonizes its localization to P-bodies. Tdh3, on the other hand, promotes Scd6 interaction with Hmt1, thereby promoting the arginine methylation of Scd6 and enhanced eIF4G1 interaction, which is known to promote its repression activity. Identifying these novel modulators provides exciting new insights into the role of a metabolic enzyme of the glycolytic pathway and guanine nucleotide exchange factor implicated in the cell wall integrity pathway in regulating Scd6 function and, thereby, cytoplasmic mRNA fate.

Direct single-cell observation of a key Escherichia coli cell-cycle oscillator.

Initiation of DNA replication in Escherichia coli is coupled to cell size via the DnaA protein, whose activity is dependent on its nucleotide-bound state. However, the oscillations in DnaA activity have never been observed at the single-cell level. By measuring the volume-specific production rate of a reporter protein under control of a DnaA-regulated promoter, we could distinguish two distinct cell-cycle oscillators. The first, driven by both DnaA activity and SeqA repression, shows a causal relationship with cell size and divisions, similarly to initiation events. The second one, a reporter of DnaA activity alone, loses the synchrony and causality properties. Our results show that transient inhibition of gene expression by SeqA keeps the oscillation of volume-sensing DnaA activity in phase with the subsequent division event and suggest that DnaA activity peaks do not correspond directly to initiation events.

HOS15-mediated turnover of PRR7 enhances freezing tolerance.

Arabidopsis PSEUDO RESPONSE REGULATOR7 (PRR7) is a core component of the circadian oscillator which also plays a crucial role in freezing tolerance. PRR7 undergoes proteasome-dependent degradation to discretely phase maximal expression in early evening. While its transcriptional repressive activity on downstream genes is integral to cold regulation, the mechanism of the conditional regulation of the PRR7 protein activity is unknown. We used double mutant analysis, protein interaction and ubiquitylation assays to establish that the ubiquitin ligase adaptor, HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENE 15 (HOS15), controls the protein accumulation pattern of PRR7 through direct protein-protein interactions. Freezing tolerance and electrolyte leakage assays show that PRR7 enhances cold temperature sensitivity, supported by ChIP-qPCR at C-REPEAT BINDING FACTOR (CBF) and COLD REGULATED 15A (COR15A) promoters where PRR7 levels were higher in hos15 mutants. We establish that HOS15 mediates PRR7 protein turnover through enhanced ubiquitylation at low temperature in the dark. Under the same conditions, increased PRR7 association with the promoter regions of CBFs and COR15A in hos15 correlates with decreased CBF1 and COR15A transcription and enhanced freezing sensitivity. We propose a novel mechanism whereby HOS15-mediated regulation of PRR7 provides an intersection between the circadian system and other cold acclimation pathways leading to freezing tolerance through upregulation of CBF1 and COR15A.

An ‘activator-repressor’ loop controls the anthocyanin biosynthesis in red-skinned pear

The color of red-skinned pear (Pyrus spp.) is primarily attributed to accumulation of anthocyanins, which provide nutritional benefits for human health and are closely associated with the commercial value of fruits. Here, we reported the functional characterization of a R2R3-MYB repressor PyMYB107, which forms an ‘activator-repressor’ loop to control anthocyanin accumulation in the red-skinned pear. PyMYB107 overexpression inhibited anthocyanin biosynthesis in both pear calli and fruits, while virus-induced gene silencing of PyMYB107 increased anthocyanin accumulation in pear fruits. Furthermore, ectopic expression of PyMYB107 decreased anthocyanin accumulation in tomato, strawberry and tobacco. PyMYB107 can competitively bind to PybHLH3 with PyMYB10/MYB114, thereby suppressing the transcriptional activation of key anthocyanin biosynthesis genes, PyANS and PyUFGT. Site-directed mutagenesis showed that mutations within the R3 domain and EAR motif of PyMYB107 eliminated its repressive activity. Additionally, PyMYB107 exhibited a comparable expression pattern to PyMYB10/MYB114 and was transcriptionally activated by them. Our finding advanced comprehension of the repression mechanism underlying anthocyanin accumulation, providing valuable molecular insights into improving quality of pear fruits.

Identifying regulatory elements and their RNA-binding proteins in the 3' untranslated regions of papillomavirus late mRNAs.

Human papillomaviruses (HPVs) infect cutaneous and mucosal epithelia to cause benign (warts) and malignant lesions (e.g. cervical cancer). Bovine papillomaviruses (BPVs) infect fibroblasts to cause fibropapillomas but can also infect cutaneous epithelial cells. For HPV-1, -16, -31 and BPV-1, cis-acting RNA elements in the late 3' untranslated region (3'UTR) control expression of virus proteins by binding host cell proteins. The present study compared the effects on gene expression of the cis-acting elements of seven PV late 3'UTRs (HPV-6b, -11, -16, -31 and BPV-1, -3 and -4) representing a range of different genera and species and pathological properties. pSV-beta-galactosidase reporter plasmids containing the late 3'UTRs from seven PVs were transiently transfected into cervical adenocarcinoma HeLa cells, and reporter gene expression quantified by reverse transcription-quantitative PCR and a beta-galactosidase assay. All elements inhibited gene expression in keratinocytes. Cancer-related types HPV-16 and -31, had the greatest inhibitory activity whereas the lowest inhibition was found in the non-cancer related types, BPV-3 and HPV-11. Using RBPmap version 1.1, bioinformatics predictions of factors binding the elements identified proteins which function mainly in mRNA splicing. Markedly, in terms of protein binding motifs, BPV late 3'UTR elements were similar to those of HPV-1a but not to other HPVs. Using HPV-1a as a model and siRNA depletion, the bioinformatics predictions were tested and it was found that PABPC4 was responsible for some of the 3'UTR repressive activity. The data revealed candidate proteins that could control PV late gene expression.

Framing Analysis of Increasing Fuel Prices News on cnnindonesia.com

This research discusses the framing of issues carried out by the online media cnnindonesia.com in reporting on the increase in fuel prices officially announced by President Joko Widodo. The aim of this research is to analyze the issue framing strategy used by cnnindonesia.com in packaging news about fuel price increases. This type of research is qualitative research using media text analysis techniques in the form of Robert N. Entman's framing model analysis of 18 news stories released by cnnindonesia.com on Saturday 3 September 2022. The results of the research show that the issue framing strategy used by cnnindonesia.com is in its reporting. provides a definition of the problem as a global economic problem and has an impact on social problems. An increase in the APBN is the cause of problems and places the government as an actor or source of problems. The moral decision was framed from the president's statement that it was difficult to make a decision regarding the increase in fuel prices and constructed the repressive actions of members of the National Police against demonstrators. Presenting a solution to the problem by framing a political narrative battle between the government and the opposition and explaining that the National Police Chief must be responsible for the repressive actions carried out by the police against students and workers in the action against the increase in fuel prices in all regions.

PERLINDUNGAN HUKUM TERHADAP HAK-HAK ISTRI KORBAN KDRT PASCA PERCERAIAN BERBASIS NILAI KEADILAN DALAM HUKUM ISLAM DAN HUKUM NASIONAL

This article examines the issue of forms of legal protection for the rights of wives of domestic violence victims based on the values of justice. This is because victims of domestic violence are increasing from year to year, even though there is a Law on the Elimination of Domestic Violence, this phenomenon still continues. Therefore, this issue is important to study in order to get a clear picture of the forms of legal protection that can be obtained by victims of domestic violence. The research approach is a qualitative approach with a normative juridical scientific approach, the data is in the form of secondary data sourced from statutory regulations and studies of Islamic jurisprudence literature. In the discussion it was revealed that: Firstly, the forms of legal protection in legislation are classified into: 1). Preventive action, namely a form of legal protection by clearly regulating the rights and obligations of husband and wife, this has been regulated in the Marriage Law and KHI. 1). Repressive action, namely a form of legal protection when domestic violence has occurred, then this falls into the category of criminal law where the perpetrator is threatened with a crime, this has been regulated in the 2004 Domestic Violence Law. Secondly, in Islam legal protection is more comprehensive, by regulating the laws between husband and wife, both laws relating to civil matters during and after divorce. Likewise, Islam clearly provides legal protection for victims of domestic violence, by enforcing hudud penalties for perpetrators of domestic violence.

Revolutionary tribunals of the Tambov province 1918–1922

Importance. Reforming the public administration system is impossible without analyzing and taking into account the historical experience of the activities of punitive authorities. Revolutionary tribunals, created as a weapon in the fight against opponents of the Bolshevik regime, became a form of legitimization of state violence. Studying the mechanism of functioning of these bodies of the Soviet system has important heuristic significance, along with the need for public understanding of the role of repression in the fight against social protest. Modern scientific publications testify to the attention of researchers to this problem. An analysis of the historiography of the issue gives grounds to assert that a promising direction in the study of the topic of “revolutionary justice” is the analysis of the activities of provincial revolutionary tribunals, as well as clarification of the nature of their relationships with other repressive authorities.Materials and Methods. The source base for this work consists of materials identified in the funds of central and local archives and introduced into scientific circulation, most of them for the first time. The documents used made it possible to study the process of organization and practical activities of revolutionary tribunals in the Tambov province of the period 1918–1922. Factual material related to the struggle of these bodies with peasant protest is extracted from materials of local periodicals. The work used a systematic approach, as well as general scientific and historical research methods.Results and Discussion. An analysis of the process of creating revolutionary tribunals in the Tambov province is carried out. Their place and functionality in the management system, as well as the criteria for personnel selection of their employees, are established. The role of the military revolutionary tribunal in the fight against mass desertion is studied. The nature of the relationship between the provincial regional tribunal and the local Cheka is clarified. Based on investigative materials and sentences, the nature of the charges and penalties applied to peasants, participants in rural “rebellions”, as well as food workers who committed violence during the seizure of grain are established. The repressive activities of the Tambov provincial RVT and its visiting sessions to combat and prosecute both armed rebels and the civilian population of the village assisting them are considered.Conclusion. Based on a wide range of archival and other sources, it is established that the activities of the revolutionary tribunals of the Tambov province in the period 1918–1922 was punitive in nature and aimed at suppressing anti-government protest.

PRIMITI: A computational approach for accurate prediction of miRNA-target mRNA interaction

Current medical research has been demonstrating the roles of miRNAs in a variety of cellular mechanisms, lending credence to the association between miRNA dysregulation and multiple diseases. Understanding the mechanisms of miRNA is critical for developing effective diagnostic and therapeutic strategies. miRNA-mRNA interactions emerge as the most important mechanism to be understood despite their experimental validation constraints. Accordingly, several computational models have been developed to predict miRNA-mRNA interactions, albeit presenting limited predictive capabilities, poor characterisation of miRNA-mRNA interactions, and low usability. To address these drawbacks, we developed PRIMITI, a PRedictive model for the Identification of novel miRNA-Target mRNA Interactions. PRIMITI is a novel machine learning model that utilises CLIP-seq and expression data to characterise functional target sites in 3’-untranslated regions (3’-UTRs) and predict miRNA-target mRNA repression activity. The model was trained using a reliable negative sample selection approach and the robust extreme gradient boosting (XGBoost) model, which was coupled with newly introduced features, including sequence and genetic variation information. PRIMITI achieved an area under the receiver operating characteristic (ROC) curve (AUC) up to 0.96 for a prediction of functional miRNA-target site binding and 0.96 for a prediction of miRNA-target mRNA repression activity on cross-validation and an independent blind test. Additionally, the model outperformed state-of-the-art methods in recovering miRNA-target repressions in an unseen microarray dataset and in a collection of validated miRNA-mRNA interactions, highlighting its utility for preliminary screening. PRIMITI is available on a reliable, scalable, and user-friendly web server at https://biosig.lab.uq.edu.au/primiti.

AMPK activation reduces cancer cell aggressiveness via inhibition of monoamine oxidase A (MAO-A) expression/activity

AimAMPK can be considered as an important target molecule for cancer for its unique ability to directly recognize cellular energy status. The main aim of this study is to explore the role of different AMPK activators in managing cancer cell aggressiveness and to understand the mechanistic details behind the process. Main methodsFirst, we explored the AMPK expression pattern and its significance in different subtypes of lung cancer by accessing the TCGA data sets for LUNG, LUAD and LUSC patients and then established the correlation between AMPK expression pattern and overall survival of lung cancer patients using Kaplan-Meire plot. We further carried out several cell-based assays by employing different wet lab techniques including RT-PCR, Western Blot, proliferation, migration and invasion assays to fulfil the aim of the study. Key findings•Expression of AMPK is correlated with survival and prognosis of lung cancer patients.•AMPK activators like Metformin and Phenformin downregulate A549 and HCT-116 cell proliferation and migration via repression of p38MAPK activity, subsequent augmentation of R1 repressor and corresponding downregulation of MAO-A expression/activity resulting reduction in the intracellular ROS.•SRT-1720 directly activates AMPK in LKB1 mutant A549 cells either alone or in combination with Metformin resulting regulation of cancer cell aggressiveness. SignificanceThis study identifies the importance of AMPK activators as a repurposing agent for combating lung and colon cancer cell aggressiveness. It also suggests SRT-1720 as a potent repurposing agent for cancer treatment especially in NSCLC patients where a point mutation is present in LKB1.

Speaking Against Silence: Examining Social Work’s Response to Genocide

Since October 7, 2023, the world has witnessed Israel’s unrelenting mass assault against the people of Gaza, killing more than 37,000 Palestinians. The response to this genocide in most sectors of professional society has largely been one of denial and suppression of solidarity with Palestine, unveiling extremes of the longstanding Palestine exception in progressive politics. This article contextualizes the social work profession’s response to Israel’s ongoing genocide of Palestinian people after October 7, 2023, including responses from schools of social work, social work agencies and organizations, and academic journals. This examination finds that social work institutions continue to engage in three primary silencing tactics: passive silence, active repression, and the drawing of false equivalences. Despite the profession’s pervasive silencing, many of us in social work continue to engage in efforts toward a free Palestine, aligned with the profession’s stated values. This article highlights and juxtaposes the grassroots efforts of social workers and social work students for a free Palestine with the repression from our professional institutions. We demonstrate a range of existing and emerging possibilities for sustained solidarity among social workers seeking to end rather than manage state violence, with Palestine as no exception.

β-Cyclocitral from Lavandula angustifolia Mill. Exerts Anti-Aging Effects on Yeasts and Mammalian Cells via Telomere Protection, Antioxidative Stress, and Autophagy Activation.

We used a replicative lifespan (RLS) experiment of K6001 yeast to screen for anti-aging compounds within lavender extract (Lavandula angustifolia Mill.), leading to the discovery of β-cyclocitral (CYC) as a potential anti-aging compound. Concurrently, the chronological lifespan (CLS) of YOM36 yeast and mammalian cells confirmed the anti-aging effect of CYC. This molecule extended the yeast lifespan and inhibited etoposide (ETO)-induced cell senescence. To understand the mechanism of CYC, we analyzed its effects on telomeres, oxidative stress, and autophagy. CYC administration resulted in notable increases in the telomerase content, telomere length, and the expression of the telomeric shelterin protein components telomeric-repeat binding factor 2 (TRF2) and repressor activator protein 1 (RAP1). More interestingly, CYC reversed H2O2-induced telomere damage and exhibited strong antioxidant capacity. Moreover, CYC improved the survival rate of BY4741 yeast under oxidative stress induced by 6.2 mM H2O2, increasing the antioxidant enzyme activity while reducing the reactive oxygen species (ROS), reactive nitrogen species (RNS), and malondialdehyde (MDA) levels. Additionally, CYC enhanced autophagic flux and free green fluorescent protein (GFP) expression in the YOM38-GFP-ATG8 yeast strain. However, CYC did not extend the RLS of K6001 yeast mutants, such as Δsod1, Δsod2, Δcat, Δgpx, Δatg2, and Δatg32, which lack antioxidant enzymes or autophagy-related genes. These findings reveal that CYC acts as an anti-aging agent by modifying telomeres, oxidative stress, and autophagy. It is a promising compound with potential anti-aging effects and warrants further study.