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Clear cell renal cell carcinoma is a prevalent urological malignancy, imposing substantial burdens on both patients and society. In our study, we used bioinformatics methods to select four putative target genes associated with EMT and prognosis and developed a nomogram model which could accurately predicting 5-year patient survival rates. We further analyzed proteome and single-cell data and selected PLCG2 and TMEM38A for the following experiments. Overexpression models of PLCG2 and TMEM38A were generated in Caki-1 and 786-O cell lines using plasmids. The in vitro experiments demonstrated that both of them exerted pro-apoptotic effects on Caki-1 and 786-O cells, inducing G2/M phase arrest, inhibiting proliferation, and suppressing EMT. In summary, we identified potential tumor suppressor factors and stratified ccRCC patients into high-risk and low-risk groups based on these factors. Furthermore, we elucidated the impact of PLCG2 and TMEM38A in Caki-1 and 786-O cell lines, offering novel avenues for therapeutic target exploration. [ABSTRACT FROM AUTHOR]

Deactivation of the mitochondrial pyruvate dehydrogenase complex (PDC) is important for the metabolic switching of cancer cell from oxidative phosphorylation to aerobic glycolysis. Studies examining PDC activity regulation have mainly focused on the phosphorylation of pyruvate dehydrogenase (E1), leaving other post-translational modifications largely unexplored. Here, we demonstrate that the acetylation of Lys 488 of pyruvate dehydrogenase complex component X (PDHX) commonly occurs in hepatocellular carcinoma, disrupting PDC assembly and contributing to lactate-driven epigenetic control of gene expression. PDHX, an E3-binding protein in the PDC, is acetylated by the p300 at Lys 488, impeding the interaction between PDHX and dihydrolipoyl transacetylase (E2), thereby disrupting PDC assembly to inhibit its activation. PDC disruption results in the conversion of most glucose to lactate, contributing to the aerobic glycolysis and H3K56 lactylation-mediated gene expression, facilitating tumor progression. These findings highlight a previously unrecognized role of PDHX acetylation in regulating PDC assembly and activity, linking PDHX Lys 488 acetylation and histone lactylation during hepatocellular carcinoma progression and providing a potential biomarker and therapeutic target for further development. [ABSTRACT FROM AUTHOR]

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by an overactive immune response, particularly involving excessive production of type I interferons. This overproduction is driven by the phosphorylation of IRF7, a crucial factor in interferon gene activation. Current treatments for SLE are often not very effective and can have serious side effects. Methods: Our study introduces clobenpropit, a histamine analogue, as a potential new therapy targeting the CXCR4 receptor to reduce IRF7 phosphorylation and subsequent interferon production. We employed various laboratory techniques to investigate how clobenpropit interacts with CXCR4 and its effects on immune cells from healthy individuals and SLE patients. Results: Clobenpropit binds effectively to CXCR4, significantly inhibiting IRF7 phosphorylation and reducing interferon production. Additionally, clobenpropit lowered levels of pro-inflammatory cytokines in a mouse model of lupus, demonstrating efficacy comparable to the standard treatment, prednisolone. Discussion: These results suggest that clobenpropit could be a promising new treatment for SLE, offering a targeted approach with potential advantages over current therapies. [ABSTRACT FROM AUTHOR]

AbstractThe diagnosis of myeloid neoplasms with plasmacytoid dendritic cell (pDC) differentiation can be challenging due to immunophenotypic overlap requiring detailed characterization by flow cytometry and immunohistochemistry. We describe two patients with a history of myeloproliferative neoplasm (MPN) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN) who presented years later with leukocytosis, lymphadenopathy, splenomegaly, and cachexia, with rapid clinical deterioration and death. Lymph node biopsy specimens revealed involvement by myeloid sarcoma with prominent pDC differentiation. Furthermore, concomitant bone marrow aspiration and biopsy showed involvement by the underlying myeloid neoplasm but no parallel expansion of pDC, as seen in the lymph node specimens, suggesting that pDC differentiation is fostered in the lymph node microenvironment. These two cases could represent the “myeloid sarcoma” counterpart of the recently described acute myeloid leukemia with pDC differentiation (pDC-AML). Although patients with pDC-AML have an inferior outcome when treated with conventional therapies, the recognition of a pDC component in these neoplasms potentially expands the therapeutic options [ABSTRACT FROM AUTHOR]

To reduce the fuel consumption rate of the pulse detonation combustor (PDC), an experimental study was carried out to study the influence of the injector aperture on the atomization particle size of the pneumatic atomization injector and its combustion characteristics of the PDC. The test used gasoline\air as the fuel and oxidant, tested the atomization particle size and obtained the detonation characteristics of PDC. The research results show that the atomization particle size of the injector under the three apertures decreases with the increase of the mixed air volume and increases with the increase of the fuel flow rate. The injector atomization effect is better when the aperture is 1.4 mm, the atomization particle size range is 71.8–119.8 μm. PDC using different injectors can achieve stable operation in the range of 5–20 Hz. Under the same working conditions, the smaller the injector aperture, the higher the average detonation pressure of the PDC. [ABSTRACT FROM AUTHOR]

Intratumoral TLR9 agonists and anti-PD-1 produce clinical responses and broad immune activation. We conducted a single-arm study of neoadjuvant TLR9 agonist vidutolimod combined with anti-PD-1 nivolumab in high-risk resectable melanoma. In 31 evaluable patients, 55% major pathologic response (MPR) was observed, meeting primary endpoint. MPR was associated with necrosis, and melanophagocytosis with increased CD8+ tumor-infiltrating lymphocytes and plasmacytoid dendritic cells (pDCs) in the tumor microenvironment, and increased frequencies of Ki67+CD8+ T cells peripherally. MPRs had an enriched pre-treatment gene signature of myeloid cells, and response to therapy was associated with gene signatures of immune cells, pDCs, phagocytosis, and macrophage activation. MPRs gut microbiota were enriched for Gram-negative bacteria belonging to the Bacteroidaceae and Enterobacteriaceae families and the small subgroup of Gram-negative Firmicutes. Our findings support that combined vidutolimod and nivolumab stimulates a broad anti-tumor immune response and is associated with distinct baseline myeloid gene signature and gut microbiota. ClinicalTrials.gov identifier: NCT03618641. [Display omitted] • Neoadjuvant intratumoral vidu/nivo produces pathologic responses in stage III melanoma • Response is linked to myeloid cells, pDCs, and CD8+ T cells within tumor • Responder gut microbiota signatures vidu/nivo are distinct from those in anti-PD-1 Neoadjuvant immunotherapy improves relapse-free survival in stage III melanoma. The novel combination of intratumoral vidu/nivo produces 55% major pathologic response (MPR) with an acceptable safety profile. MPR was associated with intratumoral myeloid cells, pDCs, and CD8+ TIL. Gut microbiota signatures in vidu/nivo MPR are distinct from those in anti-PD-1 responders. [ABSTRACT FROM AUTHOR]

Cobalt removal is considered a common method to improve the performance of polycrystalline diamond compact (PDC). To effectively reduce the pollution during the process of cobalt removal, a neutral electrolyte was used in this work to remove cobalt from PDC by electrolysis with ultrasonication. The electrode process and mass transfer model of cobalt removal in a NaCl–KCl solution were established by performing electrochemical impedance spectroscopy (EIS) measurements. Different electrode potentials and electrolytic durations were set to investigate the limits of cobalt removal in the neutral electrolyte. Cobalt removal was assessed by conducting potentiodynamic polarisation, scanning electron microscopy (SEM), and energy dispersive spectroscopy (EDS) measurements. The ImageJ2x image analysis software was used to study the collected spectra. The experimental results indicated that cobalt was successfully removed in the neutral electrolyte and that ultrasonication enhanced its removal. The optimal electrode potential for cobalt removal in the NaCl–KCl solution was less than 500 mV or more than 2000 mV. As the electrolysis time increased, the porosity of the PDC surface first increased to 9.4 % and then decreased to 7.2 %, and the depth of cobalt removal was up to 224 μm. Over time, the rate of cobalt removal decreased, suggesting that the efficacy of ultrasonication in promoting the cobalt removal process gradually weakened as electrolysis products continued to accumulate. [ABSTRACT FROM AUTHOR]

IntroductionSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by an overactive immune response, particularly involving excessive production of type I interferons. This overproduction is driven by the phosphorylation of IRF7, a crucial factor in interferon gene activation. Current treatments for SLE are often not very effective and can have serious side effects.MethodsOur study introduces clobenpropit, a histamine analogue, as a potential new therapy targeting the CXCR4 receptor to reduce IRF7 phosphorylation and subsequent interferon production. We employed various laboratory techniques to investigate how clobenpropit interacts with CXCR4 and its effects on immune cells from healthy individuals and SLE patients.ResultsClobenpropit binds effectively to CXCR4, significantly inhibiting IRF7 phosphorylation and reducing interferon production. Additionally, clobenpropit lowered levels of pro-inflammatory cytokines in a mouse model of lupus, demonstrating efficacy comparable to the standard treatment, prednisolone.DiscussionThese results suggest that clobenpropit could be a promising new treatment for SLE, offering a targeted approach with potential advantages over current therapies.

It is well known that medication adherence is critical to patient outcomes and can decrease patient mortality. The Pharmacy Quality Alliance (PQA) has recognized and identified medication adherence as an important indicator of medication‐use quality. Hence, there is a need to use the right methods to assess medication adherence. The PQA has endorsed the proportion of days covered (PDC) as the primary method of measuring adherence. Although easy to calculate, the PDC has however several drawbacks as a method of measuring adherence. PDC is a deterministic approach that cannot capture the complexity of a dynamic phenomenon. Group‐based trajectory modeling (GBTM) is increasingly proposed as an alternative to capture heterogeneity in medication adherence. The main goal of this paper is to demonstrate, through a simulation study, the ability of GBTM to capture treatment adherence when compared to its deterministic PDC analogue and to the nonparametric longitudinal K‐means. A time‐varying treatment was generated as a quadratic function of time, baseline, and time‐varying covariates. Three trajectory models are considered combining a cat's cradle effect, and a rainbow effect. The performance of GBTM was compared to the PDC and longitudinal K‐means using the absolute bias, the variance, the c‐statistics, the relative bias, and the relative variance. For all explored scenarios, we find that GBTM performed better in capturing different patterns of medication adherence with lower relative bias and variance even under model misspecification than PDC and longitudinal K‐means. [ABSTRACT FROM AUTHOR]

Polycrystalline diamond compacts (PDC) with three different substrate geometries and trimodal diamond particle formulation were fabricated. The properties of prepared PDC including Vickers hardness, toughness, wear performance, and thermal stability were evaluated. The microscopic features including morphology, elemental and phase composition, and residual stress state were systematically investigated. The optimal substrate contributing to best comprehensive properties of PDC was singled out. Discrepancies in the properties of PDCs with different substrate geometries were mainly in fracture toughness and impact toughness, with maximum and minimum values of 6.54 MPa m1/2/3120 J and 5 MPa m1/2/1680 J, respectively. The best wear performance was 5.88 mm2/60P. The results showed that the tendency of wear performance was consistent with toughness and thermal stability, showing a strong correlation. The substrate geometry affected the morphology and composition of the cobalt transition layer in the interface, which had a significant impact on its toughness. Differences in residual stress states induced by the interfacial geometries were also important determining PDC's impact toughness. [ABSTRACT FROM AUTHOR]

This study analysed and discussed the friction and wear properties, as well as the interface evolution behaviour of polycrystalline diamond compact (PDC) under various base oils, through conducting friction experiments on PDC/Si3N4 with different base oils. The friction and lubrication mechanism of PDC under different base oils were examined using scanning electron microscopy (SEM), x‐ray energy dispersive spectrometry (EDS), three‐dimensional white light interferometry, and Raman spectroscopy. The results of the study demonstrated that PDC exhibited the best friction and wear performance when lubricated with synthetic oil PAO, followed by castor oil. The inferior performance of paraffin oil can be attributed to its low viscosity, resulting in a lower presence of ions capable of passivating the carbon dangling bond. Consequently, paraffin oil displayed inadequate oxidation stability and increased susceptibility to oil film destruction, ultimately leading to suboptimal friction and wear characteristics. Overall, this study provides valuable insights for industrial applications, aiding in the selection of appropriate base oils as cutting fluids for PDC cutting tools and enhancing the friction and wear properties of PDC. [ABSTRACT FROM AUTHOR]

Background: Anticoagulation therapy plays a crucial role in the management of atrial fibrillation (AF) by significantly reducing the risk of stroke. Direct oral anticoagulants (DOAC) became preferred over warfarin due to their superior safety and efficacy profile. Assessing adherence to anticoagulation therapy is necessary in clinical practice for optimising patient outcomes and treatment efficacy, thus emphasising its significance. Methods: A retrospective study utilised the Latvian National Health Service reimbursement prescriptions database, covering prescriptions for AF and flutter from January 2012 to December 2022. The proportion of days covered method was selected for adherence assessment, categorising it into three groups: (1) below 80%, (2) between 80% and 90%, and (3) above 90%. Results: A total of 1,646,648 prescriptions were analysed. Dabigatran prescriptions started declining after 2020, coinciding with a decrease in warfarin prescriptions since 2018. The total adherence levels to DOAC therapy were 69.4%. Only 44.2% of users achieved an adherence level exceeding 80%. The rate of paper prescriptions decreased from 98.5% in 2017 to 1.3% in 2022. Additionally, the utilisation of international non-proprietary names reached 79.7% in 2022. Specifically, 16.7% of patients selected a single pharmacy, whereas 27.7% visited one or two pharmacies. Meanwhile, other patients obtained medicines from multiple pharmacies. Conclusions: The total adherence level to DOAC therapy is evaluated as low and there was no significant difference in age, gender, or "switcher" status among adherence groups. Physicians' prescribing habits have changed over a decade. [ABSTRACT FROM AUTHOR]

To investigate the tribological properties of polycrystalline diamond compact (PDC), different additives including graphene, molybdenum disulfide (MoS 2), and a combination of graphene + MoS 2 were utilized. The microstructure and chemical reactions of PDC were analyzed using techniques such as atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS). The focus was on the formation and degradation of the friction film. The findings revealed that both graphene + MoS 2 exhibit excellent lubrication properties, forming a protective friction film on the surface of PDC. Furthermore, the combined use of graphene + MoS 2 demonstrated a synergistic effect, resulting in enhanced wear resistance of PDC compared to the individual use of graphene or MoS 2 alone. [ABSTRACT FROM AUTHOR]

Background: Globally, esophageal squamous cell carcinoma (ESCC) stands out as a common cancer type, characterized by its notably high rates of occurrence and mortality. Recent advancements in treatment methods, including immunotherapy, have shown promise, yet the prognosis remains poor. In the context of tumor development and treatment outcomes, the tumor microenvironment (TME), especially the function of dendritic cells (DCs), is significantly influential. Our study aims to delve deeper into the heterogeneity of DCs in ESCC using single-cell RNA sequencing (scRNA-seq) and bulk RNA analysis. Methods: In the scRNA-seq analysis, we utilized the SCP package for result visualization and functional enrichment analysis of cell subpopulations. CellChat was employed to identify potential oncogenic mechanisms in DCs, while Monocle 2 traced the evolutionary trajectory of the three DC subtypes. CopyKAT assessed the benign or malignant nature of cells, and SCENIC conducted transcription factor regulatory network analysis, offering a preliminary exploration of DC heterogeneity. In Bulk-RNA analysis, we constructed a prognostic model for ESCC prognosis and immunotherapy response, based on DC marker genes. This model was validated through quantitative PCR (qPCR) and immunohistochemistry (IHC), confirming the gene expression levels. Results: In this study, through intercellular communication analysis, we identified GALECTIN and MHC-I signaling pathways as potential oncogenic mechanisms within dendritic cells. We categorized DCs into three subtypes: plasmacytoid (pDC), conventional (cDC), and tolerogenic (tDC). Our findings revealed that pDCs exhibited an increased proportion of cells in the G2/M and S phases, indicating enhanced cellular activity. Pseudotime trajectory analysis demonstrated that cDCs were in early stages of differentiation, whereas tDCs were in more advanced stages, with pDCs distributed across both early and late differentiation phases. Prognostic analysis highlighted a significant correlation between pDCs and tDCs with the prognosis of ESCC (P< 0.05), while no significant correlation was observed between cDCs and ESCC prognosis (P = 0.31). The analysis of cell malignancy showed the lowest proportion of malignant cells in cDCs (17%), followed by pDCs (29%), and the highest in tDCs (48%), with these results being statistically significant (P< 0.05). We developed a robust ESCC prognostic model based on marker genes of pDCs and tDCs in the GSE53624 cohort (n = 119), which was validated in the TCGA-ESCC cohort (n = 139) and the IMvigor210 immunotherapy cohort (n = 298) (P< 0.05). Additionally, we supplemented the study with a novel nomogram that integrates clinical features and risk assessments. Finally, the expression levels of genes involved in the model were validated using qPCR (n = 8) and IHC (n = 16), thereby confirming the accuracy of our analysis. Conclusion: This study enhances the understanding of dendritic cell heterogeneity in ESCC and its impact on patient prognosis. The insights gained from scRNA-seq and Bulk-RNA analysis contribute to the development of novel biomarkers and therapeutic targets. Our prognostic models based on DC-related gene signatures hold promise for improving ESCC patient stratification and guiding treatment decisions. [ABSTRACT FROM AUTHOR]

Simple Summary: The extraordinary growth in the global pharmaceutical industry has extended to include peptides, which are amino acids linked together with an amide bond. Due to their well-tolerable safety profile and specificity, therapeutic peptides offer a means to address unmet medical challenges. A well-known example of a commonly administered peptide is insulin. Peptides are considered excellent complements and, in some cases, preferable alternatives to both small molecules such as paracetamol and very large antibodies. At present, around 100 peptide drugs are available on the global market, with ongoing research yielding over 150 peptides in clinical development and an additional 400–600 peptides undergoing preclinical studies. Peptides play a crucial role in cancer research and treatment, and they can be involved in various aspects of cancer development, detection, and treatment. These medicines demonstrate exceptional efficacy in combating cancer, contributing to improved survival rates for cancer patients. The United States Food and Drug Administration (FDA) has approved a plethora of peptide-based drugs as effective drugs in cancer therapy. Peptides possess high specificity, permeability, target engagement, and a tolerable safety profile. They exhibit selective binding with cell surface receptors and proteins, functioning as agonists or antagonists. They also serve as imaging agents for diagnostic applications or can serve a dual-purpose as both diagnostic and therapeutic (theragnostic) agents. Therefore, they have been exploited in various forms, including linkers, peptide conjugates, and payloads. In this review, the FDA-approved prostate-specific membrane antigen (PSMA) peptide antagonists, peptide receptor radionuclide therapy (PRRT), somatostatin analogs, antibody–drug conjugates (ADCs), gonadotropin-releasing hormone (GnRH) analogs, and other peptide-based anticancer drugs are analyzed in terms of their chemical structures and properties, therapeutic targets and mechanisms of action, development journey, administration routes, and side effects. [ABSTRACT FROM AUTHOR]

Anna Gavrilova,1 Maksims Zolovs,2,3 Inga Urt&amacr;ne,1 Dins Šmits4 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, R&imacr;ga Stradi&ncedil;š University, Riga, LV-1007, Latvia; 2Statistical Unit, Faculty of Medicine, R&imacr;ga Stradi&ncedil;š University, Riga, LV-1048, Latvia; 3Institute of Life Sciences and Technology, Daugavpils University, Daugavpils, LV-5401, Latvia; 4Department of Public Health and Epidemiology, Faculty of Public Health and Social Welfare, R&imacr;ga Stradi&ncedil;š University, Riga, LV-1007, LatviaCorrespondence: Anna Gavrilova, Pharmaceutical Education and Research Centre, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 21 Konsula street, Riga, LV-1007, Latvia, Email Anna.Gavrilova@rsu.lvIntroduction: The global prevalence of human immunodeficiency virus (HIV) remains substantial, particularly in regions with limited resources, despite the progress in scientific knowledge and the accessibility of antiretroviral therapy (ART). ART is the cornerstone of HIV treatment. Ensuring proper adherence to medication therapy is essential for effective HIV infection control. Meanwhile, Latvia reported one of the highest rates of HIV infections among EU countries.Purpose: This study aimed to assess adherence levels to ART among long-term users by utilizing the National Health Service prescription electronic database records. It is essential to determine whether non-adherence is a problem at the state level.Patients and Methods: This retrospective study was conducted utilizing the Latvian National Health Service’s reimbursed prescription database, covering the period from January 2017 to December 2018. The analysis included ART prescriptions. Medication adherence was assessed using a Proportion of Days Covered (PDC) calculation. The adherence rates were categorized into three groups: (1) < 80% (non-adherence), (2) 80% to 90% (suboptimal adherence), and (3) > 90% (optimal adherence) groups.Results: A total of 25,892 ARV medicines prescription records for 1471 patients were analysed. The adherence level of long-term ART was 38.3%. Of all patients, only 37 (2.5%) had achieved an optimal and 25 (1.7%) suboptimal adherence level. Meanwhile, the remaining patients (95.8%) were identified as non-adherent to therapy. It has been determined that 96.1% (n=1414) of patients experienced a time gap of more than 90 days between their prescriptions at least once. On average, each patient had 3.5 of these gaps, with a maximum of 7 times.Conclusion: Medication adherence level to ART is low in Latvia. Less than 3% of patients achieved optimal adherence levels with a PDC higher than 90%. These results are concerning. Further studies and interventions must be conducted to enhance adherence levels.Keywords: HIV, AIDS, ART, PDC, National Health Service

Polycrystalline diamond compact (PDC) cutters, the most widely used cutting tool in oil and gas drilling, often fail very quickly because of excessive wear and poor impact toughness in hard and complex formations. In this study, dense PDC samples doped with SiC whiskers (SiCw) were successfully synthesized under high pressure and high temperature (HPHT) conditions. The microstructures, elemental distributions, and phase compositions of the PDC samples were systematically investigated. The mechanical properties including the Vickers hardness, wear resistance, impact toughness and thermal stability, were tested. The introduction of SiCw reduced the Co content in the polycrystalline diamond layer. The testing results showed that the hardness of PDC doped with 0.5 wt% SiCw was 75.25 GPa, wear ratio was 145.6 × 104 and impact toughness reached 4020 J, which were 12.2%, 30.9%, and 142.2% higher than those of the control group (CG), respectively. The PDC-0.5 wt% SiCw had the lowest thermal expansion value, with a 57.5% reduction compared with the CG. In addition, the strengthening mechanism of SiCw was explored. SiCw partially replaced the weakening cobalt phase in the binder phase, thus improving the hardness, wear resistance, and thermal stability of the PDC. The introduction of SiCw inhibited the abnormal growth of WC at the interface of the cemented carbide substrate and changed the fracture mode from intergranular to transgranular, which were the main mechanisms responsible for the significant increase in the impact toughness of PDC.

The proportion of the integrated converters using PSC （power synchronization control） in power systems is increasing year by year， but there is a lack of in-depth research on the transient synchronization stability. Therefore， the transient synchronization stability mechanism of integrated grid-forming converters using PSC is analyzed， and measures to improve the transient stability of the converter are proposed. First， the transient stability model of the grid-forming converters with PSC during grid fault is established. Subsequently， based on the phase diagram curve （PDC） method， the destabilization mechanism of the converters and the effect of voltage coupling on the transient synchronous stability are investigated. Moreover， a control strategy to improve the transient synchronous stability by dynamically adjusting the active power command value is proposed based on the effect of voltage coupling. Finally， the electromagnetic transient simulation model of an equivalent system in a city is constructed by using PSCAD/EMTDC， which verifies the correctness of the transient stabilization mechanism of the converter-connected power system and the effectiveness of the stabilization enhancement measures under different fault conditions.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic cancer originating from the malignant transformation of plasmacytoid dendritic cell precursors. This malignancy progresses rapidly, with frequent relapses and a poor overall survival rate, underscoring the urgent need for effective treatments. However, diagnosing and treating BPDCN have historically been challenging due to its rarity and the lack of standardized approaches. The recognition of BPDCN as a distinct disease entity is recent, and standardized treatment protocols are yet to be established. Traditionally, conventional chemotherapy and stem cell transplantation have been the primary methods for treating BPDCN patients. Advances in immunophenotyping and molecular profiling have identified potential therapeutic targets, leading to a shift toward CD123-targeted immunotherapies in both clinical and research settings. Ongoing developments with SL-401, IMGN632, CD123 chimeric antigen receptor (CAR) T-cells, and bispecific antibodies (BsAb) show promising advancements. However, the therapeutic effectiveness of CD123-targeting treatments needs improvement through innovative approaches and combinations of treatments with other anti-leukemic drugs. The exploration of combinations such as CD123-targeted immunotherapies with azacitidine and venetoclax is suggested to enhance antineoplastic responses and improve survival rates in BPDCN patients. In conclusion, this multifaceted approach offers hope for more effective and tailored therapeutic interventions against this challenging hematologic malignancy. [ABSTRACT FROM AUTHOR]

LN005 is a peptide–drug conjugate (PDC) targeting glucose-regulated protein 78 (GRP78) to treat several types of cancer, such as breast, colon, and prostate cancer. As a new drug modality, understanding its metabolism and elimination pathways will help us to have a whole picture of it. Currently, there are no metabolic studies on LN005; therefore, this study aimed to investigate the metabolism of LN005, clarify its metabolic profile in the liver S9s of different species, and identify the major metabolic pathways and differences between species. The incubation samples were measured by ultra-high performance liquid chromatography combined with orbitrap tandem mass spectrometry (UHPLC-Orbitrap-HRMS). The results showed that LN005 was metabolised by liver S9s, and four metabolites were identified. The main metabolic pathway of LN005 in liver S9s was oxidative deamination to ketone or hydrolysis. Similar metabolic profiles were observed in mouse, rat, dog, monkey, and human liver S9s, indicating no differences between these four animal species and humans. This study provides information for the structural modification and optimisation of LN005 and affords a reference for subsequent animal experiments and human metabolism of other PDCs. [ABSTRACT FROM AUTHOR]

Purpose. Determination of the dependence of the depth of penetration of the PDC cutter into the bottom hole rock, taking into account its geometric parameters and spatial placement in relation to the destroyed array. Methodology. The tasks were solved by a comprehensive research method, including analysis and generalization of literary and patent sources, conducting theoretical research, which consists in solving the theoretical problem of the impact of a superhard circular cutter on an elastically fragile mountain range, using computer and mathematical modeling methods. Findings. A simplified expression has been obtained that allows taking into account the features of the PDC cutter with sufficient accuracy for engineering calculations when determining the depth of its penetration into the bottom hole rock. A method is proposed for calculating the depth of fracture in one revolution of a diamond carbide cutter PDC into the rock of the bottom of the well. The patterns of destruction by the proposed diamond-hard-alloy PDC chisel of a rock mass at the bottom of the well from the parameters of the drilling regime and the hardness of the drilled rocks have been established. Originality. For the first time, the dependence has been obtained of the influence of the geometric parameters of the shape of a single diamond-carbide PDC cutter and its spatial placement in the body of the bit matrix on the magnitude of the technological parameters of drilling a well, and their effect on the nature of the destruction of the array PDC cutter. Practical value. A technique for determining the depth of penetration of a single PDC cutter is proposed, the use of which will allow predicting the mechanical speed, depending on the geological and technical conditions of drilling wells. And taking into account the abrasive properties of rocks, it is possible to reduce the wear of the bits, and therefore the amount of necessary rock-crushing tools for the entire volume of drilling operations during the construction of the well. [ABSTRACT FROM AUTHOR]

The effects of nano-molybdenum disulfide (nano-MoS2) on the tribological behavior of polycrystalline diamond compact (PDC) with a cobalt leaching depth of 422 μm were studied in this research. Ball-on-disk friction tests were conducted to evaluate the impact of nano-MoS2 concentration and bearing capacity on the lubrication effect of drilling fluid and the friction performance of PDC. The results demonstrated that the addition of nano-MoS2 enhanced the lubrication effect of drilling fluid and improved the friction performance of PDC. The study also discussed the lubrication mechanism of drilling fluid and the mechanism by which adding nano-MoS2 enhances tribological properties. These findings contribute to deepen the understanding of the friction and wear mechanism of PDC in lubricating environment, and provide a theoretical reference for the future application of PDC in the petroleum field. [ABSTRACT FROM AUTHOR]

Carotenoids are lipophilic compounds found in the membranes of various organisms. Individual carotenoids are also commodity chemicals, produced industrially for use as food additives, nutritional supplements, cosmetics, and pharmaceuticals. The alphaproteobacterium Novosphingobium aromaticivorans has previously been established as a potential platform microbe for converting aromatic compounds derived from lignocellulosic plant biomass into valuable extracellular products. Here, we show that N. aromaticivorans DSM 12444 cells naturally produce the carotenoid nostoxanthin, and we construct a set of gene deletion mutants that accumulate β-carotene, lycopene, or zeaxanthin, which are predicted intermediates in nostoxanthin biosynthesis as well as commodity chemicals. We also show that a mutant strain heterologously expressing a CrtW protein accumulates the carotenoid astaxanthin. When grown on vanillate as the carbon source, we find that the levels of carotenoids are not significantly affected by O2 concentration in the tested range of 5% to 21% O2. We also show that these carotenoids are produced at comparable levels when strains are grown in liquor from alkaline pretreated sorghum biomass [sorghum alkaline pretreatment liquor (APL)], which contains a mixture of aromatics. Finally, we construct strains that produce zeaxanthin, β-carotene, or astaxanthin concurrently with 2-pyrone-4,6-dicarboxylic acid, a potential building block for biodegradable polymers, when grown in sorghum APL. Combined, our results show that N. aromaticivorans can simultaneously produce valuable intracellular and extracellular commodities when grown in the presence of either pure aromatics or pretreated lignocellulosic biomass. IMPORTANCE There is economic and environmental interest in generating commodity chemicals from renewable resources, such as lignocellulosic biomass, that can substitute for chemicals derived from fossil fuels. The bacterium Novosphingobium aromaticivorans is a promising microbial platform for producing commodity chemicals from lignocellulosic biomass because it can produce these from compounds in pretreated lignocellulosic biomass, which many industrial microbial catalysts cannot metabolize. Here, we show that N. aromaticivorans can be engineered to produce several valuable carotenoids. We also show that engineered N. aromaticivorans strains can produce these lipophilic chemicals concurrently with the extracellular commodity chemical 2-pyrone-4,6-dicarboxylic acid when grown in a complex liquor obtained from alkaline pretreated lignocellulosic biomass. Concurrent microbial production of valuable intra- and extracellular products can increase the economic value generated from the conversion of lignocellulosic biomass-derived compounds into commodity chemicals and facilitate the separation of water- and membrane-soluble products. [ABSTRACT FROM AUTHOR]

Objective(s): Our study was conducted to evaluate the synergistic effect of arginine (ARG) and Lactobacillus plantarum against potassium dichromate (K2Cr2O7) induced-acute hepatic and kidney injury.Materials and Methods: Fifty male Wistar rats were divided into five groups. The control group received distilled water. The potassium dichromate group (PDC) received a single dose of PDC (20 mg/kg; SC). The arginine group (ARG) and Lactobacillus plantarum group received either daily doses of ARG (100 mg/kg, PO) or L. plantarum (109 CFU/ml, PO) for 14 days. The combination group (ARG+L. plantarum) received daily doses of ARG (100 mg/kg) with L. plantarum (109 CFU/ml), orally for 14 days, before induction of acute liver and kidney injury. Forty eight hours after the last dose of PDC, serum biochemical indices, oxidative stress biomarkers, pro-inflammatory cytokines, histopathological and immunohistochemical analysis were evaluated.Results: Combining ARG with L. plantarum restored the levels of serum hepatic & kidney enzymes, hepatic & renal oxidative stress biomarkers, and TLR 4/ NF-κB signaling pathway. Furthermore, they succeeded in decreasing the expression of iNOS and ameliorate the hepatic and renal markers of apoptosis: Caspase-3, Bax, and Bcl2.Conclusion: This study depicts that combining ARG with L. plantarum exerted a new bacteriotherapy against hepatic and renal injury caused by PDC.

Spherical and whisker-like cobalt particles were doped into the diamond powders to synthesize the PDC compacts under the HPHT conditions, to investigate the effect of their morphology on the properties of PDC. It was found that the two morphologies of cobalt powder have significant differences in physical characteristics, such as microstructure, porosity, magnetic properties, and crystallinity. When they were used to synthesize PDC samples, it was found that there were noticeable differences in interface bonding morphology, abnormal growth of interface WC, impact strength, and wear resistance. PDC synthesized with spherical cobalt powder had better comprehensive performance than PDC synthesized with whisker-like cobalt powder.

The increased rate of energy crises around the world results in expanding the role of Concentrating Solar Power (CSP) technology for different applications, comprising heating process and power generation applications. The Parabolic Dish Concentrator (PDC) with its large concentration ratio and its modular capacity attracts researchers’ efforts. In this research work, we have designed and developed a PDC with back silvered mirrors as reflector material. Then we have sized the following geometric parameters: the dish diameter, the focal length, the aperture area, the rim angle, the geometric concentration ratio, the receiver material, and the receiver diameter. Furthermore, a dual-axis manual tracking system has been built for this PDC. It should be mentioned that the different components of the PDC have been recycled from a scrap yard to develop a low-cost PDC system. Finally, we have investigated the temperature evolution as a function of time at the focus spot. The maximum temperature obtained is 112 °C for the PDC with mirror. The findings of the study reveal the possibility of building a low-cost solar concentrator with good performance and high quality, only by employing recycled materials, and it could be operated in various applications.

Objectives: To assess the patterns and risk factors associated with selective serotonin reuptake inhibitor (SSRI) medication adherence among enrollees of a multiple employer welfare beneficiary association operating in Florida. Methods: This study used a pharmacy claims database for beneficiaries of the Independent Colleges and Universities Benefits Association. The sample of 2541 patients were enrollees who filled two or more consecutive SSRI prescriptions during the analysis period 2015–20. Adherence was measured as the proportion of days covered by a medication. Multiple logistic regression analysis was used to explore the relationship between sociodemographic, healthcare access, and clinical and medication-related factors and adherence. Key findings: Adherence was associated with higher odds of being female [odds ratio (OR): 1.2, 95% confidence interval (CI): 0.995–1.464, P <.10] and higher pill burden (OR: 1.3, CI: 1.021–1.642, P< 0.05). Patients using only retail pharmacies (OR: 0.356, CI: 0.196–0.645, P <.01), having any out-of-pocket costs (OR: 0.552, CI: 0.348–0.875, P <.50), changing the prescriber over the duration of the treatment (OR: 0.708, CI: 0.589–0.851, P <.01), taking antihypertensive (OR: 0.708, CI: 0.5077–0.988, P < 0.50), and asthma (OR: 0.609, CI: 0.450–0.826, P <.01) medications were less likely to be adherent. Prescriber specialty was not found to be associated with adherence. Conclusion: These findings can inform policymakers and healthcare insurance companies on barriers to medication access and recommend strategies to eliminate these barriers and design interventions to improve the adherence of groups at risk for nonadherence. Healthcare providers can identify patients who are less likely to be adherent and customize counseling interventions for these patients. [ABSTRACT FROM AUTHOR]

Theiler's murine encephalomyelitis virus (TMEV) causes a chronic demyelinating disease similar to multiple sclerosis in mice. Although sialic acids have been shown to be essential for TMEV attachment to the host, the surface receptor has not been identified. While type I interferons play a pivotal role in the elimination of the chronic infectious Daniel (DA) strain, the role of plasmacytoid dendritic cells (pDCs) is controversial. We herein found that TMEV binds to conventional DCs but not to pDCs. A glycomics analysis showed that the sialylated N‐glycan fractions were lower in pDCs than in conventional DCs, indicating that pDCs are not susceptible to TMEV infection due to the low levels of sialic acid. TMEV capsid proteins contain an integrin recognition motif, and dot blot assays showed that the integrin proteins bind to TMEV and that the viral binding was reduced in the desialylated αXβ2. αXβ2 protein suppressed TMEV replication in vivo, and TMEV co‐localized with integrin αM at the cell membrane and TLR 3 in the cytoplasm, suggesting that αM serves as the viral attachment and entry. These results show that the chronic encephalomyelitis virus utilizes sialylated integrins as cell surface receptors, leading to cellular tropism to evade pDC activation. [ABSTRACT FROM AUTHOR]

Copyright of Zhejiang Electric Power is the property of Zhejiang Electric Power Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Submergence in rice fields creating inundation stress and realizing anoxia or hypoxia is a problem in agriculture. Seeds under this oxygen deficit are faced with fermentative respiration, where the end product would be poisoning the tissue viability. This is more aggravated in direct seeded rice cultivation with the accumulation of lactate as a poison. This review is concerned with the basic insights into anoxia tolerance in seeds and possible strategies to reduce anoxic shock through the modification of metabolism preceded by gene expression. The major concern of anoxic germination is starch metabolism and downstream physiological realization to facilitate escape or quiescence strategy, overcoming submergence stress. The coleoptiles facing hypoxic stress mated with transcripts for oxidative traits, energy metabolism, and proteins for membrane peroxidation in support of energy metabolism are the most important. Hypoxic genes are recovered from traditional indica and japonica land races of rice, and show changes in glycolytic flux and sugar sensing. Anoxic germination and seedling vigor are based on a combinational regulation of oxidative stress and fermentative catabolism. De novo antioxidant and antioxidative enzyme production can support improved seed germination in this condition. Pre-harvest spouting with seed-coat-induced dormancy, hormonal ratios, and hydrolyses would be of concern. Therefore, comprehensive analysis aimed to understand rice seed priming for better gas exchange, diffusion, temperature sensitivity, ion uptake, redox balance, and others. Still, in-depth insights are being awaited for better understanding the physiological and molecular basis using a multi-omics approach for better seed priming to overcome the anoxic/hypoxic revelation mostly acquainted with submergence stress. [ABSTRACT FROM AUTHOR]

Inhibitors of phosphodiesterase-4 (PDE4) are small-molecule drugs that, by increasing the intracellular levels of cAMP in immune cells, elicit a broad spectrum of anti-inflammatory effects. As such, PDE4 inhibitors are actively studied as therapeutic options in a variety of human diseases characterized by an underlying inflammatory pathogenesis. Dendritic cells (DCs) are checkpoints of the inflammatory and immune responses, being responsible for both activation and dampening depending on their activation status. This review shows evidence that PDE4 inhibitors modulate inflammatory DC activation by decreasing the secretion of inflammatory and Th1/Th17-polarizing cytokines, although preserving the expression of costimulatory molecules and the CD4+ T cell-activating potential. In addition, DCs activated in the presence of PDE4 inhibitors induce a preferential Th2 skewing of effector T cells, retain the secretion of Th2-attracting chemokines and increase the production of T cell regulatory mediators, such as IDO1, TSP-1, VEGF-A and Amphiregulin. Finally, PDE4 inhibitors selectively induce the expression of the surface molecule CD141/Thrombomodulin/BDCA-3. The result of such fine-tuning is immunomodulatory DCs that are distinct from those induced by classical anti-inflammatory drugs, such as corticosteroids. The possible implications for the treatment of respiratory disorders (such as COPD, asthma and COVID-19) by PDE4 inhibitors will be discussed. [ABSTRACT FROM AUTHOR]

Abstract Aims We aimed to study initiation, adherence, and long‐term persistence to beta‐blockers (BB), renin–angiotensin system inhibitors (RASi), and mineralocorticoid receptor antagonists (MRA) in a nationwide cohort of patients with heart failure (HF). Methods Patients aged 18–80 years in Norway with a first diagnosis of HF from 2014 until 2020 that survived ≥30 days were identified from the Norwegian Patient Registry and linked to the Norwegian Prescription Database. We collected information about BB, RASi [angiotensin‐converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), and angiotensin receptor‐neprilysin inhibitors (ARNI)], and MRA. Dual HF therapy was defined as taking at least two out of three drug classes, whereas triple HF therapy was defined as taking all three. Initiation (time to initiation) and persistence (time to discontinuation using a grace period of 30 days) of HF drugs was calculated by the Kaplan–Meier method, followed to outcome of interest, death, or December 2020. One‐year adherence was measured as proportion of days covered (PDC) using a cut‐off at 80%. For adherence and persistence measurements, we allowed for maximum 60 days of stockpiling and switching within drug groups. We performed sensitivity analyses to test the robustness of our findings. Results Out of 54 899 patients included in the cohort, 75%, 69%, and 21% initiated a BB, RASi, and MRA, respectively, whereas 13% did not receive any. Dual and triple HF therapy was prescribed to 61% and 16%, respectively. The proportion of adherent patients during the first year following initiation was 83%, 81%, 84%, and 61% for BB, RASi, ARNI, and MRA, whereas 42% and 5% were adherent to dual and triple HF therapy, respectively. From 2 to 5 years following initiation, persistence decreased from 58% to 38%, 57% to 37%, and 31% to 15% for BB, RASi, and MRA, respectively. Within the RASi group, persistence was higher for ARNI than for ACEI and ARB. There were no major changes in either initiation or adherence of the drug classes from 2014 to 2019, except for an increase in initiation and adherence of MRA. Conclusions We found low adherence to dual and triple HF therapies in this nationwide cohort study of newly diagnosed HF patients. Efforts are needed to increase adherence and persistence to HF therapies into clinical practice, emphasizing maintenance of multiple drug therapies in patients with such an indication.

The increased rate of energy crises around the world results in expanding the role of Concentrating Solar Power (CSP) technology for different applications, comprising heating process and power generation applications. The Parabolic Dish Concentrator (PDC) with its large concentration ratio and its modular capacity attracts researchers’ efforts. In this research work, we have designed and developed a PDC with back silvered mirrors as reflector material. Then we have sized the following geometric parameters: the dish diameter, the focal length, the aperture area, the rim angle, the geometric concentration ratio, the receiver material, and the receiver diameter. Furthermore, a dual-axis manual tracking system has been built for this PDC. It should be mentioned that the different components of the PDC have been recycled from a scrap yard to develop a lowcost PDC system. Finally, we have investigated the temperature evolution as a function of time at the focus spot. The maximum temperature obtained is 112 °C for the PDC with mirror. The findings of the study reveal the possibility of building a lowcost solar concentrator with good performance and high quality, only by employing recycled materials, and it could be operated in various applications. [ABSTRACT FROM AUTHOR]

Copyright of Diamond & Abrasives Engineering is the property of Zhengzhou Research Institute for Abrasives & Grinding and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Innate immune responses are important in the control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. We have previously found a lactic acid bacteria species, Lactococcus lactis strain Plasma (LC-Plasma), which possesses specific feature to activate plasmacytoid dendritic cells (pDCs) and thus may affect innate immune responses. Here, we investigated the impact of pDC activation by LC-Plasma on SARS-CoV-2 replication in vitro. Addition of the culture supernatant of pDCs stimulated with LC-Plasma resulted in suppression of SARS-CoV-2 replication in Vero and Calu-3 cells. We confirmed interferon-α (IFN-α) secretion in the supernatant of pDCs stimulated with LC-Plasma and induction of IFN-stimulated genes in cells treated with the pDC supernatant. Anti–IFN–α antibody impaired the suppression of SARS-CoV-2 replication by the supernatant of LC-Plasma-stimulated pDCs, suggesting that IFN-α plays an important role in the SARS-CoV-2 suppression. Our results indicate the potential of LC-Plasma to induce inhibitory responses against SARS-CoV-2 replication through pDC stimulation with IFN-α secretion. • Secretion from pDCs stimulated with LC-Plasma suppresses SARS-CoV-2 replication. • Stimulation of pDCs with LC-Plasma results in IFN-α induction. • IFN-α plays an important role in the LC-Plasma-mediated SARS-CoV-2 suppression. [ABSTRACT FROM AUTHOR]

The increasing penetration of distributed generation sources in low-voltage distribution grids, electric vehicles, and new appliances from the consumer side can generate short repetitive overloads on the low-voltage cable network. This work investigates the change in the dielectric properties of low-voltage cable insulation caused by short-term overloads, examining how the cable structure affects the dielectric characteristics of the cable specimens in the case of cyclic short-term thermal aging. PVC-insulated low-voltage cable samples were exposed to an accelerated aging test in a temperature-controlled oven after changing their structures by removing different layers. Three aging cycles, each of six hours, were applied to the samples. After each cycle, the tan δ and capacitance were measured by an Omicron DIRANA Dielectric Response Analyzer in the laboratory at room temperature 24 ±   0.5 °C. Furthermore, the polarization and depolarization currents were also studied. The results show that changing the cable structure impacts the dielectric parameters; in particular, the effect of the belting layer is significant. From the point of view of aging, the PVC belting layer protects the diffusion of the plasticizers of the inner structure. The findings of the study show that an asymmetric aging phenomenon can be observed in different polymeric components of the cables, even though the cables were aged in an air-circulated oven ensuring a homogeneous temperature distribution in the samples. [ABSTRACT FROM AUTHOR]

Background: M2-type anti-mitochondrial autoantibodies are considered the hallmark of primary biliary cholangitis and are directed mainly against the E2 subunits of the 2-oxo acid dehydrogenase complex enzymes (PDC, BCOADC and OGDC). The aim of this study was to determine whether a Dot-blot that includes these E2 subunits separately could confirm the results of methods with non-separated subunits in patients with low positive or discordant results between techniques. Methods: Sera of 24 patients with low positive or discordant results and of 10 patients with clear positive results by non-separated subunits methods were analyzed by Dot-blot with separated subunits. Results: Autoantibodies against E2 subunits of PDC, BCOADC or OGDC were detected in all patients, except in one case from the low positive or discordant results group, by Dot-blot with separated subunits. Conclusions: It would be advisable to use methods that include the three E2 subunits, and a Dot-blot with separated subunits could confirm doubtful cases by non-separated assays. [ABSTRACT FROM AUTHOR]

Abstract Background Plasmacytoid and myeloid dendritic cells play a vital role in the protection against viral infections. In COVID-19, there is an impairment of dendritic cell (DC) function and interferon secretion which has been correlated with disease severity. Results In this study, we described the frequency of DC subsets and the plasma levels of Type I (IFNα, IFNβ) and Type III Interferons (IFNλ1), IFNλ2) and IFNλ3) in seven groups of COVID-19 individuals, classified based on days since RT-PCR confirmation of SARS-CoV2 infection. Our data shows that the frequencies of pDC and mDC increase from Days 15–30 to Days 61–90 and plateau thereafter. Similarly, the levels of IFNα, IFNβ, IFNλ1, IFNλ2 and IFNλ3 increase from Days 15–30 to Days 61–90 and plateau thereafter. COVID-19 patients with severe disease exhibit diminished frequencies of pDC and mDC and decreased levels of IFNα, IFNβ, IFNλ1, IFNλ2 and IFNλ3. Finally, the percentages of DC subsets positively correlated with the levels of Type I and Type III IFNs. Conclusion Thus, our study provides evidence of restoration of homeostatic levels in DC subset frequencies and circulating levels of Type I and Type III IFNs in convalescent COVID-19 individuals.

Rock breaking efficiency of drill bits is an important index for measuring the drilling efficiency in the oil and gas drilling field, and it is influenced by many factors, such as structure and material. This study developed a calculation model and an experimental model of rock breaking of polycrystalline diamond compact (PDC) and diamond impregnated cutter (DIC) hybrid bit to reveal the influence of bit structure and material on tangential force, axial force and wear height. On the basis of the calculation model of the co-rail arrangement of the PDC--DIC hybrid bit and the rock breaking mode, a rock breaking mechanical parameter prediction model and a rock breaking performance test model were established. Rock stress calculation method, rock failure criterion, and mechanical specific energy (MSE) calculation method were used to analyze the rock stress and the relationship between MSE and tangential force, axial force, and wear height during combined rock breaking. The accuracy of the model was verified by experiments. Results show that the specific work of rock breaking of the PDC-DIC hybrid bit is less than that of PDC, and a reverse nonlinear relationship exists between specific work of rock breaking and wear height. The energy required for hybrid bit to break rock is less than that of PDC bit. A positive nonlinear relationship exists between the energy of PDC-DIC hybrid bit and the wear height, whereas the cutting depth and the wear height show a negative nonlinear relationship. The stress distribution of PDC rock breaking is uniform, and the maximum equivalent stress is up to 104 MPa. The stress distribution of rock breaking of the hybrid PDC-DIC is extremely nonuniform, and stress concentration occurs with a minimum equivalent stress of 84 MPa and a maximum stress of 161 MPa, which is beneficial to rock breaking. Rock breaking of PDC-DIC hybrid bit can promote the generation and development of rock cracks, thereby reducing the crushing strength of the rock. The study provides a design method and theoretical basis for designing a new type of PDC-DIC hybrid bit, with certain reference for exploring the rock breaking mechanism of various bits. [ABSTRACT FROM AUTHOR]

Despite the increasing evidence of the clinical impact of Pseudomonas-derived cephalosporinase (PDC) sequence polymorphisms, the molecular evolution of its encoding gene, blaPDC, remains elusive. To elucidate this, we performed a comprehensive evolutionary analysis of blaPDC. A Bayesian Markov Chain Monte Carlo phylogenetic tree revealed that a common ancestor of blaPDC diverged approximately 4660 years ago, leading to the formation of eight clonal variants (clusters A–H). The phylogenetic distances within clusters A to G were short, whereas those within cluster H were relatively long. Two positive selection sites and many negative selection sites were estimated. Two PDC active sites overlapped with negative selection sites. In docking simulation models based on samples selected from clusters A and H, piperacillin was bound to the serine and the threonine residues of the PDC active sites, with the same binding mode for both models. These results suggest that, in P. aeruginosa, blaPDC is highly conserved, and PDC exhibits similar antibiotic resistance functionality regardless of its genotype. [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa exhibits significant antibiotic resistance facilitated by both intrinsic and acquired mechanisms, prominently through Pseudomonas-derived cephalosporinase (PDC), serine Ambler class C β-lactamases encoded by the AmpC. AmpC, involved in the peptidoglycan recycling pathway, is regulated by genes such as ampD, ampR, and ampG, leading to increased expression and resistance to various beta-lactams. PDCs are classified into three main types: classical class C β-lactamases, extended-spectrum class C β-lactamases (ESAC β-lactamases), and inhibitor-resistant class C β-lactamases. This study aimed to identify prevalent PDC variants and its genetic characteristics in Indian and global P. aeruginosa isolates, focusing on their role in β-lactam resistance. Analyzing PDC sequences from 111 P. aeruginosa isolates collected at Christian Medical College (CMC), Vellore, we found the ESAC allele PDC-447 to be the most widespread among Indian isolates, present in 18 % of carbapenem-resistant and 11 % of carbapenem-susceptible strains. Global and Indian isolates PDC variants were validated using the NCBI PathogenWatch database, and the sequenced PDC region compared to PDC-1. PDC-398 and PDC-397 followed in prevalence among carbapenem-resistant isolates, while PDC-5 (ESAC) and PDC-1 (classical class C) were common in carbapenem-susceptible strains. A global analysis of 19,478 genomes revealed significant prevalence of ESAC variants such as PDC-3 (17.28 %) and PDC-5 (12.91 %), alongside classical class C beta-lactamases like PDC-8 (10.65 %). Indian isolates exhibited distinct patterns with PDC-3 and PDC-5 prevailing at 19.84 % and 10 %, respectively. Mutations in the omega loop, H-helix, and R2 region of PDCs were linked to enhanced antibiotic resistance, particularly the T105A mutation in the H-helix region. These findings underscore the complexity of antimicrobial resistance mechanisms in P. aeruginosa and highlight the need for novel therapeutic strategies and continuous surveillance to manage infections by this versatile pathogen. Understanding the prevalence and genetic characteristics of PDC variants is crucial for effective treatment strategies against P. aeruginosa and combating antibiotic resistance. [Display omitted] • PDC-3 and PDC-5 are the most prevalent globally at 17.28% and 12.91 %, respectively. • In Indian isolates, PDC-3 (19.84 %) is most common, followed by PDC-5 (9.92 %), PDC-11 (15.26 %) and PDC-19a (14.50 %). • Global PDC-5, PDC-8, PDC-35; Indian PDC-11, PDC-19a, PDC-447 evolved from PDC-3; T105A mutation in H-helix of PDC-3 • Mutations in PDC conserved regions (omega loop, R2 domain, helix H) enhance catalytic efficiency and cephalosporin resistance [ABSTRACT FROM AUTHOR]