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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.

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]

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]

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.

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.

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]

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]

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]

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]

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]

Experimental data regarding the modeling of shaving and rolling of cylindrical gears are considered. In the experiments, a cylindrical workpiece divided into sections is turned by means of a special hybrid cutting and deforming tool (a chisel). Analysis of the data permits modeling of tooth cutting for a relatively large batch of gears in laboratory conditions. The basic parameters of the tool's mechanical action on the workpiece in cutting—the microhardness, the chip removed, and the shrinkage—are determined. Their relationship with tool wear is established. [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]

Transcription factor (TF) residence on chromatin translates into quantitative transcriptional or structural outcomes on genome. Commonly used formaldehyde crosslinking fixes TF-DNA interactions cumulatively and compromises the measured occupancy level. Here we mapped the occupancy level of global or individual zinc finger TFs like CTCF and MAZ, in the form of highly resolved footprints, on native chromatin. By incorporating reinforcing perturbation conditions, we established S-score, a quantitative metric to proxy the continuum of CTCF or MAZ retention across different motifs on native chromatin. The native chromatin-retained CTCF sites harbor sequence features within CTCF motifs better explained by S-score than the metrics obtained from other crosslinking or native assays. CTCF retention on native chromatin correlates with local SUMOylation level, and anti-correlates with transcriptional activity. The S-score successfully delineates the otherwise-masked differential stability of chromatin structures mediated by CTCF, or by MAZ independent of CTCF. Overall, our study established a paradigm continuum of TF retention across binding sites on native chromatin, explaining the dynamic genome organization. Synopsis: The measured TF occupancy level is compromised when chromatin is chemically crosslinked. Profiling TF occupancy on native chromatin restores a more unperturbed picture of TF retention and better explains dynamic genome organization. loMNase-seq and N-ChIP identify highly resolved TF footprints on native chromatin. TFs are continuously "stripped off" across binding sites on native chromatin under increasing salt concentration. The S-score derived from such series of N-ChIP experiments delineates TF binding sites with differential stability under stress. The S-score explains a spectrum of stability of TF-mediated chromatin loops under stress. The measured TF occupancy level is compromised when chromatin is chemically crosslinked. Profiling TF occupancy on native chromatin restores a more unperturbed picture of TF retention and better explains dynamic genome organization. [ABSTRACT FROM AUTHOR]

During the machining of aluminum alloys, the adhesion of chips to the tool affects the performance characteristics. Today, different cooling systems are used to eliminate these negativities. In this study, the effects of end milling using HSS and carbide cutting tools of 6061-T6 aluminum alloy on surface roughness, chip thickness ratio and tool wear were examined using different cooling techniques (dry, minimum quantity lubrication (MQL) and nanocutting fluid). Different cutting speeds (180, 200, 220 m/min) and different feed rates (0.05, 0.06, 0.07 mm/rev) were used in the experiments. According to experimental findings, tool wear and surface roughness decreased at low cutting speed and feed rate by using nanocutting fluid with carbide cutting tools. It has been observed that the chip thickness ratio increases with high cutting speeds using nanocutting fluid and decreases with dry machining and high feed rates. The best milling performance of the aluminum alloy was achieved in experiments using carbide cutting tools and nanocutting fluid. [ABSTRACT FROM AUTHOR]

The involvement of the molecular clock in regulating cell physiological processes on a specific time scale is a recognized concept, yet its specific impact on optimizing androgen production in Leydig cells has been unclear. This study aimed to confirm the role of the REVERBA (NR1D1) gene in controlling the transcription of key genes related to Leydig cell steroid production. We investigated daily variations by collecting Leydig cells from rats at various times within a 24‐h period. Chromatin immunoprecipitation study showed a time‐dependent pattern for genes linked to steroid production (Nur77, Star, Cyp11a1, and Cyp17a1), which closely matched the 24‐h REVERBA levels in Leydig cells, peaking between zeitgeber time (ZT) 7–11. To understand the physiological significance of REVERBA's interaction with promoters of steroidogenesis‐related genes, Leydig cells from rats at two different times (ZT7 and ZT16; chosen based on REVERBA expression levels), were treated with either an agonist (GSK4112) or an antagonist (SR8278). The results revealed that the REVERBA agonist stimulated gene transcription, while the antagonist inhibited it, but only when REVERBA was sufficiently present, indicating a reliance on REVERBA's circadian fluctuation. Moreover, this REVERBA‐dependent stimulation had a clear impact on testosterone production in the culture medium, underscoring REVERBA's involvement in the circadian regulation of testosterone. This study indicates that REVERBA, in addition to being a core component of the cellular clock, plays a key role in regulating androgen production in Leydig cells by influencing the transcription of critical steroidogenesis‐related genes. [ABSTRACT FROM AUTHOR]

Introduction: High-risk procedures in interventional cardiology include a wide spectrum of clinical and anatomical scenarios related to a higher periprocedural morbidity and mortality. The prophylactic use of short-term mechanical circulatory support (ST-MCS) may improve both the safety and efficacy of the intervention by leading to more stable procedural hemodynamics. However, the significant costs may limit its use in resource constrained settings. To overcome this limitation, we ideated a modified, low-cost, veno-arterial extracorporeal membrane oxygenator (V-A ECMO) setup. Methods: We conducted an observational prospective study including all patients undergoing a high-risk interventional cardiology procedure at our institution under prophylactic ST-MCS using a modified, low-cost version of V-A ECMO, where some components of the standard V-A ECMO circuit were replaced by supplies used for cardiac surgical cardiopulmonary bypass, achieving a cost reduction of 72%. We assessed in-hospital and mid-term outcomes, including procedural success, post-procedure complications and mortality. Results: Between March 2016 and December 2021, ten patients underwent high-risk IC procedures with prophylactic use of V-A ECMO. Isolated percutaneous intervention (PCI) was performed in six patients, isolated transcatheter aortic valve replacement (TAVR) in two, and a combined procedure (PCI + TAVR) in two. Mean ejection fraction was 34% (range 20–64%). Mean STS PROM was 16.2% (range 9.5–35.8%) and mean EuroScore was 23.7% (range 1.5–60%). The planned intervention was successfully performed in all cases. There were no reports of V-A ECMO malfunction. In nine patients the VA-ECMO was withdrawn immediately after the procedure but one patient required extended - 24 h - support with no significant issues. One patient experienced a periprocedural myocardial infarction and another developed a femoral pseudoaneurysm. In-hospital and 30-day survival were 100%, and 1-year survival was 80%. Conclusions: High-risk procedures in interventional cardiology can be successfully performed under prophylactic ST-MCS using a modified, low-cost V-A ECMO, suitable for limited-resource settings. [ABSTRACT FROM AUTHOR]

In the field of biomedicine, efficiently and non-invasively isolating target cells has always been one of the core challenges. Optical fiber tweezers offer precise and non-invasive manipulation of cells within a medium and can be easily integrated with microfluidic systems. Therefore, this paper investigated the mechanism of cell manipulation using scattering force with optical fiber tweezers. We employed flat-ended single-mode fiber to drive and sort cells and derived the corresponding scattering force formula based on the T-matrix model. A single-mode optical tweezers system for cell sorting was developed, and an optofluidic experimental platform was constructed that effectively integrates the optical system with microfluidic chips. The chip, featuring an expanded cross-channel design, successfully achieved continuous separation of yeast cells (8~10 µm in diameter) and polystyrene microspheres (15~20 µm in diameter), with a sorting efficiency of up to 86% and maintaining viability in approximately 90% of the yeast cells. Compared to other sorting systems, this system does not require labeling and can achieve continuous sorting with cell viability at a lower cost of instrumentation. [ABSTRACT FROM AUTHOR]

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.

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.

Chromatin immunoprecipitation (ChIP-seq) is the most common approach to observe global binding of proteins to DNA in vivo. The occupancy of transcription factors (TFs) from ChIP-seq agrees well with an alternative method, chromatin endogenous cleavage (ChEC-seq2). However, ChIP-seq and ChEC-seq2 reveal strikingly different patterns of enrichment of yeast RNA polymerase II (RNAPII). We hypothesized that this reflects distinct populations of RNAPII, some of which are captured by ChIP-seq and some of which are captured by ChEC-seq2. RNAPII association with enhancers and promoters - predicted from biochemical studies - is detected well by ChEC-seq2 but not by ChIP-seq. Enhancer/promoter-bound RNAPII correlates with transcription levels and matches predicted occupancy based on published rates of enhancer recruitment, preinitiation assembly, initiation, elongation, and termination. The occupancy from ChEC-seq2 allowed us to develop a stochastic model for global kinetics of RNAPII transcription which captured both the ChEC-seq2 data and changes upon chemical-genetic perturbations to transcription. Finally, RNAPII ChEC-seq2 and kinetic modeling suggests that a mutation in the Gcn4 transcription factor that blocks interaction with the NPC destabilizes promoter-associated RNAPII without altering its recruitment to the enhancer.

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.

Abstract Transcription factor (TF) residence on chromatin translates into quantitative transcriptional or structural outcomes on genome. Commonly used formaldehyde crosslinking fixes TF-DNA interactions cumulatively and compromises the measured occupancy level. Here we mapped the occupancy level of global or individual zinc finger TFs like CTCF and MAZ, in the form of highly resolved footprints, on native chromatin. By incorporating reinforcing perturbation conditions, we established S-score, a quantitative metric to proxy the continuum of CTCF or MAZ retention across different motifs on native chromatin. The native chromatin-retained CTCF sites harbor sequence features within CTCF motifs better explained by S-score than the metrics obtained from other crosslinking or native assays. CTCF retention on native chromatin correlates with local SUMOylation level, and anti-correlates with transcriptional activity. The S-score successfully delineates the otherwise-masked differential stability of chromatin structures mediated by CTCF, or by MAZ independent of CTCF. Overall, our study established a paradigm continuum of TF retention across binding sites on native chromatin, explaining the dynamic genome organization.

FNDC3B (fibronectin type III domain containing 3B) is highly expressed in hepatocellular carcinoma (HCC) and other cancer types, and fusion genes involving FNDC3B have been identified in HCC and leukemia. Growing evidence suggests the significance of FNDC3B in tumorigenesis, particularly in cell migration and tumor metastasis. However, its regulatory mechanisms remain elusive. In this study, we employed bioinformatic, gene regulation, and protein‐DNA interaction screening to investigate the transcription factors (TFs) involved in regulating FNDC3B. Initially, 338 candidate TFs were selected based on previous chromatin immunoprecipitation (ChIP)‐seq experiments available in public domain databases. Through TF knockdown screening and ChIP coupled with Droplet Digital PCR assays, we identified that E2F1 (E2F transcription factor 1) is crucial for the activation of FNDC3B. Overexpression or knockdown of E2F1 significantly impacts the expression of FNDC3B. In conclusion, our study elucidated the mechanistic link between FNDC3B and E2F1. These findings contribute to a better understanding of FNDC3B in tumorigenesis and provide insights into potential therapeutic targets for cancer treatment.

We fabricated a microfluidic chip (osteoblast [OB]–osteoclast [OC] chip) that could regulate the mixture amounts of OB and OC supernatants to investigate the effect of different supernatant distributions on osteogenesis or osteoclastogenesis. Computer-aided design was used to produce an OB–OC chip from polydimethylsiloxane. A pressure controller was assembled and different blends of OB and OC supernatants were correctly determined. OB and OC supernatants were placed on the upper panels of the OB–OC chip after differentiation for an in vitro evaluation. We then tested the changes in osteogenesis using MC3T3-E1 cells in the middle chambers. We observed that a 75:25 distribution of OB and OC supernatants was the most potent in osteogenesis. We then primed the osteogenic differentiation of MC3T3-E1 cells using an OB–OC mixed supernatant or an OB supernatant alone (supernatant ratios of 75:25 or 100:0, respectively). These cells were placed on the calvarial defect sites of rats. Microcomputed tomography and histological analyses determined a significantly higher bone formation in the group exposed to the OB–OC supernatant at a ratio of 75:25. In this study, we demonstrate the applicability of an OB–OC chip to evaluate the effect of different supernatant distributions of OB and OC. We observed that the highest bone-forming potential was in MC3T3-E1 cells treated with conditioned media, specifically the OB–OC supernatant at a ratio of 75:25. [ABSTRACT FROM AUTHOR]

Purpose: Cancer cells are characterized as the uncontrolled proliferation, which demands high levels of nucleotides that are building blocks for DNA synthesis and replication. CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase and dihydroorotase) is a trifunctional enzyme that initiates the de novo pyrimidine synthesis, which is normally enhanced in cancer cells to preserve the pyrimidine pool for cell division. Glioma, representing most brain cancer, is highly addicted to nucleotides like pyrimidine to sustain the abnormal growth and proliferation of cells. CAD is previously reported to be dysregulated in glioma, but the underlying mechanism remains unclear. Methods: The expression of CAD and CHIP (carboxyl terminus of Hsc70-interacting protein) protein in normal brain cells and three glioblastoma (GBM) cell lines were measured by immunoblots. Lentiviruses-mediated expression of target proteins or shRNAs were used to specifically overexpress or knock down CAD and CHIP. Cell counting, colony formation, apoptosis and cell cycle assays were used to assess the roles of CAD and CHIP in GBM cell proliferation and survival. Co-immunoprecipitation and ubiquitination assays were used to examine the interaction of CHIP with CAD and the ubiquitination of CAD. The correlation of CAD and CHIP expression with GBM patients' survival was obtained by analyzing the GlioVis database. Results: In this study, we showed that the expression of CAD was upregulated in glioma, which was positively correlated with the tumor grade and survival of glioma patients. Knockdown of CAD robustly inhibited the cell proliferation and colony formation of GBM cells, indicating the essential role of CAD in the pathogenesis of GBM. Mechanistically, we firstly identified that CAD was modified by the K29-linked polyubiquitination, which was mediated by the E3 ubiquitin ligase CHIP. By interacting with and ubiquitinating CAD, CHIP enhanced its proteasomal and lysosomal degradation, which accounted for the anti-proliferative role of CHIP in GBM cells. To sustain the expression of CAD, CHIP is significantly downregulated, which is correlated with the poor prognosis and survival of GBM patients. Notably, the low level of CHIP and high level of CAD overall predict the short survival of GBM patients. Conclusion: Altogether, these results illustrated the essential role of CAD in GBM and revealed a novel therapeutic strategy for CAD-positive and CHIP-negative cancer. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Tiangong University is the property of Journal of Tianjin Polytechnic University 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.)

The thickness of the maximum undistorted chip (agmax) is a crucial component of the machining arguments and significantly affects the quality of the grind. For the purpose of investigating the impact of the agmax on the grinding removal properties of SiO2f/SiO2 composites, grinding experiments of SiO2f/SiO2 composites were conducted. The findings indicate that crack propagation, fiber cracking, matrix breaking, and interface debonding are the primary removal modes of SiO2f/SiO2 composites. Grinding force, surface roughness, and chip size all have a positive correlation with the maximum undeformed chip thickness. Surface brittle fracture brought on by SiO2 fiber microcrack results in little surface roughness. The surface quality degrades when bending fracture and compression fracture take place. Controlling the agmax can enhance the grinding surface quality of SiO2f/SiO2 composites. [ABSTRACT FROM AUTHOR]

Summary: Recursive partitioning of healthy consortia led to the development of the Clonal Hematopoiesis Risk Score (CHRS) for clonal haematopoiesis (CH); however, in the practical setting, most cases of CH are diagnosed after patients present with cytopenias or related symptoms. To address this real‐world population, we characterize the clinical trajectories of 94 patients with CH and distinguish CH harbouring canonical DNMT3A/TET2/ASXL1 mutations alone ('sole DTA') versus all other groups ('non‐sole DTA'). TET2, rather than DNMT3A, was the most prevalent mutation in the real‐world setting. Sole DTA patients did not progress to myeloid neoplasm (MN) in the absence of acquisition of other mutations. Contrastingly, 14 (20.1%) of 67 non‐sole DTA patients progressed to MN. CHRS assessment showed a higher frequency of high‐risk CH in non‐sole DTA (vs. sole DTA) patients and in progressors (vs. non‐progressors). RUNX1 mutation conferred the strongest risk for progression to MN (odds ratio [OR] 10.27, 95% CI 2.00–52.69, p = 0.0053). The mean variant allele frequency across all genes was higher in progressors than in non‐progressors (36.9% ± 4.62% vs. 24.1% ± 1.67%, p = 0.0064). This analysis in the post‐CHRS era underscores the natural history of CH, providing insight into patterns of progression to MN. [ABSTRACT FROM AUTHOR]

Main conclusion: Six grape centromere-specific markers for cytogenetics were mined by combining genetic and immunological assays, and the possible evolution mechanism of centromeric repeats was analyzed. Centromeric histone proteins are functionally conserved; however, centromeric repetitive DNA sequences may represent considerable diversity in related species. Therefore, studying the characteristics and structure of grape centromere repeat sequences contributes to a deeper understanding of the evolutionary process of grape plants, including their origin and mechanisms of polyploidization. Plant centromeric regions are mainly composed of repetitive sequences, including SatDNA and transposable elements (TE). In this research, the characterization of centromere sequences in the whole genome of grapevine (Vitis vinifera L.) has been conducted. Five centromeric tandem repeat sequences (Vv1, Vv2, Vv5, Vv6, and Vv8) and one long terminal repeat (LTR) sequence Vv24 were isolated. These sequences had different centromeric distributions, which indicates that grape centromeric sequences may undergo rapid evolution. The existence of extrachromosomal circular DNA (eccDNA) and gene expression in CenH3 subdomain region may provide various potential mechanisms for the generation of new centromeric regions. [ABSTRACT FROM AUTHOR]

Background There is a growing need for percutaneous coronary intervention (PCI) to be performed within the same transcatheter aortic valve implantation (TAVI) procedure. In such cases, cangrelor, a fast-acting intravenous P2Y12-inhibitor with a short offset, is potential clinical utility to minimize bleeding and vascular complications during large-bore arterial access (LBAA) as well as the thrombotic risk associated with concomitant PCI. Case summary We report two cases of TAVI with an indication to concomitant, high-risk PCI. In the first one, cangrelor was started only after LBAA was secured and TAVI completed, just before the initiation of complex PCI. In the second case, due to predicted complex coronary cannulation after TAVI, complex PCI was performed before TAVI and cangrelor started just after LBAA. In both cases, use of cangrelor (vs. pre-treatment with oral P2Y12-i) allowed for a tailored minimization of the risk of bleeding and vascular complications during LBAA while offering full platelet inhibition during a complex/high-risk PCI. Discussion In this case series, we illustrate a possible approach to the use of cangrelor for patients undergoing TAVI and complex/high-risk PCI. In such complex cases, thorough pre-procedural planning might include a cangrelor to minimize vascular, bleeding, and ischaemic complications. [ABSTRACT FROM AUTHOR]

Copyright of Food Research & Development is the property of Food Research & Development Editorial Department 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.)

Key Clinical Message: Hematopoietic neoplasms can cause adrenal infarction. In cases of thrombosis occurring at uncommon sites, it is necessary to consider evaluating for the JAK2V617F mutation, even in the absence of notable abnormalities in blood counts. Adrenal infarction, a rare ailment, has been sporadically linked to hematopoietic neoplasms. A 46‐year‐old male encountered left adrenal infarction, which coincided with a progressive rise in platelet counts. Subsequent diagnosis revealed myelodysplastic/myeloproliferative neoplasm‐unclassifiable, featuring a JAK2V617F mutation. Simultaneously, the patient manifested multiple arteriovenous thromboses, necessitating treatment with edoxaban, aspirin, and hydroxyurea. Following thrombosis resolution, he was transferred to a transplantation center. This report delves into the thrombogenicity linked to the JAK2V617F mutation, while also examining documented instances of adrenal infarction in myeloid neoplasms. We should consider evaluating for JAK2V617F mutation even in cases of thrombosis at unusual sites, including adrenal infarction, even if there are no considerable abnormalities in blood counts. [ABSTRACT FROM AUTHOR]

FNDC3B (fibronectin type III domain containing 3B) is highly expressed in hepatocellular carcinoma (HCC) and other cancer types, and fusion genes involving FNDC3B have been identified in HCC and leukemia. Growing evidence suggests the significance of FNDC3B in tumorigenesis, particularly in cell migration and tumor metastasis. However, its regulatory mechanisms remain elusive. In this study, we employed bioinformatic, gene regulation, and protein‐DNA interaction screening to investigate the transcription factors (TFs) involved in regulating FNDC3B. Initially, 338 candidate TFs were selected based on previous chromatin immunoprecipitation (ChIP)‐seq experiments available in public domain databases. Through TF knockdown screening and ChIP coupled with Droplet Digital PCR assays, we identified that E2F1 (E2F transcription factor 1) is crucial for the activation of FNDC3B. Overexpression or knockdown of E2F1 significantly impacts the expression of FNDC3B. In conclusion, our study elucidated the mechanistic link between FNDC3B and E2F1. These findings contribute to a better understanding of FNDC3B in tumorigenesis and provide insights into potential therapeutic targets for cancer treatment. [ABSTRACT FROM AUTHOR]

While machining of high-strength alloy steel materials, poor surface quality and decreased tool life are result by an increase in the cutting zone temperature close to the machining region. To overcome this, surface texture with green manufacturing environment is an alternate path to enhancing machining performance. In the present work, novel Parallel Grooved Textured Tools (PGT) was developed and studied the performance of so developed tools. Further, the Untextured Tool (UT) and PGT performance was compared while machining EN24 alloy steel under Minimum Quantity Lubrication (MQL) condition. It was perceived from result that textured tools reduced the cutting temperature (CT), rake wear (RW), flank wear (FW), surface roughness (Ra) and cutting force (CF) up to 18.96%, 18.79%, 24.31%, 12.69%, and18.96% respectively compared to UT. [ABSTRACT FROM AUTHOR]