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Cancer is the second leading cause of death affecting nearly one in two people, and the appearance of new cases is projected to rise by >70% by 2030. To effectively combat the menace of cancer, a variety of strategies have been exploited. Among them, the development of peptide–drug conjugates (PDCs) is considered as an inextricable part of this armamentarium and is continuously explored as a viable approach to target malignant tumors. The general architecture of PDCs consists of three building blocks: the tumor-homing peptide, the cytotoxic agent and the biodegradable connecting linker. The aim of the current review is to provide a spherical perspective on the basic principles governing PDCs, as also the methodology to construct them. We aim to offer basic and integral knowledge on the rational design towards the construction of PDCs through analyzing each building block, as also to highlight the overall progress of this rapidly growing field. Therefore, we focus on several intriguing examples from the recent literature, including important PDCs that have progressed to phase III clinical trials. Last, we address possible difficulties that may emerge during the synthesis of PDCs, as also report ways to overcome them.

The Stinger PDC cutter has superior impact resistance, wear resistance, and rock-breaking efficiency compared to the conventional PDC cutter. Thus, hybrid PDC bits that combine conventional and Stinger PDC cutters have significant advantages in drilling hard, interbedded, and highly abrasive rocks. Although the hybrid PDC bit has demonstrated outstanding performance in improving the rate of penetration and prolonging the life of PDC bits, the arrangement of mixed cutters still awaits a thorough understanding and optimization. In this research, 14 groups of mixed cutting granite experiments were carried out with the Stinger and conventional PDC cutters. The influences of the cutting sequence, spacing, and depth difference of mixed cutters on the cutting force, broken rock volume, and mechanical specific energy (MSE) were compared and analyzed. The results show that the Stinger PDC cutter followed by the conventional PDC cutter can provide a higher rock-breaking efficiency. Additionally, the total rock breaking efficiency increases with the increase of cutter depth difference for single-track cutting. For multi-track cutting, the cutting force and mechanical specific energy (MSE) first decreases and then increases with an increase in the Stinger PDC cutter spacing. The optimal Stinger PDC cutter spacing is 18 mm for the tested granite. With the increase of cutter depth difference, the rock broken volume gradually increases, the cutting force and MSE first decrease and then rise rapidly. The optimal cutter depth difference is 0.5 mm. The characteristics of the cracks around the cutting groove of the Stinger PDC cutter were observed by optical microscope and the experimental results were further explained from the point of cracks and damage. This work explains the mixed cutting mechanism and provides experimental and theoretical guidance for the design of hybrid PDC bits.

Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson’s disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.

Hydrogen sulphide (H2S) inhibits vascular smooth muscle cell (VSMC) proliferation induced by hyperglycaemia and hyperlipidaemia; however, the mechanisms are unclear. Here, we observed lower H2S levels and higher expression of the proliferation‐related proteins PCNA and cyclin D1 in db/db mouse aortae and vascular smooth muscle cells treated with 40 mmol/L glucose and 500 μmol/L palmitate, whereas exogenous H2S decreased PCNA and cyclin D1 expression. The nuclear translocation of mitochondrial pyruvate dehydrogenase complex‐E1 (PDC‐E1) was significantly increased in VSMCs treated with high glucose and palmitate, and it increased the level of acetyl‐CoA and histone acetylation (H3K9Ac). Exogenous H2S inhibited PDC‐E1 translocation from the mitochondria to the nucleus because PDC‐E1 was modified by S‐sulfhydration. In addition, PDC‐E1 was mutated at Cys101. Overexpression of PDC‐E1 mutated at Cys101 increased histone acetylation (H3K9Ac) and VSMC proliferation. Based on these findings, H2S regulated PDC‐E1 S‐sulfhydration at Cys101 to prevent its translocation from the mitochondria to the nucleus and to inhibit VSMC proliferation under diabetic conditions.

Metabolic flexibility is the capacity of a system to adjust fuel (primarily glucose and fatty acids) oxidation based on nutrient availability. The ability to alter substrate oxidation in response to nutritional state depends on the genetically influenced balance between oxidation and storage capacities. Competition between fatty acids and glucose for oxidation occurs at the level of the pyruvate dehydrogenase complex (PDC). The PDC is normally active in most tissues in the fed state, and suppressing PDC activity by pyruvate dehydrogenase (PDH) kinase (PDK) is crucial to maintain energy homeostasis under some extreme nutritional conditions in mammals. Conversely, inappropriate suppression of PDC activity might promote the development of metabolic diseases. This review summarizes PDKs’ pivotal role in control of metabolic flexibility under various nutrient conditions and in different tissues, with emphasis on the best characterized PDK4. Understanding the regulation of PDC and PDKs and their roles in energy homeostasis could be beneficial to alleviate metabolic inflexibility and to provide possible therapies for metabolic diseases, including type 2 diabetes (T2D).

The enhanced drilling parameters and custom-designed polycrystalline diamond compact (PDC) bits have greatly improved both rate of penetration (ROP) and footage. Then how to further improve the bit’s ROP and how to deal with the side effects caused by the enhanced drilling parameters remain a challenge. In this work, the single-cutter rock-cutting tests and full-sized bit drilling tests were conducted to investigate the effects of rock types, drilling parameters, and bit designs on ROP. The results showed that in the easy-to-drill formations, the enhanced drilling parameters had a more pronounced effect on improving the bit’s ROP than the optimizations of bit designs such as changing the cutter shape and size. On the other hand, in the hard-to-drill formations, smaller-sized and shaped PDC cutters combined with high-torque tools offered a promising approach to increase ROP. To further improve ROP and footage, two innovative approaches were introduced: improving the bit durability without compromising ROP to ensure one-trip drilling, and using extended directional nozzles together with enhanced hydraulic parameters. The bit durability was improved by optimizing the cutter shape and diamond materials, which helped complete the single-run footage of 2986 m in the field trial of Shengli Oilfield. It was also found that the extended directional nozzle was less effective under conventional hydraulic parameters, but increased the ROP by 32.1% under enhanced hydraulic parameters because of improving jet impact performance through reduced jet diffusion. The findings provided insights for ROP improvement in the oil and gas drilling operations.

Information flow between brain areas is difficult to estimate from EEG measurements due to the presence of noise as well as due to volume conduction. We here test the ability of popular measures of effective connectivity to detect an underlying neuronal interaction from simulated EEG data, as well as the ability of commonly used inverse source reconstruction techniques to improve the connectivity estimation. We find that volume conduction severely limits the neurophysiological interpretability of sensor-space connectivity analyses. Moreover, it may generally lead to conflicting results depending on the connectivity measure and statistical testing approach used. In particular, we note that the application of Granger-causal (GC) measures combined with standard significance testing leads to the detection of spurious connectivity regardless of whether the analysis is performed on sensor-space data or on sources estimated using three different established inverse methods. This empirical result follows from the definition of GC. The phase-slope index (PSI) does not suffer from this theoretical limitation and therefore performs well on our simulated data. We develop a theoretical framework to characterize artifacts of volume conduction, which may still be present even in reconstructed source time series as zero-lag correlations, and to distinguish their time-delayed brain interaction. Based on this theory we derive a procedure which suppresses the influence of volume conduction, but preserves effects related to time-lagged brain interaction in connectivity estimates. This is achieved by using time-reversed data as surrogates for statistical testing. We demonstrate that this robustification makes Granger-causal connectivity measures applicable to EEG data, achieving similar results as PSI. Integrating the insights of our study, we provide a guidance for measuring brain interaction from EEG data. Software for generating benchmark data is made available. ► We assess methods for EEG-based connectivity analysis on realistically simulated data. ► We demonstrate a number of pitfalls occurring depending on the method used. ► Granger-causal approaches are obscured by so-called weak data asymmetries. ► We propose a simple strategy for alleviating the impact of weak asymmetries. ► Code for data generation and analysis is provided for benchmarking purposes.

In this paper, a stability analysis and the controller improvement of T-S fuzzy Descriptor system are studied. Firstly, by making full use of the related theory of fuzzy affiliation function and combining the design method of fuzzy Lyapunov function with the method of inequality deflation, a stability condition with wider admissibility and less system conservatism is proposed. The advantage of this method is that it is not necessary to ensure that each fuzzy subsystem is progressively stable. We also maximise the boundary of the derivatives of the affiliation function mined. Secondly, a PDC controller and a Non-PDC controller are designed, and the deflation conditions for the linear matrix inequalities of the two controllers are constructed. Finally, some arithmetic simulations and practical examples are given to demonstrate the effectiveness of the method studied in this paper, and the results obtained are less conservative and have larger feasible domains than previous methods.

Particular interest to harness the innate immune system for cancer immunotherapy is fueled by limitations of immune checkpoint blockade. Plasmacytoid dendritic cells (pDC) are detected in a variety of solid tumors and correlate with poor clinical outcome. Release of type I interferons in response to toll-like-receptor (TLR)7 and TLR9 activation is the pDC hallmark. Mouse and human pDC differ substantially in their biology concerning surface marker expression and cytokine production. Here, we employed humanized mouse models (HIS) to study pDC function. We performed a comprehensive characterization of transgenic, myeloid-enhanced mouse strains (NOG-EXL and NSG-SGM3) expressing human interleukin-3 (hIL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF) using identical humanization protocols. Only in HIS-NOG-EXL mice sufficient pDC infiltration was detectable. Therefore, we selected this strain for subsequent tumor studies. We analyzed pDC frequency in peripheral blood and tumors by comparing HIS-NOG-EXL with HIS-NOG mice bearing three different ovarian and breast tumors. Despite the substantially increased pDC numbers in peripheral blood of HIS-NOG-EXL mice, we detected TLR7/8 agonist responsive and thus functional pDCs only in certain tumor models independent of the mouse strain employed. However, HIS-NOG-EXL mice showed in general a superior humanization phenotype characterized by reconstitution of different myeloid subsets, NK cells and B cells producing physiologic IgG levels. Hence, we provide first evidence that the tumor milieu but not genetically introduced cytokines defines intratumoral (i.t.) frequencies of the rare pDC subset. This study provides model systems to investigate pro- and anti-tumoral human pDC functions.

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.