Unconventional Spectral Gaps Induced by Charge Density Waves in the Weyl Semimetal (TaSe4)2I.

Coupling Weyl quasiparticles and charge density waves (CDWs) can lead to fascinating band renormalization and many-body effects beyond band folding and Peierls gaps. For the quasi-one-dimensional chiral compound (TaSe4)2I with an incommensurate CDW transition at TC = 263 K, photoemission mappings thus far are intriguing due to suppressed emission near the Fermi level. Models for this unconventional behavior include axion insulator phases, correlation pseudogaps, polaron subbands, bipolaron bound states, etc. Our photoemission measurements show sharp quasiparticle bands crossing the Fermi level at T > TC, but for T < TC, these bands retain their dispersions with no Peierls or axion gaps at the Weyl points. Instead, occupied band edges recede from the Fermi level, opening a spectral gap. Our results confirm localization of quasiparticles (holes created by photoemission) is the key physics, which suppresses spectral weights over an energy window governed by incommensurate modulation and inherent phase defects of CDW.

Fast and precise single-frame phase demodulation interferometry.

To achieve real-time phase detection, this paper presents a fast and precise spatial carrier phase-shifting interferometry based on the dynamic mode decomposition strategy. The algorithm initially produces a series of phase-shifted sub-interferograms with the aid of a spatial carrier interferogram. Subsequently, the measured phases are derived with great accuracy from these sub-interferograms through the use of the dynamic mode decomposition strategy, an outstanding non-iterative algorithm. Numerical simulation and experimental comparison show that this method is an efficient and accurate single-frame phase demodulation algorithm. The paper also analyzes the performance of the proposed method based on influencing factors such as random noise level, carrier frequency size, and carrier frequency direction. The results indicate that this method is a fast and accurate phase solution method, offering another effective solution for dynamic real-time phase measurement.

Evaluation of the immunogenicity and protective efficacy of an inactivated vaccine candidate for sheep infected with ovine parainfluenza virus type 3.

Respiratory diseases constitute a major health problem for ruminants, resulting in considerable economic losses throughout the world. Parainfluenza type 3 virus (PIV3) is one of the most important respiratory pathogens of ruminants. The pathogenicity and phylogenetic analyses of PIV3 virus have been reported in sheep and goats. However, there are no recent studies of the vaccination of sheep or goats against PIV3. Here, we developed a purified inactivated ovine parainfluenza virus type 3 (OPIV3) vaccine candidate. In addition, we immunized sheep with the inactivated OPIV3 vaccine and evaluated the immune response and pathological outcomes associated with OPIV3 TX01 infection. The vaccinated sheep demonstrated no obvious symptoms of respiratory tract infection, and there were no gross lesions or pathological changes in the lungs. The average body weight gain significantly differed between the vaccinated group and the control group (P < 0.01). The serum neutralization antibody levels rapidly increased in sheep post-vaccination and post-challenge with OPIV3. Furthermore, viral shedding in nasal swabs and viral loads in the lungs were reduced. The results of this study suggest that vaccination with this candidate vaccine induces the production of neutralizing antibodies and provides significant protection against OPIV3 infection. These results may be helpful for further studies on prevention and control strategies for OPIV3 infections.

Efficient Identification of Tembusu Virus CTL Epitopes in Inbred HBW/B4 Ducks Using a Novel MHC Class I-Restricted Epitope Screening Scheme.

The identification of MHC class I-restricted CTL epitopes in certain species, particularly nonmammals, remains a challenge. In this study, we developed a four-step identification scheme and confirmed its efficiency by identifying the Anpl-UAA*76-restricted CTL epitopes of Tembusu virus (TMUV) in inbred haplotype ducks HBW/B4. First, the peptide binding motif of Anpl-UAA*76 was determined by random peptide library in de novo liquid chromatography-tandem mass spectrometry, a novel nonbiased, data-independent acquisition method that we previously established. Second, a total of 38 TMUV peptides matching the motif were screened from the viral proteome, among which 11 peptides were conserved across the different TMUV strains. Third, the conserved TMUV peptides were refolded in vitro with Anpl-UAA*76 and Anpl-ß2-microglobulin to verify the results from the previous two steps. To clarify the structural basis of the obtained motif, we resolved the crystal structure of Anpl-UAA*76 with the TMUV NS3 peptide LRKRQLTVL and found that Asp34 is critical for the preferential binding of the B pocket to bind the second residue to arginine as an anchor residue. Fourth, the immunogenicity of the conserved TMUV peptides was tested in vivo using specific pathogen-free HBW/B4 ducks immunized with the attenuated TMUV vaccine. All 11 conserved TMUV epitopes could bind stably to Anpl-UAA*76 in vitro and stimulate the secretion of IFN-γ and lymphocyte proliferation, and three conserved and one nonconserved peptides were selected to evaluate the CTL responses in vivo by flow cytometry and their tetramers. We believe that this new scheme could improve the identification of MHC class I-restricted CTL epitopes, and our data provide a foundation for further study on duck anti-TMUV CTL immunity.

Exploiting Photoinduced Atom Transfer Radical Polymerizations with Boron-Dopant and Nitrogen-Defect Synergy in Carbon Nitride Nanosheets.

Graphitic carbon nitrides (g-C3N4) possess various benefits as heterogeneous photocatalysts, including tunable bandgaps, scalability, and chemical robustness. However, their efficacy and ongoing advancement are hindered by challenges like limited charge-carrier separation rates, insufficient driving force for photocatalysis, small specific surface area, and inadequate absorption of visible light. In this study, boron dopants and nitrogen defects synergy are introduced into bulk g-C3N4 through the calcination of a blend of nitrogen-defective g-C3N4 and NaBH4 under inert conditions, resulting in the formation of BCN nanosheets characterized by abundant porosity and increased specific surface area. These BCN nanosheets promote intermolecular single electron transfer to the radical initiator, maintaining radical intermediates at a low concentration for better control of photoinduced atom transfer radical polymerization (photo-ATRP). Consequently, this method yields polymers with low dispersity and tailorable molecular weights under mild blue light illumination, outperforming previous reports on bulk g-C3N4. The heterogeneity of BCN enables easy separation and efficient reuse in subsequent polymerization processes. This study effectively showcases a simple method to alter the electronic and band structures of g-C3N4 with simultaneously introducing dopants and defects, leading to high-performance photo-ATRP and providing valuable insights for designing efficient photocatalytic systems for solar energy harvesting.

Development of an index system for the scientific literacy of medical staff: a modified Delphi study in China.

BACKGROUND: Scientific research activity in hospitals is important for promoting the development of clinical medicine, and the scientific literacy of medical staff plays an important role in improving the quality and competitiveness of hospital research. To date, no index system applicable to the scientific literacy of medical staff in China has been developed that can effectively evaluate and guide scientific literacy. This study aimed to establish an index system for the scientific literacy of medical staff in China and provide a reference for improving the evaluation of this system. METHODS: In this study, a preliminary indicator pool for the scientific literacy of medical staff was constructed through the nominal group technique (n = 16) with medical staff. Then, two rounds of Delphi expert consultation surveys (n = 20) were conducted with clinicians, and the indicators were screened, revised and supplemented using the boundary value method and expert opinions. Next, the hierarchical analysis method was utilized to determine the weights of the indicators and ultimately establish a scientific literacy indicator system for medical staff. RESULTS: Following expert opinion, the index system for the scientific literacy of medical staff featuring 2 first-level indicators, 9 second-level indicators, and 38 third-level indicators was ultimately established, and the weights of the indicators were calculated. The two first-level indicators were research literacy and research ability, and the second-level indicators were research attitude (0.375), ability to identify problems (0.2038), basic literacy (0.1250), ability to implement projects (0.0843), research output capacity (0.0747), professional capacity (0.0735), data-processing capacity (0.0239), thesis-writing skills (0.0217), and ability to use literature (0.0181). CONCLUSIONS: This study constructed a comprehensive scientific literacy index system that can assess medical staff's scientific literacy and serve as a reference for evaluating and improving their scientific literacy.

Dirac Nodal Line in Hourglass Semimetal Nb3SiTe6.

Glide-mirror symmetry in nonsymmorphic crystals can foster the emergence of novel hourglass nodal loop states. Here, we present spectroscopic signatures from angle-resolved photoemission of a predicted topological hourglass semimetal phase in Nb3SiTe6. Linear band crossings are observed at the zone boundary of Nb3SiTe6, which could be the origin of the nontrivial Berry phase and are consistent with a predicted glide quantum spin Hall effect; such linear band crossings connect to form a nodal loop. Furthermore, the saddle-like Fermi surface of Nb3SiTe6 observed in our results helps unveil linear band crossings that could be missed. In situ alkali-metal doping of Nb3SiTe6 also facilitated the observation of other band crossings and parabolic bands at the zone center correlated with accidental nodal loop states. Overall, our results complete the system's band structure, help explain prior Hall measurements, and suggest the existence of a nodal loop at the zone center of Nb3SiTe6.

Analysis of flavor substances in Shaoxing traditional hand-made Jiafan wine with different amounts of ZaoShao liquor.

BACKGROUND: Adding ZaoShao liquor (high-concentration liquor) is one of the most important steps in the brewing process of Shaoxing Jiafan wine, a product protected by Chinese geographical indications. The focus of this study is the effect of different additive amounts of liquor on the flavor of end products. RESULTS: In this study, four kinds of Shaoxing Jiafan wine were brewed by changing the amount of ZaoShao liquor. Headspace solid-phase microextraction and gas chromatography-mass spectrometry were used to detect the flavor substances of four kinds of Jiafan wine. The difference in flavor of four kinds of Jiafan wine was evaluated by electronic nose analysis technology and verified by sensory evaluation. Finally, the reliability of the experimental results was verified through an aroma reconstruction experiment of rice wine. In this study, the differences in flavoring substances under different amounts of ZaoShao liquor were verified from various angles. The results showed that the flavors of the four kinds of wines were significantly different. CONCLUSION: The composition of flavor substances in Shaoxing rice wine varies with the amount of ZaoShao liquor. This study provided a scientific basis for the improvement of production technology of Shaoxing wine. © 2024 Society of Chemical Industry.

Research progress of the Fanconi anemia pathway and premature ovarian insufficiency†.

The Fanconi anemia pathway is a key pathway involved in the repair of deoxyribonucleic acidinterstrand crosslinking damage, which chiefly includes the following four modules: lesion recognition, Fanconi anemia core complex recruitment, FANCD2-FANCI complex monoubiquitination, and downstream events (nucleolytic incision, translesion synthesis, and homologous recombination). Mutations or deletions of multiple Fanconi anemia genes in this pathway can damage the interstrand crosslinking repair pathway and disrupt primordial germ cell development and oocyte meiosis, thereby leading to abnormal follicular development. Premature ovarian insufficiency is a gynecological clinical syndrome characterized by amenorrhea and decreased fertility due to decreased oocyte pool, accelerated follicle atresia, and loss of ovarian function in women <40 years old. Furthermore, in recent years, several studies have detected mutations in the Fanconi anemia gene in patients with premature ovarian insufficiency. In addition, some patients with Fanconi anemia exhibit symptoms of premature ovarian insufficiency and infertility. The Fanconi anemia pathway and premature ovarian insufficiency are closely associated.

ANP32B-mediated repression of p53 contributes to maintenance of normal and CML stem cells.

Proper regulation of p53 signaling is critical for the maintenance of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). The hematopoietic cell-specific mechanisms regulating p53 activity remain largely unknown. Here, we demonstrate that conditional deletion of acidic leucine-rich nuclear phosphoprotein 32B (ANP32B) in hematopoietic cells impairs repopulation capacity and postinjury regeneration of HSCs. Mechanistically, ANP32B forms a repressive complex with p53 and thus inhibits the transcriptional activity of p53 in hematopoietic cells, and p53 deletion rescues the functional defect in Anp32b-deficient HSCs. Of great interest, ANP32B is highly expressed in leukemic cells from patients with chronic myelogenous leukemia (CML). Anp32b deletion enhances p53 transcriptional activity to impair LSC function in a murine CML model and exhibits synergistic therapeutic effects with tyrosine kinase inhibitors in inhibiting CML propagation. In summary, our findings provide a novel strategy to enhance p53 activity in LSCs by inhibiting ANP32B and identify ANP32B as a potential therapeutic target in treating CML.

Protective Effect of Vaccine Doses and Antibody Titers Against SARS-CoV-2 Infection in Kidney Transplant Recipients.

Patients undergoing kidney transplantation have a poor response to vaccination and a higher risk of disease progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The effectiveness of vaccine doses and antibody titer tests against the mutant variant in these patients remains unclear. We retrospectively analyzed the risk of SARS-CoV-2 infection in a single medical center according to vaccine doses and immune responses before the outbreak. Among 622 kidney transplant patients, there were 77 patients without vaccination, 26 with one dose, 74 with two doses, 357 with three, and 88 with four doses. The vaccination status and infection rate proportion were similar to the general population. Patients undergoing more than three vaccinations had a lower risk of infection (odds ratio = 0.6527, 95% CI = 0.4324-0.9937) and hospitalization (odds ratio = 0.3161, 95% CI = 0.1311-0.7464). Antibody and cellular responses were measured in 181 patients after vaccination. Anti-spike protein antibody titer of more than 1,689.3 BAU/mL is protective against SARS-CoV-2 infection (odds ratio = 0.4136, 95% CI = 0.1800-0.9043). A cellular response by interferon-γ release assay was not correlated with the disease (odds ratio = 1.001, 95% CI = 0.9995-1.002). In conclusion, despite mutant strain, more than three doses of the first-generation vaccine and high antibody titers provided better protection against the omicron variant for a kidney transplant recipient.

Prevailing Role of Mucosal Igs and B Cells in Teleost Skin Immune Responses to Bacterial Infection.

The skin of vertebrates is the outermost organ of the body and serves as the first line of defense against external aggressions. In contrast to mammalian skin, that of teleost fish lacks keratinization and has evolved to operate as a mucosal surface containing a skin-associated lymphoid tissue (SALT). Thus far, IgT representing the prevalent Ig in SALT have only been reported upon infection with a parasite. However, very little is known about the types of B cells and Igs responding to bacterial infection in the teleost skin mucosa, as well as the inductive or effector role of the SALT in such responses. To address these questions, in this study, we analyzed the immune response of trout skin upon infection with one of the most widespread fish skin bacterial pathogens, Flavobacterium columnare This pathogen induced strong skin innate immune and inflammatory responses at the initial phases of infection. More critically, we found that the skin mucus of fish having survived the infection contained significant IgT- but not IgM- or IgD-specific titers against the bacteria. Moreover, we demonstrate the local proliferation and production of IgT+ B cells and specific IgT titers, respectively, within the SALT upon bacterial infection. Thus, our findings represent the first demonstration that IgT is the main Ig isotype induced by the skin mucosa upon bacterial infection and that, because of the large surface of the skin, its SALT probably represents a prominent IgT-inductive site in fish.

Mechanism of intracellular allosteric ß2AR antagonist revealed by X-ray crystal structure.

G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ligands may bind to less-conserved regions of these receptors and therefore are more likely to be selective. Unlike orthosteric ligands, which tonically activate or inhibit signalling, allosteric ligands modulate physiologic responses to hormones and neurotransmitters, and may therefore have fewer adverse effects. The majority of GPCR crystal structures published to date were obtained with receptors bound to orthosteric antagonists, and only a few structures bound to allosteric ligands have been reported. Compound 15 (Cmpd-15) is an allosteric modulator of the ß2 adrenergic receptor (ß2AR) that was recently isolated from a DNA-encoded small-molecule library. Orthosteric ß-adrenergic receptor antagonists, known as beta-blockers, are amongst the most prescribed drugs in the world and Cmpd-15 is the first allosteric beta-blocker. Cmpd-15 exhibits negative cooperativity with agonists and positive cooperativity with inverse agonists. Here we present the structure of the ß2AR bound to a polyethylene glycol-carboxylic acid derivative (Cmpd-15PA) of this modulator. Cmpd-15PA binds to a pocket formed primarily by the cytoplasmic ends of transmembrane segments 1, 2, 6 and 7 as well as intracellular loop 1 and helix 8. A comparison of this structure with inactive- and active-state structures of the ß2AR reveals the mechanism by which Cmpd-15 modulates agonist binding affinity and signalling.

Effect of multiple chronic conditions on family doctor contracting in the elderly in China: the moderating role of socioeconomic status.

BACKGROUND: China's family doctor contracting service is an important part of deepening the reform of the healthcare systems, aiming to further develop chronic disease management services, enhance the capacity of primary health care services and improve the health of residents. The purpose of this study was to explore the influence of multiple chronic conditions in the elderly on family doctor contracting and whether socioeconomic status played a moderating role. METHODS: A cross-sectional survey was conducted in Beijing, China. A total of 1814 elderly people over 60 years old were included in this study using a whole-group sampling method. The univariate analysis and logistic regression analysis was used to analyze the data. RESULTS: 21.72% of the elderly signed up with family doctors. The multiple chronic conditions was a factor influencing the elderly to sign up with family doctors (OR = 1.44, 95%CI = 1.28-1.61), and the higher the degree of multiple chronic conditions, the stronger willingness to sign up. Socioeconomic status positively moderates the effect of multiple chronic conditions on signing. Also, physical activity intensity (OR = 1.25, 95%CI = 1.03-1.54) and willingness to first visit primary care facilities (OR = 1.38, 95%CI = 1.25-1.54) influenced the elderly to sign up with family doctors. CONCLUSIONS: The elderly with a high degree of multiple chronic conditions, high activity intensity, and a strong willingness to first visit primary care facilities were more likely to sign up with family doctors. The health literacy of the elderly should be further improved, and publicity on the family doctor contracting service policies for the elderly with lower socioeconomic status should be strengthened to guide them to sign up with family doctors. At the same time, the service capacity of primary care facilities should be further improved to meet the health needs of the elderly.

How to become an excellent pediatric resident: a qualitative comparative study from China.

BACKGROUND: Competency-oriented medical education has become a global trend. However, most current studies focus on the independent effects of various competencies and lack an examination of the combined effects. Therefore, the purpose of this study was to explore the competency configurations of excellent pediatric residents and general pediatric residents and to provide a scientific reference for the talent training and career development of pediatric residents. METHODS: Behavioral event interviews were conducted with 23 pediatric residents at a children's hospital in Beijing in July and August 2019. Two researchers coded the interview data to summarize the competency of pediatric residents. The research group scored the performance of 23 pediatric residents in various aspects of competency and used the crisp-set qualitative comparative analysis method to explore the competency configurations of excellent pediatric residents and general pediatric residents. RESULTS: This study concludes that pediatric residents should have six core competencies: professional spirit, clinical skills, communication ability, learning ability, mental capacity and research ability. There are 4 combinations of competencies for becoming an excellent pediatric resident: the clinical type, scientific research type, all-around development type and high emotional intelligence type. In addition, there are 3 combinations of competencies for becoming a general pediatric resident: the comprehensive ability deficiency type, lack of professionalism and mental capacity type, lack of communication ability type. CONCLUSIONS: There are differences in competence between excellent and general pediatric residents. Excellent pediatric residents do not need to possess all competencies but should specialize in clinical practice, scientific research or communication skills. This study suggests that training in mental capacity, professional spirit and communication ability should be strengthened during pediatric resident training. Pediatric residents should make career development plans according to their actual situation, and hospitals should arrange suitable positions according to the characteristics of pediatric residents.

Depression among schoolchildren and adolescents aged 9-17 years during the outbreak of COVID­19 in Beijing: a cross-sectional online survey.

The COVID-19 outbreak and related confinement have highly impacted psychological health among children and adolescents. This study aimed to explore the potential risk factors for depression among primary and middle school students and provide advices for psychological interventions during the outbreaks. An online cross-sectional survey was conducted among 18 primary and middle school students via quota sampling in Beijing during March 2020. The Center for Epidemiological Studies Depression Scale (CES-D) was used to assess depression. Differences between characteristics and depression were examined by chi-square tests. Multivariate logistic regression was used to reveal the potential risk factors for depression. A total of 7377 participants were included. The proportion of depression was 29.7%. Students in rural areas, with higher school categories, in graduating grades, with poor or excessive sleep duration, and without daily exercise were associated with a higher proportion of depression. Furthermore, students with a higher knowledge performance of COVID-19 showed a lower proportion of depression (odds ratio [OR] = 0.900, 95% confidence intervals [95% CI]: 0.888-0.913). Students who worried about academic performance (OR = 1.919, 95% CI: 1.718-2.144) or COVID-19 infection (OR = 1.450, 95% CI: 1.268-1.658) exhibited a high proportion of depression. The proportion of depression among primary and middle school students was negatively associated with the knowledge score and positively associated with their worry. Our findings suggest that psychological intervention might be more necessary for students with specific characteristics.

BEXCIS: Bayesian methods for estimating the degree of the skewness of X chromosome inactivation.

BACKGROUND: X chromosome inactivation (XCI) is an epigenetic phenomenon that one of two X chromosomes in females is transcriptionally silenced during early embryonic development. Skewed XCI has been reported to be associated with some X-linked diseases. There have been several methods measuring the degree of the skewness of XCI. However, these methods may still have several limitations. RESULTS: We propose a Bayesian method to obtain the point estimate and the credible interval of the degree of XCI skewing by incorporating its prior information of being between 0 and 2. We consider a normal prior and a uniform prior for it (respectively denoted by BN and BU). We also propose a penalized point estimate based on the penalized Fieller's method and derive the corresponding confidence interval. Simulation results demonstrate that the BN and BU methods can solve the problems of extreme point estimates, noninformative intervals, empty sets and discontinuous intervals. The BN method generally outperforms other methods with the lowest mean squared error in the point estimation, and well controls the coverage probability with the smallest median and the least variation of the interval width in the interval estimation. We apply all the methods to the Graves' disease data and the Minnesota Center for Twin and Family Research data, and find that SNP rs3827440 in the Graves' disease data may undergo skewed XCI towards the allele C. CONCLUSIONS: We recommend the BN method for measuring the degree of the skewness of XCI in practice. The R package BEXCIS is publicly available at https://github.com/Wen-YiYu/BEXCIS .

A genetically novel avian Hepatitis E virus in China.

Hepatitis E virus (HEV) infection has a global distribution with diverse hosts, including mammals and avians. In this study, an avian Hepatitis E virus (aHEV) strain with a high mortality rate of about 30%, designated as SDXT20, was obtained from the liver of 30-week-old Hubbard chickens with severe hepatosplenomegaly in 2020 in Eastern China and HEV was proved to be the only pathogen by next-generation sequencing. Its complete genome, which encodes three open reading frames (ORFs), is 6649 nt in length. ORF1-3 encodes three proteins with lengths of 1532 aa, 606 aa, and 82 aa, respectively, and ORF2 and ORF3 overlap with each other. BLAST-based similarity analysis of the complete viral genome demonstrated that SDXT20 had merely 80.5-92.2% similarity with avian Avihepevirus magniiecur strains and 50.4%-54.8% lower similarity with Paslahepevirus balayani, Rocahepevirus ratti, and Chirohepevirus eptesici species. Further genetic evolution analysis of the complete genome and ORF2 revealed that the isolate was genetically distinct from known aHEVs, and it belonged to a novel genetically distinct aHEV. This study provides data for further analysis of the multi-host and cross-host genetic evolution of HEVs.

Theoretical insights into photo-induced isomerization mechanisms of phenylsulfinyl radical PhSO˙.

Sulfinyl radicals (R-SO˙) play important roles in lots of reactions, while the isomer oxathiyl radicals (R-OS˙) and the isomerization between them are rarely observed due to the poor stability of R-OS˙. In this work, the complete active space self-consistent field (CASSCF) and its multi-state second order perturbation (MS-CASPT2) methods were employed to study the photo-induced reaction mechanisms of phenylsulfinyl radical PhSO˙ 1 and its isomer phenoxathiyl radical PhOS˙ 2. Our results show that 1 and 2 have similar singly occupied molecular orbitals in the ground state but different properties in the excited state, which determine their diverse behaviors after irradiation. Radical 1 can generate 2 by light irradiation, but 2 produces isomerization product 3 (2-hydroxyphenylthiyl radical) and ring-opening product 4 (acyclic thioketoketene radical) in two paths via S atom migration intermediate Int1 (2-carbonylcyclohexadienthiyl radical). The former path involves consequent hydrogen shift reactions with a strongly exothermic process while the latter path involves both ring-expansion and ring-opening processes with a high barrier, resulting in a structural and energetic preference for the former path. Moreover, we revealed several conical intersections that participate in the reactions and facilitate the photochemical processes. Our calculations not only remain consistent with and clarify the experimental observations (X. Zeng, et al., J. Am. Chem. Soc., 2018, 140(31), 9972-9978) but also enrich the knowledge of sulfinyl radicals and isomer oxathiyl radicals.

Exclusion of NUMB Exon12 Controls Cancer Cell Migration through Regulation of Notch1-SMAD3 Crosstalk.

NUMB is an endocytic adaptor protein that contains four isoforms (p65, p66, p71 and p72) due to alternative splicing regulation. Here, we show that NUMB exon12 (E12)-skipping isoforms p65/p66 promote epithelial to mesenchymal transition (EMT) and cancer cell migration in vitro, and facilitate cancer metastasis in mice, whereas E12-included p71/p72 isoforms attenuate these effects. Mechanistically, p65/p66 isoforms significantly increase the sorting of Notch1 through early endosomes (EEs) for enhanced Notch1 activity. In contrast, p71/p72 isoforms act as negative regulators of Notch1 by ubiquitylating the Notch1 intracellular domain (N1ICD) and promoting its degradation. Moreover, we observed that the interaction between N1ICD and SMAD3 is important for their own stabilization, and for NUMB-mediated EMT response and cell migration. Either N1ICD or SMAD3 overexpression could significantly recuse the migration reduction seen in the p65/p66 knockdown, and Notch1 or SMAD3 knockdown rescued the migration advantage seen in the overexpression of p66. Taken all together, our study provides mechanistic insights into the opposite regulation of Notch1-SMAD3 crosstalk by NUMB isoforms and identifies them as critical regulators of EMT and cancer cell migration.