Discovery of deaminase functions by structure-based protein clustering.

The elucidation of protein function and its exploitation in bioengineering have greatly advanced the life sciences. Protein mining efforts generally rely on amino acid sequences rather than protein structures. We describe here the use of AlphaFold2 to predict and subsequently cluster an entire protein family based on predicted structure similarities. We selected deaminase proteins to analyze and identified many previously unknown properties. We were surprised to find that most proteins in the DddA-like clade were not double-stranded DNA deaminases. We engineered the smallest single-strand-specific cytidine deaminase, enabling efficient cytosine base editor (CBE) to be packaged into a single adeno-associated virus (AAV). Importantly, we profiled a deaminase from this clade that edits robustly in soybean plants, which previously was inaccessible to CBEs. These discovered deaminases, based on AI-assisted structural predictions, greatly expand the utility of base editors for therapeutic and agricultural applications.

Cbln1 regulates axon growth and guidance in multiple neural regions.

The accurate construction of neural circuits requires the precise control of axon growth and guidance, which is regulated by multiple growth and guidance cues during early nervous system development. It is generally thought that the growth and guidance cues that control the major steps of axon development have been defined. Here, we describe cerebellin-1 (Cbln1) as a novel cue that controls diverse aspects of axon growth and guidance throughout the central nervous system (CNS) by experiments using mouse and chick embryos. Cbln1 has previously been shown to function in late neural development to influence synapse organization. Here, we find that Cbln1 has an essential role in early neural development. Cbln1 is expressed on the axons and growth cones of developing commissural neurons and functions in an autocrine manner to promote axon growth. Cbln1 is also expressed in intermediate target tissues and functions as an attractive guidance cue. We find that these functions of Cbln1 are mediated by neurexin-2 (Nrxn2), which functions as the Cbln1 receptor for axon growth and guidance. In addition to the developing spinal cord, we further show that Cbln1 functions in diverse parts of the CNS with major roles in cerebellar parallel fiber growth and retinal ganglion cell axon guidance. Despite the prevailing role of Cbln1 as a synaptic organizer, our study discovers a new and unexpected function for Cbln1 as a general axon growth and guidance cue throughout the nervous system.

Photochemical Formation and Electronic Structure of an Alkane σ-Complex from Time-Resolved Optical and X-ray Absorption Spectroscopy.

C-H bond activation reactions with transition metals typically proceed via the formation of alkane σ-complexes, where an alkane C-H σ-bond binds to the metal. Due to the weak nature of metal-alkane bonds, σ-complexes are challenging to characterize experimentally. Here, we establish the complete pathways of photochemical formation of the model σ-complex Cr(CO)5-alkane from Cr(CO)6 in octane solution and characterize the nature of its metal-ligand bonding interactions. Using femtosecond optical absorption spectroscopy, we find photoinduced CO dissociation from Cr(CO)6 to occur within the 100 fs time resolution of the experiment. Rapid geminate recombination by a fraction of molecules is found to occur with a time constant of 150 fs. The formation of bare Cr(CO)5 in its singlet ground state is followed by complexation of an octane molecule from solution with a time constant of 8.2 ps. Picosecond X-ray absorption spectroscopy at the Cr L-edge and O K-edge provides unique information on the electronic structure of the Cr(CO)5-alkane σ-complex from both the metal and ligand perspectives. Based on clear experimental observables, we find substantial destabilization of the lowest unoccupied molecular orbital upon coordination of the C-H bond to the undercoordinated Cr center in the Cr(CO)5-alkane σ-complex, and we define this as a general, orbital-based descriptor of the metal-alkane bond. Our study demonstrates the value of combining optical and X-ray spectroscopic methods as complementary tools to study the stability and reactivity of alkane σ-complexes in their role as the decisive intermediates in C-H bond activation reactions.

Appropriate mowing can promote the growth of Anabasis aphylla through the auxin metabolism pathway.

Anabasis aphylla (A. aphylla), a species of the Amaranthaceae family, is widely distributed in northwestern China and has high pharmacological value and ecological functions. However, the growth characteristics are poorly understood, impeding its industrial development for biopesticide development. Here, we explored the regenerative capacity of A. aphylla. To this end, different lengths of the secondary branches of perennial branches were mowed at the end of March before sprouting. The four treatments were no mowing (M0) and mowing 1/3, 2/3, and the entire length of the secondary branches of perennial branches (M1-M3, respectively). Next, to evaluate the compensatory growth after mowing, new assimilate branches' related traits were recorded every 30 days, and the final biomass was recorded. The mowed plants showed a greater growth rate of assimilation branches than un-mowed plants. Additionally, with the increasing mowing degree, the growth rate and the final biomass of assimilation branches showed a decreasing trend, with the greatest growth rate and final biomass in response to M1. To evaluate the mechanism of the compensatory growth after mowing, a combination of dynamic (0, 1, 5, and 8 days after mowing) plant hormone-targeted metabolomics and transcriptomics was performed for the M0 and M1 treatment. Overall, 26 plant hormone metabolites were detected, 6 of which significantly increased after mowing compared with control: Indole-3-acetyl-L-valine methyl ester, Indole-3-carboxylic acid, Indole-3-carboxaldehyde, Gibberellin A24, Gibberellin A4, and cis (+)-12-oxo-phytodienoic acid. Additionally, 2,402 differentially expressed genes were detected between the mowed plants and controls. By combining clustering analysis based on expression trends after mowing and gene ontology analysis of each cluster, 18 genes related to auxin metabolism were identified, 6 of which were significantly related to auxin synthesis. Our findings suggest that appropriate mowing can promote A. aphylla growth, regulated by the auxin metabolic pathway, and lays the foundation for the development of the industrial value of A. aphylla.

Land-use change interacts with island biogeography to alter bird community assembly.

Anthropogenic activities have reshaped biodiversity on islands worldwide. However, it remains unclear how island attributes and land-use change interactively shape multiple facets of island biodiversity through community assembly processes. To answer this, we conducted bird surveys in various land-use types (mainly forest and farmland) using transects on 34 oceanic land-bridge islands in the largest archipelago of China. We found that bird species richness increased with island area and decreased with isolation, regardless of the intensity of land-use change. However, forest-dominated habitats exhibited lower richness than farmland-dominated habitats. Island bird assemblages generally comprised species that share more similar traits or evolutionary histories (i.e. functional and/or phylogenetic clustering) than expected if assemblages were randomly assembled. Contrary to our expectations, we observed that bird assemblages in forest-dominated habitats were more clustered on large and close islands, whereas assemblages in farmland-dominated habitats were more clustered on small islands. These contrasting results indicate that land-use change interacts with island biogeography to alter the community assembly of birds on inhabited islands. Our findings emphasize the importance of incorporating human-modified habitats when examining the community assembly of island biota, and further suggest that agricultural landscapes on large islands may play essential roles in protecting countryside island biodiversity.

YTHDF2 in dentate gyrus is the m6A reader mediating m6A modification in hippocampus-dependent learning and memory.

N6-methyladenosine (m6A) has been demonstrated to regulate learning and memory in mice. To investigate the mechanism by which m6A modification exerts its function through its reader proteins in the hippocampus, as well as to unveil the specific subregions of the hippocampus that are crucial for memory formation, we generated dentate gyrus (DG)-, CA3-, and CA1-specific Ythdf1 and Ythdf2 conditional knockout (cKO) mice, respectively. Surprisingly, we found that only the DG-specific Ythdf2 cKO mice displayed impaired memory formation, which is inconsistent with the previous report showing that YTHDF1 was involved in this process. YTHDF2 controls the stability of its target transcripts which encode proteins that regulate the elongation of mossy fibers (MF), the axons of DG granule cells. DG-specific Ythdf2 ablation caused MF overgrowth and impairment of the MF-CA3 excitatory synapse development and transmission in the stratum lucidum. Thus, this study identifies the m6A reader YTHDF2 in dentate gyrus as the only regulator that mediates m6A modification in hippocampus-dependent learning and memory.

Radiomics in cone-beam breast CT for the prediction of axillary lymph node metastasis in breast cancer: a multi-center multi-device study.

OBJECTIVES: To develop a radiomics model in contrast-enhanced cone-beam breast CT (CE-CBBCT) for preoperative prediction of axillary lymph node (ALN) status and metastatic burden of breast cancer. METHODS: Two hundred and seventy-four patients who underwent CE-CBBCT examination with two scanners between 2012 and 2021 from two institutions were enrolled. The primary tumor was annotated in each patient image, from which 1781 radiomics features were extracted with PyRadiomics. After feature selection, support vector machine models were developed to predict ALN status and metastatic burden. To avoid overfitting on a specific patient subset, 100 randomly stratified splits were made to assign the patients to either training/fine-tuning or test set. Area under the receiver operating characteristic curve (AUC) of these radiomics models was compared to those obtained when training the models only with clinical features and combined clinical-radiomics descriptors. Ground truth was established by histopathology. RESULTS: One hundred and eighteen patients had ALN metastasis (N + (≥ 1)). Of these, 74 had low burden (N + (1~2)) and 44 high burden (N + (≥ 3)). The remaining 156 patients had none (N0). AUC values across the 100 test repeats in predicting ALN status (N0/N + (≥ 1)) were 0.75 ± 0.05 (0.67~0.93, radiomics model), 0.68 ± 0.07 (0.53~0.85, clinical model), and 0.74 ± 0.05 (0.67~0.88, combined model). For metastatic burden prediction (N + (1~2)/N + (≥ 3)), AUC values were 0.65 ± 0.10 (0.50~0.88, radiomics model), 0.55 ± 0.10 (0.40~0.80, clinical model), and 0.64 ± 0.09 (0.50~0.90, combined model), with all the ranges spanning 0.5. In both cases, the radiomics model was significantly better than the clinical model (both p < 0.01) and comparable with the combined model (p = 0.56 and 0.64). CONCLUSIONS: Radiomics features of primary tumors could have potential in predicting ALN metastasis in CE-CBBCT imaging. CLINICAL RELEVANCE STATEMENT: The findings support potential clinical use of radiomics for predicting axillary lymph node metastasis in breast cancer patients and addressing the limited axilla coverage of cone-beam breast CT. KEY POINTS: • Contrast-enhanced cone-beam breast CT-based radiomics could have potential to predict N0 vs. N + (≥ 1) and, to a limited extent, N + (1~2) vs. N + (≥ 3) from primary tumor, and this could help address the limited axilla coverage, pending future verifications on larger cohorts. • The average AUC of radiomics and combined models was significantly higher than that of clinical models but showed no significant difference between themselves. • Radiomics features descriptive of tumor texture were found informative on axillary lymph node status, highlighting a higher heterogeneity for tumor with positive axillary lymph node.

Improved Water Collection from Short-Term Fog on a Patterned Surface with Interconnected Microchannels.

Fog harvesting is considered a promising freshwater collection strategy for overcoming water scarcity, because of its environmental friendliness and strong sustainability. Typically, fogging occurs briefly at night and in the early morning in most arid and semiarid regions. However, studies on water collection from short-term fog are scarce. Herein, we developed a patterned surface with highly hydrophilic interconnected microchannels on a superhydrophobic surface to improve droplet convergence driven by the Young-Laplace pressure difference. With a rationally designed surface structure, the optimized water collection rate from mild fog could reach up to 67.31 g m-2 h-1 (6.731 mg cm-2 h-1) in 6 h; this value was over 130% higher than that observed on the pristine surface. The patterned surface with interconnected microchannels significantly shortened the startup time, which was counted from the fog contact to the first droplet falling from the fog-harvesting surface. The patterned surface was also facilely prepared via a controllable strategy combining laser ablation and chemical vapor deposition. The results obtained in outdoor environments indicate that the rationally designed surface has the potential for short-term fog harvesting. This work can be considered as a meaningful attempt to address the practical issues encountered in fog-harvesting research.

Application of metagenomic next-generation sequencing in the clinical diagnosis of infectious diseases after allo-HSCT: a single-center analysis.

BACKGROUND: We investigated the value of metagenomic next-generation sequencing (mNGS) in diagnosing infectious diseases in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Fifty-four patients who had fever following allo-HSCT from October 2019 to February 2022 were enrolled. Conventional microbiological tests (CMTs) and mNGS, along with imaging and clinical manifestations, were used to diagnose infection following allo-HSCT. The clinical diagnostic value of mNGS was evaluated. RESULTS: A total of 61 mNGS tests were performed, resulting in the diagnosis of 46 cases of infectious diseases. Among these cases, there were 22 cases of viral infection, 13 cases of fungal infection, and 11 cases of bacterial infection. Moreover, 27 cases (58.7%) were classified as bloodstream infections, 15 (32.6%) as respiratory infections, 2 (4.3%) as digestive system infections, and 2 (4.3%) as central nervous system infections. Additionally, there were 8 cases with non-infectious diseases (8/54, 14.81%), including 2 cases of interstitial pneumonia, 2 cases of bronchiolitis obliterans, 2 cases of engraftment syndrome, and 2 cases of acute graft-versus-host disease. The positive detection rates of mNGS and CMT were 88.9% and 33.3%, respectively, with significant differences (P < 0.001). The sensitivity of mNGS was 97.82%, the specificity was 25%, the positive predictive value was 93.75%, and the negative predictive value was 50%. Following treatment, 51 patients showed improvement, and 3 cases succumbed to multidrug-resistant bacterial infections. CONCLUSIONS: mNGS plays an important role in the early clinical diagnosis of infectious diseases after allo-HSCT, which is not affected by immunosuppression status, empiric antibiotic therapy, and multi-microbial mixed infection.

Amphiphilic Superspreading Polymer Membranes Prepared by Capillary Force-Driven Self-Assembly.

To overcome the two main obstacles of large-scale application of superspreading material, self assembly is used to prepare superspreading polymer membrane (SPPM) in this work. An amphiphilic SPPM is prepared by capillary force-driven self assembly using PP melt-blown nonwovens and polyvinyl alcohol (PVA). The prepared SPPM has low preparation cost and stable performance since self assembly needs low energy consumption, and the production is thermodynamically stable. By using cryo-electron microscopy, transmission electron microscopy, X-ray photoelectron spectrum and scanning electron microscope with energy dispersive X-ray spectroscopy. It is proved that PVA is successfully assembled on the fiber surface of PP melt-blown nonwovens. The prepared SPPM has excellent spreading performance, the "spreading times" of both water and oil are less than 0.5 s. They showed much superior performance compared to traditional materials when applied in oil-water separation, seawater desalination, and ion separation. This work will definitely promote the development of self assembly, superspreading materials, and related sciences.

Generation of the stable propagation Bessel beam and the axial multifoci beam with pure phase elements.

A recently proposed method is upgraded to convert two amplitude phase modulation systems (APMSs) to pure phase elements (PPEs), for generating the stable propagation Bessel beam and the axial multifoci beam, respectively. Phase functions of the PPEs are presented analytically. Numerical simulations by the complete Rayleigh-Sommerfeld method demonstrate that the converted PPE has implemented the same optical functionalities as the corresponding APMS, in either the longitudinal or the transverse direction. Compared with the traditional APMS, the converted PPE possesses many advantages such as fabrication process simplification, system complexity reduction, production cost conservation, alignment error avoidance, and experimental precision enhancement. These inherent advantages position the PPE as an ideal choice and driving force behind further advancements in optical system technology.

Mothers' experiences of breast milk expression during separation from their hospitalized infants: a systematic review of qualitative evidence.

BACKGROUND: Mother-infant separation, which is occurring with an increasing incidence, is a barrier to direct breastfeeding. Owing to the importance of breast milk to hospitalized infants, mothers are actively encouraged to express milk during their infants' neonatal intensive care unit (NICU) stay. However, mothers are often faced with a number of challenges in this process. There is a need to understand such mothers' real-life experiences of breast milk expression to develop supportive strategies to reduce the burden on mothers and increase breastfeeding rates. METHODS: A comprehensive search of 12 databases was conducted for relevant studies published from database construction to December 2022. All qualitative and mixed-method studies published in English and Chinese that reported on mothers' experiences of human milk expression during separation from their hospitalized infants were included. Two reviewers independently conducted screening, data extraction, and quality appraisal, with disagreements resolved by a third reviewer. The process of searching followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. The JBI Qualitative Assessment and Review Instrument was used to assess study quality and the credibility of study findings. Meta-aggregation was performed to integrate the results. RESULTS: This systematic review aggregated mothers' experiences of milk expression during separation from their hospitalized infants. Database search yielded 600 records, of which 19 full-text documents were screened. Finally, 13 studies of good quality were included with data from 332 mothers across seven countries. A total of 61 primary findings with illustrations were extracted from the 13 eligible studies, the findings were generalized into 16 categories, and further were concluded as four synthesized findings: purpose and motivation, physical and emotional experiences, barrier factors, and coping styles. CONCLUSION: Mothers were driven by extrinsic motivation in their decision to express breast milk. They experienced physical exhaustion and many negative emotional feelings while expressing. This process was affected by numerous barriers. Social support was essential to the initiation and maintenance of milk expression. Medical staff and families should pay more attention to the mental health of mothers with infants in the NICU. Future research should incorporate strategies to cope with emotional responses and offer practical strategies for managing milk expression. SYSTEMATIC REVIEW REGISTRATION: [ www.crd.york.ac.uk ], identifier [PROSPERO 2022 CRD42022383080].

Genome-wide characterization of extrachromosomal circular DNA in gastric cancer and its potential role in carcinogenesis and cancer progression.

Extrachromosomal circular DNAs (eccDNAs) carrying random genomic segments are broadly found across different cancer types, but their molecular functions and impact in gastric cancer (GC) are rarely known. In this study, we aimed to investigate the potential role of eccDNA in GC. Using the Circle-seq strategy, we observed the eccDNA abundance in gastric cancer tissues (GCT) was aberrantly higher than that of normal adjacent tissues (NAT). The high abundance of eccDNAs carrying oncogene-segments in GCT may represent the DNA damage products of amplified oncogenes. Analysis of GCT over-represented eccDNA carrying enhancer (eccEnhancer) based on data from FANTOM5 project combined with TCGA database suggested the GC over-represented eccEnhancers may contribute to development of GC. GC over-represented eccDNAs carrying pre-miRNA (eccMIR) were enriched to multiple cancer-relevant signal pathways by KEGG analysis. We then synthesized the top six GC over-represented eccMIRs and found four of them enabled high expression of miRNAs and down-regulation of miRNA-target genes in MGC803 cells. Furthermore, we observed the inheritance of GC over-represented eccMIRs benefited host cell proliferation and promoted the aggressive features of host cells. Altogether, this study revealed the GC over-represented eccDNAs carrying functional genomic segments were related to the carcinogenesis of GC and presented the capability to facilitate cancer progression, suggesting the cancerous eccDNAs may serve as a dynamic reservoir for genome plasticity and rapid adaptive evolution of cancer. Therefore, blocking the pathways for eccDNAs generation may provide a novel therapeutic strategy for the treatment of gastric cancer.

RECENT TRENDS IN THE CUMULATIVE INCIDENCE AND INTERVENTION PATTERNS OF RETINOPATHY OF PREMATURITY IN JAPAN: A Multicenter Analysis, 2011-2020.

PURPOSE: To investigate recent trends in the cumulative incidence and treatment patterns of retinopathy of prematurity (ROP) in Japan. METHODS: A retrospective multicenter cohort was conducted from 2011 to 2020 using the Diagnosis Procedure Combination inpatient database. Preterm newborns with birth weight <2,500 g were categorized by birth weight. The cumulative incidence of ROP, treatment patterns, and association between treatment and birth weight were investigated. RESULTS: A total of 82,683 preterm infants were identified, of whom 9,335 (11.3%) were diagnosed with ROP. The cumulative incidence of ROP increased by 15% in those with birth weight <500 g over the study period. Among the ROP infants, 20.2% received treatment, including laser photocoagulation (94.8%), intravitreal injection (3.8%), or both (1.8%). The proportion receiving laser photocoagulation decreased followed by an increase in intravitreal injection. This shift in intervention pattern was most conspicuous for those with birth weight 750 to 1,249 g. The risk ratio of receiving laser and intravitreal injection for those weighing <500 g was 24.7 (95% confidence interval, 10.5-58.2) and 28.4 (5.8-138.1), respectively, as compared with infants weighing >1,500 g. CONCLUSION: The cumulative incidence of ROP increased in infants with birth weight <500 g. A shift from laser photocoagulation to intravitreal injection was observed in the more recent years.

The non-telomeric evolutionary trajectory of TRF2 in zebrafish reveals its specific roles in neurodevelopment and aging.

The shelterin protein complex is required for telomere protection in various eukaryotic organisms. In mammals, the shelterin subunit TRF2 is specialized in preventing ATM activation at telomeres and chromosome end fusion in somatic cells. Here, we demonstrate that the zebrafish ortholog of TRF2 (encoded by the terfa gene) is protecting against unwanted ATM activation genome-wide. The terfa-compromised fish develop a prominent and specific embryonic neurodevelopmental failure. The heterozygous fish survive to adulthood but exhibit a premature aging phenotype. The recovery from embryonic neurodevelopmental failure requires both ATM inhibition and transcriptional complementation of neural genes. Furthermore, restoring the expression of TRF2 in glial cells rescues the embryonic neurodevelopment phenotype. These results indicate that the shelterin subunit TRF2 evolved in zebrafish as a general factor of genome maintenance and transcriptional regulation that is required for proper neurodevelopment and normal aging. These findings uncover how TRF2 links development to aging by separate functions in gene expression regulation and genome stability control.

The relationship between changes in peak expiratory flow and asthma exacerbations in asthmatic children.

BACKGROUND: Asthma is one of the most common chronic airway diseases in children. Preventing asthma exacerbation is one of the objectives of all asthma action plans. In patients with poor perception, it is difficult to identify acute asthma exacerbations by clinical asthma score, asthma control test or asthma control questionnaire. The aim of this study is to analyze whether children with asthma have changes in peak expiratory flow(PEF)before an acute asthma exacerbation and to evaluate the relationship between PEF and asthma exacerbation. METHODS: Basic information (including sex, age, atopy, etc.) and clinical information of asthmatic children who registered in the Electronic China Children's Asthma Action Plan (e-CCAAP) from 1 September 2017 to 31 August 2021 were collected. Subjects with 14 consecutive days of PEF measurements were eligible. Subjects in this study were divided into an exacerbation group and a control group. We analyzed the relationship between changes in PEF% pred and the presence of asthma symptoms. RESULT: A total of 194 children with asthma who met the inclusion criteria were included, including 144 males (74.2%) and 50 females (25.8%), with a male-to-female ratio of 2.88:1. The mean age of the subjects was 9.51 ± 2.5 years. There were no significant differences in sex, age, allergy history or baseline PEF between the two groups. In children with and without a history of allergy, there was no significant difference between the variation in PEF at 14 days. Patients who only had a reduced in PEF but no symptoms of asthma exacerbation had the greatest reduction in PEF compared to the other groups. The most common cause of acute exacerbations of asthma is upper respiratory tract infection. Among the causes of acute exacerbations of asthma, the variation in PEF caused by air pollution was significantly higher than that of other causes (P < 0.05). In acute exacerbations, the decrease in PEF was significantly greater in the exacerbation group than in the control group. In children with asthma symptoms, there was a decrease in PEF approximately 1.34 days before the onset of symptoms. CONCLUSION: Children with asthma show a decrease in PEF 1.34 days before the onset of asthma symptoms. We recommend that asthmatic children who show a decrease in PEF should step-up asthma therapy. The most common cause of acute exacerbations of asthma was upper respiratory tract infections, and the variation in PEF caused by air pollution was significantly higher than that caused by other factors.

Icaritin exhibits potential drug-drug interactions through the inhibition of human UDP-glucuronosyltransferase in vitro.

Icaritin is a prenylflavonoid derivative of the genus Epimedium (Berberidaceae) and has a variety of pharmacological actions. Icaritin is approved by the National Medical Products Administration as an anticancer drug that exhibits efficacy and safety advantages in patients with hepatocellular carcinoma cells. This study aimed to evaluate the inhibitory effects of icaritin on UDP-glucuronosyltransferase (UGT) isoforms. 4-Methylumbelliferone (4-MU) was employed as a probe drug for all the tested UGT isoforms using in vitro human liver microsomes (HLM). The inhibition potentials of UGT1A1 and 1A9 in HLM were further tested by employing 17ß-estradiol (E2) and propofol (PRO) as probe substrates, respectively. The results showed that icaritin inhibits UGT1A1, 1A3, 1A4, 1A7, 1A8, 1A10, 2B7, and 2B15. Furthermore, icaritin exhibited a mixed inhibition of UGT1A1, 1A3, and 1A9, and the inhibition kinetic parameters (Ki) were calculated to be 3.538, 2.117, and 0.306 (µM), respectively. The inhibition of human liver microsomal UGT1A1 and 1A9 both followed mixed mechanism, with Ki values of 2.694 and 1.431 (µM). This study provides supporting information for understanding the drug-drug interaction (DDI) potential of the flavonoid icaritin and other UGT-metabolized drugs in clinical settings. In addition, the findings provide safety evidence for DDI when liver cancer patients receive a combination therapy including icaritin.

Preclinical Pharmacokinetics and Biodistribution of LR004, a Novel Antiepidermal Growth Factor Receptor Monoclonal Antibody.

LR004 is a novel chimeric (human/mouse) monoclonal antibody developed for the treatment of advanced colorectal carcinoma with detectable epidermal growth factor receptor (EGFR) expression. We aimed to investigate the preclinical pharmacokinetics (PK) and in vivo biodistribution of LR004. The PK profiles of LR004 were initially established in rhesus monkeys. Subsequently, 125I radionuclide-labeled LR004 was developed and the biodistribution, autoradiography, and NanoSPECT/CT of 125I-LR004 in xenograft mice bearing A431 tumors were examined. The PK data revealed a prolonged half-life and nonlinear PK characteristics of LR004 within the dose range of 6-54 mg/kg. The radiochemical purity of 125I-LR004 was approximately 98.54%, and iodination of LR004 did not affect its specific binding activity to the EGFR antigen. In a classical biodistribution study, 125I-LR004 exhibited higher uptake in highly perfused organs than in poorly perfused organs. Prolonged retention properties of 125I-LR004 in tumors were observed at 4 and 10 days. Autoradiography and NanoSPECT/CT confirmed the sustained retention of 125I-LR004 at the tumor site in xenograft mice. These findings demonstrated the adequate tumor targeting capabilities of 125I-LR004 in EGFR-positive tumors, which may improve dosing strategies and future drug development.

Lewis-Acid-Catalyzed (3+2) Annulation of 2-Indolylmethanols with Propargylic Alcohols to Access Cyclopenta[b]indoles.

Herein, a Sc(OTf)3-catalyzed (3+2) annulation of 2-indolylmethanols with propargylic alcohols is reported. The reaction proceeds via a Friedel-Crafts-type allenylation/5-exo-annulation cascade. In the reaction, 2-indolylmethanol is used as a three-carbon synthon, and propargyl alcohol is used as a two-carbon synthon. This method provides a direct and high-yield pathway for synthetically useful cyclopenta[b]indoles. In general, the method features easily accessible substrates with broad scope and generality, the formation of multiple bonds with high efficiency, and easy scale-up.

The early career resilience experience of generation Z newly graduated registered nurses in standardized training in the emergency department: a qualitative study in Shanghai.

BACKGROUND: The period of standardized training is a transitional stage when Generation Z newly graduated registered nurses (Gen Z NGRNs) change their role from student to nurse. Affected by the COVID-19, they lack clinical practice and practicum experience in emergency departments in their university studies. At the beginning of career, they are under great pressure. Resilience is one of the factors that reduce their stress level and increases endurance. It is of interest to understand how this representative group of nurses gained and played the experience of resilience early in their careers. OBJECTIVE: To explore Gen Z NGRNs' experience and process of resilience, to provide a new perspective and theoretical basis for psychological rehabilitation or intervention of medical staff who experienced transition shock. METHODS: This study employed a qualitative design based on the phenomenological approach. 18 nurses from a third-level class-A hospital in Shanghai who participated in standardized training in emergency department were enrolled using purposive sampling. Data collection was through in-depth and semi-structured interviews and continued until reaching data saturation. RESULTS: The investigation uncovered three themes and ten subthemes. Pressure and challenge contained high workload and high risk coexist, death's stress response, more emergencies and high professional requirements. Coping and adaptation contained team help, psychological restructuring, peer support, transformational leadership. Reflection and planning contained enhance learning, appreciate life. CONCLUSIONS: Our study described the embodiment and coping experience of the physical and mental stress faced by Gen Z NGRNs during their standardized training in the emergency department. It is emphasized that nurse educators should pay attention to the character and actual needs of Gen Z NGRNs, explore and formulate strategies, so as to guide NGRNs to quickly adapt and grow in the new role. The ultimate goal is to increase nurse retention and improve the quality of nursing.