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1.
Opt Lett ; 47(11): 2758-2761, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35648923

RESUMO

The 2-µm wave band has attracted significant research interest due to its potential applications for next-generation high-capacity optical communication and sensing. As the key component, fast optical switches are essential for an advanced and reconfigurable optical network. Motivated by this prospect, we propose and demonstrate two typical silicon PIN diode switches at 2 µm. One is based on a coupled microring resonator (CMRR), and the other is based on a Mach-Zehnder interferometer (MZI) with a push-pull-like configuration. The measured insertion loss of the CMRR switch is <2.5 dB, and the cross talk is <-10.8 dB. The insertion loss of the MZI switch is <2 dB, and the cross talk is <-15.6 dB. The switch times of these two structures are both lower than 12.5 ns.

2.
Redox Rep ; 27(1): 119-127, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35735222

RESUMO

OBJECTIVE: The inhibiting effect of Norcantharidin (NCTD) on IL-6 (interleukin-6) and STAT3 and the involvement of the IL-6/STAT3 pathway in hepcidin expression prompted us to speculate that NCTD could affect iron metabolism.We examined the effects of NCTD on serum iron (SI) and transferrin (Tf) saturation, iron and ferritin light chain (FTL), transferrin receptor 1 (TfR1), divalent metal transporter 1 (DMT1), ferroportin 1 (Fpn1), iron regulatory protein 1 (IRP1) and hepcidin, as well as IL-6 and STAT3 in the liver, spleen and duodenum of mice treated with lipopolysaccharide (LPS) in vivo, using RT-PCR, Western blotting and immunofluorescence analysis.NCTD could increase SI and Tf saturation and reduce tissue iron and FTL content by affecting expression of cell-iron transport proteins TfR1, DMT1 and Fpn1. The impact of NCTD on TfR1, DMT1 and Fpn1 expression is mediated by up-regulating IRP1 and down-regulating hepcidin expression, while NCTD-induced down-regulation of hepcidin is mediated by the IL-6/STAT3 signalling pathway in LPS-treated mice.NCTD affects iron metabolism by modifying the expression of IL-6/JAK2/STAT3/hepcidin and IRP1 and suggest that the ability of NCTD to reduce tissue iron contents may be a novel mechanism associated with the anti-cancer effects of NCTD.


Assuntos
Hepcidinas , Ferro , Animais , Compostos Bicíclicos Heterocíclicos com Pontes , Hepcidinas/genética , Hepcidinas/metabolismo , Interleucina-6 , Ferro/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/metabolismo , Camundongos , Baço/metabolismo
3.
Sheng Li Xue Bao ; 74(3): 370-380, 2022 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-35770635

RESUMO

Polycystic ovary syndrome (PCOS) is a common disease caused by complex endocrine and metabolic abnormalities in women of childbearing age. Metformin is the most widely used oral hypoglycemic drug in clinic. In recent years, metformin has been used in the treatment of PCOS, but its mechanism is not clear. In this study, we aimed to investigate the effect of metformin on PCOS and its mechanism through PCOS mouse model. Female C57BL/6J mice aged 4-5 weeks were intragastrically given letrozole (1 mg/kg daily) combined with a high-fat diet (HFD) for 21 days to establish the PCOS model. After modeling, metformin (200 mg/kg daily) was intragastrically administered. One month later, the body weight and oral glucose tolerance test (OGTT) were measured. Hematoxylin eosin (H&E) staining was used to detect the pathological changes of ovary. The serum levels of anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2 and testosterone (T) were measured by ELISA. The expression of DDX4/MVH was detected by immunohistochemistry. DDX4/MVH and PCNA were co-labeled by immunofluorescence. The protein levels of DDX4/MVH, PCNA, cyclin D2, AMPK and mTOR were detected by Western blot. The results showed that after metformin treatment, the body weights of PCOS mice were gradually returned to normal, glucose tolerance was significantly improved, serum E2 levels were increased, while AMH, LH, T levels and LH/FSH ratio were decreased. Ovarian polycystic lesions were reduced with reduced atresia follicles. Furthermore, the number of proliferative female germline stem cells (FGSCs) and levels of proliferation related proteins (PCNA, cyclin D2) were significantly increased, and the p-mTOR and p-AMPK levels were markedly up-regulated. These results suggest that metformin treatment not only improves hyperandrogenemia, glucose intolerance and polycystic ovarian lesions in PCOS, but also activates the function of FGSCs. The underlying mechanism may be related to the phosphorylation of AMPK and mTOR. These findings provide new evidence to use metformin in the treatment of PCOS and follicular development disorder.


Assuntos
Metformina , Células-Tronco de Oogônios , Cistos Ovarianos , Neoplasias Ovarianas , Síndrome do Ovário Policístico , Proteínas Quinases Ativadas por AMP , Animais , Ciclina D2 , Feminino , Hormônio Foliculoestimulante/uso terapêutico , Humanos , Hormônio Luteinizante/uso terapêutico , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco de Oogônios/metabolismo , Cistos Ovarianos/tratamento farmacológico , Síndrome do Ovário Policístico/tratamento farmacológico , Antígeno Nuclear de Célula em Proliferação/uso terapêutico , Serina-Treonina Quinases TOR
5.
Clin Cancer Res ; : OF1-OF9, 2022 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-35766967

RESUMO

PURPOSE: This study aimed to assess the antitumor activity and safety of neoadjuvant chemotherapy combined with PD-1 inhibitor camrelizumab in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). EXPERIMENTAL DESIGN: In this single-center, single-arm, phase 2 trial, patients with resectable stage III-IVB HNSCC received chemotherapy [albumin-bound paclitaxel 260 mg/m2 (or docetaxel 75 mg/m2) plus cisplatin 75 mg/m2] and camrelizumab 200 mg on day 1 of each 21-day cycle for three cycles, followed by surgery, and adjuvant radiotherapy. Co-primary end points were pathological complete response (pCR) rate and safety. RESULTS: Thirty patients were enrolled and completed the neoadjuvant therapy, with an objective response rate (ORR) of 96.7% (29/30). Twenty-seven patients underwent surgery without delay, with an R0 resection rate of 92.6% (25/27). The clinical to pathological downstaging rate was 100% (27/27). The pCR rate was 37.0% [95% confidence interval (CI), 19.4%-57.6%], and the major pathological response (MPR) rate was 74.1% (95% CI, 53.7%-88.9%). The median follow-up duration was 16.1 months (range, 8.3-28.5), and the disease-free survival rate at 12 months was 95.8% (95% CI, 73.9%-99.4%). Grade 3 neoadjuvant therapy-related adverse events included rash (1; 3.3%), pruritis (1; 3.3%), and thrombocytopenia (1; 3.3%), and no grade 4 or 5 treatment-related events occurred. The most common surgical complication was delayed wound healing (5; 18.5%). CONCLUSIONS: Neoadjuvant chemotherapy plus camrelizumab for locally advanced HNSCC showed high ORR, pCR, and MPR rates, with an acceptable safety profile. These data support further evaluation of neoadjuvant chemoimmunotherapy for the treatment of locally advanced HNSCC.

6.
ACS Appl Mater Interfaces ; 14(25): 29431-29440, 2022 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-35709434

RESUMO

Information metasurfaces have attracted much attention in recent years due to the capability to link the physical world and information science. However, most of the current information metasurfaces are either phase-only coding or amplitude-only coding, limiting their functions and applications. Here, a broadband and programmable amplitude-phase-joint-coding (APJC) information metasurface is proposed and experimentally demonstrated, from which the phase and amplitude of reflected electromagnetic waves can be independently controlled by adjusting the bias voltage of PIN diode integrated in the meta-atom. In particular, the reflection amplitude can be continuously controlled from 0.1 to 0.9, and the reflection phase can be switched between two states with about 180° phase difference. Thus, the proposed metasurface is capable of realizing independent 1-bit or multibit amplitude coding and 1-bit phase coding, and both of them can be reprogrammed in real time in broad band from 8 to 13 GHz. The abilities of the programmable APJC information metasurface in manipulating the electromagnetic waves are demonstrated by both numerical simulations and experiments, including to suppress the sidelobes of scattering beam, generate the diffractive waves with arbitrary magnitudes, and so on. These results show unique advantages of APJC information metasurface in real-time independent controls of energy allocation and wavefront tailoring of the electromagnetic waves in a wide frequency band.

7.
Int J Mol Sci ; 23(12)2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35742973

RESUMO

Non-obstructive azoospermia (NOA), characterized by spermatogenesis failure and the absence of sperm in ejaculation, is the most severe form of male infertility. However, the etiology and pathology between meiosis-associated monogenic alterations and human NOA remain largely unknown. A homozygous MSH5 mutation (c.1126del) was identified from two idiopathic NOA patients in the consanguineous family. This mutation led to the degradation of MSH5 mRNA and abolished chromosome axial localization of MutSγ in spermatocytes from the affected males. Chromosomal spreading analysis of the patient's meiotic prophase I revealed that the meiosis progression was arrested at a zygotene-like stage with extensive failure of homologous synapsis and DSB repair. Therefore, our study demonstrates that the MSH5 c.1126del could cause meiotic recombination failure and lead to human infertility, improving the genetic diagnosis of NOA clinically. Furthermore, the study of human spermatocytes elucidates the meiosis defects caused by MSH5 variant, and reveals a conserved and indispensable role of MutSγ in human synapsis and meiotic recombination, which have not previously been well-described.


Assuntos
Azoospermia , Proteínas MutS/metabolismo , Azoospermia/genética , Proteínas de Ciclo Celular/metabolismo , Humanos , Masculino , Meiose/genética , Mutação , Sementes , Espermatócitos/metabolismo , Suporte de Carga
8.
Front Psychiatry ; 13: 861930, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35669265

RESUMO

Mood disorders are ubiquitous mental disorders with familial aggregation. Extracting family history of psychiatric disorders from large electronic hospitalization records is helpful for further study of onset characteristics among patients with a mood disorder. This study uses an observational clinical data set of in-patients of Nanjing Brain Hospital, affiliated with Nanjing Medical University, from the past 10 years. This paper proposes a pretrained language model: Bidirectional Encoder Representations from Transformers (BERT)-Convolutional Neural Network (CNN). We first project the electronic hospitalization records into a low-dimensional dense matrix via the pretrained Chinese BERT model, then feed the dense matrix into the stacked CNN layer to capture high-level features of texts; finally, we use the fully connected layer to extract family history based on high-level features. The accuracy of our BERT-CNN model was 97.12 ± 0.37% in the real-world data set from Nanjing Brain Hospital. We further studied the correlation between mood disorders and family history of psychiatric disorder.

9.
Front Cardiovasc Med ; 9: 857933, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35669479

RESUMO

The role of iron in atherosclerosis is still a controversial and unsolved issue. Here, we investigated serum iron, expression of iron regulatory, transport and storage proteins, pro-inflammatory chemokines and cytokines in ApoE-/- mice. We demonstrated that ApoE-/- induced atherosclerosis and an increase in iron contents, expression of transferrin receptor 1 (TfR1), iron regulatory proteins (IRPs), heme oxygenase 1 (HO1), cellular adhesion molecules and pro-inflammatory cytokines, production of reactive oxygen species (ROS), and a reduction in expression of superoxide dismutase and glutathione peroxidase enzyme in aortic tissues. All of these changes induced by ApoE deficiency could be significantly abolished by deferoxamine. The data showed that the increased iron in aortic tissues was mainly due to the increased iron uptake via IRP/TfR1 upregulation. These findings plus a brief analysis of the controversial results reported previously showed that ApoE deficiency-induced atherosclerosis is partly mediated by the increased iron in aortic tissues.

10.
Lab Chip ; 2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35762978

RESUMO

Paper-fluidic devices are a popular platform for point-of-care diagnostics due to their low cost, ease of use, and equipment-free detection of target molecules. They are limited, however, by their lack of sensitivity and inability to incorporate more complex processes, such as nucleic acid amplification or enzymatic signal enhancement. To address these limitations, various valves have previously been implemented in paper-fluidic devices to control fluid obstruction and release. However, incorporation of valves into new devices is a highly iterative, time-intensive process due to limited experimental data describing the microscale flow that drives the biophysical reactions in the assay. In this paper, we tested and modeled different geometries of thermally actuated valves to investigate how they can be more easily implemented in an LFIA with precise control of actuation time, flow rate, and flow pattern. We demonstrate that bulk flow measurements alone cannot estimate the highly variable microscale properties and effects on LFIA signal development. To further quantify the microfluidic properties of paper-fluidic devices, micro-particle image velocimetry was used to quantify fluorescent nanoparticle flow through the membranes and demonstrated divergent properties from bulk flow that may explain additional variability in LFIA signal generation. Altogether, we demonstrate that a more robust characterization of paper-fluidic devices can permit fine-tuning of parameters for precise automation of multi-step assays and inform analytical models for more efficient design.

11.
Genes Dis ; 9(4): 1086-1098, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35685460

RESUMO

Epithelial-to-mesenchymal transition (EMT) activation is important in cancer progression and metastasis. Evidence indicates that nc886 is a representative Pol III gene that processes microRNA products via Dicer and further downregulates its target gene transforming growth factor- ß1 (TGF-ß1), which is the most prominent inducer of EMT in prostate cancer (PC). Consistent with the previous literature, we found that nc886 downregulation was strongly associated with metastatic behavior and showed worse outcomes in PC patients. However, little is known about the association between nc886 and the EMT signaling pathway. We developed a PC cell model with stable overexpression of nc886 and found that nc886 changed cellular morphology and drove MET. The underlying mechanism may be related to its promotion of SNAIL protein degradation via ubiquitination, but not to its neighboring genes, TGFß-induced protein (TGFBI) and SMAD5, which are Pol II-transcribed. TGF-ß1 also override nc886 promotion of MET via transient suppression the transcription of nc886, promotion of TGFBI or increase in SMAD5 phosphorylation. Both nc886 inhibition and TGFBI activation occur regardless of their methylation status. The literature suggests that MYC inhibition by TGF-ß1 is attributed to nc886 downregulation. We incidentally identified MYC-associated zinc finger protein (MAZ) as a suppressive transcription factor of TGFBI, which is controlled by TGF-ß1. We elucidate a new mechanism of TGF-ß1 differential control of Pol II and the transcription of its neighboring Pol III gene and identify a new EMT unit consisting of nc886 and its neighboring genes.

12.
J Gastrointest Surg ; 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35508683

RESUMO

BACKGROUND AND PURPOSE: The present study aimed to establish a γ-glutamyl transpeptidase-to-albumin ratio (GAR)-based nomogram model to predict early recurrence of hepatocellular carcinoma (HCC) after radical surgery. METHODS: Patients enrolled in this study were randomly allocated into a train and validation cohort in a ratio of 7:3. The Least Absolute Shrinkage and Selection Operator (LASSO) proportional hazards model and cox regression model were combined to identify independent risk factors related to HCC recurrence. Based on these risk factors, a predictive nomogram was constructed and validated in both inner and outer test cohorts. The performance of the nomogram was evaluated by C-index, the area under the receiver operating characteristic curve (AUC), the calibration curve and decision curve analysis. RESULTS: The tumor size, tumor number, BCLC stage, microvascular invasion (MVI) and GAR value were identified as independent risk factors related to HCC recurrence and used to construct the predictive nomogram. AUC of the nomogram showed satisfactory accuracy in predicting 1-, 3- and 5-year disease-free survival. The calibration curve showed agreement between the ideal and predicted values. The risk score more than 72 as calculated by the nomogram was related to early recurrence of HCC after radical surgery. DCA plots showed better clinical usability of the nomogram as compared with the BCLC staging system in all three included cohorts. CONCLUSION: The nomogram based on the GAR value may provide a new option for screening of the target HCC cohort of patients who need anti-recurrence therapy after surgery.

13.
Artigo em Inglês | MEDLINE | ID: mdl-35609819

RESUMO

BACKGROUND: Previous studies have presented inconsistent results on the relationship between serum uric acid and skeletal muscle mass (SMM). We aimed to explore whether a higher serum uric acid level was associated with low SMM in the Chinese population. METHODS: We performed a cross-sectional analysis of 6595 subjects aged 45 years or older. They were tested for fasting blood glucose, total cholesterol, triglycerides, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, uric acid, blood urea nitrogen, creatinine, and estimated glomerular filtration rate. SMM was accessed by dual-energy x-ray absorptiometry using two approaches: weight-adjusted appendicular skeletal muscle mass (ASM)% and ASM/BMI (body mass index (kg/m2)). Low SMM was defined as a cut-off point of ASM/BMI<0.789 for men and<0.512 for women. RESULTS: Compared with their normal group, patients with hyperuricemia had lower ASM% (29.33±2.33 vs 30.03±2.34 for males and 24.71±1.99 vs 25.19±2.07 for females, P<0.01) and ASM/BMI (0.83±0.10 vs 0.85±0.10 for male and 0.60±0.07 vs 0.62±0.07 for female), with a higher prevalence of the associated low SMM in both sexes (35.2 vs 26.5% for male and 10.5 vs 5.9% for female, P<0.01). Pearson analysis showed that ASM% and ASM/BMI were negatively correlated with SUA (male: ASM/BMI, r=-0.097, ASM%, r=-0.146; female: ASM/BMI, r=-0.151, ASM%, r=-0.157; all P<0.001). Logistic regression analysis showed a positive association of hyperuricemia with adjusted risk of low SMM association. CONCLUSIONS: In a middle-aged and elderly Chinese population, hyperuricemia is independently and positively associated with low SMM and can vary by age and gender.

14.
Molecules ; 27(9)2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35566303

RESUMO

Quality control methods of current traditional Chinese medicine (TCM) preparation is time-consuming and difficult to assess in terms of overall efficiency of the drug. A non-destructive rapid near-infrared spectroscopy detection system for key chemical components and biological activity of Lanqin oral solution (LOS), one of the best-selling TCM formulations, was established for comprehensive quality evaluation. Near infrared spectral scanning was carried out on 101 batches of commercial LOS under the penetrated vial state and traditional state. RAW 264.7 cells were cultured to detect the anti-inflammatory ability of LOS, and the reference concentrations of epigoitrin, geniposide, and baicalin were obtained by HPLC. The quantitative models were optimized by three kinds of variable selection methods. The correlation coefficients of prediction value of the models were greater than 0.94. The system also passed the external validation. The performance of the non-invasive models was similar to the traditional models. The established non-destructive system can be applied to the rapid quality inspection of LOS to avoid unqualified drugs from entering the market and ensure drug effectiveness. The biological activity index of LOS was introduced and predicted by NIRs for the first time, which provides a new idea about the quality control of TCM formulations.


Assuntos
Medicamentos de Ervas Chinesas , Espectroscopia de Luz Próxima ao Infravermelho , Anti-Inflamatórios/farmacologia , Medicamentos de Ervas Chinesas/química , Análise dos Mínimos Quadrados , Medicina Tradicional Chinesa , Controle de Qualidade , Espectroscopia de Luz Próxima ao Infravermelho/métodos
15.
Biol Reprod ; 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35532179

RESUMO

It is estimated that approximately 25% of nonobstructive azoospermia (NOA) cases are caused by single genetic anomalies, including chromosome aberrations and gene mutations. The identification of these mutations in NOA patients has always been a research hot spot in the area of human infertility. However, compared with more than 600 genes reported to be essential for fertility in mice, mutations in approximately 75 genes have been confirmed to be pathogenic in patients with male infertility, in which only 14 were identified from NOA patients. The small proportion suggested that there is much room to improve the methodology of mutation screening and functional verification. Fortunately, recent advances in whole exome sequencing and CRISPR-Cas9 have greatly promoted research on the etiology of human infertility and made improvements possible. In this review, we summarized the pathogenic mutations found in NOA patients and the efforts we have made to improve the efficiency of mutation screening from NOA patients and functional verification with the application of new technologies.

16.
Biosensors (Basel) ; 12(5)2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35624622

RESUMO

Suspended particles play a vital role in aquatic environments. We propose a method to rapidly measure the scattered polarization parameters of individual suspended particles with continuously large angular range (PCLAR), from 60° to 120° in one shot. A conceptual setup is built to measure PCLAR with 20 kHz; to verify the setup, 10 µm-diameter silica microspheres suspended in water, whose PCLAR are consistent with those simulated by Mie theory, are measured. PCLAR of 6 categories of particles are measured, which enables high-accuracy classification with the help of a convolutional neural network algorithm. PCLAR of different mixtures of Cyclotella stelligera and silica microspheres are measured to successfully identify particulate components. Furthermore, classification ability comparisons of different angular-selection strategies show that PCLAR enables the best classification beyond the single angle, discrete angles and small-ranged angles. Simulated PCLAR of particles with different size, refractive index, and structure show explicit discriminations between them. Inversely, the measured PCLAR are able to estimate the effective size and refractive index of individual Cyclotella cells. Results demonstrate the method's power, which intrinsically takes the advantage of the optical polarization and the angular coverage. Future prototypes based on this concept would be a promising biosensor for particles in environmental monitoring.


Assuntos
Refratometria , Dióxido de Silício , Microesferas , Tamanho da Partícula , Espalhamento de Radiação , Dióxido de Silício/química
17.
Pest Manag Sci ; 2022 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-35598076

RESUMO

BACKGROUND: Aerial spray is one of the most important applications of unmanned aerial vehicles (UAVs) in agriculture. This work aimed to promote the use of UAVs as an alternative to knapsack electric sprayers in pesticide application in Nanguo pear orchards planted in mountain terraced orchard scenarios. The spray deposition of four types of nozzles (SX110015, XR80015, IDK90015 and TR80015), two spray volume rates (45 and 90 L ha-1 ) and with or without a commercial surfactant adjuvant were evaluated based on the spot spray mode. RESULTS: The air- assisted IDK90015 nozzle showed significantly higher deposition and penetration, and its large droplet size also reduced the risk of drift. Increasing the spray volume rate can increase the amount of droplets deposition. The adjuvant showed excellent potential to improve spray technology in Nanguo pear trees, with a mean deposition of 0.175-0.574 µL cm-2 and penetration of 3.09-66.73%. The droplet size also increased significantly, with volume median diameter (DV0.5 ) of 469 µm. CONCLUSION: The nozzle type, spray volume rate and adjuvant should be well considered when using the spot spray in orchard. Compared with increasing spray volume rate, the use of air-induction nozzles and surfactant-based adjuvants can improve the spray deposition better. © 2022 Society of Chemical Industry.

18.
Hum Reprod ; 37(7): 1664-1677, 2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35526155

RESUMO

STUDY QUESTION: Do variants in helicase for meiosis 1 (HFM1) account for male infertility in humans? SUMMARY ANSWER: Biallelic variants in HFM1 cause human male infertility owing to non-obstructive azoospermia (NOA) with impaired crossover formation and meiotic metaphase I (MMI) arrest. WHAT IS KNOWN ALREADY: HFM1 encodes an evolutionarily conserved DNA helicase that is essential for crossover formation and completion of meiosis. The null mutants of Hfm1 or its ortholog in multiple organisms displayed spermatogenic arrest at the MMI owing to deficiencies in synapsis and severe defects in crossover formation. Although HFM1 variants were found in infertile men with azoospermia or oligozoospermia, the causal relationship has not yet been established with functional evidence. STUDY DESIGN, SIZE, DURATION: A Pakistani family, having two infertile brothers born to consanguineous parents, and three unrelated Chinese men diagnosed with NOA were recruited for pathogenic variants screening. PARTICIPANTS/MATERIALS, SETTING, METHODS: All the patients were diagnosed with idiopathic NOA and, for the Chinese patients, meiotic defects were confirmed by histological analyses and/or immunofluorescence staining on testicular sections. Exome sequencing and subsequent bioinformatic analyses were performed to screen for candidate pathogenic variants. The pathogenicity of identified variants was assessed and studied in vivo in mice carrying the equivalent mutations. MAIN RESULTS AND THE ROLE OF CHANCE: Six variants (homozygous or compound heterozygous) in HFM1 were identified in the three Chinese patients with NOA and two brothers with NOA from the Pakistani family. Testicular histological analysis revealed that spermatogenesis is arrested at MMI in patients carrying the variants. Mice modeling the HFM1 variants identified in patients recapitulated the meiotic defects of patients, confirming the pathogenicity of the identified variants. These Hfm1 variants led to various reductions of HFM1 foci on chromosome axes and resulted in varying degrees of synapsis and crossover formation defects in the mutant male mice. In addition, Hfm1 mutant female mice displayed infertility or subfertility with oogenesis variously affected. LIMITATIONS, REASONS FOR CAUTION: A limitation of the current study is the small sample size. Owing to the unavailability of fresh testicular samples, the defects of synapsis and crossover formation could not be detected in spermatocytes of patients. Owing to the unavailability of antibodies, we could not quantify the impact of these variants on HFM1 protein levels. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide direct clinical and in vivo functional evidence that HFM1 variants cause male infertility in humans and also suggest that HFM1 may regulate meiotic crossover formation in a dose-dependent manner. Noticeably, our findings from mouse models showed that HFM1 variants could impair spermatogenesis and oogenesis with a varying degree of severity and might also be compatible with the production of a few spermatozoa in men and subfertility in women, extending the phenotypic spectrum of patients with HFM1 variants. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (31890780, 32070850, 32061143006, 32000587 and 31900398) and the Fundamental Research Funds for the Central Universities (YD2070002007 and YD2070002012). The authors declare no potential conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

19.
Small ; 18(25): e2106357, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35607752

RESUMO

It is well-known that tissue engineering scaffolds that feature highly interconnected and size-adjustable micropores are oftentimes desired to promote cellular viability, motility, and functions. Unfortunately, the ability of precise control over the microporous structures within bioinks in a cytocompatible manner for applications in 3D bioprinting is generally lacking, until a method of micropore-forming bioink based on gelatin methacryloyl (GelMA) was reported recently. This bioink took advantage of the unique aqueous two-phase emulsion (ATPE) system, where poly(ethylene oxide) (PEO) droplets are utilized as the porogen. Considering the limitations associated with this very initial demonstration, this article has furthered the understanding of the micropore-forming GelMA bioinks by conducting a systematic investigation into the additional GelMA types (porcine and fish, different methacryloyl-modification degrees) and porogen types (PEO, poly(vinyl alcohol), and dextran), as well as the effects of the porogen concentrations and molecular weights on the properties of the GelMA-based ATPE bioink system. This article exemplifies not only the significantly wider range of micropore sizes achievable and better emulsion stability, but also the improved suitability for both extrusion and digital light processing bioprinting with favorable cellular responses.


Assuntos
Bioimpressão , Animais , Emulsões , Gelatina/química , Hidrogéis/química , Metacrilatos , Impressão Tridimensional , Suínos , Engenharia Tecidual , Tecidos Suporte/química
20.
FASEB J ; 36(6): e22376, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35616355

RESUMO

Pulsed electromagnetic fields (PEMFs) have long been recognized being safe and effective in treating bone fracture nonunion and osteoporosis. However, the mechanism of osteogenic action of PEMFs is still unclear. While primary cilia are reported to be a sensory organelle for PEMFs, and nitric oxide (NO) plays an indispensable role in osteogenic effect of PEMFs, the relationship between NO and primary cilia is unknown. In this study, effects of treatment with 50 Hz 0.6 mT PEMFs on osteogenic differentiation and mineralization, NO secretion, and ciliary location of specific proteins were examined in rat calvarial osteoblasts (ROBs) with normal or abrogated primary cilia. It was found that PEMFs stimulated the osteogenic differentiation by activating the NOS/NO/sGC/cGMP/PKG signaling pathway, which need the existence of primary cilia. All components of the signaling pathway including iNOS, eNOS, sGC, PKG-1, and PKG-2 were localized to primary cilia, and eNOS was phosphorylated inside the primary cilia. Besides, primary cilia were elongated significantly by PEMF treatment and changed dynamically with the activation NO/cGMP pathway. When the pathway was blocked by L-NAME, PEMFs could no longer elongate the primary cilia and stimulate the osteoblastic differentiation. Thus, this study for the first time observed activation of the NO/cGMP signaling pathway in ciliary compartment of osteoblasts, and PEMFs could not stimulate the osteoblastic differentiation if the NO signaling pathway was blocked or the ciliogenesis was inhibited. Our findings indicate the interdependent relationship between NO and primary cilia in the PEMF-promoted osteogenesis.


Assuntos
Campos Eletromagnéticos , Osteogênese , Animais , Diferenciação Celular , Cílios/metabolismo , GMP Cíclico/metabolismo , Óxido Nítrico/metabolismo , Osteoblastos/metabolismo , Ratos , Transdução de Sinais
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