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Multitarget strategies are essential in addressing complex diseases, yet developing multitarget-directed ligands (MTDLs) is particularly challenging when aiming to engage multiple therapeutic targets across different tissues. Here, we present a molecular transformer strategy, enhancing traditional MTDLs. By utilizing esterase-driven hydrolysis, this approach mimics the adaptive nature of transformers for enabling molecules to modify their pharmacological effects in response to the biological milieu. By virtual screening and biological evaluation, we identified KGP-25, a novel compound initially targeting the voltage-gated sodium channel 1.8 (Nav1.8) in the peripheral nervous system (PNS) for analgesia, and later the γ-aminobutyric acid subtype A receptor (GABAA) in the central nervous system (CNS) for general anesthesia. Our findings confirm KGP-25's dual efficacy in cellular and animal models, effectively reducing opioid-related side effects. This study validates the molecular transformer approach in drug design and highlights its potential to overcome the limitations of conventional MTDLs, paving new avenues in innovative therapeutic strategies.
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Analgésicos , Esterasas , Ligandos , Analgésicos/farmacología , Analgésicos/química , Animales , Humanos , Esterasas/metabolismo , Anestésicos/farmacología , Anestésicos/química , Receptores de GABA-A/metabolismo , Receptores de GABA-A/química , Diseño de Fármacos , Ratones , MasculinoRESUMEN
On September 2, 2022, the Food and Drug Administration (FDA) approved durvalumab in combination with cisplatin and gemcitabine, for the treatment of patients with unresectable or metastatic biliary tract cancers (BTC). On October 31, 2023, the FDA approved pembrolizumab in combination with cisplatin and gemcitabine for the same indication. Approvals were based on two randomized, multiregional, placebo-controlled trials that randomly allocated patients to receive durvalumab (TOPAZ-1) or pembrolizumab (KEYNOTE-966) in combination with chemotherapy or placebo in combination with chemotherapy. Overall survival (OS) was the primary endpoint in both studies. In both studies, a statistically significant and clinically meaningful improvement in OS was demonstrated. In the TOPAZ-1 trial, the median OS of patients receiving durvalumab was 12.8 months [95% confidence interval (CI), 11.1-14.0] and 11.5 months (95% CI, 10.1-12.5) in patients receiving placebo [hazard ratio (HR), 0.80 (95% CI, 0.66-0.97)]. In the KEYNOTE-966 trial, the median OS of patients receiving pembrolizumab was 12.7 months (95% CI, 11.5-13.6) and 10.9 months (95% CI, 9.9-11.6) in patients receiving placebo [HR, 0.83 (95% CI, 0.72-0.95)]. The addition of checkpoint inhibitors to standard of care chemotherapy for this indication did not reveal any new adverse event signals, and the safety profile was generally consistent with the known clinical experience with durvalumab, pembrolizumab, and the backbone chemotherapy regimen. The approvals of durvalumab and pembrolizumab in combination with standard of care cisplatin and gemcitabine for the treatment of unresectable or metastatic BTC add two new therapeutic options for these patients.
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Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias del Sistema Biliar , Aprobación de Drogas , Inhibidores de Puntos de Control Inmunológico , United States Food and Drug Administration , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Estados Unidos , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Gemcitabina , AdultoRESUMEN
Chronic pain is a common and challenging clinical problem that significantly impacts patients' quality of life. The sodium channel Nav1.8 plays a crucial role in the occurrence and development of chronic pain, making it one of the key targets for treating chronic pain. In this article, we combined virtual screening with cell membrane chromatography techniques to establish a novel method for rapid high-throughput screening of selective Nav1.8 inhibitors. Using this approach, we identified a small molecule compound 6, which not only demonstrated high affinity and inhibitory activity against Nav1.8 but also exhibited significant inhibitory effects on CFA-induced chronic inflammatory pain. Compared to the positive drug VX-150, compound 6 showed a more prolonged analgesic effect, making it a promising candidate as a Nav1.8 inhibitor with potential clinical applications. This discovery provides a new therapeutic option for the treatment of chronic pain.
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Analgésicos , Canal de Sodio Activado por Voltaje NAV1.8 , Sulfonamidas , Analgésicos/farmacología , Analgésicos/química , Analgésicos/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , Animales , Humanos , Canal de Sodio Activado por Voltaje NAV1.8/metabolismo , Relación Estructura-Actividad , Bencenosulfonamidas , Estructura Molecular , Ratones , Relación Dosis-Respuesta a Droga , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacología , Bloqueadores del Canal de Sodio Activado por Voltaje/química , Bloqueadores del Canal de Sodio Activado por Voltaje/síntesis químicaRESUMEN
BACKGROUND: Terpenes are important components of plant aromas, and terpene synthases (TPSs) are the key enzymes driving terpene diversification. In this study, we characterized the volatile terpenes in five different Chrysanthemum nankingense tissues. In addition, genome-wide identification and expression analysis of TPS genes was conducted utilizing an improved chromosome-scale genome assembly and tissue-specific transcriptomes. The biochemical functions of three representative TPSs were also investigated. RESULTS: We identified tissue-specific volatile organic compound (VOC) and volatile terpene profiles. The improved Chrysanthemum nankingense genome assembly was high-quality, including a larger assembled size (3.26 Gb) and a better contig N50 length (3.18 Mb) compared to the old version. A total of 140 CnTPS genes were identified, with the majority representing the TPS-a and TPS-b subfamilies. The chromosomal distribution of these TPS genes was uneven, and 26 genes were included in biosynthetic gene clusters. Closely-related Chrysanthemum taxa were also found to contain diverse TPS genes, and the expression profiles of most CnTPSs were tissue-specific. The three investigated CnTPS enzymes exhibited versatile activities, suggesting multifunctionality. CONCLUSIONS: We systematically characterized the structure and diversity of TPS genes across the Chrysanthemum nankingense genome, as well as the potential biochemical functions of representative genes. Our results provide a basis for future studies of terpene biosynthesis in chrysanthemums, as well as for the breeding of improved chrysanthemum varieties.
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Transferasas Alquil y Aril , Chrysanthemum , Genoma de Planta , Familia de Multigenes , Terpenos , Transferasas Alquil y Aril/genética , Transferasas Alquil y Aril/metabolismo , Chrysanthemum/genética , Chrysanthemum/enzimología , Terpenos/metabolismo , Filogenia , Compuestos Orgánicos Volátiles/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , TranscriptomaRESUMEN
To combat with climate change, most countries have set carbon neutrality target. However, our understanding on carbon removal, release and sequestration by mariculture remains unclear. Here, carbon removal, release and sequestration by maricultured seaweeds, shellfish and fish in Shandong Province during 2003-2022 were assessed using a comprehensive method that considers the processes of biological metabolism, seawater chemistry and carbon footprint. Saccharina japonica productivity has been largely enhanced since 2014, resulting in increased production and CO2 removal and sequestration. Seaweeds removed 172 Gg C and sequestered 62 Gg C in 2022. CO2 removal and release by shellfish demonstrated a slow increase trend, ranging from 231 to 374 Gg C yr-1 and 897 to 1438 Gg C yr-1 during 2003-2022, respectively. Contrary to seaweed and shellfish, maricultured fish added CO2 to seawater due to the use of feeds. The added CO2 by fish culture achieved the peak of 60 Gg C in 2011 and decreased to 25 Gg C in 2022. Most of this added CO2 was released to atmosphere by microbial mineralization and it was in the range of 21-52 Gg C yr-1 during 2003-2022. After summing up the contribution of seaweeds, shellfish and fish, both total CO2 removal (from 110 to 259 Gg C yr-1) and total CO2 release (from 929 to 1429 Gg C yr-1) increased remarkably during the past 20 years. To neutralize CO2 release by shellfish and fish, Pyropia yezoensis needs the largest culture area (1.65 ± 0.15 × 106 ha) while Gracilariopsis lemaneiformis requires the smallest area (0.11 ± 0.03 × 106 ha). In addition, there are enough available areas for culturing G. lemaneiformis, Ulva prolifera and Sargassum fusifarme to neutralize total CO2 emission in Shandong Province. This study elucidates carbon removal, release and sequestration capacities of mariculture and indicates that seaweed culture has a tremendous potential to achieve carbon neutrality target in Shandong.
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Acuicultura , Secuestro de Carbono , China , Algas Marinas/metabolismo , Dióxido de Carbono/análisis , Cambio Climático , Agua de Mar/química , Animales , Carbono/metabolismo , Carbono/análisis , Mariscos , Peces/metabolismo , Monitoreo del AmbienteRESUMEN
The current high-capacity lithium-ion batteries (LIBs), reliant on flammable liquid electrolytes (LEs) and nickel-rich cathodes, are plagued by safety hazards, especially the risk of hazardous gas release stemming from internal side reactions. To address these safety concerns, an electron beam (E-beam)-induced gel polymer electrolyte (E-Gel) is introduced, employing dipentaerythritol hexaacrylate (DPH) as a bi-functional cross-linkable additive (CIA). The dual roles of DPH are exploited through a strategically designed E-beam irradiation process. Applying E-beam irradiation on the pre-cycled cells allows DPH to function as an additive during the initial cycle, establishing a protective layer on the surface of the anode and cathode and as a cross-linker during the E-beam irradiation step, forming a polymer framework. The prepared E-Gel with CIA has superior interfacial compatibility, facilitating lithium-ion diffusion at the electrode/E-Gel interface. The electrochemical assessment of 1.2 Ah pouch cells demonstrates that E-Gel substantially reduces gas release by 2.5 times compared to commercial LEs during the initial formation stage and ensures superior reversible capacity retention even after prolonged cycling at 55 °C. The research underscores the synergy of bifunctional CIA with E-beam technology, paving the way for large-scale production of safe, high-capacity, and commercially viable LIBs.
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Mentha is a commonly used spice worldwide, which possesses medicinal properties and fragrance. These characteristics are conferred, at least partially, by essential oils such as menthol. In this study, a gap-free assembly with a genome size of 414.3 Mb and 31,251 coding genes was obtained for Mentha suaveolens 'Variegata'. Based on its high heterozygosity (1.5%), two complete haplotypic assemblies were resolved, with genome sizes of 401.9 and 405.7 Mb, respectively. The telomeres and centromeres of each haplotype were almost fully annotated. In addition, we detected a total of 41,135 structural variations. Enrichment analysis demonstrated that genes involved in terpenoid biosynthesis were affected by these structural variations. Analysis of volatile metabolites showed that M. suaveolens mainly produces piperitenone oxide rather than menthol. We identified three genes in the M. suaveolens genome which encode isopiperitenone reductase (ISPR), a key rate-limiting enzyme in menthol biosynthesis. However, the transcription levels of ISPR were low. Given that other terpenoid biosynthesis genes were expressed, M. suaveolens ISPRs may account for the accumulation of piperitenone oxide in this species. The findings of this study may provide a valuable resource for improving the detection rate and accuracy of genetic variants, thereby enhancing our understanding of their impact on gene function and expression. Moreover, our haplotype-resolved gap-free genome assembly offers novel insights into molecular marker-assisted breeding of Mentha.
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Metagenomic binning is an essential technique for genome-resolved characterization of uncultured microorganisms in various ecosystems but hampered by the low efficiency of binning tools in adequately recovering metagenome-assembled genomes (MAGs). Here, we introduce BASALT (Binning Across a Series of Assemblies Toolkit) for binning and refinement of short- and long-read sequencing data. BASALT employs multiple binners with multiple thresholds to produce initial bins, then utilizes neural networks to identify core sequences to remove redundant bins and refine non-redundant bins. Using the same assemblies generated from Critical Assessment of Metagenome Interpretation (CAMI) datasets, BASALT produces up to twice as many MAGs as VAMB, DASTool, or metaWRAP. Processing assemblies from a lake sediment dataset, BASALT produces ~30% more MAGs than metaWRAP, including 21 unique class-level prokaryotic lineages. Functional annotations reveal that BASALT can retrieve 47.6% more non-redundant opening-reading frames than metaWRAP. These results highlight the robust handling of metagenomic sequencing data of BASALT.
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Ecosistema , Metagenoma , Silicatos , Metagenoma/genética , Metagenómica/métodosRESUMEN
Exosomes are small extracellular vesicles that play a crucial role in intercellular communication and offer significant potential for a wide range of biomedical applications. However, conventional methods for exosome isolation have limitations in terms of purity, scalability, and preservation of exosome structural integrity. To address these challenges, an exosome isolation platform using chitosan oligosaccharide lactate conjugated 1-pyrenecarboxylic acid (COL-Py) based self-assembled magnetic nanoclusters (CMNCs), is presented. CMNCs are characterized to optimize their size, stability, and interaction dynamics with exosomes. The efficiency of CMNCs in isolating exosomes is systematically evaluated using various analytical methods to demonstrate their ability to capture exosomes based on amphiphilic lipid bilayers. CMNC-based exosome isolation consistently yields exosomes with structural integrity and purity similar to those obtained using traditional methods. The reusability of CMNCs over multiple exosome isolation cycles underscores their scalability and offers an efficient solution for biomedical applications. These results are supported by western blot analysis, which demonstrated the superiority of CMNC-based isolation in terms of purity compared to conventional methods. By providing a scalable and efficient exosome isolation process that preserves both structural integrity and purity, CMNCs can constitute a new platform that can contribute to the field of exosome studies.
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Quitosano , Exosomas , Quitosano/química , Exosomas/química , Exosomas/metabolismo , Humanos , Oligosacáridos/química , Pirenos/química , Nanopartículas de Magnetita/química , Ácido Láctico/química , Ácidos Carboxílicos/químicaRESUMEN
Cepharanthine is a secondary metabolite isolated from Stephania. It has been reported that it has anti-conronaviruses activities including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Here, we assemble three Stephania genomes (S. japonica, S. yunnanensis, and S. cepharantha), propose the cepharanthine biosynthetic pathway, and assess the antiviral potential of compounds involved in the pathway. Among the three genomes, S. japonica has a near telomere-to-telomere assembly with one remaining gap, and S. cepharantha and S. yunnanensis have chromosome-level assemblies. Following by biosynthetic gene mining and metabolomics analysis, we identify seven cepharanthine analogs that have broad-spectrum anti-coronavirus activities, including SARS-CoV-2, Guangxi pangolin-CoV (GX_P2V), swine acute diarrhoea syndrome coronavirus (SADS-CoV), and porcine epidemic diarrhea virus (PEDV). We also show that two other genera, Nelumbo and Thalictrum, can produce cepharanthine analogs, and thus have the potential for antiviral compound discovery. Results generated from this study could accelerate broad-spectrum anti-coronavirus drug discovery.
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Alphacoronavirus , Benzodioxoles , Bencilisoquinolinas , Stephania , Animales , Porcinos , China/epidemiología , SARS-CoV-2 , Antivirales/farmacologíaRESUMEN
With the increasing prevalence of Staphylococcus aureus infections, rapid emergence of drug resistance and the slow healing of infected wounds, developing an efficient antibiotic-free multifunctional wound dressing for inhibiting S. aureus and simultaneously facilitating wound healing have become a huge challenge. Due to their excellent biocompatibility and biodegradability, some carbopol hydrogels based on plant extracts or purified compounds have already been applied in wound healing treatment. In China, Euphorbia humifusa Willd. (EuH) has been traditionally used as a medicine and food homologous medicine for the treatment of furuncles and carbuncles mainly caused by S. aureus infection. In an earlier study, EuH-originated flavonoids quercetin (QU) and luteolin (LU) could serve as a potential source for anti-S. aureus drug discovery when used in synergy. However, the in vivo effects of QU and LU on S. aureus-infected wound healing are still unknown. In this study, we found a series of Carbopol 940-based hydrogels loading QU and LU in combination could disinfect S. aureus and also could promote wound healing. In the full-thickness skin defect mouse model infected with S. aureus, the wound contraction ratio, bacterial burden, skin hyperplasia and inflammation score, as well as collagen deposition and blood vessels were then investigated. The results indicate that the optimized QL2 [QU (32 µg mL-1)-LU (8 µg mL-1)] hydrogel with biocompatibility significantly promoted S. aureus-infected wound healing through anti-infection, anti-inflammation, collagen deposition, and angiogenesis, revealing it as a promising alternative for infected wound repair.
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Actinomicosis , Gastroscopía , Humanos , Biopsia , Estómago/patología , Actinomicosis/patologíaRESUMEN
PURPOSE: A clinically meaningful attribute of some immune-oncology (IO) regimens is potential durable clinical benefit during a treatment-free interval. We characterize treatment-free survival (TFS) with and without ongoing toxicity in trials of frontline IO-VEGF tyrosine kinase inhibitor (TKI) combinations in patients with advanced renal cell carcinoma (aRCC). EXPERIMENTAL DESIGN: Individual patient data were pooled by treatment arm from randomized trials submitted to the FDA evaluating IO-TKI combination in treatment-naïve aRCC with at least 30 months of median follow-up. OS, TFS, TFS with and without toxicity, and time to all protocol therapy cessation were assessed. TFS was estimated by 30-month restricted mean times, defined as area between Kaplan-Meier curves for two time-to-event endpoints originating at randomization: time to all protocol therapy cessation and time to subsequent systemic therapy initiation or death. RESULTS: Three trials met criteria for analysis; 1,183 patients received IO-TKI versus 1,184 on control arms receiving TKI alone (sunitinib, SUN). IO-TKI and SUN groups spent 9% {2.7 months [95% confidence interval (CI), 1.8-3.5]} and 10% [2.9 months (95% CI, 2.1-3.8)] of the 30-month period alive and treatment-free, respectively. Mean TFS without grade ≥3 toxicity was 1.7 and 2.3 months in IO-TKI and SUN groups, respectively. CONCLUSIONS: In this post hoc partitioned survival analysis, TFS and TFS without toxicity appeared similar in the IO-TKI group compared with the SUN group. These findings may reflect contin-uation of TKI until progression per protocol design in all trials and discontinuation of IO after 2 years in two trials. See related commentary by Stadler and Karrison, p. 3098.
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Carcinoma de Células Renales , Neoplasias Renales , Inhibidores de Proteínas Quinasas , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Estimación de Kaplan-Meier , Adulto , Sunitinib/uso terapéutico , Sunitinib/administración & dosificación , Sunitinib/efectos adversosRESUMEN
To investigate the role of a fully digital process in the surgical treatment of mandibular fractures in children. We analyzed a complete dataset from 22 children with mandibular fractures treated with digital surgical assistance. The patient's treatment process included preoperative thin layer CT (Computed Tomography) scanning, computer-aided design (3D reconstruction, virtual reduction, and internal fixation device determination and shaping), and 3D printing (jaw model, bite plate). We used occlusal and shaping plates during surgery to assist in fracture reduction and fixation. During the follow-up, we observed the occurrence of fracture healing, occlusal relationships, opening degrees, and complications in pediatric patients after surgery. Next, we used the 3D overlay function of MIMICS software to compare the preoperative surgical design with postoperative jaw imaging data to evaluate the overall surgical effect. The postoperative imaging data showed good fracture healing, normal occlusion during follow-up, and significant improvement in opening degrees. The mean preoperative opening degree was 23.59 ± 2.89 mm, and the mean postoperative opening degree was 29.82 ± 1.79 mm; there was a significant difference between these two parameters (p < 0.05). There were no complications such as tooth germ injury, nerve injury or fracture block displacement. The postoperative mandibular imaging data was imported into MIMICS software for 3D overlay visualization, and the postoperative mandibular morphology recovery was well-matched with the preoperative design. We measured the average upper deviation (0.65 ± 0.09) mm and the average lower deviation (-0.57 ± 0.14) mm. The fully digital process has a precise, minimally invasive, and safe effect in the surgical treatment of mandibular fractures in children, and the clinical effect is satisfactory.
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Fracturas Mandibulares , Humanos , Niño , Fracturas Mandibulares/diagnóstico por imagen , Fracturas Mandibulares/cirugía , Fijación Interna de Fracturas/métodos , Curación de Fractura , Impresión Tridimensional , Diseño Asistido por ComputadoraRESUMEN
In 2020, Novartis Pharmaceuticals Corporation and the U.S. Food and Drug Administration (FDA) started a 4-year scientific collaboration to approach complex new data modalities and advanced analytics. The scientific question was to find novel radio-genomics-based prognostic and predictive factors for HR+/HER- metastatic breast cancer under a Research Collaboration Agreement. This collaboration has been providing valuable insights to help successfully implement future scientific projects, particularly using artificial intelligence and machine learning. This tutorial aims to provide tangible guidelines for a multi-omics project that includes multidisciplinary expert teams, spanning across different institutions. We cover key ideas, such as "maintaining effective communication" and "following good data science practices," followed by the four steps of exploratory projects, namely (1) plan, (2) design, (3) develop, and (4) disseminate. We break each step into smaller concepts with strategies for implementation and provide illustrations from our collaboration to further give the readers actionable guidance.
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Inteligencia Artificial , Multiómica , Humanos , Aprendizaje Automático , GenómicaRESUMEN
BACKGROUND: The interaction between microorganisms and medicinal plants is a popular topic. Previous studies consistently reported that microorganisms were mainly considered pathogens or contaminants. However, with the development of microbial detection technology, it has been demonstrated that fungi and bacteria affect beneficially the medicinal plant production chain. AIM OF REVIEW: Microorganisms greatly affect medicinal plants, with microbial biosynthesis a high regarded topic in medicinal plant-microbial interactions. However, it lacks a systematic review discussing this relationship. Current microbial detection technologies also have certain advantages and disadvantages, it is essential to compare the characteristics of various technologies. KEY SCIENTIFIC CONCEPTS OF REVIEW: This review first illustrates the role of fungi and bacteria in various medicinal plant production procedures, discusses the development of microbial detection and identification technologies in recent years, and concludes with microbial biosynthesis of natural products. The relationship between fungi, bacteria, and medicinal plants is discussed comprehensively. We also propose a future research model and direction for further studies.
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Rumpless chickens exhibit an abnormality in their tail development. The genetics and biology of this trait has been studied for decades to illustrate a broad variation in both the types of inheritance and the severity in the developmental defects of the tail. In this study, we created a backcross pedigree by intercrossing Piao (rumpless) with Xianju (normal) to investigate the genetic mechanisms and molecular basis of the rumpless trait in Piao chicken. Through genome-wide association and linkage analyses, the candidate region was fine-mapped to 798.5â kb (chromosome 2: 86.9 to 87.7â Mb). Whole-genome sequencing analyses identified a single variant, a 4.2â kb deletion, which was completely associated with the rumpless phenotype. Explorations of the expression data identified a novel causative gene, Rum, that produced a long, intronless transcript across the deletion. The expression of Rum is embryo-specific, and it regulates the expression of MSGN1, a key factor in regulating T-box transcription factors required for mesoderm formation and differentiation. These results provide genetic and molecular experimental evidence for a novel mechanism regulating tail development in chicken and report the likely causal mutation for the tail abnormity in the Piao chicken. The novel regulatory gene, Rum, will, due to its role in fundamental embryo development, be of interest for further explorations of a potential role in tail and skeletal development also in other vertebrates.
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Pollos , Estudio de Asociación del Genoma Completo , Animales , Pollos/genética , Mutación con Pérdida de Función , Mutación , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
In cancer treatment, the first-generation, cytotoxic drugs, though effective against cancer cells, also harmed healthy ones. The second-generation targeted cancer cells precisely to inhibit their growth. Enter the third-generation, consisting of immuno-oncology drugs, designed to combat drug resistance and bolster the immune system's defenses. These advanced therapies operate by obstructing the uncontrolled growth and spread of cancer cells through the body, ultimately eliminating them effectively. Within the arsenal of cancer treatment, monoclonal antibodies offer several advantages, including inducing cancer cell apoptosis, precise targeting, prolonged presence in the body, and minimal side effects. A recent development in cancer therapy is Antibody-Drug Conjugates (ADCs), initially developed in the mid-20th century. The second generation of ADCs addressed this issue through innovative antibody modification techniques, such as DAR regulation, amino acid substitutions, incorporation of non-natural amino acids, and enzymatic drug attachment. Currently, a third generation of ADCs is in development. This study presents an overview of 12 available ADCs, reviews 71 recent research papers, and analyzes 128 clinical trial reports. The overarching objective is to gain insights into the prevailing trends in ADC research and development, with a particular focus on emerging frontiers like potential targets, linkers, and drug payloads within the realm of cancer treatment.
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This study investigated the tenderizing and flavor-enhancing effects of koji, a fermented grain cultured with a single microorganism, on chicken breasts during curing. Chicken breasts were cured with different ingredients, including 4% (w/w) curing agent (GC), 5% (w/w) Aspergillus oryzae with rice (FR), A. oryzae with soybean (FS), and Bacillus subtilis with soybean (BS) for 4 h at 4 °C prior to cooking. After the superheated steam procedure, all samples were cooked in a convection oven, and their physicochemical properties were analyzed. Koji-treated samples exhibited significantly higher expressible moisture due to the degradation of the protein matrix (p < 0.05). Texture profile analysis showed that the tenderness of koji-treated samples was significantly higher than that of GC (p < 0.05). Furthermore, koji-treated samples were regarded as tenderer, and they were preferred over GC (p < 0.05) in the sensory evaluation. Principal attributes analysis revealed that the overall preference for koji-treated samples was highly correlated with umami, juiciness, and tenderness (p < 0.05). Overall, this study provides insights into applying koji as a potential curing treatment to improve the eating quality of chicken breasts. Koji can be used as a novel technology in the food industry to improve taste and tenderness simultaneously.
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Polygala tenuifolia is a perennial medicinal plant that has been widely used in traditional Chinese medicine for treating mental diseases. However, the lack of genomic resources limits the insight into its evolutionary and biological characterization. In the present work, we reported the P. tenuifolia genome, the first genome assembly of the Polygalaceae family. We sequenced and assembled this genome by a combination of Illumnina, PacBio HiFi, and Hi-C mapping. The assembly includes 19 pseudochromosomes covering ~92.68% of the assembled genome (~769.62 Mb). There are 36 463 protein-coding genes annotated in this genome. Detailed comparative genome analysis revealed that P. tenuifolia experienced two rounds of whole genome duplication that occurred ~39-44 and ~18-20 million years ago, respectively. Accordingly, we systematically reconstructed ancestral chromosomes of P. tenuifolia and inferred its chromosome evolution trajectories from the common ancestor of core eudicots to the present species. Based on the transcriptomics data, enzyme genes and transcription factors involved in the synthesis of triterpenoid saponin in P. tenuifolia were identified. Further analysis demonstrated that whole-genome duplications and tandem duplications play critical roles in the expansion of P450 and UGT gene families, which contributed to the synthesis of triterpenoid saponins. The genome and transcriptome data will not only provide valuable resources for comparative and functional genomic researches on Polygalaceae, but also shed light on the synthesis of triterpenoid saponin.