Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery.

To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRß chain sequences from 178 non-small cell lung cancer patients using the GLIPH2 (grouping of lymphocyte interactions with paratope hotspots 2) algorithm. We identified over 66,000 shared specificity groups, of which 435 were clonally expanded and enriched in tumors compared to adjacent lung. The antigenic epitopes of one such tumor-enriched specificity group were identified using a yeast peptide-HLA A∗02:01 display library. These included a peptide from the epithelial protein TMEM161A, which is overexpressed in tumors and cross-reactive epitopes from Epstein-Barr virus and E. coli. Our findings suggest that this cross-reactivity may underlie the presence of virus-specific T cells in tumor infiltrates and that pathogen cross-reactivity may be a feature of multiple cancers. The approach and analytical pipelines generated in this work, as well as the specificity groups defined here, present a resource for understanding the T cell response in cancer.

UM171 suppresses breast cancer progression by inducing KLF2.

PURPOSE: Breast cancer is the most frequent cancer in women with significant death rate. Morbidity is associated with drug resistance and metastasis. Development of novel drugs is unmet need. The aim of this study is to show potent anti-neoplastic activity of the UM171 compound on breast cancer cells and its mechanism of action. METHODS: The inhibitory effect of UM171 on several breast cancer (BC) cell lines was examined using MTT and colony-forming assays. Cell cycle and apoptosis assays were utilized to determine the effect of UM171 on BC cell proliferation and survival. Wound healing scratch and transwell migration assays were used to examine the migration of BC cell lines in culture. Xenograft of mouse model with 4T1 cells was used to determine inhibitory effect of UM171 in vivo. Q-RT-PCR and western blotting were used to determine the expression level of genes effected by UM171. Lentivirus-mediated shRNAs were used to knockdown the expression of KLF2 in BC cells. RESULTS: UM171 was previously identified as a potent agonist of human hematopoietic stem cell renewal and inhibitor of leukemia. In this study, UM171 was shown to inhibit the growth of multiple breast cancer cell lines in culture. UM171-mediated growth inhibition was associated with the induction of apoptosis, G2/M cell cycle arrest, lower colony-forming capacity, and reduced motility. In a xenotransplantation model of mouse triple-negative breast cancer 4T1 cells injected into syngeneic BALB/c mice, UM171 strongly inhibited tumor growth at a level comparable to control paclitaxel. UM171 increased the expression of the three PIM genes (PIM1-3) in breast cancer cells. Moreover, UM171 strongly induced the expression of the tumor suppressor gene KLF2 and cell cycle inhibitor P21CIP1. Accordingly, knockdown of KLF2 using lentivirus-mediated shRNA significantly attenuated the growth suppressor activity of UM171. As PIM1-3 act as oncogenes and are involved in breast cancer progression, induction of these kinases likely impedes the inhibitory effect of KLF2 induction by UM171. Accordingly, combination of UM171 with a PAN-PIM inhibitor LGH447 significantly reduced tumor growth in culture. CONCLUSION: These results suggested that UM171 inhibited breast cancer progression in part through activation of KLF2 and P21. Combination of UM171 with a PAN-PIM inhibitor offer a novel therapy for aggressive forms of breast cancer.

The function of the cytoplasmic dynein light chain PTKM23 in the transport of PTSMAD2 during spermatogenesis in Portunus trituberculatus†.

Cytoplasmic dynein participates in transport functions and is essential in spermatogenesis. KM23 belongs to the dynein light chain family. The TGFß signaling pathway is indispensable in spermatogenesis, and Smad2 is an important member of this pathway. We cloned PTKM23 and PTSMAD2 from Portunus trituberculatus and measured their expression during spermatogenesis. PTKM23 may be related to cell division, acrosome formation, and nuclear remodeling, and PTSMAD2 may participate in regulating the expression of genes related to spermatogenesis. We assessed the localization of PTKM23 with PTDHC and α-tubulin, and the results suggested that PTKM23 functions in intracellular transport during spermatogenesis. We knocked down PTKM23 in vivo, and the expression of p53, B-CATAENIN and CYCLIN B decreased significantly, further suggesting a role of PTKM23 in transport and cell division. The localization of PTDIC with α-tubulin and that of PTSMAD2 with PTDHC changed after PTKM23 knockdown. We transfected PTKM23 and PTSMAD2 into HEK-293 T cells and verified their colocalization. These results indicate that PTKM23 is involved in the assembly of cytoplasmic dynein and microtubules during spermatogenesis and that PTKM23 mediates the participation of cytoplasmic dynein in the transport of PTSMAD2 during spermatogenesis.

A TLR7-nanoparticle adjuvant promotes a broad immune response against heterologous strains of influenza and SARS-CoV-2.

The ideal vaccine against viruses such as influenza and SARS-CoV-2 must provide a robust, durable and broad immune protection against multiple viral variants. However, antibody responses to current vaccines often lack robust cross-reactivity. Here we describe a polymeric Toll-like receptor 7 agonist nanoparticle (TLR7-NP) adjuvant, which enhances lymph node targeting, and leads to persistent activation of immune cells and broad immune responses. When mixed with alum-adsorbed antigens, this TLR7-NP adjuvant elicits cross-reactive antibodies for both dominant and subdominant epitopes and antigen-specific CD8+ T-cell responses in mice. This TLR7-NP-adjuvanted influenza subunit vaccine successfully protects mice against viral challenge of a different strain. This strategy also enhances the antibody response to a SARS-CoV-2 subunit vaccine against multiple viral variants that have emerged. Moreover, this TLR7-NP augments antigen-specific responses in human tonsil organoids. Overall, we describe a nanoparticle adjuvant to improve immune responses to viral antigens, with promising implications for developing broadly protective vaccines.

FLI1 induces erythroleukemia through opposing effects on UBASH3A and UBASH3B expression.

BACKGROUND: FLI1 is an oncogenic transcription factor that promotes diverse malignancies through mechanisms that are not fully understood. Herein, FLI1 is shown to regulate the expression of Ubiquitin Associated and SH3 Domain Containing A/B (UBASH3A/B) genes. UBASH3B and UBASH3A are found to act as an oncogene and tumor suppressor, respectively, and their combined effect determines erythroleukemia progression downstream of FLI1. METHODS: Promoter analysis combined with luciferase assays and chromatin immunoprecipitation (ChIP) analysis were applied on the UBASH3A/B promoters. RNAseq analysis combined with bioinformatic was used to determine the effect of knocking-down UBASH3A and UBASH3B in leukemic cells. Downstream targets of UBASH3A/B were inhibited in leukemic cells either via lentivirus-shRNAs or small molecule inhibitors. Western blotting and RT-qPCR were used to determine transcription levels, MTT assays to assess proliferation rate, and flow cytometry to examine apoptotic index. RESULTS: Knockdown of FLI1 in erythroleukemic cells identified the UBASH3A/B genes as potential downstream targets. Herein, we show that FLI1 directly binds to the UBASH3B promoter, leading to its activation and leukemic cell proliferation. In contrast, FLI1 indirectly inhibits UBASH3A transcription via GATA2, thereby antagonizing leukemic growth. These results suggest oncogenic and tumor suppressor roles for UBASH3B and UBASH3A in erythroleukemia, respectively. Mechanistically, we show that UBASH3B indirectly inhibits AP1 (FOS and JUN) expression, and that its loss leads to inhibition of apoptosis and acceleration of proliferation. UBASH3B also positively regulates the SYK gene expression and its inhibition suppresses leukemia progression. High expression of UBASH3B in diverse tumors was associated with worse prognosis. In contrast, UBASH3A knockdown in erythroleukemic cells increased proliferation; and this was associated with a dramatic induction of the HSP70 gene, HSPA1B. Accordingly, knockdown of HSPA1B in erythroleukemia cells significantly accelerated leukemic cell proliferation. Accordingly, overexpression of UBASH3A in different cancers was predominantly associated with good prognosis. These results suggest for the first time that UBASH3A plays a tumor suppressor role in part through activation of HSPA1B. CONCLUSIONS: FLI1 promotes erythroleukemia progression in part by modulating expression of the oncogenic UBASH3B and tumor suppressor UBASH3A.

Repeated sexual intercourse as a coping strategy for men with premature ejaculation.

BACKGROUND: Patients with premature ejaculation (PE) are often concerned and distressed about their sexual performance. Hence, they may be more willing to exploit their refractory period to employ sexual coping strategies in order to improve their unsatisfactory sexual intercourse compared with patients without PE. AIM: The study sought to verify the sexual coping strategies of patients with PE in the daily sexual activities. METHODS: We included both patients with PE and individuals without PE and analyzed their sexual behaviors and attitudes by means of detailed interviews and questionnaires. OUTCOMES: The main outcomes were perceived intravaginal ejaculatory latency time recording, Premature Ejaculation Diagnostic Tool score, and sexual frequency, attitudes, and behavior log. RESULTS: A total of 182 young patients with PE (age 31.2 ± 6.2 years) and 92 individuals without PE (age 30.7 ± 5.1 years) were included in the study. A total of 53.3% of patients with PE vs 17.4% of individuals without PE reported engaging in multiple sexual intercourse sessions within a single day in the past 4 weeks. PE patients who engaged in multiple intercourse sessions displayed better performance during the second attempt but performed poorly compared with individuals without PE. Scores for the first attempt in PE vs second attempt in individuals with PE vs without PE were the following: intravaginal ejaculatory latency time, 2.4 ± 1.6 vs 4.8 ± 5.7 vs 9.9 ± 9.4 (P < .001); Premature Ejaculation Diagnostic Tool, 14.9 ± 3.1 vs 12.7 ± 4.8 vs 5.2 ± 2.5 (P < .001); satisfaction, 2.9 ± 1.0 vs 3.1 ± 0.8 vs 3.7 ± 1.4 (P < .001). A total of 57.1% of patients held a negative attitude toward precoital masturbation, for reasons such as a reduced sexual desire (21.2%), the belief that masturbation is harmful (17.6%), concerns about erectile function (15.7%), fatigue (9.8%), and other mixed reasons (35.3%). CLINICAL IMPLICATIONS: Engaging in multiple intercourse sessions within a day is more common among the young PE population, and using precoital masturbation as a coping strategy is not universally applicable among patients with PE. STRENGTHS AND LIMITATIONS: This is the first study to explore symptom-coping strategies in patients with PE compared with individuals without PE. However, the conclusions cannot be generalized to the entire male population. CONCLUSION: Patients with PE, compared with individuals without PE, are more inclined to engage in multiple sexual intercourse sessions within a single sexual session, likely in an attempt to compensate for their first unsatisfactory sexual encounter. Moreover, the majority of patients with PE here studied hold a negative attitude toward using precoital masturbation as a coping strategy for symptoms.

Perception of normal and treatment level ejaculatory latency times in men with premature ejaculation.

BACKGROUND: Although the normal intravaginal ejaculation latency time (NIELT) as subjectively perceived by patients with premature ejaculation (PE) and expected IELT (EIELT), which represents the individual's expectations of what treatment for PE would achieve, are critically influential in the treatment of patients with PE, there is a significant dearth of exploratory research on NIELT and EIELT among patients with PE. AIM: To explore the NIELT and EIELT of patients with PE, understand why patients with PE perceive such a long IELT as normal, and identify factors associated with EIELT. METHODS: We recruited both patients with PE and control subjects, and analyzed the parameters related to IELT using detailed interviews and questionnaires. OUTCOMES: Parameters related to IELT. RESULTS: A total of 592 individuals (mean age 29.6 ± 6.2) were included in the study, comprising 466 patients with PE (mean age 28.3 ± 5.4) and 126 non-PE individuals (mean age 34.6 ± 6.5). The actual perceived intravaginal ejaculation latency time (PIELT), referring to the patient's self-assessed IELT at baseline, as well as NIELT, and EIELT of patients with PE, were 1.0 (1.0 - 2.0), 14.0 (10.0 - 15.0), and 15.0 (10.0 - 20.0), respectively. The control group's PIELT and EIELT were 15.0 (10.0 - 20.0) and 20.0 (15.0 - 24.3), respectively, showing statistical differences compared with the PIELT and EIELT in the PE group. In the PE group and the control group, 31.5% and 57.9% of individuals, respectively, have an EIELT greater than the average actual normal ejaculatory latency time of 15.0 minutes. Among patients with PE, 51.3% expressed a NIELT >10 minutes, identical to the EIELT in a higher percentage (59.4%). The control group's EIELT is 5 minutes longer than the PE group's EIELT. Multivariable linear regression analysis showed that age, marital status, education level, BMI, satisfaction evaluation of PIELT, PEDT score, and IIEF-6 score were not associated with EIELT; only NIELT (beta = 0.817, P < 0.001) and PIELT (beta = 0.056, P = 0.044) were related to EIELT. CLINICAL IMPLICATIONS: Sexual health care providers should be aware that patients with PE have excessively high expectations for IELT. STRENGTHS AND LIMITATION: The first study explores why patients with clinically diagnosed PE perceive long IELT as normal and examines factors associated with EIELT. Further validation is needed in different cultural contexts. CONCLUSION: Patients with PE often have excessively high expectations regarding IELT, primarily due to their insufficient understanding of IELT.

Using a monotonic density ratio model to increase the power of the goodness-of-fit test for logistic regression models with case-control data.

Logistic regression models are widely used in case-control data analysis, and testing the goodness-of-fit of their parametric model assumption is a fundamental research problem. In this article, we propose to enhance the power of the goodness-of-fit test by exploiting a monotonic density ratio model, in which the ratio of case and control densities is assumed to be a monotone function. We show that such a monotonic density ratio model is naturally induced by the retrospective case-control sampling design under the alternative hypothesis. The pool-adjacent-violator algorithm is adapted to solve for the constrained nonparametric maximum likelihood estimator under the alternative hypothesis. By measuring the discrepancy between this estimator and the semiparametric maximum likelihood estimator under the null hypothesis, we develop a new Kolmogorov-Smirnov-type statistic to test the goodness-of-fit for logistic regression models with case-control data. A bootstrap resampling procedure is suggested to approximate the p $$ p $$ -value of the proposed test. Simulation results show that the type I error of the proposed test is well controlled and the power improvement is substantial in many cases. Three real data applications are also included for illustration.

Effectiveness of masturbation Premature ejaculation diagnostic tool in diagnosing premature ejaculation in men without vaginal intercourse over the past six months: an observational study.

BACKGROUND: Premature ejaculation (PE) is a common concern for men and their partners, but current diagnostic tools mainly focus on men who have vaginal intercourse. The Masturbation Premature Ejaculation Diagnostic Tool (MPEDT) was created to address this gap, but its effectiveness for men who only engage in self-masturbation has not been studied. This research aimed to determine the frequency of self-reported PE patients who do not have vaginal intercourse and to evaluate the diagnostic accuracy of MPEDT for this group. METHOD: The study involved 446 male patients aged 18 to 40, and 40 non-self-reported-PE and non-vaginal-intercourse healthy males. Participants completed the MPEDT questionnaire and reported their recent six-months sex frequency. RESULT: Among the patients seeking treatment for PE, 21.75% had not engaged in vaginal intercourse in the past six months. Of the PE patients who completed the MPEDT questionnaire (86 patients), 90.7% were diagnosed with masturbatory-PE (MPE). The sensitivity for self-reported MPE and specificity for self-reported non-MPE were 93.02% and 72.5%, respectively. DISCUSSION: For patients who have not had vaginal intercourse in the past six months but engage in masturbation and seek treatment for PE, the PEDT may not effectively assess their ejaculatory function. The MPEDT, however, can effectively evaluate their ejaculatory function. This study also emphasizes the need for diagnostic tools tailored to this population.

Efficacy and safety of PDE5 inhibitors in middle-aged and old patients with and without hypogonadism.

PURPOSE: Although several reviews have evaluated the use of PDE5 inhibitors (PDE5i) for treating erectile dysfunction (ED), their specific use in middle-aged and old patients has not been fully evaluated. Given that elderly patients with ED often have a complex combination of systemic and sexual health risk factors, the safety and efficacy of PDE5i in such a context are hereby reviewed. MATERIALS AND METHODS: A thorough examination of existing literature has been conducted on PubMed. RESULTS: PDE5i has good safety and efficacy, but the situation is more complex for patients with hypogonadism than those with normal testosterone levels, with reduced responsiveness to PDE5i. In this case, combination therapy with testosterone is recommended, safe and effective. CONCLUSIONS: Eliminating or reducing reversible risk factors and controlling or slowing the development of irreversible factors is an important foundation for using PDE5i to treat ED in all patients, especially middle-aged and elderly ones.

Study on the mechanism of miR-7562 regulating ATG5 and ATG12 genes in Penaeus monodon under Vibrio harveyi infection.

MicroRNAs (miRNAs) play a fundamental role in the post-transcriptional regulation of genes and are pivotal in modulating immune responses in marine species, particularly during pathogen assaults. This study focused on the function of miR-7562 and its regulatory effects on autophagy against Vibrio harveyi infection in the black tiger shrimp (Penaeus monodon), an economically important aquatic species. We successfully cloned and characterized two essential autophagy-related genes (ATGs) from P. monodon, PmATG5 and PmATG12, and then identified the miRNAs potentially involved in co-regulating these genes, which were notably miR-7562, miR-8485, and miR-278. Subsequent bacterial challenge experiments and dual-luciferase reporter assays identified miR-7562 as the principal regulator of both genes, particularly by targeting the 3'UTR of each gene. By manipulating the in vivo levels of miR-7562 using mimics and antagomirs, we found significant differences in the expression of PmATG5 and PmATG12, which corresponded to alterations in autophagic activity. Notably, miR-7562 overexpression resulted in the downregulation of PmATG5 and PmATG12, leading to a subdued autophagic response. Conversely, miR-7562 knockdown elevated the expression levels of these genes, thereby enhancing autophagic activity. Our findings further revealed that during V. harveyi infection, miR-7562 continued to influence the autophagic pathway by specifically targeting the ATG5-ATG12 complex. This research not only sheds light on the miRNA-dependent mechanisms governing autophagic immunity in shrimp but also proposes miR-7562 as a promising target for therapeutic strategies intended to strengthen disease resistance within the crustacean aquaculture industry.

Cellular localization and potential ligands of a novel scavenger receptor class B/CD36 protein homolog (Pt-SRB2) identified in the marine crab, Portunustrituberculatus.

The scavenger receptor class B family proteins (SRB) are multiligand membrane receptor proteins. Herein, a novel SRB homolog (Pt-SRB2) was identified in Portunus trituberculatus. The open reading frame of Pt-SRB2 was predicted to encode 520 amino acid residues comprising a typical CD36 domain. Phylogenetic analysis showed that Pt-SRB2 distinctly clustered with the SRB homologs of most crustaceans and Drosophila but was separate from all vertebrate CD36/SRB. Semi-quantitative and Real-time quantitative PCR revealed that the abundance of Pt-SRB2 transcripts was the highest in hepatopancreas than in other tested tissues. Overexpressed Pt-SRB2 was distributed primarily in the cell membrane and cytoplasm of HEK293T or Drosophila Schneider 2 cells. In crab hemocytes, Pt-SRB2 was distributed primarily in the cell membrane by immunofluorescence staining. In addition, the immunofluorescence staining showed that green fluorescence signals were mainly located in the inner lumen membrane of the hepatopancreatic tubules. Moreover, solid-phase enzyme-linked immunosorbent assay revealed that rPt-SRB2-L exhibited relative high affinity with lipopolysaccharides, and relative moderate binding affinity with lipoteichoic acid or peptidoglycan. Of note, rPt-SRB2-L showed high binding affinity with eicosapentaenoic acid among a series of long-chain polyunsaturated fatty acids. Taken together, this study provided valuable data for understanding the functions of the crab CD36/SRB.

The Association Between Atypical Masturbation and Male Sexual Dysfunction: A Study Based on Men in Heterosexual Relationships.

We aimed to establish the prevalence of atypical masturbation in the general population and explore the association between atypical masturbation and male sexual dysfunction in heterosexual males. Atypical masturbation refers to stimulation significantly distinct from that encountered during partnered sexual activity. We posted questionnaires that contained the abridged International Index of Erectile Function (IIEF-6) and the premature ejaculation diagnostic tool on social media in China. We collected 2743 valid questionnaires from December 9, 2020, to April 18, 2021. We found that the prevalence of atypical masturbation in the general population was 10.97%. Men with atypical masturbation had lower IIEF-6 scores and higher rates of erectile dysfunction (ED) than men with typical masturbation. The prevalence of premature ejaculation and estimated intravaginal ejaculatory latency time were not significantly different among men with different patterns of masturbation. Our study demonstrated that atypical masturbation is associated with ED, and a clinician dealing with sexual issues should inquire more fully about masturbation patterns than has been done to date.

Gene variants and clinical characteristics of children with sitosterolemia.

OBJECTIVE: To enhance the detection, management and monitoring of Chinese children afflicted with sitosterolemia by examining the physical characteristics and genetic makeup of pediatric patients. METHODS: In this group, 26 children were diagnosed with sitosterolemia, 24 of whom underwent genetic analysis. Patient family medical history, physical symptoms, tests for liver function, lipid levels, standard blood tests, phytosterol levels, cardiac/carotid artery ultrasounds, fundus examinations, and treatment were collected. RESULTS: The majority (19, 73.1%) of the 26 patients exhibited xanthomas as the most prevalent manifestation. The second most common symptoms were joint pain (7, 26.9%) and stunted growth (4, 15.4%). Among the 24 (92.3%) patients whose genetics were analyzed, 16 (66.7%) harbored ABCG5 variants (type 2 sitosterolemia), and nearly one-third (8, 33.3%) harbored ABCG8 variants (type 1 sitosterolemia). Additionally, the most common pathogenic ABCG5 variant was c.1166G > A (p.Arg389His), which was found in 10 patients (66.7%). Further analysis did not indicate any significant differences in pathological traits among those carrying ABCG5 and ABCG8 variations (P > 0.05). Interestingly, there was a greater abundance of nonsense variations in ABCG5 than in ABCG8 (P = 0.09), and a greater frequency of splicing variations in ABCG8 than ABCG5 (P = 0.01). Following a change in diet or a combination of ezetimibe, the levels of cholesterol and low-density lipoprotein were markedly decreased compared to the levels reported before treatment. CONCLUSION: Sitosterolemia should be considered for individuals presenting with xanthomas and increased cholesterol levels. Phytosterol testing and genetic analysis are important for early detection. Managing one's diet and taking ezetimibe can well control blood lipids.

Genome-Wide Analysis of Aquaporins Gene Family in Populus euphratica and Its Expression Patterns in Response to Drought, Salt Stress, and Phytohormones.

Aquaporins (AQPs) play an essential role in membrane water transport during plant responses to water stresses centered on conventional upstream signals. Phytohormones (PHs) regulate plant growth and yield, working with transcription factors to help plants withstand environmental challenges and regulate physiological and chemical processes. The AQP gene family is important, so researchers have studied its function and regulatory system in numerous species. Yet, there is a critical gap the understanding of many of their molecular features, thus our full knowledge of AQPs is far-off. In this study, we undertook a broad examination of the AQP family gene in Populus euphratica via bioinformatics tools and analyzed the expression patterns of certain members in response to drought, salt, and hormone stress. A total of 22 AQP genes were examined in P. euphratica, and were categorized into four main groups, including TIPs, PIPs, SIPs, and NIPs based on phylogenetic analysis. Comparable exon-intron gene structures were found by gene structure examination, and similarities in motif number and pattern within the same subgroup was determined by motif analysis. The PeuAQP gene family has numerous duplications, and there is a distinct disparity in how the members of the PeuAQP family react to post-translational modifications. Abiotic stress and hormone responses may be mediated by AQPs, as indicated by the abundance of stress response elements found in 22 AQP genes, as revealed by the promoter's cis-elements prediction. Expression pattern analysis reveals that selected six AQP genes from the PIP subgroup were all expressed in the leaves, stem, and roots with varying expression levels. Moreover, qRT-PCR analysis discovered that the majority of the selected AQP members were up- or down-regulated in response to hormone treatment and abiotic stress. Remarkably, PeuAQP14 and PeuAQP15 appeared to be highly responsive to drought stress and PeuAQP15 exhibited a high response to salt stress. The foliar application of the phytohormones (SA, IAA, GA3, MeJA, and ABA) were found to either activate or inhibit PeuAQP, suggesting that they may mitigate the effects of water shortage of poplar water stress. The present work enhances our knowledge of the practical roles of AQPs in stress reactions and offers fundamental information for the AQP genes in poplar species. It also highlights a direction for producing new varieties of poplar species with drought, salt, and hormone tolerance and holds substantial scientific and ecological importance, offering a potential contribution to the conservation of poplar species in arid regions.

The dominant influencing factors of desertification and ecological risk changes in Qinghai Area of Qilian Mountains National Park: Climate change or human activity?

Transitional features of desert environments partially determine the risks associated with ecosystems. Influenced by climate change and human activities, the variability and uncertainty of desertification levels and ecological risks in the Qinghai Area of Qilian Mountain National Park (QMNPQA) has become increasingly prominent. As a critical ecological barrier in northwest China, monitoring desertification dynamics and ecological risks is crucial for maintaining ecosystem stability. This study identifies the optimal monitoring model from four constructed desertification monitoring models and analyzes spatiotemporal changes in desertification. The spatial and temporal changes in ecological risks and their primary driving factors were analyzed using methods such as raster overlay calculation, geographic detector, cloud model, and trend analysis. The main conclusions are as follows: The desertification feature spatial model based on GNDVI-Albedo demonstrates better applicability in the study area, with an inversion accuracy of 81.24%. The levels of desertification and ecological risks in QMNPQA exhibit significant spatial heterogeneity, with a gradual decrease observed from northwest to southeast. From 2000 to 2020, there is an overall decreasing trend in desertification levels and ecological risks, with the decreasing trend area accounting for 89.82% and 85.71% respectively, mainly concentrated in the southeastern and northwestern parts of the study area. The proportion of areas with increasing trends is 4.49% and 7.05% respectively, scattered in patches in the central and southern edge areas. Surface temperature (ST), Digital Elevation Map (DEM), and Green normalized difference vegetation index (GNDVI) are the most influential factors determining the spatial distribution of ecological risks in QMNPQA. The effects of management and climatic factors on ecological risks demonstrate a significant antagonistic effect, highlighting the positive contributions of human activities in mitigating the driving effects of climate change on ecological risks. The research results can provide reference for desertification prevention and ecological quality improvement in QMNPQA.

Design, Synthesis, and Anti-Leukemic Evaluation of a Series of Dianilinopyrimidines by Regulating the Ras/Raf/MEK/ERK and STAT3/c-Myc Pathways.

Although the long-term survival rate for leukemia has made significant progress over the years with the development of chemotherapeutics, patients still suffer from relapse, leading to an unsatisfactory outcome. To discover the new effective anti-leukemia compounds, we synthesized a series of dianilinopyrimidines and evaluated the anti-leukemia activities of those compounds by using leukemia cell lines (HEL, Jurkat, and K562). The results showed that the dianilinopyrimidine analog H-120 predominantly displayed the highest cytotoxic potential in HEL cells. It remarkably induced apoptosis of HEL cells by activating the apoptosis-related proteins (cleaved caspase-3, cleaved caspase-9 and cleaved poly ADP-ribose polymerase (PARP)), increasing apoptosis protein Bad expression, and decreasing the expression of anti-apoptotic proteins (Bcl-2 and Bcl-xL). Furthermore, it induced cell cycle arrest in G2/M; concomitantly, we observed the activation of p53 and a reduction in phosphorylated cell division cycle 25C (p-CDC25C) / Cyclin B1 levels in treated cells. Additionally, the mechanism study revealed that H-120 decreased these phosphorylated signal transducers and activators of transcription 3, rat sarcoma, phosphorylated cellular RAF proto-oncogene serine / threonine kinase, phosphorylated mitogen-activated protein kinase kinase, phosphorylated extracellular signal-regulated kinase, and cellular myelocytomatosis oncogene (p-STAT3, Ras, p-C-Raf, p-MEK, p-MRK, and c-Myc) protein levels in HEL cells. Using the cytoplasmic and nuclear proteins isolation assay, we found for the first time that H-120 can inhibit the activation of STAT3 and c-Myc and block STAT3 phosphorylation and dimerization. Moreover, H-120 treatment effectively inhibited the disease progression of erythroleukemia mice by promoting erythroid differentiation into the maturation of erythrocytes and activating the immune cells. Significantly, H-120 also improved liver function in erythroleukemia mice. Therefore, H-120 may be a potential chemotherapeutic drug for leukemia patients.

[Analysis of clinical features of 193 Chinese patients with McCune-Albright syndrome through a literature review].

OBJECTIVE: To retrospectively analyze the clinical characteristics of 193 Chinese patients with McCune-Albright syndrome (MAS). METHODS: By using keywords "McCune-Albright syndrome", "Albright syndrome", or " fibrous dysplasia " as the search terms, 193 cases of MAS reported in China from January 1990 to November 2022 from the Wanfang data, CNKI, VIP, PubMed, and Embase databases were obtained, and their clinical data was retrospectively analyzed. Intergroup comparisons were carried out by using t test, Mann-Whitney U test, and X2 test. RESULTS: The 193 MAS patients had included 42 males and 151 females, with the median first-visit age of females being younger than males. The typical triad group had accounted for 46.1% of patients, and the middle first-visit and diagnosis age was younger than the atypical group. The primary reason for first-visit in males of MAS was fibrous dysplasia (FD), whilst that in females of MAS was peripheral precocious puberty (PPP). FD has occurred in 84.5% of the patients, with an average age of onset age being 6.1 years old, and 90% was ≤ 16 years of age. Endocrine hyperfunction was found in 79.3% of the patients, with a higher proportion in females compared with males (P < 0.05). Pituitary involvement was seen in 21.8% of the patients, and the incidence of craniofacial FD and cranial nerve compression was significantly higher in those with elevated growth hormone (GH) than without (P < 0.05). Café-au-Lait Spots were noted in 86.5% of the patients, and 28.3% (28/99) had located on the different side of FD. CONCLUSION: Most MAS patients had atypical manifestations and multi-systemic involvement. It is more common and occurs earlier in females. The most common reasons for initial diagnosis in male and female patients were FD and PPP, respectively. Patients with elevated GH should be examined for cranial nerve compression.

CAD/CAM design and 3D printing of a personalised rapid palatal expander for maxillary transverse deficiency.

Bone -borne ra pid ma xilla ry expansion appliances can achieve skeletal expansion while avoiding the undesirable dental side effec ts caused by a conventional rapid palatal expansion appliance. Typically, t hese (bone-bo rne appliances) included prefabricated devices, which can have limitations such as inadequate palatal adaptation leading to anch orage los s. In addit ion, a s bone thickness is not accounted for, prefabricated expanders cannot ensure the primary stability of the mini-implants. These disadvantages can be overcom e by customisation. This repor t aims to describe the digital design and three-dimensional printing workflow for constructing a personali sed M iniscrewassisted rapid palatal expansion (pMARPE) and present a case depicting its application in a 27-year-old female with 5.0 mm t ransverse discrepancy b etween the maxilla and the mandible. The result demonstrated that the pMARPE could be manufactured without the need for conventional impre s sion or laborator y p rocedures and effec tively e xpanded the palate of an ad ult pat ient with maxillar y transverse deficiency.

[Pharmacological therapies for height improvement in pubertal children with short stature]. / 青春期矮身材儿童身高改善的药物治疗.

Short stature in puberty significantly affects the physical and mental health of adolescents. The continuous acceleration of skeletal maturation, caused by sex hormones during puberty, limits the time available for growth and poses a considerable challenge for the treatment of short stature. To date, there is still no standardized treatment protocol for this disorder. However, puberty is the last period to improve the final adult height. Currently, commonly used pharmacological treatments in clinical settings include recombinant human growth hormone, gonadotropin-releasing hormone analogs, and third-generation aromatase inhibitors. In recent years, personalized treatment aiming to improve the final adult height has become a key focus in clinical practice. This article provides a comprehensive summary of research on pharmacological therapies for height improvement in pubertal children with short stature, offering valuable insights for healthcare professionals.