SP1 undergoes phase separation and activates RGS20 expression through super-enhancers to promote lung adenocarcinoma progression.

Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide, but the underlying molecular mechanisms remain largely unclear. The transcription factor (TF) specificity protein 1 (SP1) plays a crucial role in the development of various cancers, including LUAD. Recent studies have indicated that master TFs may form phase-separated macromolecular condensates to promote super-enhancer (SE) assembly and oncogene expression. In this study, we demonstrated that SP1 undergoes phase separation and that its zinc finger 3 in the DNA-binding domain is essential for this process. Through Cleavage Under Targets & Release Using Nuclease (CUT&RUN) using antibodies against SP1 and H3K27ac, we found a significant correlation between SP1 enrichment and SE elements, identified the regulator of the G protein signaling 20 (RGS20) gene as the most likely target regulated by SP1 through SE mechanisms, and verified this finding using different approaches. The oncogenic activity of SP1 relies on its phase separation ability and RGS20 gene activation, which can be abolished by glycogen synthase kinase J4 (GSK-J4), a demethylase inhibitor. Together, our findings provide evidence that SP1 regulates its target oncogene expression through phase separation and SE mechanisms, thereby promoting LUAD cell progression. This study also revealed an innovative target for LUAD therapies through intervening in SP1-mediated SE formation.

Experimental study on monitoring microwave ablation efficacy by real-time shear wave elastography in ex vivo porcine brain.

Objective: Glioma constitutes the most common primary malignant tumor in the central nervous system. In recent years, microwave ablation (MWA) was expected to be applied in the minimally invasive treatment of brain tumors. This study aims to evaluate the feasibility and accuracy of microwave ablation in ex vivo brain tissue by Shear Wave Elastography (SWE) to explore the application value of real-time SWE in monitoring the process of MWA of brain tissue.Methods: Thirty ex vivo brain tissues were treated with different microwave power and ablation duration. The morphologic and microscopic changes of MWA tissues were observed, and the diameter of the ablation areas was measured. In this experiment, SWE is used to quantitatively evaluate brain tissue's degree of thermal injury immediately after ablation.Results: This study It is found that the ablation range measured by SWE after ablation is in good consistency with the pathological range [ICCSWEL1-L1 = 0.975(95% CI:0.959 - 0.985), ICCSWEL2-L2 = 0.887(95% CI:0.779 - 0.938)]. At the same time, the SWE value after ablation is significantly higher than before (mean ± SD,9.88 ± 2.64 kPa vs.23.6 ± 13.75 kPa; p < 0.001). In this study, the SWE value of tissues in different pathological states was further analyzed by the ROC curve (AUC = 0.86), and the threshold for distinguishing normal tissue from tissue after ablation was 13.7 kPa. The accuracy of evaluating ablation tissue using SWE can reach 84.72%, providing data support for real-time quantitative observation of the ablation range.Conclusion: In conclusion the accurate visualization and real-time evaluation of the organizational change range of the MWA process can be realized by real-time SWE.

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The global pandemic of coronavirus disease 2019 (COVID-19) poses a serious threat to human health, leading to a relatively high mortality in patients with severe or critical conditions in particular. Hyperglycemia is one of the high-risk factors for poor prognosis in these patients. Patients with COVID-19 are more likely to develop hyperglycemia, regardless of whether there is a previous history of diabetes mellitus. Glucocorticoid therapy is an important part of the anti-inflammatory regimen for COVID-19. However, the use of glucocorticoid significantly increases the occurrence of hyperglycemic events in COVID-19 patients, ultimately leading to poor prognosis. Timely monitoring of blood glucose and early intervention for hyperglycemia contribute to the improvement in the outcome of COVID-19 patients. In this paper, we comprehensively reviewed the potential mechanisms of COVID-19 and concomitant hyperglycemia. We reviewed the latest findings on the blood glucose management strategies for COVID-19 patients with concomitant hyperglycemia, aiming to optimize the management of hyperglycemia in COVID-19 patients and improve the outcome of the disease.

TCN1 Expression Is Increased in Asthma.

INTRODUCTION: Asthma is a chronic disease that affects populations worldwide. The purpose of this study was to investigate the expression of TCN1 in sputum and its correlation with inflammation and lung function in asthma. METHODS: We recruited 141 subjects, detected TCN1 mRNA level by quantitative reverse transcription polymerase chain reaction, detected TCN1 protein expression by Western blot, detected TCN1 protein level by enzyme-linked immunosorbent assay, and analyzed the correlation between TCN1 and fraction of exhaled nitric oxide (FeNO), IgE, EOS%, lung functions, and some Th2 cytokines. The diagnostic value of TCN1 was evaluated by receiver operating characteristics curve. The expression of TCN1 was further confirmed by human bronchial epithelial cell in vitro. RESULTS: Compared with the health group, the expression of TCN1 in induced sputum cells increased in asthma group and was correlated with FeNO, IgE, and EOS%. TCN1 level was also elevated in the induced sputum supernatant of asthma patients. The protein level of TCN1 in induced sputum supernatant was correlated with FeNO, IgE and PC-20, forced expiratory volume in the first second (FEV1)%pred, FEV1/FVC, and some cytokines (IL-4, IL-5, IL-10, IL-13, MUC5AC). TCN1 was also differentially expressed in patients with different severity of asthma. Four weeks after ICS treatment, the expression of TCN1 in induced sputum supernatant increased. In vitro, the protein level of TCN1 in human bronchial epithelial cells' supernatant increased after stimulated with IL-4 and IL-13. CONCLUSION: The expression of TCN1 was increased in asthma patients' sputum, and was positively correlated with some inflammatory markers, negatively correlated with lung function. TCN1 may be used as a potential biomarker for the diagnosis and treatment of asthma.

Differential Circular RNA Expression Profiles in Induced Sputum of Patients with Asthma.

INTRODUCTION: circRNA played a role in a variety of diseases. This paper aimed to explore the differentially expressed circRNA in induced sputum cells of asthma patients, so as to provide new potential biomarkers and new ideas for the study of asthma. METHODS: All subjects were from the First Affiliated Hospital of Sun Yat-sen University. Differentially expressed circRNAs of asthma patients were screened by high-throughput sequencing. qRT-PCR was used to verify the expression of differential circRNAs. The association between circRNA and asthma was explored by analyzing the correlation between circRNA and clinical data and some cytokines of asthma patients. The possible ceRNA network was analyzed and predicted by online software, and the expression of each molecule in the network was preliminary verified by qRT-PCR in induced sputum cells and 16HBE cell. RESULTS: We screened a total of 49 circRNAs differentially expressed in asthma patients (including 12 circRNAs with elevated expression and 37 circRNAs with decreased expression), among which has_circSORT1 and has_circSERPINB1 were significantly elevated. Correlation analysis showed that has_circSORT1 was correlated with FeNO, EOS%, IL-17A, IFN-γ, and PC20, and has_circSERPINB1 was correlated with IL-6, IL-17A, IFN-γ, FEV1%, and FVC%. The possible existence of has_circSORT1/has-miR-185-3p/ZNFX1, a ceRNA regulatory network, in induced sputum cells of asthma patients was hypothesized by online software prediction and qRT-PCR in sputum cells and 16HBE. CONCLUSION: Differentially expressed circRNAs existed in induced sputum cells of asthma patients, among which has_circSORT1 and has_circSERPINB1 were significantly upregulated and may be involved in the process of asthma disease, which could be expected to be a potential biomarker for asthma diagnosis. In addition, a ceRNA regulatory network, has_circSORT1/has-miR-185-3p/ZNFX1, may exist in asthma.

Quantitative assessment of thenar to evaluate hand function after stroke by Bayes discriminant.

BACKGROUND: The incidence rate of stroke or cerebrovascular accidents ranks first in China. More than 85% of stroke patients have residual upper limb motor dysfunction, especially hand dysfunction. Normalizing the rehabilitation evaluation process and standard quantitative evaluation method is a complex and key point in rehabilitation therapy. The study aimed to establish a function model based on the Bayes discriminant by measuring the thenar stiffness with shear wave elastography (SWE) to quantitatively evaluate the hand motor function of hemiplegic patients after stroke. METHODS: This study collected 60 patients diagnosed with hemiplegia after stroke from October 2021 to October 2022. Therapists used the Brunnstrom assessment (BA)scale to divide the patients into the stage. All the patients underwent the measurement of SWE examination of abductor pollicis brevis (APB), opponens pollicis (OP), flexor pollicis long tendon (FPLT), and flexor pollicis brevis (FPB) by two sonographers. The SWE change rate of four parts of the thenar area was calculated prospectively with the non-hemiplegic side as the reference, the function equation was established by the Bayes discriminant method, and the evaluation model was fitted according to the acquired training set data. Lastly, the model was verified by self-validation, cross-validation, and external data validation methods. The classification performance was evaluated regarding the area under the ROC curve (AUC), sensitivity, and specificity. RESULTS: The median SWE values of the hemiplegic side of patients were lower than those of the non-hemiplegic side. According to the BA stage and SWER of APB, OP, FPLT, and FPB, our study established the Bayes discriminative model and validated it via self-validation and cross-validation methods. Then, the discriminant equation was used to validate 18 patients prospectively, the diagnostic coincidence rate was about 78.8%, and the misjudgment rate was approximately 21.2%. The AUC of the discriminant model for diagnosing BA stage I-VI was 0.928(95% CI: 0.839-1.0),0.858(95% CI: 0.748-0.969),1.0(95% CI: 1.0-1.0), 0.777(95% CI: 0.599-0.954),0.785(95% CI: 0.593-0.977) and 0.985(95% CI: 0.959-1.0), respectively. CONCLUSION: This Bayes discriminant model built by measuring thenar stiffness was of diagnostic value and can provide an objective basis for evaluating clinical rehabilitation.

Study on the correlation between cardiac function indices measured by velocity vector imaging and disease severity in patients with Parkinson disease.

AIM: This study aimed to evaluate cardiac function, particularly left ventricular systolic function, in patients with Parkinson disease (PD) using velocity vector imaging (VVI), and to determine whether a correlation exists between left ventricular global systolic function and PD severity. METHODS: A case-control study design was used to select 56 PD patients and 30 healthy controls from January 2019 to December 2019. The characteristics of age, sex, BMI and course of disease were collected. The Hoehn-Yahr (H-Y) score was collected to record the grading of PD. The left ventricular systolic function of all patients was evaluated by variable vapor injection (VVI). The left ventricular systolic function was compared between the case group and the control group, and the correlation between cardiac dysfunction and the severity of PD symptoms was assessed using the modified H-Y scale. RESULTS: Compared with control group, left ventricular global systolic function18.22 (17.08, 19.12) vs 18.88 (18.12, 20.01) was lower in PD patients as indicated by left ventricular global longitudinal strain (GLS), and the difference was statistically significant (P = 0.039). Additionally, H-Y scores (r = -0.404) and PD duration(r = -0.323) were significantly correlated with reduced left ventricular ejection fraction (P < 0.01), GLS (P < 0.001), left ventricular global radial strain (GRS; P < 0.001), and left ventricular global circumferential strain (GCS; P < 0.001), along with their associated peak strain rates (GLSr, GRSr, and GCSr; P < 0.001). CONCLUSION: Subclinical left ventricular global systolic dysfunction in patients with PD can be detected using VVI, and reduced left ventricular systolic function correlates with the modified H-Y score and duration of the disease.

Analysis between macrophage-related genes with prognosis and tumor microenvironment in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a highly morbid and fatal disease that exhibits individualized differences in prognosis and drug efficacy. Therefore, understanding the molecular mechanism of the occurrence and progression of lung cancer can improve early diagnosis, treatment and prognosis. Macrophages are a crucial component of the tumor microenvironment (TME) due to their high plasticity and heterogeneity. They play a multifaceted role in tumor initiation and progression. In order to elucidate the pathogenesis of tumor-associated macrophages (TAMs) related genes in NSCLC, transcriptomic sequencing, univariate COX regression, LASSO regression and multivariate COX regression analyses were conducted to identify the 11 genes that have the most significant association with prognosis. These genes include FCRLA, LDHA, LMOD3, MAP3K8, NT5E, PDGFB, S100P, SFXN1, TDRD1, TFAP2A and TUBB6. The risk score (RS) was computed, and all samples were split into high- and low-risk groups based on the median RS. The correlation of RS and 11 genes with macrophages was verified by the CIBERSORT deconvolution algorithm. These above results suggest that the risk score developed in this study can be utilized for predicting patients' prognosis and evaluating their immune infiltration status. This study can serve as a guide for subsequent tumor immunotherapy and gene targeting therapy.

Reshaping the murine immunoglobulin heavy chain repertoire with bovine DH genes.

Having a limited number of VH segments, cattle rely on uniquely long DH gene segments to generate CDRH3 length variation (3-70 aa) far greater than that in humans or mice. Bovine antibodies with ultralong CDRH3s (>50 aa) possess unusual structures and abilities to bind to special antigens. In this study, we replaced most murine endogenous DH segments with bovine DH genes, generating a mouse line termed B-DH. The use of bovine DH genes significantly increased the length variation of CDRH3 and consequently the Ig heavy chain repertoire in B-DH mice. However, no ultralong CDRH3 was observed in B-DH mice, suggesting that other factors, in addition to long DH genes, are also involved in the formation of ultralong CDRH3. The B-DH mice mounted a normal humoral immune response to various antigens, although the B-cell developmental paradigm was obviously altered compared with wild-type mice. Additionally, B-DH mice are not predisposed to the generation of autoantibodies despite the interspecies DH gene replacement. The B-DH mice reported in this study provide a unique model to answer basic questions regarding the synergistic evolution of DH and VH genes, VDJ recombination and BCR selection in B-cell development.

Increased expression of IL1-RL1 is associated with type 2 and type 1 immune pathways in asthma.

BACKGROUND: Asthma is a common chronic airway disease in the world. The purpose of this study was to explore the expression of IL1-RL1 in sputum and its correlation with Th1 and Th2 cytokines in asthma. METHODS: We recruited 132 subjects, detected IL1-RL1 protein level in sputum supernatant by ELISA, and analyzed the correlation between the expression level of IL1-RL1 and fraction of exhaled nitric oxide (FeNO), IgE, peripheral blood eosinophil count (EOS#), and Th2 cytokines (IL-4, IL-5, IL-10, IL-13, IL-33 and TSLP) and Th1 cytokines (IFN-γ, IL-2, IL-8). The diagnostic value of IL1-RL1 was evaluated by ROC curve. The expression of IL1-RL1 was further confirmed by BEAS-2B cell in vitro. RESULTS: Compared with the healthy control group, the expression of IL1-RL1 in sputum supernatant, sputum cells and serum of patients with asthma increased. The AUC of ROC curve of IL1-RL1 in sputum supernatant and serum were 0.6840 (p = 0.0034), and 0.7009 (p = 0.0233), respectively. IL1-RL1 was positively correlated with FeNO, IgE, EOS#, Th2 cytokines (IL-4, IL-5, IL-10, IL-13, IL-33 and TSLP) and Th1 cytokines (IFN-γ, IL-2, IL-8) in induced sputum supernatant. Four weeks after inhaled glucocorticoids (ICS) treatment, the expression of IL1-RL1 in sputum supernatant and serum was increased. In vitro, the expression of IL1-RL1 in BEAS-2B was increased after stimulated by IL-4 or IL-13 for 24 h. CONCLUSION: The expression of IL1-RL1 in sputum supernatant, sputum cells and serum of patients with asthma was increased, and was positively correlated with some inflammatory markers in patients with asthma. IL1-RL1 may be used as a potential biomarker for the diagnosis and treatment of asthma.

Laser speckle contrast imaging for blood flow monitoring in predicting outcomes after cerebral ischemia-reperfusion injury in mice.

BACKGROUND: In the treatment of ischemic cerebral stroke (ICS), most conventional treatments, including carotid endarterectomy and carotid artery stenting, may cause cerebral ischemia-reperfusion injury (CIRI). For treated ICS patients, changes in cerebral blood flow are directly related to brain function. At present, computed tomography perfusion, dynamic susceptibility contrast-enhanced perfusion weighted imaging and magnetic resonance arterial spin labeling perfusion imaging are used to monitor cerebral blood flow, but they still have some limitations. Our study aimed to monitor the changes in cerebral cortical blood flow by laser speckle contrast imaging (LSCI) in CIRI model mice and to propose a new method for predicting outcomes after CIRI. C57BL/6 N mice were used to establish a mouse CIRI model based on a modified thread-occlusion method and divided into a good outcome group and a poor outcome group according to survival within 7 days. The cerebral cortical blood flow of the area supplied by the left middle cerebral artery was monitored by LSCI at baseline (before modeling), 1 h after ischemia, immediately after reperfusion and 24 h after reperfusion. Then, the brains of the mice were removed immediately and stained with hematoxylin and eosin to observe the pathological changes in brain neurons. RESULTS: The cerebral cortical blood flow in the poor outcome group was obviously reduced compared with that less in the good outcome group at 24 h after reperfusion (180.8 ± 20.9 vs. 113.9 ± 6.4, p = 0.001), and at 24 h after reperfusion, the cerebral cortical blood flow was negatively correlated with the severity of brain tissue injury (p = - 0.710, p = 0.010). CONCLUSIONS: LSCI can monitor the changes in cerebral cortical blood flow during CIRI in mice and could be used as a feasible method for predicting outcomes after CIRI in mice.

Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia.

To study the mechanisms of relapse in acute lymphoblastic leukemia (ALL), we performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients. Relapse-specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response. Their prevalence was 17% in very early relapse (<9 months from diagnosis), 65% in early relapse (9-36 months), and 32% in late relapse (>36 months) groups. Convergent evolution, in which multiple subclones harbor mutations in the same drug resistance gene, was observed in 6 relapses and confirmed by single-cell sequencing in 1 case. Mathematical modeling and mutational signature analysis indicated that early relapse resistance acquisition was frequently a 2-step process in which a persistent clone survived initial therapy and later acquired bona fide resistance mutations during therapy. In contrast, very early relapses arose from preexisting resistant clone(s). Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2540 pan-cancer diagnosis samples and 129 non-ALL relapses. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53. These results suggest that chemotherapy-induced drug resistance mutations facilitate a subset of pediatric ALL relapses.

Elevated CEACAM5 Levels in Patients with Asthma.

INTRODUCTION: Asthma is a common chronic respiratory disease. This study aimed to explore the expression level of carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) in induced sputum supernatant, induced sputum cells, and serum of asthma patients. METHODS: The protein levels of CEACAM5 in induced sputum supernatant and serum were detected by enzyme-linked immunosorbent assay. The expression of CEACAM5 in induced sputum cells was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). We analyzed the correlations between CEACAM5 expression and the clinical characteristics (FeNO and IgE) of asthma. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of CEACAM5 in asthma. The expression level of CEACAM5 in 16HBE and BEAS-2B cells was detected by qRT-PCR. RESULTS: The expression of CEACAM5 in induced sputum supernatant, induced sputum cells, and serum of asthma patients was significantly upregulated. Asthma patients with high CEACAM5 expression in induced sputum supernatant had higher levels of FeNO, IgE, and IL-13. The expression levels of CEACAM5 in induced sputum supernatant and induced sputum cells were positively correlated with FeNO and IgE. The ROC curve showed that CEACAM5 had a good diagnostic value in asthma. CEACAM5 expression was upregulated in BEAS-2B and 16HBE cells after IL-4 or IL-13 stimulation for 48 h. CONCLUSION: The expression levels of CEACAM5 in induced sputum supernatant, induced sputum cells, and serum of asthma patients were significantly increased. CEACAM5 may be involved in eosinophilic inflammation of asthma and may be used as a diagnostic biomarker and therapeutic target of asthma.

Elevated CXCL14 in Induced Sputum Was Associated with Eosinophilic Inflammation and Airway Obstruction in Patients with Asthma.

INTRODUCTION: CXCL14 involved in inflammatory processes was upregulated in the asthma expression profile datasets in our pilot study. However, the expression of CXCL14 in induced sputum and its potential clinical role in asthma were poorly reported. OBJECTIVE: We sought to detect CXCL14 expression in airway epithelium and induced sputum cells of asthma and explore its potential clinical implications. METHODS: The expression of CXCL14 in asthma was analyzed using R software based on multiple microarray datasets, including GSE43696, GSE63142, GSE67940, and GSE76262. Subsequent verification of the CXCL14 expression pattern in induced sputum and bronchial epithelium cells was performed by qRT-PCR and ELISA. Besides, the correlations between CXCL14 and eosinophilic inflammation indicators (FeNO, EOS#, and IgE), Th2 signature genes (SERPINB2, POSTN, and CLCA1), inflammatory cytokines (IL-4, IL-5, IL-10, IL-13, IL-25, IL-33, TSLP, IL-8, IL-17A, IFN-γ, and IL-2), and airway obstruction indicators (pulmonary function and mucin secretion) were further explored. RESULTS: The expression of CXCL14 in epithelium and sputum cells was upregulated in asthma and positively correlated with clinical eosinophilic indicators. The protein levels of CXCL14 were positively associated with Th2 signature genes (SERPINB2, POSTN, and CLCA1) and Th2 cytokines (IL-4, IL-5, IL-10, IL-13, IL-25, IL-33, and TSLP). Increased expression of CXCL14 was also observed in BEAS-2B cells stimulated by the cytokine IL-4. Furthermore, the expression of CXCL14 was positively correlated with MUC5AC secretion and negatively associated with pulmonary function. CONCLUSIONS: Upregulated CXCL14 in asthma was positively correlated with inflammatory indicators and negatively correlated with pulmonary function, which indicated that upregulated CXCL14 might act as a pathogenic gene through involvement in Th2 inflammation in asthma.

Exploration of induced sputum BIRC3 levels and clinical implications in asthma.

BACKGROUND: Baculoviral IAP repeat-containing 3 (BIRC3) which encodes a member of the IAP family of proteins upregulated in the asthma expression profile dataset. However, there was few research on studying the clinical implication of BIRC3 in asthma. OBJECTIVE: To validate BIRC3 expression and its clinical implications in induced sputum of asthma. METHODS: Based on the GSE76262 (118 asthma cases and 21 healthy controls) dataset, differentially expressed genes were screened using R software. Subsequently, BIRC3 mRNA and protein were clinically verified in induced sputum samples through quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Besides, the correlations between BIRC3 expression and asthmatic eosinophilic/allergic inflammation indicators (FeNO, IgE, and EOS%), pulmonary function (FEV1, FEV1% pred, FVC% pred, and FEV1/FVC), and inflammatory cytokines (IL-4, IL-5, IL-13, IL-25, IL-10, IL-33, and TSLP) were analyzed. Finally, BIRC3 mRNA was detected in human primary bronchial epithelial cells stimulated by cytokines (IL-4 or IL-13). RESULTS: BIRC3 was screened as a candidate gene in the GSE76262, which was highly expressed in asthma. Highly expressed BIRC3 was positively correlated with eosinophilic and allergic indicators, including FeNO, blood eosinophil, and serum IgE. Moreover, BIRC3 protein was positively associated with inflammation cytokines, like IL-4, IL-5, IL-13, IL-25, IL-10, IL-33, and TSLP, while negatively correlated with FEV1, FEV1%pred, FVC% pred, and FEV1/FVC. Furthermore, the expression of BIRC3 could be induced in primary bronchial epithelial cells treated by cytokines IL-4 or IL-13. CONCLUSIONS: BIRC3 significantly increased in induced sputum of asthma and positively correlated with airway eosinophilic and peripheral blood allergic inflammation, type 2 cytokines, and airway obstruction. Increased BIRC3 might be involved in the pathogenesis of asthma by affecting the eosinophilic and allergic inflammation.

FcRn is not the receptor mediating the transfer of serum IgG to colostrum in pigs.

In contrast to humans or rabbits, in which maternal IgG is transmitted to offspring prenatally via the placenta or the yolk sac, large domestic animals such as pigs, cows and sheep transmit IgG exclusively through colostrum feeding after delivery. The extremely high IgG content in colostrum is absorbed by newborns via the small intestine. Although it is widely accepted that the neonatal Fc receptor, FcRn, is the receptor mediating IgG transfer across both the placenta and small intestine, it remains unclear whether FcRn also mediates serum IgG transfer across the mammary barrier to colostrum/milk, especially in large domestic animals. In this study, using a FcRn knockout pig model generated with a CRISPR-Cas9-based approach, we clearly demonstrate that FcRn is not responsible for the IgG transfer from serum to colostrum in pigs, although like in other mammals, it is involved in IgG homeostasis and mediates IgG absorption in the small intestine of newborns.

Permanent Maxillary Odontometrics for Sex Estimation Based on a 3-Dimensional Digital Method.

BACKGROUND In the field of forensic medicine, sex estimation is a critical step in personal identification. Teeth are the hardest tissue and have high temperature resistance and corrosion resistance. In cases such as an airplane crash or the corpse of an unknown person, teeth often play a crucial role in identification. This study applied 3-dimensional technology to obtain odontometrics of permanent maxillary teeth and to examine the sexual dimorphism, finding suitable discriminant indicators to construct appropriate equations for sex estimation. MATERIAL AND METHODS A total of 204 participants (104 men and 100 women) from the Han population in Kashgar were included. Plaster models of their maxillary dentition were obtained to scan and measure through an accepted and commonly used 3-dimensional digital method. Descriptive statistics, t tests, and discriminant analyses were statistically analyzed using IBM SPSS 23.0 software. RESULTS This study showed high intra- and interexaminer reliability (intraclass correlation coefficient >0.950). There were statistically significant sex-related differences (P<0.05), with male values generally being higher for buccolingual distance, mesiodistal distance, intercanine distance, crown area, crown module, crown index, and maxillary canine index. Compared with other measurements, mesiodistal distance and crown area indicator exhibited distinct sexual dimorphism. In addition, several appropriate equations were constructed through different discriminant analyses that could be used to estimate sex in our specific population. CONCLUSIONS Three-dimensional digital technology offers a promising method for odontometry. Combining mesiodistal distance and buccolingual distance of particular teeth or using maxillary canine index in discriminant functions are acceptable auxiliary tools for sex estimation in the forensic field.

Long noncoding RNA DNAH17-AS1 promotes tumorigenesis and metastasis of non-small cell lung cancer via regulating miR-877-5p/CCNA2 pathway.

A growing number of studies have revealed that long noncoding RNAs (lncRNAs) can function as important oncogenes or tumor suppressors. This study aimed to investigate the regulatory role of lncRNA DNAH17 antisense RNA 1 (DNAH17-AS1) on non-small cell lung cancer (NSCLC) and the underlying molecular mechanisms. We observed that the expression of DNAH17-AS1 and CCNA2 mRNA was distinctly upregulated in NSCLC specimens and cell lines, while miR-877-5p expression was significantly decreased. DNAH17-AS1 could be used to distinguish NSCLC specimens from adjacent non-tumor tissues. Clinical assays revealed that high DNAH17-AS1 was associated with TNM stage, distant metastasis and shorter overall survival and disease-free survival. Functional assays indicated that knockdown of DNAH17-AS1 suppressed the proliferation, migration and invasion of H1299 and 95D cells, and promoted apoptosis. Mechanically, DNAH17-AS1 served as competing endogenous RNA (ceRNA) for miR-877-5p to positively recover CCNA2. Overall, we identified a novel NSCLC-related lncRNA, DNAH17-AS1 which may exert an oncogenic function via serving as a sponge for miR-877-5p to upregulate CCNA2. Our study presents novel insights into NSCLC progression and provided a prospective therapeutic target for NSCLC.

AICAr suppresses cell proliferation by inducing NTP and dNTP pool imbalances in acute lymphoblastic leukemia cells.

It has been shown that 5-amino-4-imidazolecarboxamide riboside (AICAr) can inhibit cell proliferation and induce apoptosis in childhood acute lymphoblastic leukemia (ALL) cells. Although AICAr could regulate cellular energy metabolism by activating AMPK, the cytotoxic mechanisms of AICAr are still unclear. Here, we knocked out TP53 or PRKAA1 gene (encoding AMPKα1) in NALM-6 and Reh cells by using the clustered regularly interspaced short palindromic repeats/Cas9 system and found that AICAr-induced proliferation inhibition was independent of AMPK activation but dependent on p53. Liquid chromatography-mass spectrometry analysis of nucleotide metabolites indicated that AICAr caused an increase in adenosine triphosphate, deoxyadenosine triphosphate, and deoxyguanosine triphosphate levels by up-regulating purine biosynthesis, while AICAr led to a decrease in cytidine triphosphate, uridine triphosphate, deoxycytidine triphosphate, and deoxythymidine triphosphate levels because of reduced phosphoribosyl pyrophosphate production, which consequently impaired the pyrimidine biosynthesis. Ribonucleoside triphosphate (NTP) pool imbalances suppressed the rRNA transcription efficiency. Furthermore, deoxy-ribonucleoside triphosphate (dNTP) pool imbalances induced DNA replication stress and DNA double-strand breaks, followed by cell cycle arrest and apoptosis in ALL cells. Exogenous uridine could rebalance the NTP and dNTP pools by supplementing pyrimidine and then attenuate AICAr-induced cytotoxicity. Our data indicate that RNA transcription inhibition and DNA replication stress induced by NTP and dNTP pool imbalances might play a key role in AICAr-mediated cytotoxic effects on ALL cells, suggesting a potential clinical application of AICAr in future ALL therapy.-Du, L., Yang, F., Fang, H., Sun, H., Chen, Y., Xu, Y., Li, H., Zheng, L., Zhou, B.-B. S. AICAr suppresses cell proliferation by inducing NTP and dNTP pool imbalances in acute lymphoblastic leukemia cells.

Genetic removal of the CH1 exon leads to the production of hypofunctional heavy chain-only IgG2a in rats.

Despite great values in many applications, heavy chain-only antibodies (HcAbs) are naturally only produced in camelids and sharks, which are not easy to access and handle. Production of the type of antibodies in small laboratory animals would remarkably facilitate their applications. We previously reported a mouse line in which the CH1 exon of mouse γ1 was deleted that could express heavy chain-only IgG1 antibodies. However, these mice showed an extremely weak IgG1 response to specific antigens when immunized, and we could only achieve single VH domains with low affinity to antigens using these mice. One possibility is that the mouse germline VH repertoire was not sufficient to support the expression of functional heavy chain-only antibodies. In this study, we report the generation of a rat line in which the CH1 exon of the γ2a gene was removed and the γ1 and γ2b genes were silenced. Although the genetically modified rats expressed heavy chain-only IgG2a, they also exhibited a very weak IgG2a response to antigen immunization. Panning of a phage library constructed using IgG2a VH segments amplified from immunized rats identified antigen-specific single VH antibodies, which also exhibited much lower affinity than that of commercial mAbs. Together with our previous report, this study suggests that the simple genetic removal of the CH1 exon does not guarantee the successful expression of functional heavy chain-only antibodies.