RESUMEN

As the first identified multidrug efflux pump in Mycobacterium tuberculosis (Mtb), EfpA is an essential protein and promising drug target. However, the functional and inhibitory mechanisms of EfpA are poorly understood. Here we report cryo-EM structures of EfpA in outward-open conformation, either bound to three endogenous lipids or the inhibitor BRD-8000.3. Three lipids inside EfpA span from the inner leaflet to the outer leaflet of the membrane. BRD-8000.3 occupies one lipid site at the level of inner membrane leaflet, competitively inhibiting lipid binding. EfpA resembles the related lysophospholipid transporter MFSD2A in both overall structure and lipid binding sites and may function as a lipid flippase. Combining AlphaFold-predicted EfpA structure, which is inward-open, we propose a complete conformational transition cycle for EfpA. Together, our results provide a structural and mechanistic foundation to comprehend EfpA function and develop EfpA-targeting anti-TB drugs.

Asunto(s)

Proteínas Bacterianas , Mycobacterium tuberculosis , Antituberculosos/farmacología , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/química , Sitios de Unión , Transporte Biológico , Microscopía por Crioelectrón , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Transporte de Membrana/química , Modelos Moleculares , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/efectos de los fármacos , Conformación Proteica

RESUMEN

BACKGROUND: Numerous studies have examined whether vitamin D is associated with gestational diabetes mellitus (GDM). Nevertheless, it is still challenging to determine the causality, due to a number of shortcomings in observational research and randomized controlled trials. OBJECTIVE: Mendelian randomization (MR) with two samples was conducted to investigate the potential causative association between 25-hydroxyvitamin D (25(OH)D), vitamin D binding protein (VDBP) and GDM risk. METHODS: Publicly accessible summary data from independent cohorts were used for two-sample MR. For 25(OH)D, we obtained data from UK Biobank, IEU and EBI, then performed a meta-analysis to enhance the statistical power (via METAL); for VDBP, data were obtained from the INTERVAL study; for GDM, data were obtained from FinnGen. The inverse variance weighted (IVW) approach was performed as the main analysis, together with several sensitivity analyses, such as MR-Egger, maximum likelihood, weighted median, and weighted mode. RESULTS: The IVW results revealed a weak negative causal connection between 25(OH)D and GDM risk [OR (95% CI) = 0.71 (0.50, 0.99), p = 0.046]. However, the causal association was unstable according to sensitivity analyses, and Cochran's Q test revealed significant heterogeneity. After removing BMI-related IVs, the causal association between 25(OH)D and GDM disappeared [OR (95% CI) = 0.76 (0.55, 1.06), p = 0.101]. In addition, our study found no proof to support the assumption that VDBP level was related to GDM risk causally [OR (95% CI) = 0.98 (0.93, 1.03), p = 0.408]. CONCLUSIONS: According to this study, a weak negative causal association between 25(OH)D and GDM risk was found, while we had little proof to support the link between VDBP and GDM. To further explore whether total or free 25(OH)D levels and GDM are causally related, GWAS data with an emphasis on women of reproductive age and other ethnic groups are required.

Asunto(s)

Diabetes Gestacional , Análisis de la Aleatorización Mendeliana , Proteína de Unión a Vitamina D , Vitamina D , Humanos , Femenino , Diabetes Gestacional/sangre , Diabetes Gestacional/genética , Proteína de Unión a Vitamina D/genética , Proteína de Unión a Vitamina D/sangre , Embarazo , Vitamina D/análogos & derivados , Vitamina D/sangre , Factores de Riesgo , Polimorfismo de Nucleótido Simple

RESUMEN

BACKGROUND: This study reported the safety and efficacy of a phase 2, open-label, single-arm, exploratory clinical trial of induction immunochemotherapy in patients with initially unresectable advanced esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: Patients underwent three cycles of induction therapy with tislelizumab, cisplatin, and 5-fluorouracil. The primary endpoints were the safety, major pathological response (MPR), and pathological complete response (pCR). Secondary endpoints included the R0 resection rate, disease-free survival (DFS), and overall survival (OS). Genomic data and immune microenvironment data were analyzed exploratively. RESULTS: The treatment was safe, with a grade 3 or higher adverse event rate of 14.9% (7/47). Of the total 47 patients enrolled in the study, 19 (40.4%) achieved MPR, 12 (25.5%) achieved pCR, 4 (8.5%) achieved complete clinical response (cCR) and declined surgery, and 23 (48.94%) underwent successful resection. Median follow-up was 18 months, with a median DFS of 24 months, a median OS of 36 months. A high tumor mutation burden was associated with a better prognosis for patients who underwent surgery. Patients who achieved pCR had higher levels of immune cell infiltration and a greater proportion and concentration of tertiary lymphoid structures compared with those who experienced a major pathological response. CONCLUSIONS: Tislelizumab combined with chemotherapy is effective for ESCC, yielding high cCR, pCR, surgical conversion, and R0 resection rates, and tolerable adverse events. TRIAL REGISTRATION: NCT05469061.

RESUMEN

 Micro-light-emitting diodes (µLEDs) hold significant promise for applications in displays and visible light communication (VLC). This study substantiates the viability of a wavelength division multiplexing (WDM)-VLC system using InGaN blue, green, and red µLED devices. The devices exhibited notable color stability and high modulation bandwidth due to the weakly polarized electric field in the blue and green semipolar devices and the stress-optimized structure in the red device. The aggregated data rate reached 11.14 Gbps. Moreover, the blue, green, and red InGaN µLEDs exhibited a wide color gamut, encompassing 119.4% of the NTSC and 89.2% of the Rec. 2020 standards, affirming the potential of blue, green, and red InGaN µLEDs for applications in full-color display and WDM-VLC systems.

RESUMEN

Mink are susceptible to viruses such as SARS-CoV-2, H1N1 and H9N2, so they are considered a potential animal model for studying human viral infections. Therefore, it is important to study the immune system of mink. Immunoglobulin (Ig) is an important component of humoral immunity and plays an important role in the body's immune defense. In this study, we described the gene loci structure of mink Ig germline by genome comparison, and analysed the mechanism of expression diversity of mink antibody library by 5'RACE and next-generation sequencing (NGS). The results were as follows: the IgH, Igκ and Igλ loci of mink were located on chromosome 13, chromosome 8 and chromosome 3, respectively, and they had 25, 36 and 7 V genes, 3, 5 and 7 J genes and 10 DH genes, respectively. Mink Ig heavy chain preferred the IGHV1, IGHD2 and IGHJ4 subgroups, κ chain mainly use the IGKV1, IGKJ1 and IGHL4 subgroups, and λ chain mainly use the IGLV3 and IGLJ3 subgroups. Linkage diversity analysis revealed that N nucleotide insertion was the main factor affecting the linkage diversity of mink Igs. On the mutation types of mink Ig Somatic Hypermutation (SHM), the high mutation types of heavy chain were mainly G > A, C > T, T > C, A > G, C > A, G > T, A > C, and T > G; the high mutation types of κ chain were G > A and T > C; and the high mutation types of λ chain were G > A and A > G. The objective of this study was to analyse the loci structure and expression diversity of Ig in mink. The results contribute to our comprehension of Ig expression patterns in mink and were valuable for advancing knowledge in mink immunogenetics, exploring the evolution of adaptive immune systems across different species, and conducting comparative genomics research.

Asunto(s)

Visón , Animales , Visón/genética , Visón/inmunología , Secuenciación de Nucleótidos de Alto Rendimiento , Inmunidad Humoral/genética , COVID-19/inmunología , COVID-19/virología , Inmunoglobulinas/genética , Humanos , Mutación/genética , Cadenas Pesadas de Inmunoglobulina/genética , SARS-CoV-2/inmunología , Sitios Genéticos

RESUMEN

The rhizome of Corydalis decumbens is a traditional Chinese medicine commonly utilized in the clinical treatment of acute ischemic stroke. Numerous phytochemical and biological investigations have demonstrated that protoberberine alkaloids from C. decumbens exhibit diverse pharmaceutical activities against various diseases. Sinometumine E (SE), a protoberberine alkaloid isolated from C. decumbens for the first time, is characterized by a complex 6/6/6/6/6/6 hexacyclic skeleton. In the current study, we investigated the protective effects of SE on endothelial cell injury and its angiogenesis effects in zebrafish. The results suggested that SE showed significant anti-ischemic effects on OGD/R-induced HBEC-5i and HUVECs cell ischemia/reperfusion injury model. Furthermore, it promoted angiogenesis in PTK787-induced, MPTP-induced, and atorvastatin-induced vessel injury models of zebrafish, while also suppressing hypoxia-induced locomotor impairment in zebrafish. Transcriptome sequencing analysis provided a sign that SE likely to promotes angiogenesis through the HIF-1/VEGF signaling pathway to exert anti-ischemic effects. Consistently, SE modulated several genes related to HIF-1/VEGF signal pathway, such as hif-1, vegf, vegfr-2, pi3k, erk, akt and plcγ. Molecular docking analysis revealed that VEGFR-2 exhibited high binding affinity with SE, and western blot analysis confirmed that SE treatment enhanced the expression of VEGFR-2. In conclusion, our study profiled the angiogenic activities of SE in vitro and in vivo. The key targets and related pathways involved in anti-ischemic effects of SE, shedding light on the pharmacodynamic components and mechanisms of Corydalis decumbens, and provides valuable insights for identifying effective substances for the treatment of ischemic stroke.

Asunto(s)

Corydalis , Simulación del Acoplamiento Molecular , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular , Pez Cebra , Animales , Corydalis/química , Humanos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Transducción de Señal/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Inductores de la Angiogénesis/farmacología , Factor 1 Inducible por Hipoxia/metabolismo , Angiogénesis

RESUMEN

Squalene is a highly sought-after triterpene compound in growing demand, and its production offers a promising avenue for circular economy practices. In this study, we applied metabolic engineering principles to enhance squalene production in the nonconventional yeast Yarrowia lipolytica, using waste cooking oil as a substrate. By overexpressing key enzymes in the mevalonate pathway - specifically ERG9 encoding squalene synthase, ERG20 encoding farnesyl diphosphate synthase, and HMGR encoding hydroxy-methyl-glutaryl-CoA reductase - we achieved a yield of 779.9 mg/L of squalene. Further co-overexpression of DGA1, encoding diacylglycerol acyltransferase, and CAT2, encoding carnitine acetyltransferase, in combination with prior metabolic enhancements, boosted squalene production to 1381.4 mg/L in the engineered strain Po1g17. To enhance the supply of the precursor acetyl-CoA and inhibit downstream squalene conversion, we supplemented with 6 g/L pyruvic acid and 0.7 mg/L terbinafine, resulting in an overall squalene titer of 2594.1 mg/L. These advancements underscore the potential for sustainable, large-scale squalene production using Y. lipolytica cell factories, contributing to circular economy initiatives by valorizing waste materials.

RESUMEN

Active learning (AL) is to design label-efficient algorithms by labeling the most representative samples. It reduces annotation cost and attracts increasing attention from the community. However, previous AL methods suffer from the inadequacy of annotations and unreliable uncertainty estimation. Moreover, we find that they ignore the intra-diversity of selected samples, which leads to sampling redundancy. In view of these challenges, we propose an inductive state-relabeling adversarial AL model (ISRA) that consists of a unified representation generator, an inductive state-relabeling discriminator, and a heuristic clique rescaling module. The generator introduces contrastive learning to leverage unlabeled samples for self-supervised training, where the mutual information is utilized to improve the representation quality for AL selection. Then, we design an inductive uncertainty indicator to learn the state score from labeled data and relabel unlabeled data with different importance for better discrimination of instructive samples. To solve the problem of sampling redundancy, the heuristic clique rescaling module measures the intra-diversity of candidate samples and recurrently rescales them to select the most informative samples. The experiments conducted on eight datasets and two imbalanced scenarios show that our model outperforms the previous state-of-the-art AL methods. As an extension on the cross-modal AL task, we apply ISRA to the image captioning and it also achieves superior performance.

RESUMEN

The gut microbiota is closely associated with human health, and alterations in gut microbiota can influence various physiological and pathological activities in the human body. Therefore, microbiota regulation has become an important strategy in current disease treatment, albeit facing numerous challenges. Nanomaterials, owing to their excellent protective properties, drug release capabilities, targeting abilities, and good biocompatibility, have been widely developed and utilized in pharmaceuticals and dietary fields. In recent years, significant progress has been made in research on utilizing nanomaterials to assist in regulating gut microbiota for disease intervention. This review explores the latest advancements in the application of nanomaterials for microbiota regulation and offers insights into the future development of nanomaterials in modulating gut microbiota.

RESUMEN

Obtaining comprehensive structural descriptions of macromolecules within their natural cellular context holds immense potential for understanding fundamental biology and improving health. Here, we present the landscape of protein synthesis inside human cells in unprecedented detail obtained using an approach which combines automated cryo-focused ion beam (FIB) milling and in situ single-particle cryo-electron microscopy (cryo-EM). With this in situ cryo-EM approach we resolved a 2.19 Å consensus structure of the human 80S ribosome and unveiled its 21 distinct functional states, nearly all higher than 3 Å resolution. In contrast to in vitro studies, we identified protein factors, including SERBP1, EDF1 and NAC/3, not enriched on purified ribosomes. Most strikingly, we observed that SERBP1 binds to the ribosome in almost all translating and non-translating states to bridge the 60S and 40S ribosomal subunits. These newly observed binding sites suggest that SERBP1 may serve an important regulatory role in translation. We also uncovered a detailed interface between adjacent translating ribosomes which can form the helical polysome structure. Finally, we resolved high-resolution structures from cells treated with homoharringtonine and cycloheximide, and identified numerous polyamines bound to the ribosome, including a spermidine that interacts with cycloheximide bound at the E site of the ribosome, underscoring the importance of high-resolution in situ studies in the complex native environment. Collectively, our work represents a significant advancement in detailed structural studies within cellular contexts.

RESUMEN

Human immunodeficiency virus (HIV) infection is still a global public health issue, and the development of an effective prophylactic vaccine inducing potent neutralizing antibodies remains a significant challenge. This study aims to explore the inflammation-related proteins associated with the neutralizing antibodies induced by the DNA/rTV vaccine. In this study, we employed the Olink chip to analyze the inflammation-related proteins in plasma in healthy individuals receiving HIV candidate vaccine (DNA priming and recombinant vaccinia virus rTV boosting) and compared the differences between neutralizing antibody-positive (nab + ) and -negative(nab-) groups. We identified 25 differentially expressed factors and conducted enrichment and correlation analysis on them. Our results revealed that significant expression differences in artemin (ARTN) and C-C motif chemokine ligand 23 (CCL23) between nab+ and -nab- groups. Notably, the expression of CCL23 was negatively corelated to the ID50 of neutralizing antibodies and the intensity of the CD4+ T cell responses. This study enriches our understanding of the immune picture induced by the DNA/rTV vaccine, and provides insights for future HIV vaccine development.

Asunto(s)

Vacunas contra el SIDA , Anticuerpos Neutralizantes , Anticuerpos Anti-VIH , Infecciones por VIH , VIH-1 , Proteómica , Virus Vaccinia , Humanos , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Virus Vaccinia/inmunología , Virus Vaccinia/genética , Anticuerpos Anti-VIH/sangre , Anticuerpos Anti-VIH/inmunología , VIH-1/inmunología , VIH-1/genética , Adulto , Vacunas contra el SIDA/inmunología , Masculino , Infecciones por VIH/inmunología , Vacunas de ADN/inmunología , Femenino , Voluntarios Sanos , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/administración & dosificación , Plasma/inmunología , Adulto Joven

RESUMEN

BACKGROUND: Kawasaki disease (KD) is an autoimmune disease with cardiovascular disease as its main complication, mainly affecting children under 5 years old. KD treatment has made tremendous progress in recent years, but intravenous immunoglobulin (IVIG) resistance remains a major dilemma. Bibliometric analysis had not been used previously to summarize and analyze publications related to IVIG resistance in KD. This study aimed to provide an overview of the knowledge framework and research hotspots in this field through bibliometrics, and provide references for future basic and clinical research. METHODS: Through bibliometric analysis of relevant literature published on the Web of Science Core Collection (WoSCC) database between 1997 and 2023, we investigated the cooccurrence and collaboration relationships among countries, institutions, journals, and authors and summarized key research topics and hotspots. RESULTS: Following screening, a total of 364 publications were downloaded, comprising 328 articles and 36 reviews. The number of articles on IVIG resistance increased year on year and the top three most productive countries were China, Japan, and the United States. Frontiers in Pediatrics had the most published articles, and the Journal of Pediatrics had the most citations. IVIG resistance had been studied by 1889 authors, of whom Kuo Ho Chang had published the most papers. CONCLUSION: Research in the field was focused on risk factors, therapy (atorvastatin, tumor necrosis factor-alpha inhibitors), pathogenesis (gene expression), and similar diseases (multisystem inflammatory syndrome in children, MIS-C). "Treatment," "risk factor," and "prediction" were important keywords, providing a valuable reference for scholars studying this field. We suggest that, in the future, more active international collaborations are carried out to study the pathogenesis of IVIG insensitivity, using high-throughput sequencing technology. We also recommend that machine learning techniques are applied to explore the predictive variables of IVIG resistance.

Asunto(s)

Bibliometría , Resistencia a Medicamentos , Inmunoglobulinas Intravenosas , Síndrome Mucocutáneo Linfonodular , Humanos , Inmunoglobulinas Intravenosas/administración & dosificación , Inmunoglobulinas Intravenosas/farmacología , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Síndrome Mucocutáneo Linfonodular/epidemiología

RESUMEN

This study provides detailed description of a newly-discovered Callicarpayongshunensis Wen B. Xu, Xiao D. Li & Yan Ling Liu (Lamiaceae) species from Hunan, China. The species shares similarities in the inflorescence, glandular colour and leaf shape features with C.luteopunctata H. T. Chang and C.giraldii Hesse ex Rehd., while its white fruits are similar to those of C.longifolia Lamk. However, its procumbent, evergreen shrub and white fruits are distinctly different from those of C.luteopunctata and C.giraldii, while its procumbent, scarless nodes and stellate pubescence free fruits distinguishes it from C.longifolia. Images, distribution, morphological features, molecular phylogenetic classification and conservation assessment of this new Callicarpa species are explored.

RESUMEN

As of December 2022, 2603 laboratory-identified Middle East respiratory syndrome coronavirus (MERS-CoV) infections and 935 associated deaths, with a mortality rate of 36%, had been reported to the World Health Organization (WHO). However, there are still no vaccines for MERS-CoV, which makes the prevention and control of MERS-CoV difficult. In this study, we generated two DNA vaccine candidates by integrating MERS-CoV Spike (S) gene into a replicating Vaccinia Tian Tan (VTT) vector. Compared to homologous immunization with either vaccine, mice immunized with DNA vaccine prime and VTT vaccine boost exhibited much stronger and durable humoral and cellular immune responses. The immunized mice produced robust binding antibodies and broad neutralizing antibodies against the EMC2012, England1 and KNIH strains of MERS-CoV. Prime-Boost immunization also induced strong MERS-S specific T cells responses, with high memory and poly-functional (CD107a-IFN-γ-TNF-α) effector CD8+ T cells. In conclusion, the research demonstrated that DNA-Prime/VTT-Boost strategy could elicit robust and balanced humoral and cellular immune responses against MERS-CoV-S. This study not only provides a promising set of MERS-CoV vaccine candidates, but also proposes a heterologous sequential immunization strategy worthy of further development.

Asunto(s)

Anticuerpos Neutralizantes , Anticuerpos Antivirales , Infecciones por Coronavirus , Inmunidad Celular , Inmunidad Humoral , Ratones Endogámicos BALB C , Coronavirus del Síndrome Respiratorio de Oriente Medio , Vacunas de ADN , Vacunas Virales , Animales , Vacunas de ADN/inmunología , Vacunas de ADN/administración & dosificación , Vacunas de ADN/genética , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunología , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Anticuerpos Antivirales/sangre , Ratones , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Vacunas Virales/inmunología , Vacunas Virales/administración & dosificación , Vacunas Virales/genética , Femenino , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/inmunología , Linfocitos T CD8-positivos/inmunología , Virus Vaccinia/genética , Virus Vaccinia/inmunología , Inmunización Secundaria , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética

RESUMEN

Eight previously undescribed cevanine-type steroidal alkaloids, cirrhosinones I-N and cirrhosinols A-B, along with five known analogs, were isolated from the bulbs of Fritillaria cirrhosa D. Don. Their structures were elucidated on the basis of comprehensive analysis of HRESIMS, 1D and 2D NMR spectroscopic data, and single-crystal X-ray diffraction analyses. All compounds revealed weak NO inhibitory activities in the LPS-stimulated NR8383 cells at the concentration of 20 µM, with inhibition ratios ranging from 5.1% to 14.3%.

Asunto(s)

Alcaloides , Fritillaria , Raíces de Plantas , Fritillaria/química , Raíces de Plantas/química , Estructura Molecular , Alcaloides/química , Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Cevanas/química , Cevanas/farmacología , Cevanas/aislamiento & purificación , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Animales , Conformación Molecular , Cristalografía por Rayos X , Línea Celular , Ratas , Esteroides/química , Esteroides/aislamiento & purificación , Esteroides/farmacología , Relación Dosis-Respuesta a Droga , Relación Estructura-Actividad , Modelos Moleculares

RESUMEN

This study explored the association between diabetes, cognitive imFpairment (CI), and mortality in a cohort of 2931 individuals aged 60 and above from the 2011 to 2014 NHANES. Mortality data was gathered through 2019, and multivariable Cox proportional hazards models were used to determine the association between diabetes, CI, and mortality adjusting for sociodemographic characteristics, lifestyle factors, and comorbidity conditions. The study spanned up to 9.17 years, observing 579 deaths, with individuals having both diabetes and CI showing the highest all-cause mortality (23.6 events per 100 patient-years). Adjusted analysis revealed a 2.34-fold higher risk of all-cause mortality for this group, surpassing those with diabetes or CI alone. These results held after a series of stratified and sensitivity analyses. In conclusion, CI was linked to higher all-cause mortality in individuals with diabetes, emphasizing the need to address cognitive dysfunction in diabetic patients.

Asunto(s)

Enfermedades Cardiovasculares , Causas de Muerte , Disfunción Cognitiva , Diabetes Mellitus , Modelos de Riesgos Proporcionales , Humanos , Masculino , Femenino , Anciano , Estudios Prospectivos , Disfunción Cognitiva/mortalidad , Disfunción Cognitiva/epidemiología , Persona de Mediana Edad , Enfermedades Cardiovasculares/mortalidad , Diabetes Mellitus/mortalidad , Diabetes Mellitus/epidemiología , Encuestas Nutricionales , Factores de Riesgo , Estados Unidos/epidemiología , Anciano de 80 o más Años , Comorbilidad

RESUMEN

Musk secreted by male forest musk deer (Moschus berezovskii) musk glands is an invaluable component of medicine and perfume. Musk secretion depends on musk gland maturation; however, the mechanism of its development remains elusive. Herein, using single cell multiome ATAC + gene expression coupled with several bioinformatic analyses, a dynamic transcriptional cell atlas of musk gland development was revealed, and key genes and transcription factors affecting its development were determined. Twelve cell types, including two different types of acinar cells (Clusters 0 and 10) were identified. Single-nucleus RNA and single-nucleus ATAC sequencing analyses revealed that seven core target genes associated with musk secretion (Hsd17b2, Acacb, Lss, Vapa, Aldh16a1, Aldh7a1, and Sqle) were regulated by 12 core transcription factors (FOXO1, CUX2, RORA, RUNX1, KLF6, MGA, NFIC, FOXO3, ETV5, NR3C1, HSF4, and MITF) during the development of Cluster 0 acinar cells. Kyoto Encyclopedia of Genes and Genomes enrichment showed significant changes in the pathways associated with musk secretion during acinar cell development. Gene set variation analysis also revealed that certain pathways associated with musk secretion were enriched in 6-year-old acinar cells. A gene co-expression network was constructed during acinar cell development to provide a precise understanding of the connections between transcription factors, genes, and pathways. Finally, intercellular communication analysis showed that intercellular communication is involved in musk gland development. This study provides crucial insights into the changes and key factors underlying musk gland development, which serve as valuable resources for studying musk secretion mechanisms and promoting the protection of this endangered species.

Asunto(s)

Ciervos , Transcriptoma , Animales , Ciervos/genética , Masculino , Ácidos Grasos Monoinsaturados/metabolismo , Cromatina/metabolismo

RESUMEN

The membrane-proximal external region (MPER) represents a highly conserved region of the Human Immunodeficiency Virus (HIV) envelope glycoprotein (env) targeted by several broadly neutralizing antibodies (bnAbs). In this study, we employed single genome amplification to amplify 34 full-length env sequences from the 2005 plasma sample of CBJC504, a chronic HIV-1 clade B infected individual. We identified three amino acid changes (N671S, D674N, and K677R) in the MPER. A longitudinal analysis revealed that the proportion of env sequences with MPER mutations increased from 26.5 % in 2005 to 56.0 % in 2009, and the sequences with the same mutation clustered together. Nine functional pseudoviruses were generated from the 34 env sequences to examine the effect of these mutations on neutralizing activity. Pseudoviruses carrying N674 or R677 mutations demonstrate increased sensitivity to autologous plasma and monoclonal antibodies 2F5, 4E10, and 10E8. Reverse mutations were performed in env including N674, R677, D659, and S671/N677 mutations, to validate the impact of the mutations on neutralizing sensitivity. Neutralization assays indicated that the N671S mutation increased neutralization sensitivity to 2F5 and 10E8. The amino acid R at position 677 increased viral resistance to 10E8, whereas N enhanced viral resistance to 4E10 and 10E8. It has been proposed that critical amino acids in the extra-MPER and the number of potential N-like glycosylation sites (PNGSs) in the V1 loop may have an impact on neutralizing activity. Understanding the mutations and evolution of MPER in chronically infected patients with HIV-1 is crucial for the design and development of vaccines that trigger bnAbs against MPER.

Asunto(s)

Sustitución de Aminoácidos , Anticuerpos Neutralizantes , Anticuerpos Anti-VIH , Infecciones por VIH , VIH-1 , Pruebas de Neutralización , Productos del Gen env del Virus de la Inmunodeficiencia Humana , Humanos , VIH-1/genética , VIH-1/inmunología , Anticuerpos Neutralizantes/inmunología , Infecciones por VIH/virología , Infecciones por VIH/inmunología , Anticuerpos Anti-VIH/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Estudios Longitudinales

RESUMEN

BACKGROUND: Spexin, a 14 amino acid peptide, has been reported to regulate obesity and its associated complications. However, little is known about the underlying molecular mechanism. Therefore, this study aimed to investigate the effects of spexin on obesity and explore the detailed molecular mechanisms in vivo and in vitro. METHODS: Male C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity, and mice fed a standard fat diet were used as controls. Then, these mice were treated with SPX or Vehicle by intraperitoneal injection for an additional 12 weeks, respectively. The metabolic profile, fat-browning specific markers and mitochondrial contents were detected. In vitro, 3T3-L1 cells were used to investigate the molecular mechanisms. RESULTS: After 12 weeks of treatment, SPX significantly decreased body weight, serum lipid levels, and improved insulin sensitivity in HFD-induced obese mice. Moreover, SPX was found to promote oxygen consumption in HFD mice, and it increased mitochondrial content as well as the expression of brown-specific markers in white adipose tissue (WAT) of HFD mice. These results were consistent with the increase in mitochondrial content and the expression of brown-specific markers in 3T3-L1 mature adipocytes. Of note, the spexin-mediated beneficial pro-browning actions were abolished by the JAK2/STAT3 pathway antagonists in mature 3T3-L1 cells. CONCLUSIONS: These data indicate that spexin ameliorates obesity-induced metabolic disorders by improving WAT browning via activation of the JAK2/STAT3 signaling pathway. Therefore, SPX may serve as a new therapeutic candidate for treating obesity.

RESUMEN

Video activity anticipation aims to predict what will happen in the future, embracing a broad application prospect ranging from robot vision and autonomous driving. Despite the recent progress, the data uncertainty issue, reflected as the content evolution process and dynamic correlation in event labels, has been somehow ignored. This reduces the model generalization ability and deep understanding on video content, leading to serious error accumulation and degraded performance. In this paper, we address the uncertainty learning problem and propose an uncertainty-boosted robust video activity anticipation framework, which generates uncertainty values to indicate the credibility of the anticipation results. The uncertainty value is used to derive a temperature parameter in the softmax function to modulate the predicted target activity distribution. To guarantee the distribution adjustment, we construct a reasonable target activity label representation by incorporating the activity evolution from the temporal class correlation and the semantic relationship. Moreover, we quantify the uncertainty into relative values by comparing the uncertainty among sample pairs and their temporal-lengths. This relative strategy provides a more accessible way in uncertainty modeling than quantifying the absolute uncertainty values on the whole dataset. Experiments on multiple backbones and benchmarks show our framework achieves promising performance and better robustness/interpretability. Source codes are available at https://github.com/qzhb/UbRV2A.