RESUMO
Type V CRISPR-associated systems (Cas)12 family nucleases are considered to have evolved from transposon-associated TnpB, and several of these nucleases have been engineered as versatile genome editors. Despite the conserved RNA-guided DNA-cleaving functionality, these Cas12 nucleases differ markedly from the currently identified ancestor TnpB in aspects such as guide RNA origination, effector complex composition, and protospacer adjacent motif (PAM) specificity, suggesting the presence of earlier evolutionary intermediates that could be mined to develop advanced genome manipulation biotechnologies. Using evolutionary and biochemical analyses, we identify that the miniature type V-U4 nuclease (referred to as Cas12n, 400-700 amino acids) is likely the earliest evolutionary intermediate between TnpB and large type V CRISPR systems. We demonstrate that with the exception of CRISPR array emergence, CRISPR-Cas12n shares several similar characteristics with TnpB-ωRNA, including a miniature and likely monomeric nuclease for DNA targeting, origination of guide RNA from nuclease coding sequence, and generation of a small sticky end following DNA cleavage. Cas12n nucleases recognize a unique 5'-AAN PAM sequence, of which the A nucleotide at the -2 position is also required for TnpB. Moreover, we demonstrate the robust genome-editing capacity of Cas12n in bacteria and engineer a highly efficient CRISPR-Cas12n (termed Cas12Pro) with up to 80% indel efficiency in human cells. The engineered Cas12Pro enables base editing in human cells. Our results further expand the understanding regarding type V CRISPR evolutionary mechanisms and enrich the miniature CRISPR toolbox for therapeutic applications.
Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Humanos , Sistemas CRISPR-Cas/genética , Edição de Genes/métodos , Endonucleases/genética , DNA/genética , RNARESUMO
Temperature is a major factor that regulates plant growth and phenotypic diversity. To ensure reproductive success at a range of temperatures, plants must maintain developmental stability of their sexual organs when exposed to temperature fluctuations. However, the mechanisms integrating plant floral organ development and temperature responses are largely unknown. Here, we generated barley and rice loss-of-function mutants in the SEPALLATA-like MADS-box gene MADS8. The mutants in both species form multiple carpels that lack ovules at high ambient temperatures. Tissue-specific markers revealed that HvMADS8 is required to maintain floral meristem determinacy and ovule initiation at high temperatures, and transcriptome analyses confirmed that temperature-dependent differentially expressed genes in Hvmads8 mutants predominantly associate with floral organ and meristem regulation. HvMADS8 temperature-responsive activity relies on increased binding to promoters of downstream targets, as revealed by a cleavage under targets and tagmentation (CUT&Tag) analysis. We also demonstrate that HvMADS8 directly binds to 2 orthologs of D-class floral homeotic genes to activate their expression. Overall, our findings revealed a new, conserved role for MADS8 in maintaining pistil number and ovule initiation in cereal crops, extending the known function of plant MADS-box proteins in floral organ regulation.
Assuntos
Grão Comestível , Genes Homeobox , Grão Comestível/genética , Temperatura , Proteínas de Plantas/metabolismo , Flores/metabolismo , Proteínas de Domínio MADS/genética , Proteínas de Domínio MADS/metabolismo , Regulação da Expressão Gênica de Plantas/genética , MeristemaRESUMO
Gastrodin, an anti-inflammatory herbal agent, is known to suppress microglia activation. Here, we investigated whether it would exert a similar effect in reactive astrocytes and whether it might act through the renin-angiotensin system (RAS) and sirtuin 3 (SIRT3). Angiotensinogen (ATO), angiotensin-converting enzyme (ACE), angiotensin II type 1 (AT1) and type 2 (AT2) receptor and SIRT3 expression was detected in TNC-1 astrocytes treated with BV-2 microglia conditioned medium (CM) with or without gastrodin and lipopolysaccharide (LPS) pre-treatment by RT-PCR, immunofluorescence and western blotting analysis. Expression of C3 (A1 astrocyte marker), S100A10 (A2 astrocyte marker), proinflammatory cytokines and neurotrophic factors was then evaluated. The results showed a significant increase of ATO, ACE, AT1, SIRT3, C3, proinflammatory cytokines and neurotrophic factors expression in TNC-1 astrocytes incubated in CM + LPS when compared with cells incubated in the CM, but AT2 and S100A10 expression was reduced. TNC-1 astrocytes responded vigorously to BV-2 CM treated with gastrodin + LPS as compared with the control. This was evident by the decreased expression of the abovementioned protein markers, except for AT2 and S100A10. Interestingly, SIRT3, IGF-1 and BDNF expression was enhanced, suggesting that gastrodin inhibited the expression of RAS and proinflammatory mediators but promoted the expression of neurotrophic factors. And gastrodin regulated the phenotypic changes of astrocytes through AT1. Additionally, azilsartan (a specific inhibitor of AT1) inhibited the expression of C3 and S100A10, which remained unaffected in gastrodin and azilsartan combination treatment. These findings provide evidence that gastrodin may have a therapeutic effect via regulating RAS-SIRT3.
Assuntos
Astrócitos , Álcoois Benzílicos , Glucosídeos , Microglia , Sistema Renina-Angiotensina , Sirtuína 3 , Glucosídeos/farmacologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Animais , Álcoois Benzílicos/farmacologia , Camundongos , Sirtuína 3/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Mediadores da Inflamação/metabolismo , Citocinas/metabolismo , Linhagem CelularRESUMO
A FMCW LiDAR system of both the distributed feedback laser and external cavity laser is established in baseband beat notes, rather than up-conversion to an intermediate frequency to exclude flicker noise. Meanwhile, utilizing fast-scanning MEMS mirrors, high-quality real-time (1 fps) 4-D images of the slow-moving object (10 mm/s) can be directly constructed at the baseband with a central frequency as low as 100 kHz and a small Doppler shift. The proposed LiDAR architecture based on such a low-frequency baseband significantly improves the optical power budget on the transmitter side and eliminates the costly high-speed sampling circuits on the receiver side.
RESUMO
One of the challenges for global food security is to reliably and sustainably improve the grain yield of cereal crops. One solution is to modify the architecture of the grain-bearing inflorescence to optimize for grain number and size. Cereal inflorescences are complex structures, with determinacy, branching patterns, and spikelet/floret growth patterns that vary by species. Recent decades have witnessed rapid advancements in our understanding of the genetic regulation of inflorescence architecture in rice, maize, wheat, and barley. Here, we summarize current knowledge on key genetic factors underlying the different inflorescence morphologies of these crops and model plants (Arabidopsis and tomato), focusing particularly on the regulation of inflorescence meristem determinacy and spikelet meristem identity and determinacy. We also discuss strategies to identify and utilize these superior alleles to optimize inflorescence architecture and, ultimately, improve crop grain yield.
Assuntos
Hordeum , Inflorescência , Grão Comestível/genética , Grão Comestível/metabolismo , Poaceae/metabolismo , Hordeum/genética , Triticum/genética , Produtos Agrícolas/genética , Produtos Agrícolas/metabolismo , Meristema , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/metabolismoRESUMO
To enable a higher transmission rate in optical camera communication (OCC) systems, severe inter-symbol interference (ISI) occurs owing to the reduction of the number of pixel-row-per-bit (PPB). Therefore, those pixels representing data bit 0 or 1 may have same gray scale values, significantly deteriorating the bit decision when using the conventional thresholding scheme. In this Letter, a simple yet efficient scheme, referred to as nearest neighbor bit assisted decision (NNBAD) scheme, is proposed and experimentally demonstrated for signal decision in OCC systems. NNBAD leverages the nearest neighbor bit to jointly assist bit decision for pixels with severe ISI. Experimental results show that, for OCC systems with on-off keying (OOK) modulation, those pixels with severe ISI cannot be distinguished by the conventional thresholding scheme. Yet, the NNBAD scheme exhibits strong robustness against ISI, remarkably improving the bit error rate (BER) performance. The proposed scheme can achieve a throughput of 8.2â kbps with OOK modulation under an illuminance of 600â lx.
RESUMO
Speckle patterns generated as coherent optical beams are reflected by scattering elements. Multimode fibers (MMFs) can modify the transverse intensity distribution of speckle patterns with macro perturbations, i.e., pressures, providing a simple and low-cost way to achieve equivalent beam-steering for indoor optical wireless communications (OWCs) with divergent optical beams. However, the received optical power (ROP) variance severely limits the mobility of user terminals. In this paper, the issue is alleviated by using the overfilled launch of MMFs and the diversity gain of multi-receivers. By adjusting the axial spatial coupling distance between the MMF and the single mode fiber (SMF) emitting coherent laser, the number of excited modes of MMF can be significantly increased at 1550â nm with negligible coupling and bending losses. In addition, the signal-to-noise ratio (SNR) enhancement obtained by applying two receivers is theoretically analyzed for the case when either thermal noise or shot noise is dominant. The experimental results demonstrate that the proposed scheme can efficiently compensate for the ROP inhomogeneity, and at the same time it can extend the achievable full steering angle up to 12° at a 1.5-m free-space distance for bit error rate (BER) values of less than 3.8 × 10-3.
RESUMO
Pathogenic bacterial membrane proteins (MPs) are a class of vaccine and antibiotic development targets with widespread clinical application. However, the inherent hydrophobicity of MPs poses a challenge to fold correctly in living cells. Herein, we present a comprehensive method to improve the soluble form of MP antigen by rationally designing multi-epitope chimeric antigen (ChA) and screening two classes of protein-assisting folding element. The study uses a homologous protein antigen as a functional scaffold to generate a ChA possessing four epitopes from transferrin-binding protein A of Glaesserella parasuis. Our engineered strain, which co-expresses P17 tagged-ChA and endogenous chaperones groEL-ES, yields a 0.346 g/L highly soluble ChA with the property of HPS-positive serum reaction. Moreover, the protein titer of ChA reaches 4.27 g/L with >90% soluble proportion in 5-L bioreactor, which is the highest titer reported so far. The results highlight a timely approach to design and improve the soluble expression of MP antigen in industrially viable applications.
Assuntos
Antígenos de Bactérias , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Reatores Biológicos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Escherichia coli/genética , Escherichia coli/metabolismo , Clostridiales/genética , Clostridiales/metabolismo , SolubilidadeRESUMO
OBJECTIVES: To explore the effect of combined hematological and physical measurement indicators on the prognosis of patients undergoing surgery for gastric or colorectal cancer and to screen for the best prognostic indicators. INTRODUCTION: Gastric and colorectal cancer is a widespread health concern worldwide and one of the major contributors to cancer-related death. The hematological and physical measurement indicators have been shown to associate with the prognosis of patients undergoing surgery for gastric or colorectal cancer, respectively, but it is still unclear whether the combination of the two can reflect the prognosis more effectively. METHODS: Thirteen hematological indicators and 5 physical measurement indicators were selected in this study, and the most promising ones were screened using LASSO regression. Then, the best prognostic indicators were selected by time-ROC curves. Survival curves were constructed using the Kaplan-Meier method, and the effects of hematological and physical measurement indicators on the prognosis of patients undergoing surgery for gastric or colorectal cancers were evaluated by Cox proportional risk regression analysis. In addition, the relationship between hematological and physical measurement indicators on secondary outcomes, including length of stay, hospitalization costs, intensive care unit (ICU) admission, and patients' subjective global assessment scores (PGSGA), was explored. RESULTS: After initial screening, among the hematological indicators, the geriatric nutritional risk index (GNRI) showed the highest mean area under the curve (AUC) values. Among body measures, calf circumference (CC) showed the highest mean AUC value. Further analyses showed that the combination of combined nutritional prognostic index (GNRI) and calf circumference (CC) (GNRI-CC) had the best performance in predicting the prognosis of patients undergoing surgery for gastric or colorectal cancers. Low GNRI, low CC, and low GNRI-low CC increased the risk of death by 44%, 48%, and 104%, respectively. Sensitivity analyses showed the same trend. In addition, low GNRI-low CC increased the risk of malnutrition by 17%. CONCLUSION: This study emphasizes that a combination of blood measures and body measures is essential to accurately assess the prognosis of patients undergoing surgery for gastric or colorectal cancers. The GNRI-CC is a good prognostic indicator and can also assess the risk of possible malnutrition.
Assuntos
Neoplasias Colorretais , Desnutrição , Humanos , Idoso , Estado Nutricional , Prognóstico , Desnutrição/diagnóstico , Avaliação Nutricional , Neoplasias Colorretais/cirurgia , Avaliação Geriátrica/métodos , Estudos Retrospectivos , Fatores de RiscoRESUMO
Sn-doped indium oxide (ITO) semiconductor nano-films are fabricated by plasma-enhanced atomic layer deposition using trimethylindium (TMIn), tetrakis(dimethylamino)tin (TDMASn), and O2plasma as the sources of In, Sn and O, respectively. A shared temperature window of 150 °C- 200 °C is observed for the deposition of ITO nano-films. The introduction of Sn into indium oxide is found to increase the concentration of oxygen into the ITO films and inhibit crystallization. Furthermore, two oxidation states are observed for In and Sn, respectively. With the increment of interfaces of In-O/Sn-O in the ITO films, the relative percentage of In3+ions increases and that of Sn4+decreases, which is generated by interfacial competing reactions. By optimizing the channel component, the In0.77Sn0.23O1.11thin-film transistors (TFTs) demonstrate high performance, includingµFEof 52.7 cm2V-1s-1, and a highION/IOFFof â¼5 × 109. Moreover, the devices show excellent positive bias temperature stress stability at 3 MV cm-1and 85 °C, i.e. a minimalVthshift of 0.017 V after 4 ks stress. This work highlights the successful application of ITO semiconductor nano-films by ALD for TFTs.
RESUMO
Although certain members of the Ubiquitin-specific peptidases (USPs) have been recognized as promising therapeutic targets for various diseases, research progress regarding USP21 has been relatively sluggish in its early stages. USP21 is a crucial member of the USPs subfamily, involved in diverse cellular processes such as apoptosis, DNA repair, and signal transduction. Research findings from the past decade demonstrate that USP21 mediates the deubiquitination of multiple well-known target proteins associated with critical cellular processes relevant to both disease and homeostasis, particularly in various cancers.This reviewcomprehensively summarizes the structure and biological functions of USP21 with an emphasis on its role in tumorigenesis, and elucidates the advances on the discovery of tens of small-molecule inhibitors targeting USP21, which suggests that targeting USP21 may represent a potential strategy for cancer therapy.
Assuntos
Neoplasias , Ubiquitina Tiolesterase , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismo , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Animais , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Estrutura MolecularRESUMO
Epithelial-mesenchymal transition (EMT) plays a critical role in hypertension-induced renal fibrosis, a final pathway that leads to end-stage renal failure. C-Atrial natriuretic peptide (ANP)4-23, a specific agonist of natriuretic peptide receptor-C (NPR-C), has been reported to have protective effects against hypertension. However, the role of C-ANP4-23 in hypertension-associated renal fibrosis has not yet been elucidated. In this study, mice were randomly divided into SHAM group, DOCA-salt group and DOCA-salt + C-ANP4-23 group. Renal morphology changes, renal function and fibrosis were detected. Human proximal tubular epithelial cells (HK2) stimulated by aldosterone were used for cell function and mechanism study. The DOCA-salt treated mice exhibited hypertension, kidney fibrosis and renal dysfunction, which were attenuated by C-ANP4-23. Moreover, C-ANP4-23 inhibited DOCA-salt treatment-induced renal EMT as evidenced by decrease of the mesenchymal marker alpha-smooth muscle actin (ACTA2) and vimentin and increase of epithelial cell marker E-cadherin. In HK2 cells, aldosterone induced EMT response, which was also suppressed by C-ANP4-23. The key transcription factors (twist, snail, slug and ZEB1) involved in EMT were increased in the kidney of DOCA-salt-treated mice, which were also suppressed by C-ANP4-23. Mechanistically, C-ANP4-23 inhibited the aldosterone-induced translocation of MR from cytosol to nucleus without change of MR expression. Furthermore, C-ANP4-23 rescued the enhanced expression of NADPH oxidase (NOX) 4 and oxidative stress after aldosterone stimulation. Aldosterone-induced Akt and Erk1/2 activation was also suppressed by C-ANP4-23. Our data suggest that C-ANP4-23 attenuates renal fibrosis, likely through inhibition of MR activation, enhanced oxidative stress and Akt and Erk1/2 signaling pathway.
Assuntos
Acetato de Desoxicorticosterona , Hipertensão , Nefropatias , Camundongos , Humanos , Animais , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Receptores do Fator Natriurético Atrial/metabolismo , Aldosterona/efeitos adversos , Aldosterona/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Acetato de Desoxicorticosterona/efeitos adversos , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Rim/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Acetatos/efeitos adversos , Acetatos/metabolismo , FibroseRESUMO
Kv1.3 belongs to the voltage-gated potassium (Kv) channel family, which is widely expressed in the central nervous system and associated with a variety of neuropsychiatric disorders. Kv1.3 is highly expressed in the olfactory bulb and piriform cortex and involved in the process of odor perception and nutrient metabolism in animals. Previous studies have explored the function of Kv1.3 in olfactory bulb, while the role of Kv1.3 in piriform cortex was less known. In this study, we investigated the neuronal changes of piriform cortex and feeding behavior after smell stimulation, thus revealing a link between the olfactory sensation and body weight in Kv1.3 KO mice. Coronal slices including the anterior piriform cortex were prepared, whole-cell recording and Ca2+ imaging of pyramidal neurons were conducted. We showed that the firing frequency evoked by depolarization pulses and Ca2+ influx evoked by high K+ solution were significantly increased in pyramidal neurons of Kv1.3 knockout (KO) mice compared to WT mice. Western blotting and immunofluorescence analyses revealed that the downstream signaling molecules CaMKII and PKCα were activated in piriform cortex of Kv1.3 KO mice. Pyramidal neurons in Kv1.3 KO mice exhibited significantly reduced paired-pulse ratio and increased presynaptic Cav2.1 expression, proving that the presynaptic vesicle release might be elevated by Ca2+ influx. Using Golgi staining, we found significantly increased dendritic spine density of pyramidal neurons in Kv1.3 KO mice, supporting the stronger postsynaptic responses in these neurons. In olfactory recognition and feeding behavior tests, we showed that Kv1.3 conditional knockout or cannula injection of 5-(4-phenoxybutoxy) psoralen, a Kv1.3 channel blocker, in piriform cortex both elevated the olfactory recognition index and altered the feeding behavior in mice. In summary, Kv1.3 is a key molecule in regulating neuronal activity of the piriform cortex, which may lay a foundation for the treatment of diseases related to piriform cortex and olfactory detection.
RESUMO
Hyaluronidases catalyze the degradation of hyaluronan (HA), which is finding rising applications in medicine, cosmetic, and food industries. Recombinant expression of hyaluronidases in microbial hosts has been given special attention as a sustainable way to substitute animal tissue-derived hyaluronidases. In this study, we focused on optimizing the secretion of hyaluronidase from Homo sapiens in Pichia pastoris by secretion pathway engineering. The recombinant hyaluronidase was first expressed under the control of a constitutive promoter PGCW14. Then, two endoplasmic reticulum-related secretory pathways were engineered to improve the secretion capability of the recombinant strain. Signal peptide optimization suggested redirecting the protein into co-translational translocation using the ost1-proα signal sequence improved the secretion level by 20%. Enhancing the co-translational translocation by overexpressing signal recognition particle components further enhanced the secretory capability by 48%. Then, activating the unfolded protein response by overexpressing a transcriptional factor ScHac1p led to a secreted hyaluronidase activity of 4.06 U/mL, which was 2.1-fold higher than the original strain. Finally, fed-batch fermentation elevated the production to 19.82 U/mL. The combined engineering strategy described here could be applied to enhance the secretion capability of other proteins in yeast hosts. KEY POINTS: ⢠Improving protein secretion by enhancing co-translational translocation in P. pastoris was reported for the first time. ⢠Overexpressing Hac1p homologous from different origins improved the rhPH-20 secretion. ⢠A 4.9-fold increase in rhPH-20 secretion was achieved after fermentation optimization and fed-batch fermentation.
Assuntos
Hialuronoglucosaminidase , Resposta a Proteínas não Dobradas , Animais , Humanos , Hialuronoglucosaminidase/genética , Transporte Proteico , Retículo EndoplasmáticoRESUMO
BACKGROUND: Aging is an inevitable biological process. Accelerated aging renders adults more susceptible to chronic diseases and increases their mortality rates. Previous studies have reported the relationship between lifestyle factors and phenotypic aging. However, the relationship between intrinsic factors, such as reproductive factors, and phenotypic aging remains unclear. METHODS: This study utilized data from the National Health and Nutrition Examination Survey (NHANES), spanning from 1999 to 2010 and 2015-2018, with 14,736 adult women. Random forest imputation was used to handle missing covariate values in the final cohort. Weighted linear regression was utilized to analyze the relationship between women-specific reproductive factors and PhenoAgeAccel. Considering the potential impact of menopausal status on the results, additional analyses were conducted on premenopausal and postmenopausal participants. Additionally, the Life's Essential 8 (LE8) was used to investigate the impact of healthy lifestyle and other factors on the relationship between women-specific reproductive factors and PhenoAgeAccel. Stratified analyses were conducted based on significant interaction p-values. RESULTS: In the fully adjusted models, delayed menarche and gynecological surgery were associated with increased PhenoAgeAccel, whereas pregnancy history were associated with a decrease. Additionally, early or late ages of menopause, first live birth, and last live birth can all negatively impact PhenoAgeAccel. The relationship between women-specific reproductive factors and PhenoAgeAccel differs between premenopausal and postmenopausal women. High LE8 scores positively impacted the relationship between certain reproductive factors (age at menarche, age at menopause, age at first live birth, and age at last live birth) and phenotypic age acceleration. Stratified analysis showed significant interactions for the following variables: BMI with age at menarche, pregnancy history, and age at menopause; ethnicity with age at menopause, age at first live birth, and parity; smoking status with use of contraceptive pills and gynecologic surgery; hypertension with use of contraceptive pills, pregnancy history, and age at menopause. CONCLUSION: Delayed menarche, gynecological surgery, and early or late ages of menopause, first live birth, and last live birth are associated with accelerated phenotypic aging. High LE8 score may alleviate the adverse effects of reproductive factors on phenotypic aging.
Assuntos
Envelhecimento , Menarca , Menopausa , Inquéritos Nutricionais , Fenótipo , Humanos , Feminino , Adulto , Envelhecimento/fisiologia , Pessoa de Meia-Idade , Inquéritos Nutricionais/estatística & dados numéricos , Inquéritos Nutricionais/métodos , Menopausa/fisiologia , Menarca/fisiologia , Gravidez , Idoso , Reprodução/fisiologia , História Reprodutiva , Estilo de VidaRESUMO
RNA-binding proteins (RBPs) are kinds of proteins with either singular or multiple RNA-binding domains (RBDs), and they can assembly into ribonucleic acid-protein complexes, which mediate transportation, editing, splicing, stabilization, translational efficiency, or epigenetic modifications of their binding RNA partners, and thereby modulate various physiological and pathological processes. CUG-BP, Elav-like family 1 (CELF1) is a member of the CELF family of RBPs with high affinity to the GU-rich elements in mRNA, and thus exerting control over critical processes including mRNA splicing, translation, and decay. Mounting studies support that CELF1 is correlated with occurrence, genesis and development and represents a potential therapeutical target for these malignant diseases. Herein, we present the structure and function of CELF1, outline its role and regulatory mechanisms in varieties of homeostasis and diseases, summarize the identified CELF1 regulators and their structure-activity relationships, and prospect the current challenges and their solutions during studies on CELF1 functions and corresponding drug discovery, which will facilitate the establishment of a targeted regulatory network for CELF1 in diseases and advance CELF1 as a potential drug target for disease therapy.
Assuntos
Descoberta de Drogas , Epigênese Genética , Homeostase , RNA , RNA MensageiroRESUMO
Twelve compounds, comprising of four new ones, 6ß,7α-limondiol (1) and ethyl 19-hydroxyisoobacunoate diosphenol (2), N-benzoyl 3-prenyltyramine (9) and 9-O-methyl integrifoliodiol (12), were isolated from the twigs with leaves of Tetradium trichotomum. The structures were elucidated by analysis of MS, NMR, and single-crystal X-ray diffraction. Compounds 1, 6, 8, 9 and 12 exhibited immunosuppressive activities in vitro against the proliferation of ConA-induced T lymphocytes and LPS-induced B cells.
RESUMO
Microplastics (MPs) and antibiotic resistance genes (ARGs) are important pollutants in waste activated sludge (WAS), but their interactions during anaerobic digestion (AD) still need to be further explored. This study investigated variations in ARGs, mobile genetic elements (MGEs), and host bacteria during AD under the pressure of polyamide (PA), polyethylene (PE), and polypropylene (PP). The results showed that the MPs increased methane production by 11.7-35.5%, and decreased ARG abundance by 5.6-24.6%. Correlation analysis showed that the decrease of MGEs (plasmid, prophage, etc.) promoted the decrease of the abundance of multidrug, aminoglycoside and tetracycline resistance genes. Metagenomic annotation revealed that the reduction of key host bacteria (Arenimonas, Lautropia, etc.) reduced the abundance of major ARGs (rsmA, rpoB2, etc.). Moreover, PP MPs contributed to a reduction in the abundance of functional genes related to the production of reactive oxygen species, ATP synthesis, and cell membrane permeability, which was conducive to reducing the potential for horizontal gene transfer of ARGs. These findings provide insights into the treatment of organic waste containing MPs.
Assuntos
Resistência Microbiana a Medicamentos , Transferência Genética Horizontal , Microplásticos , Esgotos , Resistência Microbiana a Medicamentos/genética , Anaerobiose , Esgotos/microbiologia , Antibacterianos/farmacologiaRESUMO
PURPOSE: This study evaluated the methods and clinical effects of multidisciplinary collaborative treatment for occlusal reconstruction in patients with old jaw fractures and dentition defects. METHODS: Patients with old jaw fractures and dentition defects who underwent occlusal reconstruction at the Third Affiliated Hospital of Air Force Military Medical University from January 2018 to December 2022 were enrolled. Clinical treatment was classified into 3 phases. In phase I, techniques such as orthognathic surgery, microsurgery, and distraction osteogenesis were employed to reconstruct the correct three-dimensional (3D) jaw position relationship. In phase II, bone augmentation and soft tissue management techniques were utilized to address insufficient alveolar bone mass and poor gingival soft tissue conditions. In phase III, implant-supported overdentures or fixed dentures were used for occlusal reconstruction. A summary of treatment methods, clinical efficacy evaluation, comparative analysis of imageological examinations, and satisfaction questionnaire survey were utilized to evaluate the therapeutic efficacy in patients with traumatic old jaw fractures and dentition defects. All data are summarized using the arithmetic mean and standard deviation and compared using independent sample t-tests. RESULTS: In 15 patients with old jaw fractures and dentition defects (an average age of 32 years, ranging from 18 to 53 years), there were 7 cases of malocclusion of single maxillary fracture, 6 of malocclusion of single mandible fracture, and 2 of malocclusion of both maxillary and mandible fractures. There were 5 patients with single maxillary dentition defects, 2 with single mandibular dentition defects, and 8 with both maxillary and mandibular dentition defects. To reconstruct the correct 3D jaw positional relationship, 5 patients underwent Le Fort I osteotomy of the maxilla, 3 underwent bilateral sagittal split ramus osteotomy of the mandible, 4 underwent open reduction and internal fixation for old jaw fractures, 3 underwent temporomandibular joint surgery, and 4 underwent distraction osteogenesis. All patients underwent jawbone augmentation, of whom 4 patients underwent a free composite vascularized bone flap (26.66%) and the remaining patients underwent local alveolar bone augmentation. Free gingival graft and connective tissue graft were the main methods for soft tissue augmentation (73.33%). The 15 patients received 81 implants, of whom 11 patients received implant-supported fixed dentures and 4 received implant-supported removable dentures. The survival rate of all implants was 93.82%. The final imageological examination of 15 patients confirmed that the malocclusion was corrected, and the clinical treatment ultimately achieved occlusal function reconstruction. The patient satisfaction questionnaire survey showed that they were satisfied with the efficacy, phonetics, aesthetics, and comfort after treatment. CONCLUSION: Occlusal reconstruction of old jaw fractures and dentition defects requires a phased sequential comprehensive treatment, consisting of 3D spatial jaw correction, alveolar bone augmentation and soft tissue augmentation, and implant-supported occlusal reconstruction, achieving satisfactory clinical therapeutic efficacy.
RESUMO
BACKGROUND: The rapid emergence of single-cell RNA-seq (scRNA-seq) data presents remarkable opportunities for broad investigations through integration analyses. However, most integration models are black boxes that lack interpretability or are hard to train. RESULTS: To address the above issues, we propose scInterpreter, a deep learning-based interpretable model. scInterpreter substantially outperforms other state-of-the-art (SOTA) models in multiple benchmark datasets. In addition, scInterpreter is extensible and can integrate and annotate atlas scRNA-seq data. We evaluated the robustness of scInterpreter in a variety of situations. Through comparison experiments, we found that with a knowledge prior, the training process can be significantly accelerated. Finally, we conducted interpretability analysis for each dimension (pathway) of cell representation in the embedding space. CONCLUSIONS: The results showed that the cell representations obtained by scInterpreter are full of biological significance. Through weight sorting, we found several new genes related to pathways in PBMC dataset. In general, scInterpreter is an effective and interpretable integration tool. It is expected that scInterpreter will bring great convenience to the study of single-cell transcriptomics.