Mediator structure and conformation change.

Mediator is a universal adaptor for transcription control. It serves as an interface between gene-specific activator or repressor proteins and the general RNA polymerase II (pol II) transcription machinery. Previous structural studies revealed a relatively small part of Mediator and none of the gene activator-binding regions. We have determined the cryo-EM structure of the Mediator at near-atomic resolution. The structure reveals almost all amino acid residues in ordered regions, including the major targets of activator proteins, the Tail module, and the Med1 subunit of the Middle module. Comparison of Mediator structures with and without pol II reveals conformational changes that propagate across the entire Mediator, from Head to Tail, coupling activator- and pol II-interacting regions.

Class I histone deacetylase complex: Structure and functional correlates.

The Schizosaccharomyces pombe Clr6S complex, a class I histone deacetylase complex, functions as a zinc-dependent enzyme to remove acetyl groups from lysine residues in histone tails. We report here the cryo-EM structure of Clr6S alone and a cryo-EM map of Clr6S in complex with a nucleosome. The active center, revealed at near-atomic resolution, includes features important for catalysis-A water molecule coordinated by zinc, the likely nucleophile for attack on the acetyl-lysine bond, and a loop that may position the substrate for catalysis. The cryo-EM map in the presence of a nucleosome reveals multiple Clr6S-nucleosome contacts and a high degree of relative motion of Clr6S and the nucleosome. Such flexibility may be attributed to interaction at a site in the flexible histone tail and is likely important for the function of the deacetylase, which acts at multiple sites in other histone tails.

Higher matrix stiffness promotes VSMC senescence by affecting mitochondria-ER contact sites and mitochondria/ER dysfunction.

Abdominal aortic aneurysm (AAA) is a prevalent condition characterized by the weakening and bulging of the abdominal aorta. This study aimed to investigate the impact of a stiff matrix on vascular smooth muscle cells (VSMCs) in AAA development. Bioinformatics analysis revealed that differentially expressed genes (DEGs) in VSMCs of an AAA mouse model were enriched in cellular senescence and related pathways. To simulate aging-related changes, VSMCs were cultured on stiff matrices, and compared to those on soft matrices, the VSMCs cultured on stiff matrices exhibited cellular senescence. Furthermore, the mutual distance between mitochondria and endoplasmic reticulum (ER) in VSMCs was increased, indicating altered mitochondria-endoplasmic reticulum contacts (MERCs). The observed upregulation of reactive oxygen species (ROS) levels, antioxidant gene expression, and decreased mitochondrial membrane potential suggested the presence of mitochondrial dysfunction in VSMCs cultured on a stiff matrix. Additionally, the induction of ER stress-related genes indicated ER dysfunction. These findings collectively indicated impaired functionality of both mitochondria and ER in VSMCs cultured on a stiff matrix. Moreover, our data revealed that high lipid levels exacerbated the effects of high matrix stiffness on VSMCs senescence, MERC sites, and mitochondria/ER dysfunction. Importantly, treatment with the antilipemic agent CI-981 effectively reversed these detrimental effects. These findings provide insights into the role of matrix stiffness, mitochondrial dysfunction, ER stress, and lipid metabolism in AAA development, suggesting potential therapeutic targets for intervention.

Genetic diversity of grain yield traits and identification of a grain weight gene SiTGW6 in foxtail millet.

KEY MESSAGE: Agronomic traits were evaluated in 1250 foxtail millet accessions, and a crucial gene SiTGW6 governing grain yield was identified. Elite haplotypes and dCAPS markers developed for SiTGW6 facilitate molecular breeding. A comprehensive evaluation of phenotypic characteristics and genetic diversity in germplasm resources are important for gene discovery and breeding improvements. In this study, we conducted a comprehensive evaluation of 1250 foxtail millet varieties, assessing seven grain yield-related traits and fourteen common agronomic traits over two years. Principal component analysis, correlation analysis, and cluster analysis revealed a strong positive correlation between 1000-grain weight and grain width with grain yield, emphasizing their importance in foxtail millet breeding. Additionally, we found that panicle weight positively correlated with 1000-grain weight but negatively correlated with branch and tiller numbers, indicating selection factors during domestication and breeding. Using this information, we identified 27 germplasm resources suitable for high-yield foxtail millet breeding. Furthermore, through an integration of haplotype variations and phenotype association analysis, we pinpointed a crucial gene, SiTGW6, responsible for governing grain yield in foxtail millet. SiTGW6 encodes an IAA-glucose hydrolase, primarily localized in the cytoplasm and predominantly expressed in flowering panicles. Employing RNAseq analysis, we identified 1439 differentially expressed genes across various SiTGW6 haplotypes. Functional enrichment analysis indicating that SiTGW6 regulates grain yield through the orchestration of auxin and glucan metabolism, as well as plant hormone signaling pathways. Additionally, we have identified elite haplotypes and developed dCAPS markers for SiTGW6, providing valuable technical tools to facilitate molecular breeding efforts in foxtail millet.

Nullification of GFTs fortifies bioactive folates in foxtail millet.

In foxtail millet (Setaria italica), knockout of the glutamate formiminotransferases SiGFT1 and 2 increased the accumulation of bioactive folates to approximately four times the level of wild-type plants and decreased levels of the bioinactive oxidation product MeFox by 95%, thus providing a promising route for folate biofortification in cereal crops.

Programmed genome editing by a miniature CRISPR-Cas12f nuclease.

The RNA-guided CRISPR-associated (Cas) nucleases are versatile tools for genome editing in various organisms. The large sizes of the commonly used Cas9 and Cas12a nucleases restrict their flexibility in therapeutic applications that use the cargo-size-limited adeno-associated virus delivery vehicle. More compact systems would thus offer more therapeutic options and functionality for this field. Here, we report a miniature class 2 type V-F CRISPR-Cas genome-editing system from Acidibacillus sulfuroxidans (AsCas12f1, 422 amino acids). AsCas12f1 is an RNA-guided endonuclease that recognizes 5' T-rich protospacer adjacent motifs and creates staggered double-stranded breaks to target DNA. We show that AsCas12f1 functions as an effective genome-editing tool in both bacteria and human cells using various delivery methods, including plasmid, ribonucleoprotein and adeno-associated virus. The small size of AsCas12f1 offers advantages for cellular delivery, and characterizations of AsCas12f1 may facilitate engineering more compact genome-manipulation technologies.

Genome-Wide Characterization and Haplotypic Variation Analysis of the YUC Gene Family in Foxtail Millet (Setaria italica).

Panicle development and grain production in crop species are essential breeding characteristics affected by the synthesis of auxin, which is influenced by flavin monooxygenase-encoding genes such as YUC (YUCCA) family members. In this trial, fourteen YUCs were identified and named uniformly in foxtail millet, an ancient crop species cultivated across the world. The phylogenetic analysis revealed that the SiYUCs were clustered into four subgroups; protein motif and gene structure analyses suggested that the closely clustered SiYUC genes were relatively conserved within each subgroup; while genome mapping analysis indicated that the SiYUC genes were unevenly distributed on foxtail millet chromosomes and colinear with other grass species. Transcription analysis revealed that the SiYUC genes differed greatly in expression pattern in different tissues and contained hormonal/light/stress-responding cis-elements. The haplotype characterization of SiYUC genes indicated many superior haplotypes of SiYUCs correlated with higher panicle and grain weight could be favorably selected by breeding. These results will be useful for the further study of the functional characteristics of SiYUC genes, particularly with regard to the marker-assisted pyramiding of beneficial haplotypes in foxtail millet breeding programs.

Temporal and spatial patterns of recurrence in oral squamous cell carcinoma, a single-center retrospective cohort study in China.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is an invasive cancer with a high recurrence rate. Most clinical studies have focused on the prognosis of patients with OSCC, few have investigated the causes and interventions that affect the recurrence. Our study is to explore the temporal and spatial patterns of recurrence in OSCC. METHODS: 234 OSCC patients with recurrence in our hospital and 64 OSCC patients with recurrence in TCGA database were included in the study. Log-rank test and Multivariate Cox Regression Analysis were used to determine whether there was a significant difference between each selected demographic or clinical factors and recurrence. The Kaplan-Meier method was used to plot survival curves for each recurrence interval. RESULTS: The proportion of OSCC patients in clinical and TCGA with early recurrence was 93.6% and 84.4%, respectively. Age, chewing betel nut, previous radiotherapy, histopathological grading of the primary tumor (poorly differentiated), lymph node metastasis and postoperative infection were found to be associated with the timing of recurrence. It was found that tongue cancer has more regional recurrences, while buccal cancer is mostly local and loco-regional recurrences. The earlier the recurrence, the greater the possibility of local-regional recurrence and the worse the prognosis. CONCLUSION: Most of recurrent OSCC patients present early recurrence (< 18 months) with poor prognosis, and early recurrence is more prone to local recurrence. Moreover, recurrence site is related with primary site of OSCC.

CUL4high Lung Adenocarcinomas Are Dependent on the CUL4-p21 Ubiquitin Signaling for Proliferation and Survival.

Cullin (CUL) 4A and 4B ubiquitin ligases are often highly accumulated in human malignant neoplasms and are believed to possess oncogenic properties. However, the underlying mechanisms by which CUL4A and CUL4B promote pulmonary tumorigenesis remain largely elusive. This study reports that CUL4A and CUL4B are highly expressed in patients with non-small cell lung cancer (NSCLC), and their high expression is associated with disease progression, chemotherapy resistance, and poor survival in adenocarcinomas. Depletion of CUL4A (CUL4Ak/d) or CUL4B (CUL4Bk/d) leads to cell cycle arrest at G1 and loss of proliferation and viability of NSCLC cells in culture and in a lung cancer xenograft model, suggesting that CUL4A and 4B are oncoproteins required for tumor maintenance of certain NSCLCs. Mechanistically, increased accumulation of the cell cycle-dependent kinase inhibitor p21/Cip1/WAF1 was observed in lung cancer cells on CUL4 silencing. Knockdown of p21 rescued the G1 arrest of CUL4Ak/d or CUL4Bk/d NSCLC cells, and allowed proliferation to resume. These findings reveal that p21 is the primary downstream effector of lung adenocarcinoma dependence on CUL4, highlight the notion that not all substrates respond equally to abrogation of the CUL4 ubiquitin ligase in NSCLCs, and imply that CUL4Ahigh/CUL4Bhigh may serve as a prognostic marker and therapeutic target for patients with NSCLC.

Intellectual disability-associated gene ftsj1 is responsible for 2'-O-methylation of specific tRNAs.

tRNA modifications at the anti-codon loop are critical for accurate decoding. FTSJ1 was hypothesized to be a human tRNA 2'-O-methyltransferase. tRNAPhe (GAA) from intellectual disability patients with mutations in ftsj1 lacks 2'-O-methylation at C32 and G34 (Cm32 and Gm34). However, the catalytic activity, RNA substrates, and pathogenic mechanism of FTSJ1 remain unknown, owing, in part, to the difficulty in reconstituting enzymatic activity in vitro. Here, we identify an interacting protein of FTSJ1, WDR6. For the first time, we reconstitute the 2'-O-methylation activity of the FTSJ1-WDR6 complex in vitro, which occurs at position 34 of specific tRNAs with m1 G37 as a prerequisite. We find that modifications at positions 32, 34, and 37 are interdependent and occur in a hierarchical order in vivo. We also show that the translation efficiency of the UUU codon, but not the UUC codon decoded by tRNAPhe (GAA), is reduced in ftsj1 knockout cells. Bioinformatics analysis reveals that almost 40% of the high TTT-biased genes are related to brain/nervous functions. Our data potentially enhance our understanding of the relationship between FTSJ1 and nervous system development.

Risk factors for surgical site infection in head and neck cancer.

PURPOSE: Surgical site infection (SSI) frequently occurs in patients with head and neck cancer (HNC) after tumor resection and can lead to death in severe cases. Moreover, there is no definitive conclusion about the risk factors of SSI. Therefore, it is of great clinical significance to study the factors affecting the SSI. METHODS: The HNC patients included in this study were all from the Department of Oral and Maxillofacial Surgery of the Second Xiangya Hospital of Central South University (CSU), and these patients received surgical treatment in the department from January 2018 to December 2019. The cross tabulation with chi-squared testing and multivariate regression analysis were applied to determine the risk factors of SSI. To identify the key risk factors of SSI, the caret package was used to construct three different machine learning models to investigate important features involving 26 SSI-related risk factors. RESULTS: Participants were 632 HNC patients who underwent surgery in our department from January 2018 to December 2019. During the postoperative period, 82 patients suffered from SSI, and surgical site infection rate (SSIR) was about 12.97%. Multivariate logistic regression analysis shows that diabetes mellitus, primary tumor site (floor of mouth), preoperative radiotherapy, flap failure, and neck dissection (bilateral) are risk factors for SSI of HNC. Machine learning indicated that diabetes mellitus, primary tumor site (floor of mouth), and flap failure were consistently ranked the top three in the 26 SSI-related risk factors. CONCLUSION: Diabetes mellitus, primary tumor site (floor of mouth), flap failure, preoperative radiotherapy, and neck dissection (bilateral) are risk factors for SSI of HNC.

Expanding role of nurses in management of dementia in geriatrics: improving well-being of geriatric patients through quality nursing care.

The potential nurses role to include the recognition and management of dementia has been acknowledged. Practice Nurses are well-positioned to provide comprehensive dementia information and support so that people living with dementia are better equipped to self-manage their health and live well with dementia. However, treatment of geriatric dementia has become difficult owing to co-morbidities and cognitive and physical deterioration of these patients. Thus, geriatric dementia patients require special attention during care in homes and clinical settings. In modern medical practice, the role of nurse has become dynamic, ranging from education and personal care. The profession of nursing is considered as critical to meets the needs of the elderly population with dementia and ensure the delivery of high-quality care. Since nurses play such an important role in caring for these individuals, comprehensive reviews lack on their role and experience in geriatric dementia treatment and issues. This review summarizes the expanding role of nurses in the management of geriatric dementia in terms of nurse's knowledge, role, communication, attitude and maintaining patient's quality of life through diverse activities. Furthermore, we also explain the future direction for improving the nursing care to treat dementia in elderly population.

Genome-Wide Identification and Expression Analysis of SWEET Family Genes in Sweet Potato and Its Two Diploid Relatives.

Sugar Will Eventually be Exported Transporter (SWEET) proteins are key transporters in sugar transportation. They are involved in the regulation of plant growth and development, hormone crosstalk, and biotic and abiotic stress responses. However, SWEET family genes have not been explored in the sweet potato. In this study, we identified 27, 27, and 25 SWEETs in cultivated hexaploid sweet potato (Ipomoea batatas, 2n = 6x = 90) and its two diploid relatives, Ipomoea trifida (2n = 2x = 30) and Ipomoea triloba (2n = 2x = 30), respectively. These SWEETs were divided into four subgroups according to their phylogenetic relationships with Arabidopsis. The protein physiological properties, chromosome localization, phylogenetic relationships, gene structures, promoter cis-elements, protein interaction networks, and expression patterns of these 79 SWEETs were systematically investigated. The results suggested that homologous SWEETs are differentiated in sweet potato and its two diploid relatives and play various vital roles in plant growth, tuberous root development, carotenoid accumulation, hormone crosstalk, and abiotic stress response. This work provides a comprehensive comparison and furthers our understanding of the SWEET genes in the sweet potato and its two diploid relatives, thereby supplying a theoretical foundation for their functional study and further facilitating the molecular breeding of sweet potato.

Perioperative mortality of head and neck cancers.

BACKGROUND: Head and neck cancers are aggressive cancers, most clinical studies focused on the prognosis of patients with head and neck cancer. However, perioperative mortality was rarely mentioned. METHODS: A retrospective analysis was performed using all head and neck cancer patients admitting in the Department of Oral and Maxillofacial Surgery of the Second Xiangya Hospital, Central South University from January 2010 to December 2019. The analysis of overall survival and progression-free survival were performed using the Kaplan-Meier method, and cross tabulation with chi-squared testing was applied to analyze the difference in parameters between groups. RESULTS: From January 2010 to December 2019, a total of 6576 patients with head and neck cancers were admitted to our department and 7 died in the hospital, all of whom were middle-aged and elderly patients including 6 males and 1 female. The perioperative mortality rate (POMR) was about 1‰. The causes of death included acute heart failure, rupture of large blood vessels in the neck, hypoxic ischemic encephalopathy due to asphyxia, respiratory failure and cardiopulmonary arrest. CONCLUSION: Preoperative radiotherapy, previous chemotherapy, hypertension, diabetes, advanced clinical stage and postoperative infection are risk factors for perioperative mortality of head and neck cancer.

Carrot 'antifreeze' protein has an irregular ice-binding site that confers weak freezing point depression but strong inhibition of ice recrystallization.

Ice-binding proteins (IBPs) are found in many biological kingdoms where they protect organisms from freezing damage as antifreeze agents or inhibitors of ice recrystallization. Here, the crystal structure of recombinant IBP from carrot (Daucus carota) has been solved to a resolution of 2.3 Å. As predicted, the protein is a structural homologue of a plant polygalacturonase-inhibiting protein forming a curved solenoid structure with a leucine-rich repeat motif. Unexpectedly, close examination of its surface did not reveal any large regions of flat, regularly spaced hydrophobic residues that characterize the ice-binding sites (IBSs) of potent antifreeze proteins from freeze-resistant fish and insects. An IBS was defined by site-directed mutagenesis of residues on the convex surface of the carrot solenoid. This imperfect site is reminiscent of the irregular IBS of grass 'antifreeze' protein. Like the grass protein, the carrot IBP has weak freezing point depression activity but is extremely active at nanomolar concentrations in inhibiting ice recrystallization. Ice crystals formed in the presence of both plant proteins grow slowly and evenly in all directions. We suggest that this slow, controlled ice growth is desirable for freeze tolerance. The fact that two plant IBPs have evolved very different protein structures to affect ice in a similar manner suggests this pattern of weak freezing point depression and strong ice recrystallization inhibition helps their host to tolerate freezing rather than to resist it.

Research Progress and Application of Single-Atom Catalysts: A Review.

Due to excellent performance properties such as strong activity and high selectivity, single-atom catalysts have been widely used in various catalytic reactions. Exploring the application of single-atom catalysts and elucidating their reaction mechanism has become a hot area of research. This article first introduces the structure and characteristics of single-atom catalysts, and then reviews recent preparation methods, characterization techniques, and applications of single-atom catalysts, including their application potential in electrochemistry and photocatalytic reactions. Finally, application prospects and future development directions of single-atom catalysts are outlined.

Self-Assembled Peptide Nano-Superstructure towards Enzyme Mimicking Hydrolysis.

The structural arrangement of amino acid residues in native enzymes underlies their remarkable catalytic properties, thus providing a notable point of reference for designing potent yet simple biomimetic catalysts. Herein, we describe a minimalistic approach to construct a dipeptide-based nano-superstructure with enzyme-like activity. The self-assembled biocatalyst comprises one peptide as a single building block, readily synthesized from histidine. Through coordination with zinc ion, the peptide self-assembly procedure allows the formation of supramolecular ß-sheet ordered nanocrystals, which can be used as basic units to further construct higher-order superstructure. As a result, remarkable hydrolysis activity and enduring stability are demonstrated. Our work exemplifies the use of a bioinspired supramolecular assembly approach to develop next-generation biocatalysts for biotechnological applications.

Confined Interfacial Synthesis of Highly Crystalline and Ultrathin Graphdiyne Films and Their Applications for N2 Fixation.

Graphdiyne (GDY), as a new carbon allotrope, possessing both sp- and sp2 -hybridized carbon atoms, has attracted extensive attention due to great application potentials in various fields. To realize a fundamental understanding of the intrinsic properties of GDY, the controllable synthesis of ultrathin and highly crystalline GDY is necessary and challenging. Herein, a confined interfacial synthetic strategy towards highly crystalline ultrathin GDY at the water/oil/organogel interface, with greatly improved control over GDY structures, is reported. The morphology and chemical composition of GDY was characterized accordingly. After loading with gold, the as-prepared hydrophobic Au/GDY system showed excellent performance in the nitrogen reduction reaction, reaching the highest yield of 4.15 µg cm-2 h-1 with a Faraday efficiency of 1.95 %.

Evaluation of pharmacokinetics and safety with bioequivalence of Amlodipine in healthy Chinese volunteers: Bioequivalence Study Findings.

BACKGROUND AND OBJECTIVE: Amlodipine, a main series of L-type calcium channel blockers (CCBs), exerts potent antihypertensive effects. The aim of this trial was to explore the pharmacokinetics (PK) and safety with bioequivalence of orally administered Amlodipine provided by two sponsors in healthy volunteers (HVs). METHODS: Two separate randomized, open-label, single-dose, crossover-design studies were conducted: a fasting study (n = 24) and a fed study (n = 24). In each study, HVs were randomized to Fangming Pharmaceutical Group (Test, T) followed by NORVASC® (Reference, R), or vice versa. Each study subject received a 5-mg Amlodipine tablet with a 15-day washout. The plasma concentrations of Amlodipine were measured using a LC-MS/MS method, and PK parameters were determined by noncompartmental model. RESULTS: Forty-eight healthy volunteers were enrolled. And overall demographics were as follows: the fasting study: female (n = 16/24), age (18-54 years), weight (47-76 kg), and BMI (19.5-26.0). The fed study: female (n = 16/24), age (20-49 years), weight (45.5-69 kg), and BMI (19.1-25.0). All PK endpoints met the pre-specific criteria for PK equivalence. In fasting subjects, the maximum plasma concentration (Cmax ) was 3.881 ± 0.982 ng/mL at 6 hours (median) of sponsor T, and 4.042 ± 1.147 ng/mL at 6 hours (median) of sponsor R. In fed subjects, Cmax was 3.312 ± 0.789 ng/mL at 6 hours (median) of sponsor T, and 3.392 ± 0.902 ng/mL at 5 hours (median) of sponsor R. Both fasting and fed studies achieved a plausible bioequivalence. CONCLUSIONS: Amlodipine is well tolerated and have a favorable safety profile. The observed adverse events were mild (the severity was assessed according to the Common Terminology Criteria for Adverse Events [version CTCAE4.03]) and all of them were recovered without severe sequences. And the bioequivalence is achieved under fasting and fed conditions, supporting the demonstration of biosimilarity.

Synovial sarcoma of the floor of the mouth: a rare case report.

BACKGROUND: Head and neck Synovial sarcoma (SS) accounts for 3-10% of all total body SS. It is rare to find it in the oral cavity, especially on the floor of the mouth. CASE PRESENTATION: We present a 44-year-old Chinese male, who had been misdiagnosed as fibroadenoma, with a swelling on the right submandibular region for more than 3 months. The radiology examinations and the pathology results indicate the diagnosis of SS of the floor of the mouth. The patient only had a surgical operation, without radiotherapy and chemotherapy. At the first follow-up, the patient exhibited no clinical or radiographic complications, and the patient was asymptomatic on subsequent visits. CONCLUSIONS: Misdiagnosis results the delay of diagnosis and treatment of SS. Immunohistological analysis might be the most important tool to confirm the diagnosis of SS.