Global Modification Research Articles

Transcriptional and H3K27ac related genome profiles in oral squamous cell carcinoma cells treated with metformin.

Objectives: Metformin, a first-line drug that has been used for type 2 diabetes treatment, recently attracts broad attention for its therapeutic effects on diverse human cancers. However, its effect and the underlying mechanisms on oral squamous cell carcinoma (OSCC) are not well known.Materials and Methods: OSCC cells were used to evaluate the effect of metformin on cell proliferation and colony formation in vitro. Tumor formation assay in nude mice was conducted to assess the effect of metformin in vivo. Western blotting and immunohistochemistry stain were performed to investigate the effect of metformin on the expression of acetylation at lysine 27 of histone H3 (H3K27ac) and methylation at lysine 27 of histone H3 (H3K27me3) in vitro and in vivo. RNA-seq and ChIP-seq were performed to explore the genome profile to metformin treatment in OSCC cells.Results: Metformin inhibited OSCC cell proliferation and colony formation in vitro, as well as OSCC growth in vivo. Metformin increased the global H3K27ac modification in vitro. Transcriptome analysis suggested that metformin mainly downregulated pluripotency stem cell pathway, development involved pathways and upregulated cytokine and inflammatory pathways. Additionally, H3K27ac was involved in transcription, DNA repair and replication in metformin-treated OSCC cells.Conclusions: Metformin inhibits OSCC growth concomitant upregulated global level of H3K27ac in vitro. This study provides insights into the molecule and epigenome basis on application of metformin in OSCC treatment, and highlights the underlying mechanisms of reprogrammed cancer regulation and epigenetic histone modification.

Lactate metabolism coordinates macrophage response and regeneration in zebrafish.

Rationale: Macrophages are multifunctional cells with a pivotal role on tissue development, homeostasis and regeneration. Indeed, in response to tissue injury and the ensuing regeneration process, macrophages are challenged and undergo massive metabolic adaptations and changes. However, the control of this metabolic reprogramming by macrophage microenvironment has never been deciphered in vivo.Methods: In this study, we used zebrafish model and caudal fin resection as a robust regeneration system. We explored specific changes in gene expression after tissue amputation via single-cell RNA sequencing analysis and whole-tissue transcriptomic analysis. Based on the identification of key modifications, we confirmed the role of the lactate pathway in macrophage response and fin regeneration, through the combination of chemical and genetic inhibitors of this pathway.Results: Single cell RNA sequencing revealed the upregulation of different genes associated with glycolysis and lactate metabolism in macrophages, upon fin regeneration. Hence, using chemical inhibitors of the LDH enzyme, we confirmed the role of lactate in macrophage recruitment and polarization, to promote a pro-inflammatory phenotype and enhance fin regeneration. The genetic modulation of monocarboxylate transporters illustrated a complex regulation of lactate levels, based on both intracellular and extracellular supplies. Commonly, the different sources of lactate resulted in macrophage activation with an increased expression level of inflammatory cytokines such as TNFa during the first 24 hours of regeneration. Transcriptomic analyses confirmed that lactate induced a global modification of gene expression in macrophages.Conclusion: Altogether, our findings highlight the crucial role of lactate at the onset of macrophage differentiation toward a pro-inflammatory phenotype. The deep modifications of macrophage phenotype mediated by lactate and downstream effectors play a key role to coordinate inflammatory response and tissue regeneration.

Synthesis, biological and computational studies of flavonoid acetamide derivatives.

This study reports the synthesis and characterization of a novel class of flavonoid acetamide derivatives (FA) of quercetin, apigenin, fisetin, kaempferol, and luteolin. Flavonoids display numerous biological properties but are limited by aqueous insolubility, enzymatic degradation, instability, and low bioavailability. FAs were synthesized, with 80–82% yields, through the sequential modification of the flavonoid hydroxyl groups into the acetamide moieties. Bioavailability, antioxidant, and ADMET are structure–activity-dependent properties that vary across different classes of flavonoids and dictate the prevalent biological applications of the flavonoids. Thus, the FAs were evaluated for their bioavailability, antioxidant, and ADMET toxicity properties versus the unmodified flavonoids (UFs). In vitro bioavailability analysis shows that the UFs have bio-availabilities in the range of 10.78–19.29% against that of the FAs in the range of 20.70–34.87%. The antioxidant capacity was measured using the 2,2-diphenyl-1-picrylhydrazyl (DPPH·) assay with recorded IC50 values of 2.19–13.03 μM for the UFs. Conversely, the FAs had high DPPH IC50 values ranging from 33.83 to 67.10 μM and corresponding to lower antioxidant activity. The FAs showed favorable ADMET properties. The modification of flavonoids into FAs significantly improves the bioavailability and the ADMET toxicity properties, albeit with decreased antioxidant activity. This work highlights the effect of the global modification of the flavonoids with the acetamide groups on the bioavailability, antioxidant, and ADMET toxicity properties which are critical determinants in the biological applications of the flavonoids.

Organ-Based Proteome and Post-Translational Modification Profiling of a Widely Cultivated Tropical Water Fish, Labeo rohita.

Proteomics has enormous applications in human and animal research. However, proteomic studies in fisheries science are quite scanty particularly for economically important species. Few proteomic studies have been carried out in model fish species, but comprehensive proteomics of aquaculture species are still scarce. This study aimed to perform a comprehensive organ-based protein profiling of important tissue samples for one of the most important aquaculture species,Labeo rohita.Deep proteomic profiling of 17 histologically normal tissues, blood plasma, and embryo provided mass-spectrometric evidence for 8498 proteins at 1% false discovery rate that make up about 26% of the total annotated protein-coding sequences in Rohu. Tissue-wise expression analysis was performed, and the presence of several biologically important proteins was also verified using a targeted proteomic approach. We identified the global post-translational modifications (PTMs) in terms of acetylation (N-terminus and lysine), methylation (N-terminus, lysine, and arginine), and phosphorylation (serine, threonine, and tyrosine) to present a comprehensive proteome resource. An interactive web-based portal has been developed for an overall landscape of protein expression across the studied tissues of Labeo rohita (www.fishprot.org). This draft proteome map of Labeo rohita would advance basic and applied research in aquaculture to meet the most critical challenge of providing food and nutritional security to an increasing world population.

DNA Methylation Modification Map to Predict Tumor Molecular Subtypes and Efficacy of Immunotherapy in Bladder Cancer.

Background: Considering the heterogeneity and complexity of epigenetic regulation in bladder cancer, the underlying mechanisms of global DNA methylation modification in the immune microenvironment must be investigated to predict the prognosis outcomes and clinical response to immunotherapy. Methods: We systematically assessed the DNA methylation modes of 985 integrated bladder cancer samples with the unsupervised clustering algorithm. Subsequently, these DNA methylation modes were analyzed for their correlations with features of the immune microenvironment. The principal analysis algorithm was performed to calculate the DMRscores of each samples for qualification analysis. Findings: Three DNA methylation modes were revealed among 985 bladder cancer samples, and these modes are related to diverse clinical outcomes and several immune microenvironment phenotypes, e.g., immune-desert, immune-inflamed, and immune-excluded ones. Then patients were classified into high- and low-DMRscore subgroups according to the DMRscore, which was calculated based on the expression of DNA methylation related genes (DMRGs). Patients with the low-DMRscore subgroup presented a prominent survival advantage that was significantly correlated to the immune-inflamed phenotype. Further analysis revealed that patients with low DMRscores exhibited less TP53 wild mutation, lower cancer stage and molecular subtypes were mainly papillary subtypes. In addition, an independent immunotherapy cohort confirmed that DMRscore could serve as a signature to predict prognosis outcomes and immune responses. Conclusion: Global DNA methylation modes can be used to predict the immunophenotypes, aggressiveness, and immune responses of bladder cancer. DNA methylation status assessments will strengthen our insights into the features of the immune microenvironment and promote the development of more effective treatment strategies.

Effect of injection timing and duration on the performance of diesel engine fueled with port injection of oxygenated fuels

An alarming adulteration of nature with automotive tail pipe emissions causing global warming demands suitable engine modification. Further use of alternative renewable fuels with fine-tuning the engine and required modifications could reduce the diesel engine emissions. Oxygenated fuels (such as methanol, ethanol and Butanol) act as stand-in fuel that could enrich the global energy requisites and affirmatively downsize the emissions by accelerating combustion efficiency. Under this circumstance, the experimental analysis was done on a single-cylinder four-stroke DI CI engine using conventional diesel as fuel by injection of ethanol, diethyl ether (DEE) and Butanol independently to into intake manifold at three injection timings viz., TDC, 5°ATDC and 10°ATDC respectively under the constant 27°CA injection duration with the help of a distinct setup comprises of the electronic control unit (ECU) and injector system. The resolutions drawn from the recorded results at 80% load during experimentation summarized that DEE exhibited improved BTE of 2.5% and 1% and reduced smoke emissions of 12.54% and 10.6% compared to that obtained with ethanol and Butanol, respectively. On the other hand, DEE emitted excessive NOx and inferior HC, CO emissions compared to ethanol and Butanol apart from shortened ignition delay and combustion duration. The conclusions are drawn from the injection of oxygenates that apart from the perspective of performance, DEE injection at the 5°ATDC was noticed to be optimal at 27°CA injection duration (3 ms) too for emissions characteristics of a diesel engine.

Structural and Functional Characterization of Legionella pneumophila Effector MavL.

Legionella pneumophila is a Gram-negative intracellular pathogen that causes Legionnaires’ disease in elderly or immunocompromised individuals. This bacterium relies on the Dot/Icm (Defective in organelle trafficking/Intracellular multiplication) Type IV Secretion System (T4SS) and a large (>330) set of effector proteins to colonize the host cell. The structural variability of these effectors allows them to disrupt many host processes. Herein, we report the crystal structure of MavL to 2.65 Å resolution. MavL adopts an ADP-ribosyltransferase (ART) fold and contains the distinctive ligand-binding cleft of ART proteins. Indeed, MavL binds ADP-ribose with Kd of 13 µM. Structural overlay of MavL with poly-(ADP-ribose) glycohydrolases (PARGs) revealed a pair of aspartate residues in MavL that align with the catalytic glutamates in PARGs. MavL also aligns with ADP-ribose “reader” proteins (proteins that recognize ADP-ribose). Since no glycohydrolase activity was observed when incubated in the presence of ADP-ribosylated PARP1, MavL may play a role as a signaling protein that binds ADP-ribose. An interaction between MavL and the mammalian ubiquitin-conjugating enzyme UBE2Q1 was revealed by yeast two-hybrid and co-immunoprecipitation experiments. This work provides structural and molecular insights to guide biochemical studies aimed at elucidating the function of MavL. Our findings support the notion that ubiquitination and ADP-ribosylation are global modifications exploited by L. pneumophila.

Perspectives on the Influence of Crystal Size and Morphology on the Properties of Porous Framework Materials.

Miniaturization is a key aspect of materials science. Owing to the increase in quality experimental and computational tools available to researchers, it has become clear that the crystal size and morphology of porous framework materials, including metal-organic frameworks and covalent organic frameworks, play a vital role in defining the physicochemical behaviour of these materials. However, given the multiscale and multidisciplinary challenges associated with establishing how crystal size and morphology affect the structure and behaviour of a material–from local to global structural modifications and from static to dynamic effects–a comprehensive mechanistic understanding of size and morphology effects is missing. Herein, we provide our perspective on the current state-of-the-art of this topic, drawn from various complementary disciplines. From a fundamental point of view, we discuss how controlling the crystal size and morphology can alter the mechanical and adsorption properties of porous framework materials and how this can impact phase stability. Special attention is also given to the quest to develop new computational tools capable of modelling these multiscale effects. From a more applied point of view, given the recent progress in this research field, we highlight the importance of crystal size and morphology control in drug delivery. Moreover, we provide an outlook on how to advance each discussed field by size and morphology control, which would open new design opportunities for functional porous framework materials.

How to achieve the UN Sustainable Development Goals in the field of noncommunicable diseases by 2030, according to research in 49 countries

Goal. To analyze chronic noncommunicable diseases (NCD) mortality dynamics and associated efforts to reach UN sustainable development goals (SDG) in the area of NCD “by 2030, reduce by one third premature mortality from NCD through prevention and treatment“.Methods. WHO statistics, based on the unified mortality and cause -of- death reports of Member-States countries along with the latest information from global WHO programmes, were used to evaluate NCD mortality trends in 49 countries in 2000, 2010 and 2016 and make comparisons and assessments of different types of community -based, country-wide interventions. Only countries with multiple years of national death registration data and high completeness and quality of cause-of-death assignments were included in the analysis. Cardiovascular disease (CVD) ischemic heart disease (IHD) and stroke, chronic respiratory disease (CRD) bronchial asthma and chronic obstructive pulmonary disease (COPD) lung cancer and diabetes mortality were analysed in 36 high income countries (HIC) and 13 middle income countries (MIC).Results. The most visible decline was achieved for bronchial asthma 54%, stroke 43% IHD 30% and COPD 29%. Lung cancer and diabetes mortality decline were not statistically significant. Prevalence of tobacco smoking gradually declined in 84% of countries, 55% of countries demonstrated declining prevalence of raised blood pressure. Obesity prevalence was increasing in all countries. CVD and CRD mortality were higher in MIC. HIC better implemented tobacco and diet reduction measures. Same concerns NCD management approach. Air pollution level was higher in MIC.Conclusions. NCD mortality decline is associated with multiple WHO global life style modifications campaigns, global coordinated prevention and control programmes for hypertension, asthma and COPD and WHO developed “best buy” approach. In order to achieve better results in lung cancer mortality together with early detection, more efforts should be concentrated on early diagnosis, strengthening tobacco cessation, clean air and diet actions. Diet and physical activities along with adequate management and patient education remain key elements to improve diabetes prognosis by the year 2030. Air pollution control could also facilitate achievement of the UN SDG 3.4.

Using ensemble modeling to predict breeding habitat of the red-listed Western Tragopan (Tragopan melanocephalus) in the Western Himalayas of Pakistan

Quantifying a species geographic range is a necessary requirement for targeted and effective conservation management and planning. The Western Tragopan ( Tragopan melanocephalus ) is a globally threatened Galliformes, endemic to the Western Himalayas. The breeding habitat of the species is believed to be exposed to increased anthropogenic pressures. There is a general lack of empirically-based approaches to protect the breeding habitat of this species. To this end, we used recent records of breeding tragopan to develop an ensemble model of the breeding habitat in Pakistan for this Vulnerable species. The model predicted a total area of 10,410 km 2 as potential breeding habitat for the species nationally. Of this, 2979 km 2 (28.6%) were potentially highly suitable (P > 0.4), 2544 km 2 (24.4%) were moderately suitable (0.2 >P < 0.4), and 4887 km 2 (46.9%) were of low suitability (P < 0.2). The breeding sites of the species were recorded with mean global human modification gradient of 0.33 ± 0.06 which implies that habitat suitability for the Tragopan now appears associated with areas of moderate land modification. Therefore, the predicted highly suitable area (core breeding area) was only 79 km 2 (or 2.6%) of the total predicted area suitable for breeding. Hence, the potential breeding habitat of this species may be degraded owing to human habitat interference. We propose that the remaining pockets of high suitability for breeding which remain free from human impacts are declared as protected areas with immediate effect. Areas of high suitability with already existing human disturbance should receive high attention by conservation managers and policy makers, attempting to reduce further human impact. Our model further suggests that more detailed studies at a landscape level should be carried out urgently to successfully protect this globally threatened species from further habitat deterioration.

Ціннісні засади рівноважного економічного розвитку в умовах новітніх глобальних викликів

The paper reveals that the formation of the information society at the turn of the century with a focus on a network economy marked the beginning of the economic relations and laws system global modification. This modification is due primarily to the latest technological changes and innovations in information and communication. However, in its profound nature, it has a value character and is associated with the need for a thorough understanding of the new socio-economic picture of the world. The traditional interpretation of this situation does not meet public expectations about progressive, creative development possibilities. Public dissatisfaction with globalisation is growing. Phenomena of socio-economic instability (turbulence) and uncertainty undermine the civilisational foundations of the social economy, create several global challenges and threats. It is shown that an adequate guideline for successful management is to ensure balanced social development through the development of a holistic institutional architecture, which operates under the laws of effective economic equilibrium. Economic theory is designed to substantiate the laws of operation and the principles of building the institutional architecture of management. At the same time, modern economics remains traditional, while the correct answer to the global social demand must be given by relativistic economics, which can form the socio-economic foundations of the phenomenon of relativity. It is determined that the concept of the institute as a transformed form of economic value (economic good, the only one in the triple definition of marginal utility, value, and price) is an adequate basis for building relativistic economics, methodological source of creative knowledge and formation of the latest holistic picture of the world. It is noted that the tools of value economic analysis (in particular, the model of general economic equilibrium) were formed in the depths of classical political economy, but today it needs to be updated. It is established that the methodological restoration of economics as a valuable source of a positive relativistic understanding of the latest world picture is an essential agenda for further creative research to determine the principles of building an economy of trust forerunner of the institutional architecture. The basis of such an economy is a public sector model focusing on the market of public goods, which harmonises the system of public interests, processes of self-organisation and organisation in the economy, thus contributing to the formation of effective mechanisms for stabilising social development.

Hepcidin‐Based Nanocomposites for Enhanced Cancer Immunotherapy by Modulating Iron Export‐Mediated N6‐Methyladenosine RNA Transcript

AbstractDespite recent advances in targeted therapies and immunotherapies in acute myeloid leukemia, patient prognosis is still dismal given the high frequency of refractory cases or post‐remission relapse. Ferrotherapy, a novel anti‐cancer treatment strategy using iron‐based compounds, can mechanistically bypass the chemoresistance of cancer cells. However, cancer cells often overexpress the transmembrane iron exporter ferroportin that expels accumulated iron into the plasma, which can potentially limit the efficacy of ferrotherapy and lead to systemic toxic effects. Here, a ferro‐therapeutic nanoplatform is designed using fusing hepcidin and leukemia cell‐membrane vesicles on gold nanoparticles (AuNPs)‐loaded hollow mesoporous Prussian Blue (AuPB@LMHep). AuPB@LMHep specifically targeted leukemia cells through ferroportin and is subsequently internalized and disintegrated into iron and AuNPs through autophagy. The accumulation of iron due to blockade of ferroportin‐mediated iron efflux and the depletion of glutathione by the AuNPs triggered ferroptosis. Furthermore, iron accumulation inactivated the endogenous iron‐dependent m6A demethylase, thereby increasing global m6A RNA modification and suppressing multiple oncogenes. Finally, AuPB@LMHep enhanced the immune response to anti‐programmed death ligand1 treatment via increasing cytotoxic tumor‐infiltrating T cells. Pre‐clinical findings provide the proof‐of‐concept of hepcidin‐based nanocomposite as an “epigenetic drug” and immunotherapeutic agent for treating leukemia.

Combined exposure to polychlorinated biphenyls and high-fat diet modifies the global epitranscriptomic landscape in mouse liver.

Exposure to a single dose of polychlorinated biphenyls (PCBs) and a 12-week high-fat diet (HFD) results in nonalcoholic steatohepatitis (NASH) in mice by altering intracellular signaling and inhibiting epidermal growth factor receptor signaling. Post-transcriptional chemical modification (PTM) of RNA regulates biological processes, but the contribution of epitranscriptomics to PCB-induced steatosis remains unknown. This study tested the hypothesis that PCB and HFD exposure alters the global RNA epitranscriptome in male mouse liver. C57BL/6J male mice were fed a HFD for 12 weeks and exposed to a single dose of Aroclor 1260 (20 mg/kg), PCB 126 (20 µg/kg), both Aroclor 1260 and PCB 126 or vehicle control after 2 weeks on HFD. Chemical RNA modifications were identified at the nucleoside level by liquid chromatography-mass spectrometry. From 22 PTM global RNA modifications, we identified 10 significant changes in RNA modifications in liver with HFD and PCB 126 exposure. Only two modifications were significantly different from HFD control liver in all three PCB exposure groups: 2ʹ-O-methyladenosine (Am) and N(6)-methyladenosine (m6A). Exposure to HFD + PCB 126 + Aroclor 1260 increased the abundance of N(6), O(2)-dimethyladenosine (m6Am), which is associated with the largest number of transcript changes. Increased m6Am and pseudouridine were associated with increased protein expression of the writers of these modifications: Phosphorylated CTD Interacting Factor 1 (PCIF1) and Pseudouridine Synthase 10 (PUS10), respectively, in HFD + PCB 126- + Aroclor 1260-exposed mouse liver. Increased N1-methyladenosine (m1A) and m6A were associated with increased transcript levels of the readers of these modifications: YTH N6-Methyladenosine RNA Binding Protein 2 (YTHDF2), YTH Domain Containing 2 (YTHDC2), and reader FMRP Translational Regulator 1 (FMR1) transcript and protein abundance. The results demonstrate that PCB exposure alters the global epitranscriptome in a mouse model of NASH; however, the mechanism for these changes requires further investigation.

Effect of postural alignment alteration with age on vertebral strength.

The purpose of this study was to analyze the impact of postural alignment changes with age on vertebral strength using finite element analysis and barycentremetry. A total of 117 subjects from 20 to 83years were divided in three age groups: young (20 to 40years, 62 subjects), intermediate (40 to 60years, 26 subjects), and elderly (60years and over, 29 subjects). EOS biplane radiographs were acquired, allowing 3D reconstruction of the spine and body envelope as well as spinal, pelvic, and sagittal alignment parameter measurements. A barycentremetry method allowed the estimation of the mass and center of mass (CoM) position of the upper body above L1, relatively to the center of the L1 vertebra (lever arm). To investigate the effect of this lever arm, vertebral strength of a generic finite element model (with constant geometry and mechanical properties for all subjects) was successively computed applying the personalized lever arm of each subject. A combination of an increase in thoracic kyphosis, cervical lordosis, and pelvic tilt with a loss of lumbar lordosis was observed between the young and the older groups. Sagittal alignment parameters indicated a more forward position as age increased. The lever arm of the CoM above L1 varied from an average of 1mm backward for the young group, to averages of 10 and 24mm forward, respectively, for the intermediate and elderly group. As a result, vertebral strength decreased from 2527N for the young group to 1820N for the elderly group. The global sagittal alignment modifications observed with age were consistent with the literature. Posture alteration with age reduced vertebral strength significantly in this simplified loading model. Postural alignment seems essential to be considered in the evaluation of osteoporotic patients.

A global modification in avifaunal behavior by use of waste disposal sites (waste dumps/rubbish dumps): A review paper

A global modification in avifaunal behavior by use of waste disposal sites (waste dumps/rubbish dumps): A review paper

The Digital Transformation Impact on the Participation in Global Value Chains: Latin American Countries

The article examines the changing participation of Latin American countries in global supply chains which are under the influence of digital transformation. The author considers options for global value chains modifications due to the spread of digital technologies, describes the current involvement of Latin American countries in global supply chains, and analyses the development of digital economy in the region. Basing on the collected data, the author makes a conclusion about expectable changes in the regional countries’ engagement in global value chains.

PPARγ-Induced Global H3K27 Acetylation Maintains Osteo/Cementogenic Abilities of Periodontal Ligament Fibroblasts.

The periodontal ligament is a soft connective tissue embedded between the alveolar bone and cementum, the surface hard tissue of teeth. Periodontal ligament fibroblasts (PDLF) actively express osteo/cementogenic genes, which contribute to periodontal tissue homeostasis. However, the key factors maintaining the osteo/cementogenic abilities of PDLF remain unclear. We herein demonstrated that PPARγ was expressed by in vivo periodontal ligament tissue and its distribution pattern correlated with alkaline phosphate enzyme activity. The knockdown of PPARγ markedly reduced the osteo/cementogenic abilities of PDLF in vitro, whereas PPARγ agonists exerted the opposite effects. PPARγ was required to maintain the acetylation status of H3K9 and H3K27, active chromatin markers, and the supplementation of acetyl-CoA, a donor of histone acetylation, restored PPARγ knockdown-induced decreases in the osteo/cementogenic abilities of PDLF. An RNA-seq/ChIP-seq combined analysis identified four osteogenic transcripts, RUNX2, SULF2, RCAN2, and RGMA, in the PPARγ-dependent active chromatin region marked by H3K27ac. Furthermore, RUNX2-binding sites were selectively enriched in the PPARγ-dependent active chromatin region. Collectively, these results identified PPARγ as the key transcriptional factor maintaining the osteo/cementogenic abilities of PDLF and revealed that global H3K27ac modifications play a role in the comprehensive osteo/cementogenic transcriptional alterations mediated by PPARγ.

Modifications to global supply chain management strategies resulting from recent trade disruptions: an exploratory study

PurposeThe purpose of this study is to explore modifications to the supply chain strategies of international manufacturers resulting from recent momentous trade disruptions, including the US-China trade war, global tariff escalations, Brexit and heightened geopolitical tensions.Design/methodology/approachThe research methodology consisted of a series of in-depth personal interviews with senior supply chain executives of six large US international manufacturers.FindingsThe study identified several short-term reactive strategies taken, including pulling purchase orders or production forward, building inventory and applying for exceptions from tariffs, along with longer-term proactive strategies such as shifting and expanding supplier and manufacturing locations.Research limitations/implicationsThe study’s limitations involve its small sample size and its findings being industry and company-specific to a limited number of firms. While the sample size was deemed sufficient for this exploratory study, larger sample sizes and subsequent industry-specific analyses are recommended.Practical implicationsThe global supply chain modifications effectively used by the firms in the study can offer guidance for practitioners facing similar challenges following major trade disruptions.Originality/valueDue to the very recent emergence of the trade disruptors examined in this study, extant literature is limited. Hence, the findings noted in the paper offer not only guidance for practitioners but also make a strong contribution to research and literature on global supply chain risk management and disruption risk mitigation.

MiR-7-5p inhibits thyroid cell proliferation by targeting the EGFR/MAPK and IRS2/PI3K signaling pathways.

The aberrant expression of miRNAs is often correlated to tumor development. MiR-7-5p is a recently discovered downregulated miRNA in thyroid papillary carcinoma (PTC). The goal of this project was to characterize its functional role in thyroid tumorigenesis and to identify the targeted modulated pathways. MiR-7-5p overexpression following transfection in TPC1 and HT-ori3 cells decreased proliferation of the two thyroid cell lines. Analysis of global transcriptome modifications showed that miR-7-5p inhibits thyroid cell proliferation by modulating the MAPK and PI3K signaling pathways which are both necessary for normal thyroid proliferation and play central roles in PTC tumorigenesis. Several effectors of these pathways are indeed targets of miR-7-5p, among which EGFR and IRS2, two upstream activators. We confirmed the upregulation of IRS2 and EGFR in human PTC and showed the existence of a negative correlation between the decreased expression of miR-7-5p and the increased expression of IRS2 or EGFR. Our results thus support a tumor-suppressor activity of miR-7-5p. The decreased expression of miR-7-5p during PTC tumorigenesis might give the cells a proliferative advantage and delivery of miR-7-5p may represent an innovative approach for therapy.

IDH2 contributes to tumorigenesis and poor prognosis by regulating m6A RNA methylation in multiple myeloma.

Epigenetic alterations have been previously shown to contribute to multiple myeloma (MM) pathogenesis via DNA methylations and histone modifications. RNA methylation, a novel epigenetic modification, is required for cancer cell survival, and targeting this pathway has been proposed as a new therapeutic strategy. The extent to the N6-methyladenosine (m6A)-regulatory pathway functions in MM remains unknown. Here, we show that an imbalance of RNA methylation may underlies the tumorigenesis of MM. Mechanistically, isocitrate dehydrogenase 2 (IDH2) is highly expressed in CD138+ cells from MM and its levels appear a progressive increase in the progression of plasma cell dyscrasias. Downregulation of IDH2 increases global m6A RNA levels and reduces myeloma cell growth in vitro, decreases the burden of disease and prolongs overall survival in vivo. IDH2 regulates RNA methylation by activating the RNA demethylase FTO, which is an α-KG-dependent dioxygenase. Furthermore, IDH2-mediated FTO activation decreases the m6A level on WNT7B transcripts, then increases WNT7B expression and thus activated Wnt signaling pathway. Moreover, survival analysis indicates that the elevated expression of IDH2 predicts a poor prognosis. Higher expression of FTO is related to higher International Staging System (ISS) stage and higher Revised-ISS (R-ISS) stage of MM. Collectively, our studies reveal that IDH2 regulates global m6A RNA modification in MM via targeting RNA demethylases FTO. The imbalance of m6A methylation activates the Wnt signaling pathway by enhancing the WNT7B expression, and thus promoting tumorigenesis and progression of MM. IDH2 might be used as a therapeutic target and a possible prognostic factor for MM.