Active Factor Research Articles

Increasing carotenoid production in Xanthophyllomyces dendrorhous/Phaffia rhodozyma: SREBP pathway activation and promoter engineering

The yeast Xanthophyllomyces dendrorhous synthesizes astaxanthin, a high-value carotenoid with biotechnological relevance in the nutraceutical and aquaculture industries. However, enhancing carotenoid production through strain engineering remains an ongoing challenge. Recent studies have demonstrated that carotenogenesis in X. dendrorhous is regulated by the SREBP pathway, which includes the transcription factor Sre1, particularly in the mevalonate pathway that also produces precursors used for ergosterol synthesis. In this study, we explored a novel approach to enhance carotenoid synthesis by replacing the native crtE promoter, which drives geranylgeranyl pyrophosphate synthesis (the step where carotenogenesis diverges from ergosterol biosynthesis), with the promoter of the HMGS gene, which encodes 3-hydroxy-3-methylglutaryl-CoA synthase from the mevalonate pathway. The impact of this substitution was evaluated in two mutant strains that already overproduce carotenoids due to the presence of an active Sre1 transcription factor: CBS.cyp61-, which does not produce ergosterol and strain CBS.SRE1N.FLAG, which constitutively expresses the active form of Sre1. Wild-type strain CBS6938 was used as a control. Our results showed that this modification increased the crtE transcript levels more than threefold and fourfold in CBS.cyp61−.pHMGS/crtE and CBS.SRE1N.FLAG.pHMGS/crtE, respectively, resulting in 1.43-fold and 1.22-fold increases in carotenoid production. In contrast, this modification did not produce significant changes in the wild-type strain, which lacks the active Sre1 transcription factor under the same culture conditions. This study highlights the potential of promoter substitution strategies involving genes regulated by Sre1 to enhance carotenoid production, specifically in strains where the SREBP pathway is activated, offering a promising avenue for strain improvement in industrial applications.

The codon optimised gene produces an active human basic fibroblastic growth factor in rice cell suspension culture

The coding sequence of human basic fibroblast growth factor (hbFGF) was optimised for expression in rice. An expression cassette was constructed by fusing the PCR-amplified RAmy3D promoter, along with its 5’UTR, 3’UTR, and terminator sequences, to the codon-optimised hbFGF sequence. This cassette was inserted into the pCAMBIA1304 shuttle vector, which also contained the RAmy3D signal peptide. Agrobacterium tumefaciens strain LBA 4404 was used to transform rice callus. Among the transformed lines, the callus expressing the highest level of bFGF (38.1 mg/kg fresh weight) was identified via ELISA and selected for establishing a cell suspension culture. Expression and secretion of the recombinant bFGF into the culture medium were observed three days after incubating the transgenic rice cells in sucrose-free medium. The presence of recombinant bFGF was confirmed through Western blot and SDS-PAGE analyses. Furthermore, the rice-derived bFGF effectively stimulated the proliferation of NIH/3T3 cells, demonstrating a comparable biological activity to that of commercial bFGF.

A lineage-specific nascent RNA assay unveils principles of gene regulation in tissue biology.

Gene regulatory mechanisms that modulate RNA Polymerase II activity are difficult to access in mammalian tissues composed of multiple cell lineages. Here, we develop a nascent RNA assay (PReCIS-seq) that measures lineage-specific transcriptionally-engaged Pol II on genes and DNA enhancer elements in intact mouse tissue. By employing keratinocytes as a prototype lineage, we unearth Pol II promoter-recruitment versus pause-release mechanisms operating in adult skin homeostasis. Moreover, we relate active enhancer proximity and transcription factor binding motifs on promoters to Pol II activity and promoter-proximal pausing level. Finally, we find Pol II firing rapidly into elongation on lineage identity genes and highly paused on cellular safeguarding genes in a context-dependent manner. Our work provides a basic platform to investigate mechanistic principles of gene regulation in individual lineages of complex mammalian tissues.

Soy Peptide Ameliorate TGF-β1-Mediated Osteoblast Differentiation through Smad and MAPK Signaling Pathways.

The aim of this study was to determine the osteogenic activity and mechanism of soybean peptide VVELLKAFEEKF (SOP) and the potential relationship between SOP and transforming growth factor-β1 (TGF-β1). The results show that SOP promotes MC3T3-E1 cell proliferation by altering cell progression. SOP induced cell differentiation and mineralization in a dose-dependent manner at 0.7-7 μM. Moreover, SOP stimulates osteoblast differentiation, which may be achieved through the activation of p38-MAPK and Smad2/3 signaling pathways. Furthermore, treatment with a TβRI inhibitor (SB525334) inhibited the phosphorylation levels of p38 and Smad2/3, which indicates the involvement of TβRI in the process of osteoblast differentiation caused by SOP. Besides, in non-FBS-cultured MC3T3-E1 cells, SOP and TGF-β1 promoted the phosphorylation of Smad2/3 and alkaline phosphatase (ALP) activity, but the effect was lost when SOP was incubated separately, indicating that SOP stimulated osteoblast differentiation by promoting TGF-β1 activity. In vivo, SOP significantly restores bone mineral density loss and behavioral deficits in a model of glucocorticoid-induced osteoporosis (GIOP) in zebrafish. These results suggest that SOP may have the function of promoting bone remodeling and may be used as a potential active factor for functional food development to prevent osteoporosis.

Long-Term Excretion of Roxadustat in Urine.

Roxadustat (FG-4592), an orally active hypoxia-inducible factor prolyl hydroxylase stabilizer, has been shown to enhance erythropoiesis by increasing endogenous erythropoietin. It is indicated for the treatment of anemia and chronic kidney disease and is approved for clinical use in several countries, including the European Union, Japan and others. Due to its reasonably anticipated performance-enhancing effect in athletes, roxadustat is prohibited for use in sports at all times. A few cases of adverse analytical findings in routine doping controls have been reported worldwide, some of which were claimed to be the result of contaminated dietary supplements. The present study offers new data demonstrating the long-term excretion pattern of roxadustat. Even after a single-dose administration, roxadustat can remain detectable in urine for 8 months, albeit at very low concentrations (<10 pg/mL). Following three times a week treatment with 70 to 100 mg of roxadustat, the drug was still detectable in the urine of anemic patients for between 9 and 18 months after treatment was discontinued. Lastly, an athlete who admitted use of roxadustat for almost a year (50 mg 3 to 5 times a week) has now tested positive multiple times over the course of 15 months (the first test being 12 months after the drug was discontinued), with an estimated concentration of roxadustat between 3 and 8 pg/mL. Altogether, these findings indicate the unusually prolonged terminal excretion kinetics of roxadustat, a property that testing authorities should consider in their results management process.

Efficient photocatalytic degradation of tetracycline and its derivatives by green recyclable PAN/Bi2WO6/Cu2O nanofiber membrane

The use of tetracycline antibiotics in industry, healthcare, animal husbandry, agriculture, and aquaculture has resulted in excessive concentrations in a variety of aquatic environments. In this work, PAN/Bi2WO6/Cu2O nanofibrous membranes (PBC ENMs) with photocatalytic degradation performance were successfully prepared using electrostatic spinning technique, and the morphology of catalysts and PBC ENMs were characterised by SEM, BET and UV–Vis. The results demonstrated that the prepared nanofibrous membranes could achieve 97.05 % photocatalytic degradation of TC under visible light, and the degradation efficiencies of its derivatives, chlortetracycline (CTC) and oxytetracycline (OTC), reached 90.87 % and 85.12 %, respectively. Free radical trapping experiments and mechanistic analyses showed that·O2– is the main active factor in the degradation process. The highest degradation rate of 97.05 % was achieved at initial pH = 7.2.PBC ENMs adsorbed above 87.5 % after six cycles of the experiment. The highest degradation rate of 97.05 % was achieved at initial pH = 7.2 PBC ENMs adsorbed above 87.5 % after six cycles of the experiment. Based on the above advantages, the preparation process of PBC ENMs is simple, low-cost and has good catalytic effect, which provides a simple and efficient treatment means for the treatment of TC wastewater and has a broad application prospect.

Abstract C064: Mapping cellular plasticity through the lens of FRA1 during Kras G12D mediated pancreatic acinar to ductal metaplasia

Abstract Introduction: Acinar cells have been proposed as a cell-of-origin for pancreatic ductal adenocarcinoma (PDAC) after undergoing acinar to ductal metaplasia (ADM). ADM can be triggered by pancreatitis causing acinar cells to de-differentiate to a ductal-like state. We identify FRA1 (gene name Fosl1) as the most active transcription factor during Kras G12D acute pancreatitis-mediated injury. Herein, we explore the role of the FRA1 in the onset of ADM and neoplastic transformation. Methods: We generated tamoxifen (TAM)-inducible Ptf1aCre ERT ;Kras G12D ; Rosa26 YFP/YFP (TAM-KCY Fosl1 WT ) mice and bred in the Fosl1 fl/fl allele to create TAM- KCY Fosl1 KO mice and subjected them to caerulin (CCK analog) induced acute pancreatitis. First, we performed a time course of hematoxylin and eosin (H&amp;E) images from mice either with Fosl1 WT or Fosl1 KO after induction of acute pancreatitis to understand the functional role of FRA1 during acinar de-differentiation. Next, after snap-freezing pancreata at the Day 5 post-caerulein timepoint and extracting nuclei, we sorted YFP+ nuclei for snATAC sequencing and bulk-RNA sequencing. We developed a pseudotime model and gene-regulatory network (GRN) to understand the dynamic landscape as cells transitioned from normal acinar to late ADM. Finally, to determine the functional role of in tumorigenesis, we bred an inducible mutant p53 R172H gain- of-function allele into TAM-KCY Fosl1 WT/KO mice to create TAM-KPCY Fosl1 WT/KO mice. These mice were subjected to the same tamoxifen and acute pancreatitis protocol as TAM-KCY Fosl1 WT/KO mice and monitored for tumor growth and overall survival. Results: A time course of H&amp;E images demonstrated that FRA1 depletion slowed progression to maximum ADM in the first 5 days after caerulein treatment. We additionally observed a dramatic reduction in the amount of PanIN lesions formed between TAM-KCY Fosl1 WT and TAM-KCY Fosl KO mice, which occurred on day 7 in this caerulein model. Pseudotime analysis proposed a time point when FRA1 becomes active to prime ADM cells for recovery from inflammation and simultaneously undergo PanIN transformation. Furthermore, GRN analysis validated the differentially active transcription factors identified by pseudotime analysis of snATAC-seq. To elaborate on further timepoints, we observed a delay in the progression of TAM-KCY Fosl KO PanIN lesions at later Day 21, 8-week and 12-week timepoints. In the survival analysis, TAM-KPCY Fosl1 WT mice had a median survival time of 25.86 weeks, while TAM-KPCY Fosl1 KO mice survived for almost twice as long with a median survival time of 40.57 weeks. Histologically, the percentage of Ki-67- positive cells in TAM-KPCY Fosl1 WT tumors was significantly higher than in TAM-KPCY Fosl1 KO tumors, suggesting the loss of FRA1 reduce tumor aggressiveness. Conclusions: Our findings reveal that FRA1 is a critical mediator of ADM progression to PanIN and PDAC. Fosl1 genetic depletion can alter the kinetics of ADM formation and lead to a decrease in PanIN and eventual malignant transformation. Citation Format: Alina Li, Noriyuki Nishiwaki, Kensuke Sugiura, Kensuke Suzuki, Constanza Nicole Tapia Contreras, Dorsay Sadeghian, Anirban Maitra, Jason R Pitarresi, Rohit Chandwani, Peter A Sims, Anil K Rustgi. Mapping cellular plasticity through the lens of FRA1 during Kras G12D mediated pancreatic acinar to ductal metaplasia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C064.

Inhibition of bromodomain and extra-terminal proteins targets constitutively active NFκB and STAT signaling in lymphoma and influences the expression of the antiapoptotic proteins BCL2A1 and c-MYC

The antiapoptotic protein BCL2A1 is highly, but very heterogeneously expressed in Diffuse Large B-cell Lymphoma (DLBCL). Particularly in the context of resistance to current therapies, BCL2A1 appears to play an important role in protecting cancer cells from the induction of cell death. Reducing BCL2A1 levels may have therapeutic potential, however, no specific inhibitor is currently available. In this study, we hypothesized that the signaling network regulated by epigenetic readers may regulate the transcription of BCL2A1 and hence that inhibition of Bromodomain and Extra-Terminal (BET) proteins may reduce BCL2A1 expression thus leading to cell death in DLBCL cell lines. We found that the mechanisms of action of acetyl-lysine competitive BET inhibitors are different from those of proteolysis targeting chimeras (PROTACs) that induce the degradation of BET proteins. Both classes of BETi reduced the expression of BCL2A1 which coincided with a marked downregulation of c-MYC. Mechanistically, BET inhibition attenuated the constitutively active canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) signaling pathway and inhibited p65 activation. Furthermore, signal transducer of activated transcription (STAT) signaling was reduced by inhibiting BET proteins, targeting another pathway that is often constitutively active in DLBCL. Both pathways were also inhibited by the IκB kinase inhibitor TPCA-1, resulting in decreased BCL2A1 and c-MYC expression. Taken together, our study highlights a novel complex regulatory network that links BET proteins to both NFκB and STAT survival signaling pathways controlling both BCL2A1 and c-MYC expression in DLBCL.Graphical

FRA1 controls acinar cell plasticity during murine KrasG12D-induced pancreatic acinar to ductal metaplasia.

Acinar cells have been proposed as a cell-of-origin for pancreatic ductal adenocarcinoma (PDAC) after undergoing acinar-to-ductal metaplasia (ADM). ADM can be triggered by pancreatitis, causing acinar cells to de-differentiate to a ductal-like state. We identify FRA1 (gene name Fosl1) as the most active transcription factor during KrasG12D acute pancreatitis-mediated injury, and we have elucidated a functional role of FRA1 by generating an acinar-specific Fosl1 knockout mouse expressing KrasG12D. Using a gene regulatory network and pseudotime trajectory inferred from single-nuclei ATAC-seq and bulk RNA sequencing (RNA-seq), we hypothesized a regulatory model of the acinar-ADM-pancreatic intraepithelial neoplasia (PanIN) continuum and experimentally validated that Fosl1 knockout mice are delayed in the onset of ADM and neoplastic transformation. Our study also identifies that pro-inflammatory cytokines, such as granulocyte colony stimulating factor (G-CSF), can regulate FRA1 activity to modulate ADM. Our findings identify that FRA1 is a mediator of acinar cell plasticity and is critical for acinar cell de-differentiation and transformation.

Power factor preregulation in power supplies using modified single stage non-isolated interleaved Sepic converter with minimal part count

This paper pontificates on design and realization of low-cost single phase single stage modified interleaved Sepic (MILS) converter for power supplies. On contrary to the classical Sepic power converters, the introduced active power factor correction (APFC) converter involves simple idea of paralleling that enables low input and output ripples with minimal device count. The interleaving conceptualization also lessens current stresses and static losses. Also, this modified power processing converter reveals natural power factor correction (PFC) and zero current switching (ZCS) features by discontinuous conduction mode (DCM) operation. Furthermore, the practical corroboration of the proposed converter is built and tested for 250 W hardware model to affirm benefits with 92 % efficiency and their relevant outcomes are reported in this scope. Finally, the power quality (PQ) attributes like, input power factor (PF), total harmonic distortion (THD) over input current under stable and transient cases are disclosed to prove bettered PQ limits at the AC mains as prescribed by various IEEE-519 and IEC 61,000–3-2 standards.

Anti-HDGF antibody targets EGFR tyrosine kinase inhibitor-tolerant cells in NSCLC patient-derived xenografts.

Constitutively active mutant epidermal growth factor receptor (EGFR) is one of the major oncogenic drivers in NSCLC. Targeted therapy using EGFR tyrosine kinase inhibitor (TKI) is a firstline option in patients that have metastatic or recurring disease. However, despite the high response rate to TKI, most patients have a partial response, and the disease eventually progresses in 10 to 19 months. It is believed that drug-tolerant cells that survive TKI exposure during the progression-free period facilitate the emergence of acquired resistance. Thus, targeting the drug-tolerant cells could improve the treatment of NSCLC with EGFR mutations. We demonstrated here that EGFR mutant patient-derived xenograft (PDX) tumors responded partially to osimertinib despite near complete inhibition of EGFR activation. Signaling in AKT/mTOR and MAPK pathways could be reactivated shortly after initial inhibition. As a result, many tumor cells escaped drug killing and regained growth following about 35 days of continuous osimertinib dosing. However, when an antibody to hepatoma-derived growth factor (HDGF) was given concurrently with osimertinib, tumors showed complete or near-complete responses.There was significant prolongation of progression-free survival (PFS) of tumor-bearing mice as well. Immunohistochemistry and western blot analysis of tumors collected in the early stages of treatment suggest that increased suppression of the AKT/mTOR and MAPK pathways could be a mechanism that results in enhanced efficacy of osimertinib when it is combined with anti-HDGF antibody.

EFFICIENT DSP-BASED REAL-TIME IMPLEMENTATION OF ANFIS REGULATOR FOR SINGLE-PHASE POWER FACTOR CORRECTOR

As a widely used technology, active power factor corrector (A-PFC) circuits face many control challenges, such as nonlinearity and uncertainties. With more and more power electrical appliances that are connected to the utility grid, the A-PFC is for the task of improving the power quality (PQ) to meet the requirement of the international standards, and this results in great challenges for keeping the total harmonic distortion (THD) as long as a power factor in the desired ranges. To this end, this paper focuses on the simulation and real-time implementation of a combined adaptive neural-fuzzy inference system (ANFIS) and predictive current controller for a single-phase PFC rectifier. The proposed control method has a simple, low-cost structure for better response and robustness. The performance of the proposed control approach was evaluated in real-time based on the dSPACE 1104 digital signal processor for different reference and load conditions. The results obtained from simulation and experimental tests validate the superiority of the proposed approach by evidencing a unity power factor, lower THD, fast dynamic response, and robustness against fast load and output voltage variations.

A novel feedforward narrow-broadband hybrid active noise control system for excavator interior noise control

Excavator interior noise is a mixture of engine noise and impulsive noise produced by working device. Hybrid narrow-broadband active noise control (HANC) systems can efficiently eliminate the traditional mixed broad-narrowband noise. However, these HANC systems have drawbacks such as high computational complexity, unable to cope with impulsive noise and inability to obtain the best performance due to parameter selection method. To solve these problems, a novel feedforward narrow broadband HANC system consisting of four subsystems, namely, sinusoidal noise canceller (SNC) subsystem, robust broadband active noise control (RBANC) subsystem, delay narrowband active noise control (DNANC) subsystem, and supporting error calculating subsystem, is proposed. Combining the advantages of delayed least mean square algorithm in DNANC subsystem and Versoria criterion-based filtered-x least mean square algorithm in RBANC subsystem, both the computational efficiency and the robustness when encountering impulsive noise of the proposed HANC system are efficiently improved. In addition, the performance of the proposed HANC system is further improved by changing the key parameters selection method form trial-and-error method to improved particle swarm optimization (IPSO) algorithm with active factor. Both the superiority of the proposed HANC system over existing counterparts and the advantage of the IPSO algorithm with active factor in determining the key parameters are demonstrated by extensive simulations. Real-time HANC experiments in semi-anechoic chamber based on measured excavator interior mixed noise are conducted in this article. Experimental results illustrate that the proposed HANC system achieves good noise elimination performance and also being robust when encountering impulsive noise.

The Significance of Evolutionary Concepts in Biology for the Formation of Evolutionary and Ecological Thinking

This article is devoted to the philosophical analysis of the theoretical and methodological foundations of evolutionary and ecological thinking. The conceptual development of such thinking is a crucial direction in the advancement of modern life sciences. However, within the foundations of evolutionary and ecological interpretation across various biological fields, contradictions between evolutionary and ecological approaches are explicitly evident. This situation arises because the ecological approach views humans as an active factor in the evolution of their environment while simultaneously assuming their natural immutability, i.e., considering them the pinnacle of evolution. The author attempts to identify the principles for selecting evolutionary theories and concepts that underpin the formation of evolutionary and ecological thinking. In this context, the author addresses various branches of evolutionism, such as classical Darwinism, the synthetic theory of evolution, nomogenesis, autogenesis, orthogenesis, catastrophism, neo-Lamarckism, Autopoietic Theory, mutual aid, and symbiosis in evolution. The conclusion is drawn that effective evolutionary and ecological thinking cannot rely solely on the biological characteristics of evolutionism but requires a philosophical understanding of the cultural and historical status of humans in the world.

Eukaryotic AlaX provides multiple checkpoints for quality and quantity of aminoacyl-tRNAs in translation.

Translational fidelity relies critically on correct aminoacyl-tRNA supply. The trans-editing factor AlaX predominantly hydrolyzes Ser-tRNAAla, functioning as a third sieve of alanyl-tRNA synthetase (AlaRS). Despite extensive studies in bacteria and archaea, the mechanism of trans-editing in mammals remains largely unknown. Here, we show that human AlaX (hAlaX), which is exclusively distributed in the cytoplasm, is an active trans-editing factor with strict Ser-specificity. In vitro, both hAlaX and yeast AlaX (ScAlaX) were capable of hydrolyzing nearly all Ser-mischarged cytoplasmic and mitochondrial tRNAs; and robustly edited cognate Ser-charged cytoplasmic and mitochondrial tRNASers. In vivo or cell-based studies revealed that loss of ScAlaX or hAlaX readily induced Ala- and Thr-to-Ser misincorporation. Overexpression of hAlaX impeded the decoding efficiency of consecutive Ser codons, implying its regulatory role in Ser codon decoding. Remarkably, yeast cells with ScAlaX deletion responded differently to translation inhibitor treatment, with a gain in geneticin resistance, but sensitivity to cycloheximide, both of which were rescued by editing-capable ScAlaX, alanyl- or threonyl-tRNA synthetase. Altogether, our results demonstrated the previously undescribed editing peculiarities of eukaryotic AlaXs, which provide multiple checkpoints to maintain the speed and fidelity of genetic decoding.

FURTHER: A global study to evaluate furmonertinib in patients with EGFR mutant NSCLC including uncommon EGFR mutations (FURMO-002).

TPS8666 Background: Furmonertinib (AST2818) is an oral, highly brain-penetrant, and broadly active mutation-selective epidermal growth factor receptor ( EGFR) inhibitor engineered for broad activity and selectivity across EGFRmutations (mts) (1). Furmonertinib is approved in China for first-line advanced NSCLC with EGFR Ex19del or L858R mts based on the progression-free survival benefit observed in the Phase 3 study versus gefitinib (FURLONG). Furmonertinib has also demonstrated promising interim efficacy and safety in patients (pts) with NSCLC harboring EGFR exon 20 insertion (ex20ins) mts with a confirmed overall response rate (ORR) of 78.6% (n=28) by blinded independent central review (BICR) and a preliminary median duration of response (DoR) of 15.2 months in the front-line setting (FAVOUR study; see Han et al., WCLC 2023). Furmonertinib recently obtained FDA Breakthrough Therapy Designation for the treatment of pts with advanced NSCLC with EGFR ex20ins mts. P-loop and αC-helix Compressing (PACC) mts represent another subset of uncommon EGFR mts (2) that are similar to ex20ins mts in narrowing the drug-binding pocket; including G719X, S768I, E709X, L747X, V774M. Preclinical data indicating that furmonertinib is potent in models harboring EGFR PACC mts Developing efficacious, well-tolerated, and CNS-penetrant medicines for NSCLC pts with EGFR ex20ins mts and PACC mts remains an unmet need. Methods: FURTHER (FURMO-002) is the first global trial evaluating furmonertinib in NSCLC pts with EGFR and HER2 mts in North America, Europe, and the Asia-Pacific. FURTHER is a phase 1b, open-label, multicenter study in which pts will be treated orally with furmonertinib daily. For Stage 1 dose-escalation, the primary endpoint is incidence and severity of adverse events, including dose limiting toxicities and has been completed. For Stage 2 dose expansion, approximately 120 pts will be enrolled across 4 expansion cohorts. Stage 2 Cohorts 1-3 dose expansion cohorts will enroll pts with previously treated, locally advanced or metastatic NSCLC pts with either EGFR ex20ins mts, HER2 ex20ins mts, or EGFR activating mts, respectively. Cohorts 1-3 allow enrollment of pts with prior EGFR or HER2-directed therapy. Stage 2 Cohort 4 will enroll EGFR TKI-naïve NSCLC pts with EGFR PACC mts. Key inclusion criteria include documented EGFR or HER2 mts by local testing and measurable disease per RECIST v1.1. Stage 2 primary endpoint is ORR using RECIST v1.1. Key secondary endpoints include progression-free survival and overall survival. Stage 2 enrollment is ongoing. 1. Musib et al., NACLC 2022. 2. Robichaux et al., 2021. Clinical trial information: NCT05364073 .

Цервикалгия у пациентов с мигренью – коморбидная нозология или клинический аспект центральной сенситизации?

Relevance. The phenomenon of central sensitization occurs when physiological activity in nociceptive pathways increases and leads to abnormal sensitivity; it is defined as “increased sensitivity of nociceptive neurons of the central nervous system to their normal or subthreshold afferent input,” according to the definition provided by the International Association for the Study of Pain (IASP). The excitability of spinal cord neurons significantly modifies the gain of the somatosensory system. Chronic pain syndromes, anxiety-depressive disorder, sleep disorders are currently very common in the population, significantly reducing the quality of life of the population; the pathogenesis of these nosologies lies in central sensitization. Objective. To study the clinical manifestations of central sensitization in patients with episodic migraine associated with neck pain or cervicogenic headache. Materials and methods. The longitudinal prospective study included 180 patients, divided into 3 groups: 1) patients with a combination of migraine and cervicogenic headache – 60 people (study group); 2) patients with a combination of migraine and cervicalgia diagnoses – 60 people (control group); 3) patients diagnosed with migraine without complaints of pain and limitation of movements in the cervical spine – 60 people (additional group). Results. In patients with migraine and comorbid cervical headache, more pronounced central sensitization was revealed when compared with comorbid cervicalgia. Myofascial pain syndrome involving the trapezius and temporal muscles can resolve on its own with specific migraine therapy with monoclonal antibodies, however, to relieve tension and soreness in the masseter and inferior oblique muscles, the addition of therapeutic exercises and gentle manual techniques is more effective. Taking into account the identified direct relationships of moderate strength between the number of painful points of exit of the trigeminal nerve, the muscles of the pericranial region involved, as well as the effect of treatment of migraine attacks with monoclonal antibodies, it can be concluded that central sensitization is more pronounced when the masseter and inferior oblique muscles are involved. Conclusions. During examination of patients with migraine with comorbid active cervicalgic factor or even if it is absence, it is necessary to make a thorough examination of the facial and cranioverebral region muscles, even in the absence of patient complaints of pain in the face or neck, and also prescribe specific therapeutic exercises to increase the effectiveness of treatment. In all patients with migraine, regardless of chronicity, it is necessary to assess the intensity of central sensitization for timely and more complete provision of medical care.

Study of Steroid Estrogen Loss in Soil after the Application of Composted Manure as a Fertilizer

Steroid estrogens (SEs) play a significant role as endocrine-disrupting substances, and one of their major sources is animal manure. However, there is limited information available regarding the loss of SEs in farmland soil after the application of commercial composted animal manure or fertilizers. To address this gap, our study aimed to simulate rainfall and flood irrigation scenarios and investigate the loss characteristics of SEs, as well as Chemical Oxygen Demand (COD), Total Nitrogen (TN), and Total Phosphorus (TP) in runoff from soil–manure mixtures. The results demonstrated that the loss concentrations of SEs (73.1 ng/L of the mean E2β active equivalent factor) presented a potential environmental risk. Additionally, substituting composted manure with commercial organic fertilizers lead to a significant reduction in TP (maximum 56%) and TN (maximum 24%) loss. Consequently, the application of commercial organic fertilizers offers considerable advantages in maintaining nitrogen and phosphorus fertilization efficiency while controlling SEs loss. Furthermore, our study explored the synergistic pollution mechanism among these pollutants and observed significant correlations between SEs and TN, TP, and COD loss concentrations, indicating the simultaneous occurrence and migration of these pollutants in agricultural non-point source pollution. These results provide valuable insights into the environmental risk associated with SEs from agricultural non-point sources.

The Indonesian House of Representatives and its role during democratic regression

ABSTRACT Parliament and the separation of power are essential elements of democratic consolidation. However, what role does parliament take if democracy is in retreat? Following a comparative approach, this article analyses the role of the Indonesian House of Representatives (DPR) during a process of democratic decline. Indonesia is seen as a success story of democratisation. Since 1998, the country has transitioned from an autocratic regime to a vibrant multi-party democracy. However, twenty years on, academics have been highlighting far-reaching patterns of democratic regression. Whereas there have been studies of the democratic setback globally and more in-depth analyses of aspects of the Indonesian democracy in retreat, there has been little attention on the role of the country’s legislature in this situation. This article analyses how the DPR has been executing its legislative mandate during Joko Widodo’s second presidential term from 2019 to 2024. Examining three cases of legislation, it found the DPR is not actively resisting the democratic decline. On the contrary, the hypothesis has been proven that the parliament is an active factor in autocratic legalism. This has been most visible in the reduced scrutiny of draft legislation, limited deliberation, and narrow public consultation to serve elite interests. In addition to a weakened legislative role by the DPR, there has been reduced oversight and scrutiny of government policies, visible through limited questioning of ministers or inquiries into the use of the budget and the appointment of government-favoured candidates to national commissions, courts, and state bodies. Moreover, the nature of a consensus-based decision-making system has allowed the executive to effectively control the parliament, instead of the other way around. This is despite some reminders from the Constitutional Court to respect the legal provisions that require deliberation and consultation of the people.

Accurate and Efficient Simulation Models for Power Electronics Transformers Based on Series-Connected Active Unity Power Factor Rectifier Modules

This paper contributes an efficient simulation technique for input-series output-parallel multilevel power electronics transformers based on active unity-power-factor rectifiers as building blocks. The technical motivation of the work comes from the fact that the computational burden for the simulation of these technologies tends to become unaffordable as the number of modules grows when using commercial software blocksets. This paper presents a new method to drastically reduce the simulation complexity by simplifying the switching rules: in a three-phase circuit, each phase zero-crossing condition is implemented by a single and simple algebraic rule, so the complex calculations for determining the conduction state of each single diode are removed from the model. The computational enhancement and accuracy of the proposed technique are proved by experimental verification using a single-phase single-cell prototype together with multiple simulations of full-scale systems of different sizes.