Upstream Activity Research Articles

The Political Side of Social Enterprises: A Phenomenon‐Based Study of Sociocultural and Policy Advocacy

AbstractThis study explores the often‐overlooked political dimension of social enterprises, particularly their advocacy activities aimed at influencing public policy, legislation, norms, attitudes, and behaviour. While traditional management research has focused on commercial activity and the beneficiary‐oriented aspects of social enterprises, this paper considers their upstream political activity. Using a phenomenon‐based approach, we analyse original survey data from 718 social enterprises across seven countries and six problem domains to identify factors associated with their engagement in advocacy. Our findings reveal that public spending and competition in social enterprises’ problem domains, as well as their governance choices – legal form, sources of income, and collaborations – are significantly associated with advocacy activities. We propose a new theoretical framework to understand these dynamics, positioning social enterprises as key players in markets for public purpose. This research underscores the importance of recognizing the political activities of social enterprises and offers new insights for studying hybrid organizing and organizations that address complex societal challenges. By highlighting the integral role of advocacy, our study contributes to a more comprehensive understanding of how social enterprises drive social change, not only through direct service provision but also by shaping the broader sociopolitical environment.

GSK-3β/Notch-1 Activation Promotes Radiation-Induced Renal Damage: The Role of Gallic Acid in Mitigation of Nephrotoxicity.

Despite the therapeutic advances in treating malignancies, the efficient radiotherapeutic approaches with deprived adverse reactions still represent a potential clinical inquiry. The current study aims to elucidate the role of gallic acid (GA) in modifying the hazardous renal cytotoxicity induced by acute exposure to radiation. The MTT test was used to evaluate the viability of Vero cells exposed to 2 Gy gamma radiation with or without incubation of GA. In an in vivo model, male Wistar rats were divided into four experimental groups (n = 6): Control, Irradiated (IRR, 5 Gy), GA (100 mg/kg, i.p.) + IRR, and Glycogen synthase kinase inhibitor (GSKI, 3 mg/kg, i.p.) + IRR. Based on the MTT toxicity assay, from 0 and up to 5 μM dosages of GA did not demonstrate any cytotoxicity to Vero cells. The optimal GA dose that could protect the cells from radiation was 5 μM. Furthermore, GA exerted a protective effect from gamma radiation on renal tissue as indicated by corrected renal functions, decreased LDH level in serum, and balanced oxidative status, which is indicated by decreased tissue contents of NOx and TBARS with a significant increase of reduced GSH. These outcomes were inferred by the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression. The overall molecular impact of radiation in damaging the renal tissue may be explained by modifying the upstream AKT activity and its downstream targets GSK-3β/Notch-1. Here, we concluded that the anticipated adverse reaction in the course of radiation exposure could be protected by daily administration of GA.

Geoscience skills supplement emissions reduction through carbon solutions

As the energy sector transitions, traditional geoscience occupations have been impacted by the decrease in upstream oil and gas activity. However, these roles are highly technical and innovative, and could benefit many sectors if re-deployed. Carbon offsetting is available now to support meeting emission reduction targets and is expected to be deployed in the long term for hard-to-abate areas. In 2018, Woodside started a carbon business that includes the origination of offsets through carbon farming. Millions of seedlings have been planted on less productive farmland in WA. The program has been enhanced through the transferable skills that geoscientists provide, including uncertainty analysis, software technology and data acquisition. Much like the petroleum geoscience discipline, carbon offset investment requires an assessment of a natural resource. There is uncertainty in the total volume, the future state, and the policy conditions impacting the resource. Geoscientists at Woodside have led initiatives to assess carbon yield, quantify and forecast uncertainty, and develop decision-making frameworks for project investment. These initiatives have informed the business as a market participant and project developer in the nascent carbon market. Geospatial analytics is critical throughout the value chain of a planting project, including site selection, project design, site execution, monitoring and reporting. Remote sensing and imagery analysis are used for monitoring growth and quantifying carbon sequestration. Further, geospatial projects have aided efficiency, providing accurate, real-time data to and from the field and re-deploying geoscientists from in-house has contributed towards Woodside’s success.

Abstract PO3-23-11: Multiomics analysis of ER+ breast cancer with matched primaries, lymph node metastases and recurrent cancers on adjuvant endocrine therapy

Abstract Background: 80% of all breast cancers (BCs) are ER-positive (ER+). A significant number develop endocrine therapy resistance (ETR) . Clones develop in lymph nodes (LNs) which differ from the primary and these are implicated in ETR. A multiomics analysis of primary ER+ breast cancers, matched LN metastasis (LN+), if present, and matched recurrences (primary, nodal or distant) has been performed. Patients and Methods: The patients included are: Cohort A: 95 patients with matched primary and recurrent ER+ BC on different endocrine therapies. 35% had involved LNs at diagnosis. Recurrences: local in 59/95, concurrent local and nodal in 33/95, LN-only in 3/95. Median time to recurrence 4.5 years. Cohort B: 18 patients with ER+ LN+ BC who developed multiple recurrences (local and/or nodal, >3 consecutive recurrences/patient) on different lines of sequential endocrine therapy. Cohort C: 7 patients with ER+ breast cancer with multiple involved LNs treated with 3-6 months of neoadjuvant ET before surgery. Biopsies of primary and matched LNs performed at diagnosis and throughout treatment (3-4 timepoints/patient). Clinical response by serial ultrasound. Primary and LN samples (mean 12 samples/patient) were analysed together with normal DNA. Targeted RNAseq and DNA exome sequencing and whole-genome expression analysis was performed. Somatic mutations and copy number alterations (CNA) were determined, and differential gene expression analysis was performed. Validation of pathways implicated in ETR was by spatial NanoString GeoMx. All patients have long term follow-up. Results: Cohort A: A mean of 6 potential driver mutations identified by DNA sequencing in each primary BC (range 1-16). Most commonly mutated genes were PIK3CA, TP53, ERBB4, MAP3K1 and ERBB3. Multiple aberrations and a highly diverse mutational landscape were observed in all recurrences. In the majority of recurrences significant changes in variant allele frequency (VAF) were identified across several ETR-implicated genes and in over 50% new gains/losses were identified. Most frequently, losses were seen in ERBB3, ARID1A, HRAS and FOXA1 with gains in CDH1, NF1, PIK3CA, ESR1, TBX3 and GATA3 in recurrences vs primaries. Transcriptomic analysis revealed differentially expressed pathways including ER, HER2, GATA3, AKT, RAS and p63 signalling. Integrated analysis revealed several driver mutations with corresponding changes in upstream pathway activity. 33 patients had concurrent local and nodal recurrences and 52% had similar somatic mutation profiles in both with only minor variance in VAF. In 48%, 1 or more new potential driver mutations was identified in axillary nodes compared to recurrent primary cancers with losses in AKT1, CDH1 and TP53 being most common. Multiomics profiling of Cohorts B and C is complete and analysis underway. Discussion: This multiomics study is the largest cohort to-date of matched early and recurrent ER+/HER2- cancers. It sheds new light on the complex somatic and transcriptomic changes in local and nodal recurrent disease. The mechanisms of ETR are diverse and underlying mechanisms and clinically meaningful biomarkers including potentially actionable mutations and targets have been identified. Cohort C will uniquely capture and compare clonal evolution of breast cancer in primary and multiple matched lymph during neoadjuvant ET. Citation Format: Carlos Martinez-Perez, Charlene Kay, Rebecca Swan, Lorna Renshaw, J Michael Dixon, Arran K Turnbull. Multiomics analysis of ER+ breast cancer with matched primaries, lymph node metastases and recurrent cancers on adjuvant endocrine therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-23-11.

Precipitation 17O‐Excess Altered During Tropical Convection: Evidence From Monsoon Cold Surges in Singapore

AbstractDespite the recent recognition of 17O‐excess as a promising new tracer for hydrological processes, our knowledge of the control mechanisms underlying 17O‐excess in tropical regions remains limited. To understand how microphysical processes during tropical convection affect precipitation isotope ratios, particularly 17O‐excess, in Singapore, we collected precipitation samples at minute intervals from six rain events associated with cold surges during the Northeast Monsoon seasons and analyzed their triple oxygen isotopes. Our results show that precipitation δ18O decreases in the convective zones and then gradually increases in the stratiform zones, while d‐excess exhibits an inverse trend. This correlation between δ18O and d‐excess indicates that rain evaporation plays a crucial role in regulating precipitation isotopes. Moreover, the rain events with a higher upstream rainout amount have lower δ18O and higher 17O‐excess values, suggesting that precipitation δ18O and 17O‐excess likely reflect the integrated upstream convective activity. Microphysical processes associated with upstream convection, such as rain evaporation and vapor recycling, are potential mechanisms that increase 17O‐excess values along moisture transport pathways for a rain event, and hence, undermine the effectiveness of 17O‐excess as a tracer of moisture source humidity. Contrary to the negative correlation observed in monthly precipitation, there is generally a positive correlation between d‐excess and 17O‐excess at the event scale. However, this correlation weakens as convective rain intensifies, suggesting that stronger convection can attenuate the positive correlation between d‐excess and 17O‐excess. Therefore, it is crucial to consider how tropical convection alters 17O‐excess when utilizing this tracer to interpret atmospheric dynamics and hydrological processes.

Transmission characteristics and the factors influencing stable oxygen isotopes in precipitation, soil water, and drip water in Remi Cave, Western Hunan, China

Understanding the modern transport processes of δ18O between different waters in cave systems can provide a basis for the paleoenvironmental interpretation of records of stalagmite δ18O. We conducted monthly in-situ monitoring of local precipitation, soil water at three different soil depths, five drip water sites and environmental parameters in Remi cave, Western Hunan Province, Central China, from December 2020 to January 2024. During the monitoring period, due to differences in geological structure and ventilation effect at different locations within the cave, cave air temperature and relative humidity gradually remained constant from the cave entrance to the deep parts of the cave. On intra-annual timescales, precipitation δ18Op were depleted in the wet season and enriched in the dry season, which were mainly controlled by changes in moisture sources, upstream convective activity, and rainout effects. With the increasing thickness of the soil layer above the cave, soil water δ18Osoil gradually became negative and leveled off, possibly because shallow soil water responded sensitively to local year-round precipitation, accompanied by surface evaporation. While, deep soil water with more negative δ18O, may be mainly replenished by heavy precipitation during the wet season, but the effect of water retained in the soil from preceding years couldn’t be excluded and would be needed to verify by conducting more monitoring studies on the variation of δ18Osoil covering the long period. The mean δ18O values of drip water at sites D1 and D2 near the cave entrance were heavier than that of shallow soil water and precipitation, possibly due to evaporation from the thin overlying soil layer, together with ventilation effect. There were seasonal variations of δ18Od values at site D5 in the deep parts of the cave, which may be associated with the seasonal variation of drip rate at this site. Due to the smoothing effect of soil layer and epikarst zone, there were no seasonality in δ18Od values at sites D3 and D4, in the middle and deep parts of the cave. The mean δ18Od at these two sites were lighter than amount-weighted annual mean δ18Op, and close to the deep δ18Osoil and the wet-season amount-weighted mean δ18Op values. This suggests that the thick soil layer overlying the cave raises the precipitation threshold, causing these sites to be mainly recharged by heavy rainfall in the wet season. Therefore, the δ18O of stalagmites growing under these drip sites may mainly inherit the wet-season δ18Op signal. The short monitoring period of this study (three years) and the lack of modern calcite δ18O data, mean that caution is need in interpreting stalagmite δ18O on a timescale longer than that of this study.

Neural Manifold Constraint for Spike Prediction Models Under Behavioral Reinforcement.

Spike prediction models effectively predict downstream spike trains from upstream neural activity for neural prostheses. Such prostheses could potentially restore damaged neural communication pathways using predicted patterns to guide electrical stimulations on downstream. Since the ground truth of downstream neural activity is unavailable for subjects with the damage, reinforcement learning (RL) with behavior-level rewards becomes necessary for model training. However, existing models do not involve any constraint on the generated firing patterns and neglect the correlations among neural activities. Thus, the model outputs can greatly deviate from the natural range of neural activities, causing concerns for clinical usage. This study proposes the neural manifold constraint to solve this problem, shaping RL-generated spike trains in the feature space. The constraint terms describe the first and second order statistics of the neural manifold estimated from neural recordings during subjects' freely moving period. Then, the models can be optimized within the neural manifold by behavioral reinforcement. We test the method to predict primary motor cortex (M1) spikes from medial prefrontal (mPFC) spikes when rats perform the two-lever discrimination task. Results show that the neural activity generated by constrained models resembles the real M1 recordings. Compared with models without constraints, our approach achieves similar behavioral success rates, but reduces the mean squared error of neural firing by 61%. The constraints also increase the model's robustness across data segments and induce realistic neural correlations. Our method provides a promising tool to restore transregional communication with high behavioral performance and more realistic microscopic patterns.

Hellebrigenin induces apoptosis by triggering cellular inhibitor of apoptosis 1 and Jun N-terminal kinase pathway in melanoma cells

Abstract Background: Melanoma, the malignancy of melanocytes, is the most fatal form of skin cancer. Although various interventions are currently available, advanced stages of melanoma are still associated with a risk of metastatic recurrence. Objectives: The present study examined the anticancer activity of hellebrigenin, a natural product extracted from toad skin. Methods: Two types of metastatic melanoma cell lines, A2058 and HMY-1, were selected. Results: The findings revealed that hellebrigenin had cytotoxic effects on the two melanoma cell lines by triggering apoptosis: hellebrigenin activated cell arrest during the G2/M phase and downregulated regulators’ expression (e.g., cyclin-dependent kinase [CDK] 1, CDK 4, and cyclins E1, E2, A2, and D3). In intrinsic and extrinsic pathways of apoptosis, hellebrigenin activated the expression of the proapoptotic proteins t-BID, Bak, poly-ADP-ribose polymerase, Fas-associated death domain protein, death receptors 5, and cleaved caspases 3, 8, and 9; it also reduced the expression of the antiapoptotic proteins Bcl-2 and Bcl-xL. Mitochondrial membrane depolarization and cell nucleus condensation were also observed. In addition, human apoptosis arrays revealed that hellebrigenin inhibited the expression of cellular inhibitor of apoptosis 1, which is crucial for blocking cell apoptosis. Regarding upstream signaling activity, hellebrigenin suppressed the phosphorylation of the Jun N-terminal kinase 1/2 pathway in both melanoma cell lines. Conclusion: Overall, hellebrigenin can be used as a potential anticancer agent in clinical settings for treating the advanced stages of melanoma.

Dynamics of an incoherent feedforward loop drive ERK-dependent pattern formation in the early Drosophila embryo.

Positional information in development often manifests as stripes of gene expression, but how stripes form remains incompletely understood. Here, we use optogenetics and live-cell biosensors to investigate the posterior brachyenteron (byn) stripe in early Drosophila embryos. This stripe depends on interpretation of an upstream ERK activity gradient and the expression of two target genes, tailless (tll) and huckebein (hkb), that exert antagonistic control over byn. We find that high or low doses of ERK signaling produce transient or sustained byn expression, respectively. Although tll transcription is always rapidly induced, hkb converts graded ERK inputs into a variable time delay. Nuclei thus interpret ERK amplitude through the relative timing of tll and hkb transcription. Antagonistic regulatory paths acting on different timescales are hallmarks of an incoherent feedforward loop, which is sufficient to explain byn dynamics and adds temporal complexity to the steady-state model of byn stripe formation. We further show that 'blurring' of an all-or-none stimulus through intracellular diffusion non-locally produces a byn stripe. Overall, we provide a blueprint for using optogenetics to dissect developmental signal interpretation in space and time.

Construction of Yeast One-Hybrid Library of Alternaria oxytropis and Screening of Transcription Factors Regulating swnK Gene Expression.

The indolizidine alkaloid-swainsonine (SW) is the main toxic component of locoweeds and the main cause of locoweed poisoning in grazing animals. The endophytic fungi, Alternaria Section Undifilum spp., are responsible for the biosynthesis of SW in locoweeds. The swnK gene is a multifunctional complex enzyme encoding gene in fungal SW biosynthesis, and its encoding product plays a key role in the multistep catalytic synthesis of SW by fungi using pipecolic acid as a precursor. However, the transcriptional regulation mechanism of the swnK gene is still unclear. To identify the transcriptional regulators involved in the swnK gene in endophytic fungi of locoweeds, we first analyzed the upstream non-coding region of the swnK gene in the A. oxytropis UA003 strain and predicted its high transcriptional activity region combined with dual-luciferase reporter assay. Then, a yeast one-hybrid library of A. oxytropis UA003 strain was constructed, and the transcriptional regulatory factors that may bind to the high-transcriptional activity region of the upstream non-coding region of the swnK gene were screened by this system. The results showed that the high transcriptional activity region was located at -656 bp and -392 bp of the upstream regulatory region of the swnK gene. A total of nine candidate transcriptional regulator molecules, including a C2H2 type transcription factor, seven annotated proteins, and an unannotated protein, were screened out through the Y1H system, which were bound to the upstream high transcriptional activity region of the swnK gene. This study provides new insight into the transcriptional regulation of the swnK gene and lays the foundation for further exploration of the regulatory mechanisms of SW biosynthesis in fungal endophytic locoweeds.

The Onset of a Blocking Event as a “Traffic Jam”: Characterization with Ensemble Sensitivity Analysis

Abstract Recently, Nakamura and Huang proposed a theory of blocking onset based on the budget of finite-amplitude local wave activity on the midlatitude waveguide. Blocks form in their idealized model due to a mechanism that also describes the emergence of traffic jams in traffic theory. The current work investigates the development of a winter European block in terms of finite-amplitude local wave activity to evaluate the possible relevance of the “traffic jam” mechanism for the flow transition. Two hundred members of a medium-range ensemble forecast of the blocking onset period are analyzed with correlation- and cluster-based sensitivity techniques. Diagnostic evidence points to a traffic jam onset on 17 December 2016. Block development is sensitive to upstream Rossby wave activity up to 1.5 days prior to its initiation and consistent with expectations from the idealized theory. Eastward transport of finite-amplitude local wave activity in the southern part of the block is suppressed by nonlinear flux modification from the large-amplitude blocking pattern, consistent with the expected obstruction in the traffic jam model. The relationship of finite-amplitude local wave activity and its zonal flux as mapped by the ensemble exhibits established characteristics of a traffic jam. This study suggests that the traffic jam mechanism may play an important role in some cases of blocking onset and more generally that applying finite-amplitude local wave activity diagnostics to ensemble data is a promising approach for the further examination of individual onset events in light of the Nakamura and Huang theory. Significance Statement Blocking is an occasional phenomenon in the mid- and high-latitude atmosphere characterized by the stalling of weather systems. Episodes of blocking are linked to extreme weather but their occurrence is not completely understood. A recent theory suggests that blocks may form in the jet stream like traffic jams on a highway. The onset mechanism contained in the theory could explain why forecasts of blocking are sometimes poor. In this work, we investigate the formation of a 2016 European winter block in the context of the traffic jam theory. Though questions remain regarding the implications for forecast uncertainty, our findings strongly support the notion of a traffic jam onset.

Bioinformatics Analysis to Identify Intersection Genes, Associated Pathways and Therapeutic Drugs between COVID-19 and Oral Candidiasis.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has a serious threat to human health. Oral candidiasis (OC) may be one of the causes of morbidity in severe COVID-19 patients. However, there is currently no treatment for oral candidiasis and COVID-19 (OC/COVID-19). The purpose of this study was to use text mining and data analysis to investigate the target genes for treatment and explore potential therapeutic drugs for OC/COVID-19. We used the text mining tool pubmed2ensembl to detect genes associated with OC, and the dataset GSE164805 was used for the data analysis. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on two intersection genes using the Database of Annotation, Visualization and Integrated Discovery (DAVID) platform. The protein-protein interaction (PPI) networks were constructed by STRING software, and gene module analysis was performed using Molecular Complex Detection (MCODE), a plug-in in Cytoscape. The most significant genes were selected as hub genes and their functions and pathways were analyzed using Metascape. We revealed the upstream pathway activity of the hub genes. The drug-gene interaction database (DGIdb) and the traditional Chinese medicines integrated database (TCMID) were used to discover potential drugs for the treatment of OC/COVID-19. The analysis indicated that there were 2869 differentially expressed genes (DEGs) in GSE164805. We identified 161 unique genes associated with oral candidiasis through text mining. A total of 20 intersection genes were identified as the therapeutic targets for OC/COVID-19. Based on the bioinformatics analysis, nine genes (TNF, IL1B, IFNG, CSF2, ELANE, CCL2, MMP9, CXCR4, and IL1A) were identified as hub genes that were mainly enriched in the IL-17 signaling pathway, TNF signaling pathway, AGE-RAGE signaling pathway in diabetic complications and NOD-like receptor signaling pathway. We identified four of the nine genes that target five existing drugs, including BKT140, mavorixafor, sivelestat, canakinumab, and rilonacept. Furthermore, twenty herb ingredients were also screened as potential drugs. In this study, TNF, IL1B, IFNG, CSF2, ELANE, CCL2, MMP9, CXCR4, and IL1A were potentially key genes involved in the treatment of OC/COVID-19. Taken together five drugs and twenty herb ingredients were identified as potential therapeutic agents for OC/COVID-19 treatment and management.

THE PREPARATION OF OWNER ESTIMATE IN RIG SERVICE CONTRACTS IN UPSTREAM OIL AND GAS BUSINESS ACTIVITIES ACCORDING TO LEGAL CERTAINTY PRINCIPLES.

<p>As one of the vital and strategic natural resources, due to its vital role that could impact society, oil and gas is one of the sources of state revenue to support national development. To implement Article 33 of the 1945 Constitution, in particular to realize the welfare and prosperity of the people, UU Migas No 22, 2001 mandated SKK Migas to oversee upstream activity done by contractors (KKKS).</p><p>Contractors conduct rig procurement processes with their Owner Estimate (OE) in alignment to Perpres No 12, 2021 and PTK 007, 2017. Due to that reason, legal certainty is needed to deal with problems at the implementation level.</p><p>This dissertation research covers two legal issues, namely the regulation and implementation of the preparation of the HPS Value in the Rig contract.</p><p>The theoretical basis used is agreement theory, legal certainty theory and Per Se Illegal and Rule of Reason approach. The research analysis is using normative juridicals which are supported by empirical studies.</p><p>The result of this research concludes that normatively, OE preparation guidelines provide multiple interpretations, inconsistencies and a legal vacuum.</p><p>In practice, problems related to aspects of legal certainty, namely HPS offers are not confidential and/or confidential, extreme price cut due to offers below 80% of HPS are being allowed, the existence of negotiations even though the price offer is already the lowest and below the HPS . It opens for conspiracy in the procurement. For this reason, it is necessary to amend Perpres and PTK 007 in order to achieve compliance according to the principles of agreement, legal certainty and fair business.</p><p>The change in regulation will provide legal certainty, efficiency and effectiveness so that SKK Migas and KKKS and Rig Providers can carry out upstream business activities properly and optimally to support the social welfare of the Indonesian.</p><p align="center"> </p><p><strong>Keywords:<em> </em></strong><em>Oil and Gas, Owner Estimates Development</em>, KKKS & <em>Rig Provider</em></p>

Owner Estimate of Rig Contracts in Oil and Gas Business According to Legal Certainty Principles

<p>As one of the vital and strategic natural resources and vital role that impact society, oil and gas is one of state revenue sources to support national development. To implement Article 33 of the 1945 Constitution, to obtain people welfare and prosperity, Oil and Gas Law No 22, 2001 mandated Special Task Force for Upstream Oil and Gas Business Activities to oversee upstream activity done by oil and gas contractors. Contractors conduct rig procurement processes with their Owner Estimate in alignment to Presidential decree No 12, 2021 and Summary of Procedural Guidelines of 007, 2017.By this reason, legal certainty is needed to deal with problems at implementation level. Two legal issues research, regulation and preparation implementation of Owner Estimate Value in Rig contract. The research analysis is using normative juridical which are supported by empirical studies. Owner Estimate preparation guidelines provide multiple interpretations, inconsistencies and a legal vacuum. In practice, problems related to aspects of legal certainty, Owner Estimate offers are not confidential and/or confidential, extreme price cut due to offers below 80% of Owner Estimate are being allowed, the existence of negotiations even though the price offer is already the lowest and below Owner Estimate . It opens for conspiracy in the procurement. It is necessary to amend Perpres and Procedural Guidelines of Special Task Force for Upstream Oil and Gas Migas Number 007 achieving compliance to the principles of agreement, legal certainty and fair business. Regulation change will provide legal certainty, efficiency and effectiveness so Special Task Force for Upstream Oil and Gas Migas, oil and gas contractors and Rig Providers can conduct upstream business activities properly, optimally to support Indonesian social welfare.</p><div> </div>

Dietary L-carnitine supplementation for heat stressed juvenile pearl gentian grouper(Epinephelusllanolatus (Epinephelus♂×Epinephelusfuscoguttatus♀): Effects on the antioxidant enzyme, survival, and gene expression

The effects of increasing dietary inclusion levels of L-carnitine at 0 (control group) 200, 400, 600, 1200, 1400, and 1600 mg/kg were evaluated in juvenile hybrid groupers exposed to heat shock stress. The feeding trial was conducted for eight weeks. After the feeding trial, hybrid groupers were subjected to a heat stress test for an hour at a temperature of 36 °C to determine the influence of the treatments on survival, biochemical parameters, and gene expression. The results of the current study showed that the survival rate of hybrid grouper was low in fish fed the control diet. A large number of survivors were observed in the treatment group with 400 mg/kg L-carnitine supplementation (LC 400), obtaining the highest survival rate. Heat stress decreased (P < 0.05) the activities of alkaline phosphatase and acid phosphatase in the control group but was increased in fish fed the LC 400 diet. Additionally, in the LC 400 treatment, malondialdehyde content decreased considerably (P < 0.05) compared to LC0. Hybrid grouper exposed to a high temperature of 36 °C for 1 h without L-carnitine (LC0, control group) supplementation showed the most increased Aspartate Aminotransferase activity (2.04 U L−1). Additionally, the LC 400 group reached the maximal value for the expressions of genes in the PPARs (peroxisome proliferator-activated receptors) signaling pathway, which showed a tendency of downregulation and, subsequently, up-regulation. The gene expression of FAS (fatty acid synthase) was discovered upstream and downstream (P < 0.05). The lowest mRNA level was found in the lowest L-carnitine supplementation treatment (200 mg/kg). A CPT-1 (carnitine palmitoyltransferase) that controls fatty acid oxidation showed upstream and downstream activity in response to increasing doses of L-carnitine supplementation. Our findings showed that dietary supplementation with L-carnitine 400 mg/kg reduced heat stress-related mortality and oxidative damage by enhancing the survival and oxidative enzymes of grouper, which provides a nutritional method of minimizing the consequences of heat exposure.

Isolation of the Anti-Inflammatory Agent Myceliostatin from a Methionine-Enriched Culture of Myceliophthora thermophila ATCC 42464.

Safe and effective nonsteroidal anti-inflammatory drugs are needed. Meanwhile, addition of amino acids to cultures of microorganisms is likely to increase the possibility of novel secondary metabolite isolation. In the course of screening for anti-inflammatory agents using cellular lipopolysaccharide (LPS)-induced nitric oxide (NO) production, two new related compounds with the myceliothermophin structure from a methionine-enriched culture of Myceliophthora thermophila ATCC 42464 were isolated. The new compounds have an additional methylthio group on the myceliothermophin structure and were named myceliostatins A and B. Both compounds inhibited LPS-induced NO production at nontoxic concentrations in macrophage-like mouse monocytic leukemia RAW264.7 cells. Myceliostatin B inhibited the expression of LPS-induced iNOS, IL-6, and IL-1β and the upstream NF-κB activity in situ and in vitro. Finally, it was found to inhibit NF-κB binding to DNA in the reconstruction system with purified p65. Myceliostatin B also inhibited LPS-induced reactive oxygen species (ROS) production. Thus, myceliostatin B, a novel compound derived from M. thermophila, was found to be a new anti-inflammatory and antioxidant compound directly inhibiting NF-κB.

Educational Background, Work Experience and Infrastructure Impact on Health and Safety Standards Performance at PT ABC - East Java Operations Area

PT ABC is a national oil company focusing on upstream activity, exploration, development and exploitation that enforces occupational health and safety standards through the Health Safety Environment Management System (HSEMS) with systematic efforts through the Operational Excellent framework. Based on the preliminary research conducted, it was found that the performance of PT ABC's occupational health and safety standards had not reached the maximum value, therefore the research was conducted with the aim of knowing and analyzing the Influence of Educational Background, Work Experience and Infrastructure on the Achievement of Health and Safety Standards with Employee Information Literacy as Intervening Variables. The research method used quantitative research method. The study population was 120 employees in East Java Operation, with a sample of 90 respondents. Data collection uses surveying, observation and documentation techniques. Data analysis using Outer Model (Convergent Validity, Discriminant Validity, Composite Reliability, Average Variance Extracted, Cronbach Alpha) and Inner Model (Coefficient of Determination, Predictive Relevance, Goodness of Fit (Gof) index Test, Reliability Test). Hypothesis testing used full analysis of Structural Equation Modeling (SEM) models with smartPLS. The results showed that: 1)Educational background through information literacy affects the achievement of K3 Standards at PT ABC (2,028); 2)Work experience through information literacy affects the achievement of K3 standards at PT ABC (t = 2,190); and 3)Infrastructure through information literacy has no effect on the achievement of K3 Standards at PT ABC (t = 0.008).

Intra-Seasonal Features of Winter Extreme Cold Events in Northeast–North China and Synergistic Effects of Circulation Systems in Mid-High Latitude

Based on the daily minimum air temperature (Tmin) data from the China Meteorological Data Network and the NCEP/DOE reanalysis data, the intra-seasonal circulation characteristics and evolution of extreme cold events (ECEs) in Northeast–North China (NE-N) during the winter of 1979–2018 are explored, and the synergistic effects of key circulation systems in the mid-high latitude on ECEs are discussed. The results show that: (1) the winter daily Tmin in the NE-N region presents a significant low-frequency period of 10–30 d; during the cooling phases, a pair of cyclone–anticyclone in the lower troposphere moves southeastward, accompanying the intensifying Siberian High, and leads to the abnormal northerly; the developing wave trains in the middle troposphere result in enhancing and maintaining cold air; furthermore, the situation of the upper tropospheric jet weakening in the north and strengthening in the south is favorable for cold air to move southward and accumulate in the NE-N region. (2) There are two wave trains in the Eurasian at 200 hPa level. The north one moves southeastward through the Ural Mountains to the coast of East Asia, with the upstream wave activity flux dispersing to NE-N region, causing the northeast cold vortex to develop. The south one with relatively weak intensity disperses the wave flux northward, and enhances the cold vortex. (3) The key circulation systems of ECEs are the Siberian High, the Ural Mountain Blocking High, the Northeast Cold Vortex, and the East Asian Subtropical Jet. The Ural Mountains Blocking High leads four phases earlier than low temperature, and the rest of the systems are basically in phase with low temperature. The synergistic effect of circulation systems will lead to extended-range cold in the NE-N region.

The Histone Deacetylase Inhibitor ITF2357 (Givinostat) Targets Oncogenic BRAF in Melanoma Cells and Promotes a Switch from Pro-Survival Autophagy to Apoptosis.

Histone deacetylase inhibitors (HDACI) are epigenetic compounds that have been widely considered very promising antitumor agents. Here, we focus on the effects of the pan-HDAC inhibitor ITF2357 (Givinostat) in comparison with SAHA (Vorinostat) in melanoma cells bearing BRAF V600E oncogenic mutation. Our results indicate both ITF2357 and SAHA dose-dependently reduce the viability of BRAF-mutated SK-MEL-28 and A375 melanoma cells. The comparison of IC50 values revealed that ITF2357 was much more effective than SAHA. Interestingly, both inhibitors markedly decreased oncogenic BRAF protein expression levels, ITF2357 being the most effective compound. Moreover, the BRAF decrease induced by ITF2357 was accompanied by a decrease in the level of phospho-ERK1/2. The inhibitor of upstream MEK activity, U0126, reduced ERK1/2 phosphorylation and dramatically potentiated the antitumor effect of ITF2357, exacerbating the reduction in the BRAF level. ITF2357 stimulated an early pro-survival autophagic response, which was followed by apoptosis, as indicated by apoptotic markers evaluation and the protective effects exerted by the pan-caspase inhibitor z-VADfmk. Overall, our data indicate for the first time that ITF2357 targets oncogenic BRAF in melanoma cells and induces a switch from autophagy to classic apoptosis, thus representing a possible candidate in melanoma targeted therapy.

Fbxo45-mediated NP-STEP46 degradation via K6-linked ubiquitination sustains ERK activity in lung cancer.

Lung cancer is one of the most threatening malignant tumors to human health. Epidermal growth factor receptor (EGFR)‐targeted therapy is a common and essential means for the clinical treatment of lung cancer. However, drug resistance has always affected the therapeutic effect and survival rate in non‐small cell lung cancer (NSCLC). Tumor heterogeneity is a significant reason, yielding various drug resistance mechanisms, such as EGFR‐dependent or ‐independent extracellular signal‐regulated kinase 1 and/or 2 (ERK1/2) activation in NSCLC. To examine whether this aberrant activation of ERK1/2 is related to the loss of function of its specific phosphatase, a series of in vitro and in vivo assays were performed. We found that F‐box/SPRY domain‐containing protein 1 (Fbxo45) induces ubiquitination of NP‐STEP46 , an active form of striatal‐enriched protein tyrosine phosphatase, with a K6‐linked poly‐ubiquitin chain. This ubiquitination led to proteasome degradation in the nucleus, which then sustains the aberrant level of phosphorylated‐ERK (pERK) and promotes tumor growth of NSCLC. Fbxo45 silencing can significantly inhibit cell proliferation and tumor growth. Moreover, NSCLC cells with silenced Fbxo45 showed great sensitivity to the EGFR tyrosine kinase inhibitor (TKI) afatinib. Here, we first report this critical pERK maintenance mechanism, which might be independent of the upstream kinase activity in NSCLC. We propose that inhibiting Fbxo45 may combat the issue of drug resistance in NSCLC patients, especially combining with EGFR‐TKI therapy.