RESUMO
Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 µM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.
Assuntos
Antineoplásicos , Irídio , Metano , Animais , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Irídio/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metano/análogos & derivados , Metano/química , Metano/farmacologia , Proteínas dos Microfilamentos/metabolismo , Metástase Neoplásica , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , MasculinoRESUMO
Porcine reproductive and respiratory syndrome virus (PRRSV), a highly infectious virus, causes severe losses in the swine industry by regulating the inflammatory response, inducing tissue damage, suppressing the innate immune response, and promoting persistent infection in hosts. Interleukin-13 (IL-13) is a cytokine that plays a critical role in regulating immune responses and inflammation, particularly in immune-related disorders, certain types of cancer, and numerous bacterial and viral infections; however, the underlying mechanisms of IL-13 regulation during PRRSV infection are not well understood. In this study, we demonstrated that PRRSV infection elevates IL-13 levels in porcine alveolar macrophages. PRRSV enhances m6A-methylated RNA levels while reducing the expression of fat mass and obesity associated protein (FTO, an m6A demethylase), thereby augmenting IL-13 production. PRRSV nonstructural protein 9 (nsp9) was a key factor for this modulation. Furthermore, we found that the residues Asp567, Tyr586, Leu593, and Asp595 were essential for nsp9 to induce IL-13 production via attenuation of FTO expression. These insights delineate PRRSV nsp9's role in FTO-mediated IL-13 release, advancing our understanding of PRRSV's impact on host immune and inflammatory responses.
Assuntos
Interleucina-13 , Macrófagos Alveolares , Síndrome Respiratória e Reprodutiva Suína , Vírus da Síndrome Respiratória e Reprodutiva Suína , Proteínas não Estruturais Virais , Animais , Vírus da Síndrome Respiratória e Reprodutiva Suína/genética , Suínos , Interleucina-13/metabolismo , Interleucina-13/genética , Proteínas não Estruturais Virais/metabolismo , Proteínas não Estruturais Virais/genética , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/virologia , Macrófagos Alveolares/imunologia , Síndrome Respiratória e Reprodutiva Suína/metabolismo , Síndrome Respiratória e Reprodutiva Suína/virologia , Síndrome Respiratória e Reprodutiva Suína/imunologia , Síndrome Respiratória e Reprodutiva Suína/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Regulação para CimaRESUMO
BACKGROUND: Previous studies have demonstrated the role of N6-methyladenosine (m6A) RNA methylation in various biological processes, our research is the first to elucidate its specific impact on LCAT mRNA stability and adipogenesis in poultry. RESULTS: The 6 100-day-old female chickens were categorized into high (n = 3) and low-fat chickens (n = 3) based on their abdominal fat ratios, and their abdominal fat tissues were processed for MeRIP-seq and RNA-seq. An integrated analysis of MeRIP-seq and RNA-seq omics data revealed 16 differentially expressed genes associated with to differential m6A modifications. Among them, ELOVL fatty acid elongase 2 (ELOVL2), pyruvate dehydrogenase kinase 4 (PDK4), fatty acid binding protein 9 (PMP2), fatty acid binding protein 1 (FABP1), lysosomal associated membrane protein 3 (LAMP3), lecithin-cholesterol acyltransferase (LCAT) and solute carrier family 2 member 1 (SLC2A1) have ever been reported to be associated with adipogenesis. Interestingly, LCAT was down-regulated and expressed along with decreased levels of mRNA methylation methylation in the low-fat group. Mechanistically, the highly expressed ALKBH5 gene regulates LCAT RNA demethylation and affects LCAT mRNA stability. In addition, LCAT inhibits preadipocyte proliferation and promotes preadipocyte differentiation, and plays a key role in adipogenesis. CONCLUSIONS: In conclusion, ALKBH5 mediates RNA stability of LCAT through demethylation and affects chicken adipogenesis. This study provides a theoretical basis for further understanding of RNA methylation regulation in chicken adipogenesis.
Assuntos
Adenosina , Adipogenia , Homólogo AlkB 5 da RNA Desmetilase , Galinhas , Fosfatidilcolina-Esterol O-Aciltransferase , Estabilidade de RNA , Animais , Adipogenia/genética , Galinhas/genética , Galinhas/metabolismo , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Feminino , Adenosina/análogos & derivados , Adenosina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , MetilaçãoRESUMO
Inverted p-i-n perovskite solar cells (PSCs) are easy to process but need improved interface characteristics with reduced energy loss to prevent efficiency drops when increasing the active photovoltaic area. Here, we report a series of poly ferrocenyl molecules that can modulate the perovskite surface enabling the construction of small- and large-area PSCs. We found that the perovskite-ferrocenyl interaction forms a hybrid complex with enhanced surface coordination strength and activated electronic states, leading to lower interfacial nonradiative recombination and charge transport resistance losses. The resulting PSCs achieve an enhanced efficiency of up to 26.08% for small-area devices and 24.51% for large-area devices (1.0208 cm2). Moreover, the large-area PSCs maintain >92% of the initial efficiency after 2000 h of continuous operation at the maximum power point under 1-sun illumination and 65 °C.
RESUMO
BACKGROUND: Subarachnoid hemorrhage (SAH), a severe subtype of stroke, is characterized by notably high mortality and morbidity, largely due to the lack of effective therapeutic options. Although the neuroprotective potential of PPARg and Nrf2 has been recognized, investigative efforts into oroxin A (OA), remain limited in preclinical studies. METHODS: SAH was modeled in vivo through filament perforation in male C57BL/6 mice and in vitro by exposing HT22 cells to hemin to induce neuronal damage. Following the administration of OA, a series of methods were employed to assess neurological behaviors, brain water content, neuronal damage, cell ferroptosis, and the extent of neuroinflammation. RESULTS: The findings indicated that OA treatment markedly improved survival rates, enhanced neurological functions, mitigated neuronal death and brain edema, and attenuated the inflammatory response. These effects of OA were linked to the suppression of microglial activation. Moreover, OA administration was found to diminish ferroptosis in neuronal cells, a critical factor in early brain injury (EBI) following SAH. Further mechanistic investigations uncovered that OA facilitated the translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm to the nucleus, thereby activating the Nrf2/GPX4 pathway. Importantly, OA also upregulated the expression of FSP1, suggesting a significant and parallel protective effect against ferroptosis in EBI following SAH in synergy with GPX4. CONCLUSION: In summary, this research indicated that the PPARg activator OA augmented the neurological results in rodent models and diminished neuronal death. This neuroprotection was achieved primarily by suppressing neuronal ferroptosis. The underlying mechanism was associated with the alleviation of cellular death through the Nrf2/GPX4 and FSP1/CoQ10 pathways.
Assuntos
Ferroptose , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias , Hemorragia Subaracnóidea , Animais , Hemorragia Subaracnóidea/metabolismo , Hemorragia Subaracnóidea/patologia , Hemorragia Subaracnóidea/complicações , Ferroptose/efeitos dos fármacos , Ferroptose/fisiologia , Camundongos , Masculino , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/etiologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologiaRESUMO
BACKGROUND: Xeligekimab (GR1501) is a fully human monoclonal antibody that selectively neutralizes interleukin (IL)-17A and has shown potential efficacy in treating moderate-to-severe psoriasis in preliminary trials. OBJECTIVES: To evaluate the efficacy and safety of xeligekimab in Chinese patients with moderate-to-severe psoriasis. METHODS: A total of 420 Chinese patients were randomized to 200â mg xeligekimab every 2 weeks (n = 281) or placebo (n = 139) for the first 12 weeks, followed by an extension of the treatment schedule to xeligekimab every 4 weeks for a further 40 weeks. Efficacy was assessed by evaluating achievement of Physician Global Assessment (PGA) 0/1 and 75%, 90% and 100% improvement in Psoriasis Area and Severity Index (PASI 75, PASI 90 and PASI 100, respectively). The safety profile was also evaluated. RESULTS: At week 12, PASI 75, PASI 90 and PASI 100 were achieved in 90.7%, 74.4% and 30.2% of patients in the xeligekimab group vs. 8.6%, 1.4% and 0% of patients in the placebo group, respectively. PGA 0/1 was achieved in 74.4% patients in the xeligekimab group and 3.6% of patients in the placebo group. PASI 75 and PGA 0/1 were maintained until week 52. No unexpected adverse events were recorded. CONCLUSIONS: Xeligekimab showed high efficacy and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.
Psoriasis is a skin disease characterized by scaly and raised patches of skin on any part of the body. The condition can be caused by a combination of how a person's immune system works, their genes and their environment. A cytokine is a substance secreted by certain cells of the immune system that have an effect on other cells. One such cytokine, called IL-17A, has been associated with different inflammatory diseases, including psoriasis. We conducted a large trial in Chinese people with moderate-to-severe psoriasis to look at the efficacy (ability to produce the intended result) and safety of a medicine called xeligekimab (known as a 'monoclonal antibody') which works by targeting IL-17A. We randomly assigned 420 Chinese patients to receive 200â mg of xeligekimab every 2 weeks or a 'placebo' (no active medicine) for the first 12 weeks. We extended the treatment schedule of xeligekimab to every 4 weeks for a further 40 weeks. To assess how the medicine worked, we measured people's psoriasis symptoms and severity. To assess how safe the medicine was, we looked at the side-effects (or 'adverse events'). The results of this trial showed that xeligekimab improved people's psoriasis and itching starting at week 4 of receiving treatment, and more than 60% of people achieved improvement or remission by week 6, which was sustained up to week 52. The safety of xeligekimab was similar to another medicine classed as a monoclonal antibody (called secukinumab) and there were no new or unexpected adverse events reported. Overall, our findings suggest that xeligekimab is a safe and effective medicine for the treatment of psoriasis in Chinese people.
Assuntos
Anticorpos Monoclonais Humanizados , Psoríase , Humanos , Psoríase/tratamento farmacológico , Masculino , Método Duplo-Cego , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Feminino , Pessoa de Meia-Idade , Adulto , Resultado do Tratamento , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/uso terapêutico , Fármacos Dermatológicos/administração & dosagem , Esquema de Medicação , Interleucina-17/antagonistas & inibidores , Índice de Gravidade de Doença , Idoso , Adulto JovemRESUMO
OBJECTIVES: This study aimed to assess the efficacy and safety of monoclonal antibody therapies (MATs) for interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: A systematic search was conducted across databases including PubMed, Embase, clinicalTrial.gov, and the Cochrane Library Central Register of Controlled Trials. Randomized controlled trials (RCTs) comparing MATs versus placebo were included. Primary outcomes comprised the Global Response Assessment (GRA) scale and the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI). Additional analyses encompassed mean daily frequency of voids, the O'Leary-Sant Interstitial Cystitis Problem Index, pain scores, and complications. Statistical analyses were performed using Review Manager 5.3. RESULTS: Five high-quality RCTs, comprising 263 patients with IC/BPS, were ultimately selected. MATs were generally effective in treating IC/BPS. Patients receiving MATs exhibited a higher satisfaction rate (odds ratio [OR]: 2.7, confidence interval [CI]: 1.31-5.58, p = 0.007) and lower ICSI scores (mean difference [MD]: -1.44, CI: -2.36 to -0.52, p = 0.002). Moreover, MAT recipients experienced reduced pain (MD: -0.53, CI: -0.79 to -0.26, p < 0.0001) and decreased frequency of urination (MD: -1.91, CI: -2.55 to -1.27, p < 0.00001). Importantly, there were no disparities regarding complication incidence in the MAT and control groups. CONCLUSIONS: The current findings indicate that MATs are effective and safe for treating IC/BPS. Nonetheless, future RCTs with larger sample sizes and long-term follow-up are warranted.
RESUMO
BACKGROUND: FMX101 4%, as a topical foam formulation of minocycline, has been approved by US Food and Drug Administration for the treatment of moderate-to-severe acne vulgaris (AV). OBJECTIVE: To evaluate the efficacy and safety of FMX101 4% in treating Chinese subjects with moderate-to-severe facial AV. METHODS: This was a multi-centre, randomized, double-blind, vehicle-controlled phase 3 study in Chinese subjects with moderate-to-severe AV. Eligible subjects were randomized 2:1 to receive either FMX101 4% or vehicle foam treatment for 12 weeks. The primary efficacy endpoint was the change in inflammation lesion count (ILC) from baseline at week 12. The key secondary endpoint was the treatment success rate according to Investigator's Global Assessment (IGA) at week 12. RESULTS: In total, 372 subjects were randomized into two groups (FMX101 4% group, n = 248; vehicle group, n = 124). After 12 weeks treatment, the reduction in ILC from baseline was statistically significant in favour of FMX101 4%, compared with vehicle foam (-21.0 [0.08] vs. -12.3 [1.14]; LSM [SE] difference, -8.7 [1.34]; 95% CI [-11.3, -6.0]; p < 0.001). FMX101 4% treatment yielded significantly higher IGA treatment success rate at week 12 as compared to the control treatment (8.06% vs. 0%). Applying FMX101 4% also resulted in significant reduction in noninflammatory lesion count (nILC) versus vehicle foam at week 12 (-19.4 [1.03] vs. -14.9 [1.47]; LSM [SE] difference, -4.5 [1.74]; 95% CI [-8.0, -1.1]; p = 0.009). Most treatment-emergent adverse events (TEAEs) were mild-to-moderate in severity, and no treatment-related treatment-emergent serious adverse event (TESAE) occurred. Thus, FMX101 4% was considered to be a safe and well-tolerated product during the 12-week treatment period. CONCLUSION: FMX101 4% treatment for 12 weeks could lead to significantly reduced ILC and nILC, and improved IGA treatment success rate in Chinese subjects with moderate-to-severe facial AV. It also showed a well acceptable safe and tolerability profile.
RESUMO
BACKGROUND: Lupus erythematosus (LE) is a spectrum of autoimmune diseases. Due to the complexity of cutaneous LE (CLE), clinical skin image-based artificial intelligence is still experiencing difficulties in distinguishing subtypes of LE. OBJECTIVES: We aim to develop a multimodal deep learning system (MMDLS) for human-AI collaboration in diagnosis of LE subtypes. METHODS: This is a multi-centre study based on 25 institutions across China to assist in diagnosis of LE subtypes, other eight similar skin diseases and healthy subjects. In total, 446 cases with 800 clinical skin images, 3786 multicolor-immunohistochemistry (multi-IHC) images and clinical data were collected, and EfficientNet-B3 and ResNet-18 were utilized in this study. RESULTS: In the multi-classification task, the overall performance of MMDLS on 13 skin conditions is much higher than single or dual modals (Sen = 0.8288, Spe = 0.9852, Pre = 0.8518, AUC = 0.9844). Further, the MMDLS-based diagnostic-support help improves the accuracy of dermatologists from 66.88% ± 6.94% to 81.25% ± 4.23% (p = 0.0004). CONCLUSIONS: These results highlight the benefit of human-MMDLS collaborated framework in telemedicine by assisting dermatologists and rheumatologists in the differential diagnosis of LE subtypes and similar skin diseases.
RESUMO
Vimentin is a cytoskeletal intermediate filament protein that plays pivotal roles in tumor initiation, progression, and metastasis, and its overexpression in aggressive cancers predicted poor prognosis. Herein described is a highly effective antitumor and antimetastatic metal complex [PtII(C^N^N)(NHC2Bu)]PF6 (Pt1a; HC^N^N = 6-phenyl-2,2'-bipyridine; NHC= N-heterocyclic carbene) that engages vimentin via noncovalent binding interactions with a distinct orthogonal structural scaffold. Pt1a displays vimentin-binding affinity with a dissociation constant of 1.06 µM from surface plasmon resonance measurements and fits into a pocket between the coiled coils of the rod domain of vimentin with multiple hydrophobic interactions. It engages vimentin in cellulo, disrupts vimentin cytoskeleton, reduces vimentin expression in tumors, suppresses xenograft growth and metastasis in different mouse models, and is well tolerated, attributable to biotransformation to less toxic and renal-clearable platinum(II) species. Our studies uncovered the practical therapeutic potential of platinum(II)âNHC complexes as effective targeted chemotherapy for combating metastatic and cisplatin-resistant cancers.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Compostos Organoplatínicos/uso terapêutico , Vimentina/efeitos dos fármacos , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Feminino , Células HCT116 , Humanos , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Simulação de Dinâmica Molecular , Compostos Organoplatínicos/metabolismo , Compostos Organoplatínicos/farmacologia , Ratos , Vimentina/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Four new alkaloids (1 - 4), together with five known ones (5 - 9), were isolated from the bulbs of Dactylicapnos scandens. The structures were determined by analysis of their spectroscopic data and quantum-chemical calculations. All the isolates were tested for their ability to modulate neuronal Ca2+ mobilization in primary cultured neocortical neurons. Compound 8 inhibited spontaneous Ca2+ oscillations at low micromolar concentrations.
Assuntos
Alcaloides , Alcaloides/química , Raízes de Plantas/química , NeurôniosRESUMO
Ca-type todorokite catalysts were designed and prepared by a simple redox method and applied to the selective reduction of NOx by NH3 (NH3-SCR) for the first time. Compared with the Na-type manjiroite prepared by the same method, the todorokite catalysts with different Mn/Ca ratios showed greatly improved catalytic activity for NOx reduction. Among them, Mn8Ca4 catalyst exhibited the best NH3-SCR performance, achieving 90% NOx conversion within temperature range of 70-275°C and having a high sulphur resistance. Compared to the Na-type manjiroite sample, Ca-type todorokite catalysts possessed an increased size of tunnel, resulting in a larger specific surface area. As increased the amounts of Ca doping, the Na content in Ca-type todorokite catalysts significantly decreased, providing larger amounts of Brønsted acid sites for NH3 adsorption to produce NH4+. The NH4+ species were highly active for reaction with NO + O2, playing a determining role in NH3-SCR process at low temperatures. Meanwhile, larger amounts of surface adsorbed oxygen contained over the Ca-doping samples than that over Na-type manjiroite, promoting the oxidation of NO and fast SCR processes. Over the Ca-type todorokite catalysts, furthermore, nitrates produced during the flow of NO + O2, were more active for reaction with NH3 than that over Na-type manjiroite, benefiting the occurrence of NH3-SCR process. This study provides novel insights into the design of NH3-SCR catalysts with high performance.
Assuntos
Amônia , Temperatura Baixa , Temperatura , Oxirredução , Nitratos , Oxigênio , CatáliseRESUMO
Objective: Photoelectric volumetric tracing (PPG) exhibits high sensitivity and specificity in flap monitoring. Deep learning (DL) is capable of automatically and robustly extracting features from raw data. In this study, we propose combining PPG with 1D convolutional neural networks (1D-CNN) to preliminarily explore the method's ability to distinguish the degree of embolism and to localize the embolic site in skin flap arteries. Methods: Data were collected under normal conditions and various embolic scenarios by creating vascular emboli in a dermatome artery model and a rabbit dermatome model. These datasets were then trained, validated, and tested using 1D-CNN. Results: As the degree of arterial embolization increased, the PPG amplitude upstream of the embolization site progressively increased, while the downstream amplitude progressively decreased, and the gap between the upstream and downstream amplitudes at the embolization site progressively widened. 1D-CNN was evaluated in the skin flap arterial model and rabbit skin flap model, achieving average accuracies of 98.36% and 95.90%, respectively. Conclusion: The combined monitoring approach of DL and PPG can effectively identify the degree of embolism and locate the embolic site within the skin flap artery.
Assuntos
Aprendizado Profundo , Fotopletismografia , Retalhos Cirúrgicos , Coelhos , Animais , Retalhos Cirúrgicos/irrigação sanguínea , Redes Neurais de Computação , Monitorização Fisiológica , Período Pós-Operatório , EmboliaRESUMO
BACKGROUND: The early craniofacial development is a highly coordinated process involving neural crest cell migration, proliferation, epithelial apoptosis, and epithelial-mesenchymal transition (EMT). Both genetic defects and environmental factors can affect these processes and result in orofacial clefts. Mutations in MID1 gene cause X-linked Opitz Syndrome (OS), which is a congenital malformation characterized by craniofacial defects including cleft lip/palate (CLP). Previous studies demonstrated impaired neurological structure and function in Mid1 knockout mice, while no CLP was observed. However, given the highly variable severities of the facial manifestations observed in OS patients within the same family carrying identical genetic defects, subtle craniofacial malformations in Mid1 knockout mice could be overlooked in these studies. Therefore, we propose that a detailed morphometric analysis should be necessary to reveal mild craniofacial dysmorphologies that reflect the similar developmental defects seen in OS patients. RESULTS: In this research, morphometric study of the P0 male Mid1-cKO mice were performed using Procrustes superimposition as well as EMDA analysis of the size-adjusted three-dimensional coordinates of 105 skull landmarks, which were collected on the bone surface reconstructed using microcomputed tomographic images. Our results revealed the craniofacial deformation such as the increased dimension of the frontal and nasal bone in Mid1-cKO mice, in line with the most prominent facial features such as hypertelorism, prominent forehead, broad and/or high nasal bridge seen in OS patients. CONCLUSION: While been extensively used in evolutionary biology and anthropology in the last decades, geometric morphometric analysis was much less used in developmental biology. Given the high interspecies variances in facial anatomy, the work presented in this research suggested the advantages of morphometric analysis in characterizing animal models of craniofacial developmental defects to reveal phenotypic variations and the underlining pathogenesis.
Assuntos
Fenda Labial , Fissura Palatina , Masculino , Camundongos , Animais , Fissura Palatina/genética , Fenda Labial/genética , Crânio/diagnóstico por imagem , Ubiquitina-Proteína Ligases , Camundongos KnockoutRESUMO
Solution-processed photodetectors have emerged as promising candidates for next-generation of visible-near infrared (vis-NIR) photodetectors. This is attributed to their ease of processing, compatibility with flexible substrates, and the ability to tune their detection properties by integrating complementary photoresponsive semiconductors. However, the limited performance continues to hinder their further development, primarily influenced by the difference of charge transport properties between perovskite and organic semiconductors. In this work, a perovskite-organic bipolar photodetectors (PDs) is introduced with multispectral responsivity, achieved by effectively managing charges in perovskite and a ternary organic heterojunction. The ternary heterojunction, incorporating a designed NIR guest acceptor, exhibits a faster charge transfer rate and longer carrier diffusion length than the binary heterojunction. By achieving a more balanced carrier dynamic between the perovskite and organic components, the PD achieves a low dark current of 3.74 nA cm-2 at -0.2 V, a fast response speed of <10 µs, and a detectivity of exceeding 1012 Jones. Furthermore, a bioinspired retinotopic system for spontaneous chromatic adaptation is achieved without any optical filter. This charge management strategy opens up possibilities for surpassing the limitations of photodetection and enables the realization of high-purity, compact image sensors with exceptional spatial resolution and accurate color reproduction.
RESUMO
Porcine reproductive and respiratory syndrome virus (PRRSV) is a highly infectious and pathogenic agent that causes considerable economic damage in the swine industry. It regulates the inflammatory response, triggers inflammation-induced tissue damage, suppresses the innate immune response, and leads to persistent infection. Interleukin-8 (IL-8), a pro-inflammatory chemokine, plays a crucial role in inflammatory response during numerous bacteria and virus infections. However, the underlying mechanisms of IL-8 regulation during PRRSV infection are not well understood. In this study, we demonstrate that PRRSV-infected PAMs and Marc-145 cells release higher levels of IL-8. We screened the nucleocapsid protein, non-structural protein (nsp) 9, and nsp11 of PRRSV to enhance IL-8 promoter activity via the C/EBPα pathway. Furthermore, we identified that the amino acids Q35A, S36A, R113A, and I115A of the nucleocapsid protein play a crucial role in the induction of IL-8. Through reverse genetics, we generated two mutant viruses (rQ35-2A and rR113A), which showed lower induction of IL-8 in PAMs during infection. This finding uncovers a previously unrecognized role of the PRRSV nucleocapsid protein in modulating IL-8 production and provides insight into an additional mechanism by which PRRSV modulates immune responses and inflammation.
Assuntos
Síndrome Respiratória e Reprodutiva Suína , Vírus da Síndrome Respiratória e Reprodutiva Suína , Animais , Suínos , Vírus da Síndrome Respiratória e Reprodutiva Suína/metabolismo , Interleucina-8/genética , Proteínas do Nucleocapsídeo/genética , Proteínas do Nucleocapsídeo/metabolismo , Inflamação , Macrófagos Alveolares/metabolismoRESUMO
MircoRNAs (miRNAs) play an important role in skeletal muscle development. Previous study had found that miR-495-3p was differentially expressed in fetal and adult goat skeletal muscle, but its function in myogenic proliferation and differentiation are unclear. Herein, we found the expression of miR-495-3p in C2C12 was downregulated during proliferation stage and upregulated during differentiation stage. Functionally, overexpression of miR-495-3p in C2C12 inhibited proliferation, and promoted myogenic differentiation. Mechanistically, the luciferase reporter assay demonstrated that cadherin 2 (CDH2) was a potential target gene of miR-495-3p. Importantly, overexpression of miR-495-3p inhibited CDH2 expression. Furthermore, knockdown of CDH2 in C2C12 inhibited proliferation and promoted myogenic differentiation. Together, the results showed that miR-495-3p inhibits C2C12 proliferation and promotes myogenic differentiation through targeting CDH2.
Assuntos
MicroRNAs , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Mioblastos/fisiologia , Proliferação de Células/genética , Caderinas/genética , Caderinas/metabolismo , Desenvolvimento Muscular/genética , Diferenciação Celular/genéticaRESUMO
MiR-424-5p was found to be a potential regulator in the proliferation, migration, and invasion of various cancer cells. However, the effects and functional mechanism of miR-424-5p in the process of myogenesis are still unclear. Previously, using microRNA (miRNA) sequencing and expression analysis, we discovered that miR-424-5p was expressed differentially in the different skeletal muscle growth periods of Xuhuai goats. We hypothesized that miR-424-5p might play an important role in skeletal muscle myogenesis. Then, we found that the proliferation ability of the mouse myoblast cell (C2C12 myoblast cell line) was significantly augmented, whereas the C2C12 differentiation was repressed after increasing the expression of miR-424-5p. Mechanistically, HSP90AA1 presented a close interrelation with miR-424-5p, which was predicted as a target gene in the progression of skeletal muscle myogenesis, using transcriptome sequencing, dual luciferase reporter gene detection, and qRT-PCR. The silencing of HSP90AA1 obviously increased C2C12 proliferation and diminished differentiation, which is consistent with the ability of miR-424-5p in C2C12. Altogether, our findings indicated the role of miR-424-5p as a novel potential regulator via HSP90AA1 during muscle myogenesis progression.
Assuntos
MicroRNAs , Animais , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Proliferação de Células/genética , Diferenciação Celular/genética , Linhagem Celular , Desenvolvimento Muscular/genética , Cabras/genética , Músculo Esquelético/metabolismoRESUMO
Intramuscular fat content is closely related to meat quality traits and has high heritability. miRNAs are a class of small non-coding RNA, which are highly conserved in animals and play important regulatory roles in adipogenesis. Therefore, they can be used as molecular markers for meat quality traits. Herein, we used in vitro model of myoblasts adipogenic differentiation to screen differential miRNAs by RNA-seq. A total of 71 differentially miRNAs were filtered, including 31 up-regulated miRNAs and 40 down-regulated miRNAs. Since, we selected 18 miRNAs for RT-qPCR validation, including some miRNAs likely miR-146a-5p, miR-210-3p, miR-199a, miR-224, and miR-214-3p that play important regulatory roles in adipogenesis. In addition, functional enrichment analysis results revealed that members of miRNA target genes were enriched into insulin signaling pathway and MAPK signaling pathway, which are closely related to adipogenesis. Taken together, these data will contribute to further investigate the function of miRNAs in intramuscular fat deposition. These differentially miRNAs can be developed as biomarkers for animal breeding.
Assuntos
MicroRNAs , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Adipogenia/genética , Perfilação da Expressão Gênica , Transdução de Sinais , Mioblastos/metabolismo , TranscriptomaRESUMO
In pig production, pigs often show more aggressive behavior after mixing, which adversely affects animal welfare and growth performance. The Jumonji and structural domain-rich AT interaction domain 2 (JARID2) gene plays an important role in neurodevelopment in mice and various psychiatric disorders in humans. The JARID2 gene may impact the aggressive behavior of pigs. By observing the behavior of 500 weaned pigs during the first 72 h after mixing, the ear tissue samples of the 12 most aggressive and 12 least aggressive pigs were selected for DNA resequencing based on the intensity of their aggressive behavior. Large group correlation analysis indicated that the rs3262221458 site located in the 3'-UTR region of the porcine JARID2 gene has a strong relationship with the aggressive behavior of weaned pigs. Pigs with the mutant TT genotype of rs3262221458 have more aggressive behavior than those pigs with the GG and GT genotypes. The dual luciferase assay indicated that the luciferase activity of the plasmids containing the G allele of rs326221458 was significantly less than that of plasmids containing the T allele of rs326221458 and control groups. The binding ability of miR-9828-3p to sequences containing the T allele was less than that of sequences containing the G allele. The overexpression of miR-9828-3p in porcine neuroglial cells (PNGCs) and PK15 cells significantly decreased the mRNA and protein levels of the JARID2 gene. In addition, miR-9828-3p inhibited the proliferation of PNGCs. After inhibiting miR-9828-3p, the mRNA and protein expression levels of JARID2 increased, and the proliferation of PNGCs showed an opposite trend to the cells that forced the expression of miR-9828-3p. In addition, interference with the JARID2 gene by siRNA can effectively inhibit the proliferation of PNGCs. In summary, we found that the rs326221458 locus regulates the expression of the JARID2 gene by affecting the binding of miR-9828-3p and the JARID2 gene, thereby affecting the aggressive behavior of weaned pigs after mixing.