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Defects in tRNA biogenesis are associated with multiple neurological disorders, yet our understanding of these diseases has been hampered by an inability to determine tRNA expression in individual cell types within a complex tissue. Here, we developed a mouse model in which RNA polymerase III is conditionally epitope tagged in a Cre-dependent manner, allowing us to accurately profile tRNA expression in any cell type in vivo. We investigated tRNA expression in diverse nervous system cell types, revealing dramatic heterogeneity in the expression of tRNA genes between populations. We found that while maintenance of levels of tRNA isoacceptor families is critical for cellular homeostasis, neurons are differentially vulnerable to insults to distinct tRNA isoacceptor families. Cell-type-specific translatome analysis suggests that the balance between tRNA availability and codon demand may underlie such differential resilience. Our work provides a platform for investigating the complexities of mRNA translation and tRNA biology in the brain.

Spheroids, as three-dimensional (3D) cell aggregates, can be prepared using various methods, including hanging drops, microwells, microfluidics, magnetic manipulation, and bioreactors. However, current spheroid manufacturing techniques face challenges such as complex workflows, the need for specialized personnel, and poor batch reproducibility. In this study, we designed a support-free, 3D-printed microwell chip and developed a compatible low-cell-adhesion process. Through simulation and experimental validation, we rapidly optimized microwell size and the coating process. We successfully formed three types of spheroids—human immortalized epidermal cells (HaCaTs), umbilical cord mesenchymal stem cells (UC-MSCs), and human osteosarcoma cells (MG63s)—on the chip. Fluorescent viability staining confirmed the biocompatibility and reliability of the chip. Finally, drug response experiments were conducted using the chip. Compared to traditional methods, our proposed strategy enables high-throughput production of size-controlled spheroids with excellent shape retention, while enhanced gas exchange during culture improves differentiation marker expression. This platform provides an efficient and cost-effective solution for biosensing applications, such as drug screening, disease modeling, and personalized therapy monitoring. Furthermore, the chip shows significant potential for real-time in vitro monitoring of cellular viability, reaction kinetics, and drug sensitivity, offering valuable advancements in biosensor technology for life sciences and medical applications. [ABSTRACT FROM AUTHOR]

Inconel 718 superalloy has been utilized in manufacturing jet engine parts because of its exceptional performance under high temperatures. It has high work hardening tendencies and limited heat conductivity which makes machining difficult. Machining operations employ cutting fluids, which have detrimental effects on both society and the personnel involved. Drilling were accomplished on Inconel 718 at distinct cooling conditions: Dry, Flood, Minimum Quantity Lubrication (MQL), and Nano-Minimum Quantity Lubrication (N-MQL). Tool feed, cutting speed, and cooling conditions were input factors. The surface texture, wear pattern on tool, chip morphology, drilling temperature, and power consumption were taken as output. The effective cooling and lubrication provided by N-MQL showed a significant improvement in roughness by 45%,47%, and 38% and a reduction in temperature by 34%,56%, and 32% in contrast to dry, flood, and MQL conditions. Overall, N-MQL conditions were very influential during the drilling of Inconel compared to the other cooling conditions. [ABSTRACT FROM AUTHOR]

Introduction: Recent work has revealed that clonal hematopoiesis (CH) is associated with a higher risk of numerous age-related diseases, including ischemic stroke, however little is known about whether it influences stroke outcome independent of its widespread effects on cardiovascular disease. Studies suggest that leukocytes carrying CH driver mutations have an enhanced inflammatory profile, which could conceivably exacerbate brain injury after a stroke. Methods: Using a competitive bone marrow transplant model of Tet2 -mediated CH, we tested the hypothesis that CH would lead to a poorer outcome after ischemic stroke by augmenting brain inflammation. Stroke was induced in mice by middle cerebral artery occlusion and neurological outcome was assessed at acute (24 h) and subacute (14 d) timepoints. Brains were collected at both time points for histological, immunofluorescence and gene expression assays. Results: Unexpectedly, Tet2 -mediated CH had no effect on acute stroke outcome but led to a reduction in neurological deficits during the subacute phase. This improved neurological outcome was associated with lower levels of brain inflammation as evidenced by lower transcript levels of various inflammatory molecules alongside reduced astrogliosis. Discussion: These findings suggest that Tet2 -mediated CH may have beneficial effects on outcome after stroke, contrasting with the conventional understanding of CH whereby leukocytes with driver mutations promote disease by exacerbating inflammation. [ABSTRACT FROM AUTHOR]

Background: Myocarditis is an inflammation of the heart muscle most often caused by viral infections. Sex differences in the immune response during myocarditis have been well described but upstream mechanisms in the heart that might influence sex differences in disease are not completely understood. Methods: Male and female BALB/c wild type mice received an intraperitoneal injection of heart-passaged coxsackievirus B3 (CVB3) or vehicle control. Bulk-tissue RNA-sequencing was conducted to better understand sex differences in CVB3 myocarditis. We performed enrichment analysis and functional validation to understand sex differences in the transcriptional landscape of myocarditis and identify factors that might drive sex differences in myocarditis. Results: As expected, the hearts of male and female mice with myocarditis were significantly enriched for pathways related to an innate and adaptive immune response compared to uninfected controls. Unique to this study, we found that males were enriched for inflammatory pathways and gene changes that suggested worse mitochondrial electron transport function while females were enriched for pathways related to mitochondrial homeostasis. Mitochondria isolated from the heart of males were confirmed to have worse mitochondrial respiration than females during myocarditis. Unbiased TRANSFAC analysis identified estrogen-related receptor alpha (ERRα) as a transcription factor that may mediate sex differences in mitochondrial function during myocarditis. Transcript and protein levels of ERRα were confirmed as elevated in females with myocarditis compared to males. Differential binding analysis from chromatin immunoprecipitation (ChIP) sequencing confirmed that ERRα bound highly to select predicted respiratory chain genes in females more than males during myocarditis. Conclusions: Females with viral myocarditis regulate mitochondrial homeostasis by upregulating master regulators of mitochondrial transcription including ERRα. Plain English summary: Many viruses can infect the heart. Immune cells go to the heart to get rid of the virus but sometimes this response can damage the heart. When immune cells go to the heart it is called "myocarditis," which means 'myo' for muscle and 'carditis' for heart inflammation. More men get myocarditis after viral infections than women. When we study viral infection in mice as a model of human disease, we see the same sex differences as in humans. To know why this happens, we gave mice a viral infection and looked at how their hearts changed. We found that a special gene acts like a light switch to turn on the genes that help cell energy factories called "mitochondria." Females used this light switch to turn on the genes that help mitochondria, but males did not and turned most of these genes off. We learned that the light switch works better in females compared to males, so it may play an important role in protecting female's hearts during myocarditis. More research is needed to better understand how this light switch works. Understanding how to turn on mitochondria genes in the heart could help doctors also do this in men after a viral infection to prevent myocarditis and save patients' lives. Highlights: • Females maintain mitochondrial homeostasis with less severe myocarditis. • Several master regulators of mitochondrial homeostasis are elevated in females. • Transcription factor ERRα RNA and protein are elevated in female hearts. • ERRα binds mitochondrial genes more in females during myocarditis. [ABSTRACT FROM AUTHOR]

The Biden administration's escalating restrictions on China's semiconductor industry signal a shift in the U.S.-China technological competition. These measures, including sanctions, export controls, and supply chain containment, aim to deny China access to advanced semiconductor technology and expertise. This turn towards weaponizing semiconductor dominance indicates national security now drives the contest beyond purely economic interests. The U.S. has moved from a defensive posture of containing China's rise to an offensive posture of imposing steep costs by cutting off its access to cutting-edge technology. Stackelberg game theory models demonstrate how the U.S. leverages its current advantages in semiconductors to force difficult tradeoffs on China. This stranglehold aims to hobble China's technological ambitions and preserve U.S. semiconductor leadership. [ABSTRACT FROM AUTHOR]

In Very-Large-Scale-Integration (VLSI) designs, thorough testing is indispensable for identifying the structural defects of the chip. Timely detection and correcting serious defects are pivotal in preventing faulty chips from reaching customers and avoiding failures. In scan designs, the toggling activity is a critical factor due to the defects between lower cells and metal layers, exacerbated by diverse Process, Voltage, and Temperature (PVT) conditions. These defects significantly impact design testability, quality, and reliability, necessitating meticulous testing to ensure that chips meet the desired specifications. Effectively managing power consumption in the current VLSI landscape is crucial amid the ongoing energy crisis. Balancing the need for Low-Power (LP) with the complexity of integrating transistors onto a single silicon substrate poses significant challenges. As chip densities increase, power dissipation during testing surges, adversely affecting durability, performance, cost, and reliability. Engineers are racing to optimize test power usage, employing advanced Design for Test (DFT) techniques to incorporate efficient power management into Silicon-on-Chip (SoC) designs. Linear Feedback Shift Registers (LFSRs) are phenomenal in addressing DFT parameters like power, and performance, and for better pseudo-random pattern generation. Hence, this paper proposes a groundbreaking approach to power reduction techniques deploying the LFSR architecture, and thus challenging conventional scan-based testing methods. The proposed LFSR architecture is meticulously designed and rigorously tested using Cadence DFT Modus solution on ISCAS’89 benchmarking circuits. Coverage was unequivocally evaluated for Quality of Results (QoR) metrics, such as fault coverage, memory usage, pattern counts, switching activity, fault testing, and runtime. The specific evaluation clearly proved the superiority of the LFSR-based approach over the scanbased architecture. Adopting the novel LFSR architecture resulted in a ~5.6X reduction in toggling activity accompanied by a substantial ~10K pattern reduction and a runtime of nearly ~1.5 hours. Notably, the test power was reduced to 50% showcasing superior efficiency. This approach emerges as the ideal solution for industrial designs providing the best QoR for power, performance, and area. This innovative methodology marks a significant leap toward an energy-efficient and cost-effective VLSI circuit especially for stacked 2.5-3D ICs and chiplets poised to revolutionize chip manufacturing. [ABSTRACT FROM AUTHOR]

The diffusion coefficient (Dic) is an essential parameter that helps to understand various durability issues in concrete, like corrosion, alkali-silica reaction (ASR), and freeze-thaw damage. However, most research in this area has focused on homogeneous materials like paste and mortar, while concrete has proven to be challenging because of its inhomogeneous nature. This study used dental X-ray equipment adapted for transmission X-ray measurements to measure ion diffusion. This device is named CHIP (Checking Ion Penetration). This work applies the CHIP on 104 paste and 104 concrete samples with hydration times between 45 and 1100 days. This work improved the accuracy by combining measurements from multiple angles and correcting for X-ray beam hardening. This approach improved the accuracy of concrete Dic measurements by 20% (as indicated by R square) while reducing variability (expressed as the coefficient of variation) by 63%. [ABSTRACT FROM AUTHOR]

The increased sensitivity of novel DNA sequencing techniques has made it possible to identify somatic mutations in small circulating clones of haematopoietic stem cells. When the mutation affects a 'driver' gene, the mutant clone gains a competitive advantage and has the potential to expand over time, a phenomenon referred to as clonal haematopoiesis (CH), which is emerging as a new risk factor for various non-haematological conditions, most notably cardiovascular disease (e.g. heart failure). Dilated cardiomyopathy (DCM) is a form of non-ischaemic heart failure that is characterized by a heterogeneous aetiology. The first evidence is arising that CH plays an important role in the disease course in patients with DCM, and a strong association of CH with multiple aetiologies of DCM has been described (e.g. inflammation, chemotherapy, and atrial fibrillation). The myocardial inflammation induced by CH may be an important trigger for DCM development for an already susceptible heart, e.g. in the presence of genetic variants, environmental triggers, and comorbidities. Studies investigating the role of CH in the pathogenesis of DCM are expected to increase rapidly. To move the field forward, it will be important to report the methodology and results in a standardized manner, so results can be combined and compared. The accurate measurement of CH in patients with DCM can provide guidance of specific (anti-inflammatory) therapies, as mutations in the CH driver genes prime the inflammasome pathway. [ABSTRACT FROM AUTHOR]

Lightweight alloys play a vital role in the development of automotive, biomedical and aerospace industries as well as other industrial sectors. The current study investigates the machinability of AZ61 magnesium alloy within a vegetable-oil-based MQL environment through high-speed orthogonal cutting. A tool wear and chip morphology examination are conducted along a full factorial experimentation to allow for adequate machinability testing. The usage of Grey Relational Analysis was invoked to allow for a multi-variant optimisation of input parameters such as MQL flow rate, cutting speed, and feed based on output responses, such as chip compression ratio, chip segmentation ratio, tool-chip contact length, and shear angle as well as tool wear evolution. Through the analysis of the formulated signal-to-noise data, it was found that the optimal cutting parameters were an MQL flow rate of 80 ml/h, cutting speed of 250 m/min and feed of 0.3 mm/rev. The optimal cutting conditions resulted in a Grey Relational Grade improvement of 0.177 as compared to the referenced experimental trail. The analysis of variance further concluded that the feed was the highest contributing input parameter at 38.04% followed by the MQL flow rate and the cutting speed. [ABSTRACT FROM AUTHOR]

The optimum processing conditions for green laver chips were determined using response surface methodology (RSM) to improve taste and reduce off-flavors by applying reaction flavor and air-frying techniques. The optimum composition (w/w) for the chips included 20% green laver, 20% hairtail surimi, and 60% flour. Additional ingredients included distilled water (90 mL) with GDL (3 g), NaHCO₃ (2 g), salt (1 g), sugar (12 g), roasted soybean powder (1.5 g), and reaction flavor solution (RFS, 10 mL). The mixture was kneaded, shaped, dried at 50 °C for 2 h, and air-fried at 195 °C for 80 sec. The resulting green laver chips showed overall acceptance and brittleness values of 7.00 ± 0.74 and 5.89 ± 0.59 N, respectively, with absolute residual errors of 8.43% and 7.07%. The optimum reaction flavor precursors for green laver chips were determined to be threonine (1.0 g%), proline (1.0 g%), glycine (1.4 g%), methionine (0.05 g%), and glucose (2 g%). Flavor analysis revealed that green laver chips with reaction flavor (GLCR) contained 13 alkylpyrazines with corn-like and nutty odors, and 2-acetylpyrrole, which contributed a popcorn-like odor. In contrast, green laver chips without reaction flavor (GLC) predominantly contained straight-chain aldehydes with undesirable odors. The heating process in the air fryer appeared to reduce the aldehyde content and promote pyrazine formation, significantly enhancing GLCR's flavor. [ABSTRACT FROM AUTHOR]

Abstract Background Spinocerebellar ataxias (SCAs) encompass a wide spectrum of inherited neurodegenerative diseases, primarily characterized by pathological changes in the cerebellum, spinal cord, and brainstem degeneration. Autosomal dominant spinocerebellar ataxia type 48 (SCA48) is a newly identified subtype of SCA, marked by early-onset ataxia and cognitive impairment, and is associated with mutations in the STIP1 homology and U-box-containing protein 1 (STUB1) gene. The STUB1 gene encodes the protein CHIP (C-terminus of HSC70-interacting protein) which functions as E3 ubiquitin ligase and is crucial to the development of neural systems. Results Here, we reported a Chinese SCA48 family exhibited typical features and defined a novel missense mutation STUB1 c.755A>C (CHIP p. Y252S) through whole-exome sequencing. The variant was interpreted as a variant of uncertain significance, so we conducted a series of experiments using minigene plasmids to evaluate the pathogenicity of the variant. We found that the variant STUB1 c.755A>C caused a significant reduction of CHIP level and the loss function of ubiquitin ligase activity as the pathogenic STUB1 mutations reported before. Besides, we also found that the CHIP p. Y252S could cause tau aggregation, which is considered to contribute to the progression of neurodegenerative disorders. Conclusions We diagnose the SCA48 pedigree in China and highlight the role of decreased ubiquitination and increased tau aggregation in the pathogenesis of the novel STUB1 c.755C>A mutation.

Abstract Somatic mutations of hematopoietic cells in the peripheral blood of normal individuals refer to clonal hematopoiesis of indeterminate potential (CHIP), which is associated with a 0.5–1% risk of progression to hematological malignancies and cardiovascular diseases. CHIP has also been reported in Multiple Myeloma (MM) patients, but its biological relevance remains to be elucidated. In this study, high-depth targeted sequencing of peripheral blood from 76 NDMM patients revealed CHIP in 46% of them, with a variant allele frequency (VAF) ranging from ~ 1 to 34%. The most frequently mutated gene was DNMT3A, followed by TET2. More aggressive disease features were observed among CHIP carriers, who also exhibited higher proportion of high-risk stages (ISS and R-ISS 3) compared to controls. Longitudinal analyses at diagnosis and during follow-up showed a slight increase of VAFs (p = 0.058) for epigenetic (DNMT3A, TET2, and ASXL1) and DNA repair genes (TP53; p = 0.0123). A more stable frequency was observed among other genes, suggesting different temporal dynamics of CH clones. Adverse clinical outcomes, in term of overall and progression-free survivals, were observed in CHIP carriers. These patients also exhibited weakened immune T-cells and enhanced frailty, predicting greater toxicity and consequently shorter event-free survival. Finally, correlation analysis identified platelets count as biomarker for higher VAF among CHIP carriers, regardless of the specific variant. Overall, our study highlights specific biological and clinical features, paving the way for the development of tailored strategies for MM patients carrying CHIP.

Abstract Background Clonal hematopoiesis of indeterminate potential (CHIP) has been shown to increase all-cause mortality and risk of cardiomyopathy in patients with solid malignancies. CHIP has also been shown to increase T cell activation in heart failure patients. It is unclear whether CHIP can affect the risk of immune checkpoint inhibitor (ICI) myocarditis in patients with cancer treated with immunotherapy. Methods We enrolled patients with solid tumors in a prospective study, determined CHIP status at time of enrollment through blood whole exome sequencing, and assessed incidence of ICI myocarditis from time of enrollment through December 1st, 2023. We performed a competing risk cox regression to evaluate the role of CHIP in ICI myocarditis, accounting for patient demographics, cardiac comorbidities, cardiotoxic cancer therapy, and dual ICI use in our covariates. We also generated cumulative incidence curves using subdistribution hazards to evaluate development of ICI myocarditis stratified by CHIP vs no CHIP. Chart review was performed to evaluate patient co-morbidities, lab values, imaging findings and outcomes. Results Among the 88 patients receiving ICI therapy, average age was 67 ± 14 years, of which 50% harbored CHIP variants. Among all comorbidities, including diabetes, heart failure and obstructive coronary artery disease, only coronary artery calcifications were significantly increased in patients with CHIP. There were no statistically significant differences in cancer therapy or cardiovascular drugs between patients with and without CHIP. Among examined outcomes, patients with CHIP had a statistically higher rate of ICI myocarditis (overall: 57%, CHIP: 73% (32/44), no CHIP: 41% (18/44), p = 0.003) and death (CHIP: 60%, no CHIP 31%, p = 0.011). In a multivariate competing risk analysis, CHIP status doubled the risk of developing ICI myocarditis, similar to the risk of dual ICI use (CHIP status HR 2.74, 95% CI: 1.44–5.22, p = 0.002 vs dual ICI use HR 2.39, 95% CI: 1.11–5.14, p = 0.026). Conclusions This study is the first to show that CHIP independently increases risk of ICI myocarditis, with implications for risk stratification of patients prior to ICI initiation and frequency of cardiac monitoring.

Ruixue Zhang,1 Hui Xu,1 Xiaoxue Zhang,1 Hui Xiong,2 Fei Tang,3 Liping Lv,3 Xiangdong Mu,4 Wei Tian,5 Yueguang Cheng,6 JianRong Lu,6 Xiuhong Nie,7 Yang Guo,8 Yingying Liu,9 Zhi Zhang,10 Lianjun Lin1 1Department of Geriatrics, Peking University First Hospital, Beijing, People’s Republic of China; 2Department of Emergency, Peking University First Hospital, Beijing, People’s Republic of China; 3Department of Interventional Pulmonology, Anhui Province Chest Hospital, Hefei, People’s Republic of China; 4Department of Respiratory, Tsinghua Changgung Hospital, Beijing, People’s Republic of China; 5Department of Geriatrics, Jishuitan Hospital, Beijing, People’s Republic of China; 6Department of Emergency, Jingmei Group General Hospital, Beijing, People’s Republic of China; 7Department of Respiratory, Xuanwu Hospital, Beijing, People’s Republic of China; 8Department of Endoscopic Diagnosis &treatment, Beijing Chest Hospital, Capital Medical University, Beijing, People’s Republic of China; 9CapitalBio Technology Co., Ltd, Beijing, People’s Republic of China; 10Bio Biological Group Co., Ltd, Beijing, People’s Republic of ChinaCorrespondence: Lianjun Lin, Department of Geriatrics, Peking University First Hospital, No. 8 Xishiku Avenue, Beijing, 100034, People’s Republic of China, Email 06474@pkufh.comPurpose: The detection of pathogenic microorganisms plays a significant role in the diagnosis and management of pneumonia that are responsible for a substantial number of deaths worldwide. However, conventional microbiological tests (CMT) have low accuracy and are time-consuming. In this study, we aim to evaluate the clinical value of Chips for Complicated Infection Detection (CCID) in detecting pneumonia pathogens.Patients and Methods: This study was conducted at nine hospitals in China from January 2021 to September 2022. Respiratory samples from adult pneumonia patients were collected from each patient. CMT and CCID were performed in parallel to identify the pathogens.Results: A total of 245 patients were included, with 73% being elderly. CCID identified pathogenic microbes in 78.0% of patients and conventional microbiological tests (CMT) in 57.1% of the patients (p< 0.001). The overall positive and negative percent agreements between CCID and CMT for pathogen detection were 90.07% and 38.46%, respectively. 38.8% of patients were diagnosed with mixed infections with at least two pathogens by CCID. Bacterial infections identified by CCID accounted for 60.0% of 245 patients, with the top 3 being Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterococcus faecium, respectively. K. pneumoniae was the most common pathogen in elderly patients, with a significantly higher prevalence compared to non-elderly patients (p = 0.0011). Among the 197 patients who had used antibiotics before sample collection, the positive rate of CCID was significantly higher than that of CMT (p < 0.001).Conclusion: This study indicates that compared to CMT, this novel chip has significant advantages in detecting pathogens in pneumonia patients, especially in the elderly.Keywords: pneumonia, elderly, pathogens, chip, LAMP

Abstract The clinical manifestations and pathophysiology of clonal hematopoiesis (CH)‐associated immunological dysfunction are poorly understood. We describe an elderly woman with CH who developed various systemic inflammatory or autoimmune diseases (SIADs), including cutaneous Langerhans cell histiocytosis (LCH) and temporal arteritis. Sequencing of the LCH revealed somatic oncogenic mutations in MAP2K1, IDH2, and SRSF2, with enrichment of the latter two in her peripheral blood at high allele frequencies. These findings raise concern for the future development of a myeloid malignancy. Given the mounting evidence for adult‐onset autoinflammatory conditions caused by somatic blood mutations, we suspect CH‐mediated immune dysregulation is contributing to her multi‐organ involvement by a combination of SIADs.

Somatic mutations of hematopoietic cells in the peripheral blood of normal individuals refer to clonal hematopoiesis of indeterminate potential (CHIP), which is associated with a 0.5–1% risk of progression to hematological malignancies and cardiovascular diseases. CHIP has also been reported in Multiple Myeloma (MM) patients, but its biological relevance remains to be elucidated. In this study, high-depth targeted sequencing of peripheral blood from 76 NDMM patients revealed CHIP in 46% of them, with a variant allele frequency (VAF) ranging from ~ 1 to 34%. The most frequently mutated gene was DNMT3A, followed by TET2. More aggressive disease features were observed among CHIP carriers, who also exhibited higher proportion of high-risk stages (ISS and R-ISS 3) compared to controls. Longitudinal analyses at diagnosis and during follow-up showed a slight increase of VAFs (p = 0.058) for epigenetic (DNMT3A, TET2, and ASXL1) and DNA repair genes (TP53; p = 0.0123). A more stable frequency was observed among other genes, suggesting different temporal dynamics of CH clones. Adverse clinical outcomes, in term of overall and progression-free survivals, were observed in CHIP carriers. These patients also exhibited weakened immune T-cells and enhanced frailty, predicting greater toxicity and consequently shorter event-free survival. Finally, correlation analysis identified platelets count as biomarker for higher VAF among CHIP carriers, regardless of the specific variant. Overall, our study highlights specific biological and clinical features, paving the way for the development of tailored strategies for MM patients carrying CHIP. [ABSTRACT FROM AUTHOR]

Myeloproliferative neoplasms, polycythemia vera, essential thrombocytosis, and primary myelofibrosis are a unique group of clonal hematopoietic stem cell neoplasms that share somatic, gain-in-function driver mutations in JAK2, CALR, and MPL. As a consequence, these disorders exhibit similar phenotypic features, the most common of which are the ceaseless production of normal erythrocytes, myeloid cells, platelets alone or in combination, extramedullary hematopoiesis, myelofibrosis, and a potential for leukemic transformation. In the case of polycythemia vera and essential thrombocytosis, however, prolonged survival is possible. With an incidence value in the range of 0.5–2.0/100,000, myeloproliferative neoplasms are rare disorders, but they are not new disorders, and after a century of scrutiny, their clinical features and natural histories are well-defined, though their individual management continues to be controversial. With respect to polycythemia vera, there has been a long-standing dispute between those who believe that the suppression of red blood cell production by chemotherapy is superior to phlebotomy to prevent thrombosis, and those who do not. With respect to essential thrombocytosis, there is a similar dispute about the role of platelets in veinous thrombosis, and the role of chemotherapy in preventing thrombosis by suppressing platelet production. Linked to these disputes is another: whether therapy with hydroxyurea promotes acute leukemia in disorders with a substantial possibility of longevity. The 21st century revealed new insights into myeloproliferative neoplasms with the discovery of their three somatic, gain-of-function driver mutations. Almost immediately, this triggered changes in the diagnostic criteria for myeloproliferative neoplasms and their therapy. Most of these changes, however, conflicted with prior well-validated, phenotypically driven diagnostic criteria and the management of these disorders. The aim of this review is to examine these conflicts and demonstrate how genomic discoveries in myeloproliferative neoplasms can be used to effectively complement the known phenotypic features of these disorders for their diagnosis and management. [ABSTRACT FROM AUTHOR]

Mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and its dysregulation leads to a variety of human diseases. Although NPRL2, an essential component of the GATOR1 complex, is reported to effectively suppress amino acid‐induced mTORC1 activation, the regulation of NPRL2 protein stability is unclear. In this study, we show that chaperon‐associated ubiquitin ligase CHIP interacts with NPRL2 and promotes its polyubiquitination and proteasomal degradation. Moreover, HSP70 mediates CHIP‐induced ubiquitination and degradation of NPRL2. Consistently, overexpression of HSP70 enhances whereas HSP70 depletion inhibits amino acid‐induced mTORC1 activation. Accordingly, knockdown of HSP70 promotes basal autophagic flux, and inhibits cell growth and proliferation. Taken together, these results demonstrated that HSP70 is a novel activator of mTORC1 through mediating CHIP‐induced ubiquitination and degradation of NPRL2. [ABSTRACT FROM AUTHOR]

Background and Aims Somatic mutations in the TET2 gene that lead to clonal haematopoiesis (CH) are associated with accelerated atherosclerosis development in mice and a higher risk of atherosclerotic disease in humans. Mechanistically, these observations have been linked to exacerbated vascular inflammation. This study aimed to evaluate whether colchicine, a widely available and inexpensive anti-inflammatory drug, prevents the accelerated atherosclerosis associated with TET2-mutant CH. Methods In mice, TET2 -mutant CH was modelled using bone marrow transplantations in atherosclerosis-prone Ldlr −/− mice. Haematopoietic chimeras carrying initially 10% Tet2 −/− haematopoietic cells were fed a high-cholesterol diet and treated with colchicine or placebo. In humans, whole-exome sequencing data and clinical data from 37 181 participants in the Mass General Brigham Biobank and 437 236 participants in the UK Biobank were analysed to examine the potential modifying effect of colchicine prescription on the relationship between CH and myocardial infarction. Results Colchicine prevented accelerated atherosclerosis development in the mouse model of TET2 -mutant CH, in parallel with suppression of interleukin-1β overproduction in conditions of TET2 loss of function. In humans, patients who were prescribed colchicine had attenuated associations between TET2 mutations and myocardial infarction. This interaction was not observed for other mutated genes. Conclusions These results highlight the potential value of colchicine to mitigate the higher cardiovascular risk of carriers of somatic TET2 mutations in blood cells. These observations set the basis for the development of clinical trials that evaluate the efficacy of precision medicine approaches tailored to the effects of specific mutations linked to CH. [ABSTRACT FROM AUTHOR]

The machinability of various grades of austempered ductile iron (ADI) has been investigated by using the surface roughness and the resultant chip formation as criteria. Grade 1 ADI, Grade 2 ADI, and Grade 3 ADI were commercially produced, commercially heat treated and machined under controlled conditions using coated carbide inserts with coolant in the laboratory. The milling performance of the various grades was compared to that of AISI 4340, which has a similar hardness to Grade 2 ADI. Grade 100-70-03 ductile iron was used as a reference material in the drilling study. The results of this study show that the surface finish of ADI and the resultant chip formation give quick indications if proper cutting parameters were used during machining of ADI. [ABSTRACT FROM AUTHOR]

This letter to the editor discusses the prevalence and characteristics of TP53 Y220C mutations in patients with myeloid malignancies. The study found that these mutations were detected in 4.8% of patients with TP53 mutated myeloid neoplasms, most of whom had myelodysplastic syndromes or acute myeloid leukemia. The study also identified other co-occurring mutations. The authors suggest that targeted therapies may hold promise in improving outcomes for patients with this mutation, but further research is needed to address other TP53 mutations. [Extracted from the article]

Clonal hematopoiesis of indeterminate potential (CHIP) describes recurrent somatic gene mutations in the blood of healthy individuals, associated with higher risk for hematological malignancies and higher all-cause mortality by cardiovascular disease. CHIP increases with age and is more common in adult patients after chemotherapy or radiation for cancer. Furthermore, in some adult patients undergoing autologous stem cell transplantation (ASCT) or thereafter, CHIP has been identified. In children and adolescents, it remains unclear how cellular stressors such as cytotoxic therapy influence the incidence and expansion of CHIP. We conducted a retrospective study on 33 pediatric patients mostly with solid tumors undergoing ASCT for presence of CHIP. We analyzed CD34+ selected peripheral blood stem cell grafts after several cycles of chemotherapy, prior to cell infusion, by next-generation sequencing including 18 "CHIP-genes". Apart from a somatic variant in TP53 in one patient no other variants indicative of CHIP were identified. As a CHIP-unrelated finding, germline variants in CHEK2 and in ATM were identified in two and four patients, respectively. In conclusion, we could not detect "typical" CHIP variants in our cohort of pediatric cancer patients undergoing ASCT. However, more studies with larger patient numbers are necessary to assess if chemotherapy in the pediatric setting contributes to an increased CHIP incidence and at what time point. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Clonal hematopoiesis of indeterminate potential (CHIP) and dementia disproportionately burden patients with chronic kidney disease (CKD). The association between CHIP and cognitive impairment in CKD patients is unknown. METHODS: We conducted time‐to‐event analyses in up to 1452 older adults with CKD from the Chronic Renal Insufficiency Cohort who underwent CHIP gene sequencing. Cognition was assessed using four validated tests in up to 6 years mean follow‐up time. Incident cognitive impairment was defined as a test score one standard deviation below the baseline mean. RESULTS: Compared to non‐carriers, CHIP carriers were markedly less likely to experience impairment in attention (adjusted hazard ratio [HR] [95% confidence interval {CI}] = 0.44 [0.26, 0.76], p = 0.003) and executive function (adjusted HR [95% CI] = 0.60 [0.37, 0.97], p = 0.04). There were no significant associations between CHIP and impairment in global cognition or verbal memory. DISCUSSION: CHIP was associated with lower risks of impairment in attention and executive function among CKD patients. Highlights: Our study is the first to examine the role of CHIP in cognitive decline in CKD.CHIP markedly decreased the risk of impairment in attention and executive function.CHIP was not associated with impairment in global cognition or verbal memory. [ABSTRACT FROM AUTHOR]

Mollusca first evolve primitive immune cells (namely, haemocytes), which assemble a notable complex innate immune system, which are continuously produced through proliferation and differentiation and infused in the haemolymph. As a typical E3 ligase, CHIP is critical for immune cell turnover and homeostasis in vertebrates. In this study, a CHIP homolog (CgCHIP) with a high expression in haemocytes was identified in oysters to investigate its role in the proliferation and differentiation of ancient innate immune cells. CgCHIP exhibited a widespread distribution across all haemocyte subpopulations, and the knockdown of CgCHIP altered the composition of haemocytes as examined by flow cytometry. Mechanistically screened with bioinformatics and immunoprecipitation, a key haematopoietic transcription factor CgRunx was identified as a substrate of CgCHIP. Moreover, amino acids in the interacted intervals of CgCHIP and CgRunx were determined by molecular docking. Experimental evidence from an in vitro culture model of an agranulocyte subpopulation and an in vivo oyster model revealed that the knockdown of CgCHIP and CgRunx had opposing effects on agranulocyte (precursor cells) differentiation and granulocyte (effector cells) proliferation. In summary, CgCHIP negatively regulated agranulocyte differentiation and granulocyte proliferation by mediating the ubiquitination and degradation of CgRunx in oysters. These results offer insight into the involvement of ubiquitylation in controlling haemocyte turnover in primitive invertebrates. [ABSTRACT FROM AUTHOR]

As the cornerstone of the digital economy in the information age, the essence of integrated circuit (IC) chips is to represent and process information by using physical phenomena. The IC challenges faced by China are not only in the field of fabrication, but also in the fields of electronics design automation (EDA) and talent training. Based on a review of the background and current situations of IC technologies, this study analyzes advantages, issues that need attention, and potential areas of technological breakthrough in the Guangdong-Hong Kong-Macao Greater Bay Area. [ABSTRACT FROM AUTHOR]

This paper designs a bandpass filter for D‐band and 0.18 μm complementary metal oxide semiconductor (CMOS) process. The bandpass filter is composed of an inverted L‐shaped coupling microstrip line and a cross‐coupled resonator, and is coupled to produce two controlled transmission zeros. A defected ground structure is used to make a good impedance match. The designed filter has a 3 dB impedance bandwidth of 52 GHz (149–201 GHz) with a center frequency of 175 GHz and an insertion loss of 3.23 dB. The design of this paper is a CMOS 0.18 μm process capable of applying the D‐band bandpass filter with the advantages of lower insertion loss, broadband, and compact size. [ABSTRACT FROM AUTHOR]

Background Doxorubicin‐induced cardiotoxicity is still an important medical problem associated with a high mortality rate in cancer survivors. p53 plays a key role in doxorubicin‐induced cardiotoxicity. Diacylglycerol kinase ζ (Dgkζ), a 130‐kDa enzyme abundant in cardiomyocytes, regulates the p53 protein expression level in neurons. To elucidate the mechanism of doxorubicin‐induced cardiotoxicity, we focused on the functional role of Dgkζ and its interaction with heat shock protein 70 (Hsp70)–related ubiquitin E3 ligases such as E6‐associated protein (E6ap) and C‐terminus of Hsp70‐interacting protein. Methods and Results Protein interactions of Dgkζ with Hsp70 and E6ap were confirmed by immunoprecipitation, but not C‐terminus of Hsp70‐interacting protein. We administered doxorubicin in cardiac‐specific overexpression of Dgkζ transgenic (Dgkζ‐Tg) mice and wild‐type littermates. Dgkζ‐Tg mice showed lower p53 protein expression levels, preserved cardiac function, and improved survival rates compared with wild‐type littermates after doxorubicin administration. RNA sequence analysis of myocardial tissues from Dgkζ‐Tg after doxorubicin stimulation identified Hspa1b encoding Hsp70 as the differentially expressed gene. Dgkζ overexpression increased proteasomal p53 degradation and attenuated cardiomyocyte apoptosis after doxorubicin stimulation in cardiomyocytes, which was reversed by knockdown of E6ap. Dgkζ interacted with E6ap through ankyrin‐like repeats. The overexpression of mutant Dgkζ, lacking ankyrin‐like repeats, failed to inhibit p53 protein expression after doxorubicin stimulation. In Dgkζ‐overexpressing cardiomyocytes, expression levels of p53 and caspase‐3 were increased by knockdown of the C‐terminus of Hsp70‐interacting protein. Conclusions We demonstrated for the first time that Dgkζ augments p53 ubiquitin‐proteasome degradation and ameliorates doxorubicin‐induced cardiotoxicity by interacting with Hsp70 and E3 ligases such as E6ap and C‐terminus of Hsp70‐interacting protein.

IntroductionRecent work has revealed that clonal hematopoiesis (CH) is associated with a higher risk of numerous age-related diseases, including ischemic stroke, however little is known about whether it influences stroke outcome independent of its widespread effects on cardiovascular disease. Studies suggest that leukocytes carrying CH driver mutations have an enhanced inflammatory profile, which could conceivably exacerbate brain injury after a stroke.MethodsUsing a competitive bone marrow transplant model of Tet2-mediated CH, we tested the hypothesis that CH would lead to a poorer outcome after ischemic stroke by augmenting brain inflammation. Stroke was induced in mice by middle cerebral artery occlusion and neurological outcome was assessed at acute (24 h) and subacute (14 d) timepoints. Brains were collected at both time points for histological, immunofluorescence and gene expression assays.ResultsUnexpectedly, Tet2-mediated CH had no effect on acute stroke outcome but led to a reduction in neurological deficits during the subacute phase. This improved neurological outcome was associated with lower levels of brain inflammation as evidenced by lower transcript levels of various inflammatory molecules alongside reduced astrogliosis.DiscussionThese findings suggest that Tet2-mediated CH may have beneficial effects on outcome after stroke, contrasting with the conventional understanding of CH whereby leukocytes with driver mutations promote disease by exacerbating inflammation.

ABSTRACTLinks between the gut microbiota and human health have been supported throughout numerous studies, such as the development of neurological disease disorders. This link is referred to as the “microbiota-gut-brain axis” and is the focus of an emerging field of research. Microbial-derived metabolites and gut and neuro-immunological metabolites regulate this axis in health and many diseases. Indeed, assessing these signals, whether induced by microbial metabolites or neuro-immune mediators, could significantly increase our knowledge of the microbiota-gut-brain axis. However, this will require the development of appropriate techniques and potential models. Methods for studying the induced signals originating from the microbiota remain crucial in this field. This review discusses the methods and techniques available for studies of microbiota-gut-brain interactions. We highlight several much-debated elements of these methodologies, including the widely used in vivo and in vitro models, their implications, and perspectives in the field based on a systematic review of PubMed. Applications of various animal models (zebrafish, mouse, canine, rat, rabbit) to microbiota-gut-brain axis research with practical examples of in vitro methods and innovative approaches to studying gut-brain communications are highlighted. In particular, we extensively discuss the potential of “organ-on-a-chip” devices and their applications in this field. Overall, this review sheds light on the most widely used models and methods, guiding researchers in the rational choice of strategies for studies of microbiota-gut-brain interactions.

Cardiac allograft vasculopathy (CAV) is a leading cause of late graft failure and mortality after heart transplantation (HT). Sharing some features with atherosclerosis, CAV results in diffuse narrowing of the epicardial coronaries and microvasculature, with consequent graft ischemia. Recently, clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a risk factor for cardiovascular disease and mortality. We aimed to investigate the relationship between CHIP and posttransplant outcomes, including CAV. We analyzed 479 HT recipients with stored DNA samples at 2 high-volume transplant centers, Vanderbilt University Medical Center and Columbia University Irving Medical Center. We explored the association between the presence of CHIP mutations with CAV and mortality after HT. In this case-control analysis, carriers of CHIP mutations were not at increased risk of CAV or mortality after HT. In a large multicenter genomics study of the heart transplant population, the presence of CHIP mutations was not associated with an increased risk of CAV or posttransplant mortality.

Abstract Clonal haematopoiesis of indeterminate potential (CHIP) has been associated with many adverse health outcomes. However, further research is required to understand the critical genes and pathways relevant to CHIP subtypes, evaluate how CHIP clones evolve with time, and further advance functional characterisation and therapeutic studies. Large epidemiological studies are well placed to address these questions but often collect saliva rather than blood from participants. Paired saliva- and blood-derived DNA samples from 94 study participants were sequenced using a targeted CHIP-gene panel. The ten genes most frequently identified to carry CHIP-associated variants were analysed. Fourteen unique variants associated with CHIP, ten in DNMT3A, two in TP53 and two in TET2, were identified with a variant allele fraction (VAF) between 0.02 and 0.2 and variant depth ≥ 5 reads. Eleven of these CHIP-associated variants were detected in both the blood- and saliva-derived DNA sample. Three variants were detected in blood with a VAF > 0.02 but fell below this threshold in the paired saliva sample (VAF 0.008—0.013). Saliva-derived DNA is suitable for detecting CHIP-associated variants. Saliva can offer a cost-effective biospecimen that could both advance CHIP research and facilitate clinical translation into settings such as risk prediction, precision prevention, and treatment monitoring.

Purpose of reviewClonal hematopoiesis (CH) refers to the expansion of hematopoietic stem cell clones and their cellular progeny due to somatic mutations, mosaic chromosomal alterations (mCAs), or copy number variants which naturally accumulate with age. CH has been linked to increased risk of blood cancers, but CH has also been linked to adverse cardiovascular outcomes.Recent findingsA combination of clinical outcome studies and mouse models have offered strong evidence that CH mutations either correlate with or cause atherosclerosis, diabetes mellitus, chronic kidney disease, heart failure, pulmonary hypertension, aortic aneurysm, myocardial infarction, stroke, aortic stenosis, poor outcomes following transcatheter aortic valve replacement (TAVR) or orthotopic heart transplant, death or need of renal replacement therapy secondary to cardiogenic shock, death from cardiovascular causes at large, and enhance anthracycline cardiac toxicity. Mechanistically, some adverse outcomes are caused by macrophage secretion of IL-1β and IL-6, neutrophil invasion of injured myocardium, and T-cell skewing towards inflammatory phenotypes. CH mutations lead to harmful inflammation and arterial wall invasion by bone marrow-derived cells resulting in poor cardiovascular health and outcomes. Blockade of IL-1β or JAK2 signaling are potential avenues for preventing CH-caused cardiovascular morbidity and mortality.

Improved expertise and technological advancements have enabled the safe and effective performance of complex and high-risk-indicated percutaneous coronary intervention (CHIP) in patients previously considered inoperable or high-risk. Mechanical circulatory support (MCS) devices play a crucial role in stabilizing hemodynamics during percutaneous coronary intervention (PCI) -related ischemia, thereby reducing the risk of major adverse events and achieving a more complete revascularization. However, the use of MCS devices in protected PCI is not without risks, including peri-procedural myocardial infarction (MI), bleeding, and access-related complications. Despite numerous observational studies, there is a significant lack of randomized clinical trials comparing different MCS devices in various CHIP scenarios and evaluating their long-term safety and efficacy profiles. This review aims to summarize the current evidence regarding the benefits of MCS devices during CHIPs, offer a practical guide for selecting appropriate devices based on clinical scenarios, and highlight the unanswered questions that future trials need to address. [ABSTRACT FROM AUTHOR]

Clonal haematopoiesis of indeterminate potential (CHIP) has been associated with many adverse health outcomes. However, further research is required to understand the critical genes and pathways relevant to CHIP subtypes, evaluate how CHIP clones evolve with time, and further advance functional characterisation and therapeutic studies. Large epidemiological studies are well placed to address these questions but often collect saliva rather than blood from participants. Paired saliva- and blood-derived DNA samples from 94 study participants were sequenced using a targeted CHIP-gene panel. The ten genes most frequently identified to carry CHIP-associated variants were analysed. Fourteen unique variants associated with CHIP, ten in DNMT3A, two in TP53 and two in TET2, were identified with a variant allele fraction (VAF) between 0.02 and 0.2 and variant depth ≥ 5 reads. Eleven of these CHIP-associated variants were detected in both the blood- and saliva-derived DNA sample. Three variants were detected in blood with a VAF > 0.02 but fell below this threshold in the paired saliva sample (VAF 0.008—0.013). Saliva-derived DNA is suitable for detecting CHIP-associated variants. Saliva can offer a cost-effective biospecimen that could both advance CHIP research and facilitate clinical translation into settings such as risk prediction, precision prevention, and treatment monitoring. [ABSTRACT FROM AUTHOR]

Myosin Va (Myo Va) is one of three protein complexes involved in melanosome transport. In this study, we identified BMP-2 as an up-regulator of Myo Va expression using 2-methyl-naphtho[1,2,3-de]quinolin-8-one (MNQO). Our results showed that MNQO reduced the mRNA and protein expression of Myo Va and BMP-2 in melanocytes. Knockdown of BMP-2 by siRNA also affected Myo Va mRNA and protein expression, confirming that MNQO regulates Myo Va through BMP-2. Furthermore, phosphorylation of Smad1/5/8 by BMP2 treatment confirmed that the BMP-2/Smad signaling pathway regulates Myo Va expression in Melan-a melanocytes. Smad-binding elements were found in the Myo Va promoter and phosphorylated Smad1/5/8 bind directly to the Myo Va promoter to activate Myo Va transcription and BMP-2 enhances this binding. These findings provide insight into a new role for BMP-2 in Melan-a melanocytes and a mechanism of regulation of Myo Va expression that may be beneficial in the treatment of albinism or hyperpigmentation disorders. [ABSTRACT FROM AUTHOR]

Simple Summary: The expansion of mutant cells that outgrow and displace normal blood cells is called clonal hematopoiesis (CH). CH starts with the acquisition of mutations in blood stem cells that change their normal behavior and improve their fitness. Low numbers of mutant blood cells are present in many middle-aged and elderly people without noticeable effects. However, CH can progress to leukemia and contribute to diseases in other tissues, including the heart, liver, and pancreas. As these diseases progress and affect health when the number of mutant blood cells increases, preventing and/or reducing the expansion of mutant cells might delay this process. Identifying the factors driving mutant blood cell expansion is thus critical and has garnered heightened interest in the subject. Here, we review and discuss recent progress in the field that suggests that mutant blood stem cells are more resilient than normal cells and thrive in inflammatory conditions. Clonal hematopoiesis (CH), the relative expansion of mutant clones, is derived from hematopoietic stem cells (HSCs) with acquired somatic or cytogenetic alterations that improve cellular fitness. Individuals with CH have a higher risk for hematological and non-hematological diseases, such as cardiovascular disease, and have an overall higher mortality rate. Originally thought to be restricted to a small fraction of elderly people, recent advances in single-cell sequencing and bioinformatics have revealed that CH with multiple expanded mutant clones is universal in the elderly population. Just a few years ago, phylogenetic reconstruction across the human lifespan and novel sensitive sequencing techniques showed that CH can start earlier in life, decades before it was thought possible. These studies also suggest that environmental factors acting through aberrant inflammation might be a common theme promoting clonal expansion and disease progression. However, numerous aspects of this phenomenon remain to be elucidated and the precise mechanisms, context-specific drivers, and pathways of clonal expansion remain to be established. Here, we review our current understanding of the cellular mechanisms driving CH and specifically focus on how pro-inflammatory factors affect normal and mutant HSC fates to promote clonal selection. [ABSTRACT FROM AUTHOR]

A new type of passive heat sink is proposed to address the current demand for silent heat dissipation in high-power CPUs. The temperature, start-up performance, and thermal resistance of the heat sink under different heating powers were studied through numerical simulation and experimental verification. The simulation results show that under 120 W heating conditions, the temperature distribution of the radiator is uniform, with small fluctuations. The maximum temperature is only 64.00 °C, the startup time is about 900s, and the average contact thermal resistance is between 0.01~0.2 °C/W. The experimental results show that under 120 W heating conditions, the maximum temperature of the heat sink is only 68.28 °C, the startup time is about 900s, and the average contact thermal resistance is only 0. 11 °C/W, meeting the normal operation requirements of the computer CPU at this power. [ABSTRACT FROM AUTHOR]

The increased use of next‐generation sequencing has led to the detection of pathogenic TP53 variants in the germline setting in patients without a personal or family history consistent with Li–Fraumeni syndrome (LFS). These variants can represent low‐penetrance LFS, mosaic LFS, or clonal hematopoiesis of indeterminate potential. Additionally, TP53 variants of uncertain significance can be detected in patients with a history suspicious for LFS. The interpretation of the significance of these variants can be challenging but is crucial for an accurate diagnosis and appropriate medical management. This retrospective case review provides illustrative examples of the interpretation of challenging TP53 results through multidisciplinary expertise and use of a flowchart. The authors describe eight patients with TP53 variants associated with ambiguous diagnoses and, for each case, describe how the results were interpreted and the medical care that was implemented. This report presents illustrative cases to help guide clinicians to reach definitive diagnoses for patients when confronted with TP53 variants that are inconsistent with the clinical picture and to add to the body of literature regarding interpretation and medical management of TP53 variants discovered on germline testing. [ABSTRACT FROM AUTHOR]