3D Bioprinting of Liquid High-Cell-Proportion Bioinks in Liquid Granular Bath.

Embedded 3D bioprinting techniques have emerged as a powerful method to fabricate 3D engineered constructs using low strength bioinks; however, there are challenges in simultaneously satisfying the requirements of high-cell-activity, high-cell-proportion, and low-viscosity bioinks. In particular, the printing capacity of embedded 3D bioprinting is limited as two main challenges: spreading and diffusion, especially for liquid, high-cell-activity bioinks that can facilitate high-cell-proportion. Here, a liquid-in-liquid 3D bioprinting (LL3DBP) strategy is developed, which used a liquid granular bath to prevent the spreading of liquid bioinks during 3D printing, and electrostatic interaction between the liquid bioinks and liquid granular baths is found to effectively prevent the diffusion of liquid bioinks. As an example, the printing of positively charged 5% w/v gelatin methacryloyl (GelMA) in a liquid granular bath prepared with negatively charged κ-carrageenan is proved to be achievable. By LL3DBP, printing capacity is greatly advanced and bioinks with over 90% v/v cell can be printed, and printed structures with high-cell-proportion exhibit excellent bioactivity.

Enhancing ophthalmology medical record management with multi-modal knowledge graphs.

The electronic medical record management system plays a crucial role in clinical practice, optimizing the recording and management of healthcare data. To enhance the functionality of the medical record management system, this paper develops a customized schema designed for ophthalmic diseases. A multi-modal knowledge graph is constructed, which is built upon expert-reviewed and de-identified real-world ophthalmology medical data. Based on this data, we propose an auxiliary diagnostic model based on a contrastive graph attention network (CGAT-ADM), which uses the patient's diagnostic results as anchor points and achieves auxiliary medical record diagnosis services through graph clustering. By implementing contrastive methods and feature fusion of node types, text, and numerical information in medical records, the CGAT-ADM model achieved an average precision of 0.8563 for the top 20 similar case retrievals, indicating high performance in identifying analogous diagnoses. Our research findings suggest that medical record management systems underpinned by multimodal knowledge graphs significantly enhance the development of AI services. These systems offer a range of benefits, from facilitating assisted diagnosis and addressing similar patient inquiries to delving into potential case connections and disease patterns. This comprehensive approach empowers healthcare professionals to garner deeper insights and make well-informed decisions.

Urine-based SERS and multivariate statistical analysis for identification of non-muscle-invasive bladder cancer and muscle-invasive bladder cancer.

Bladder cancer (BC) is an epidemiological urologic malignancy that continues to increase each year. Early diagnosis and prognosis monitoring is always significant in clinical practice, especially in distinguishing non-muscle-invasive bladder cancer (NMIBC) from muscle-invasive bladder cancer (MIBC), due to the various depths of tumor invasion related to different therapeutic schedules and recurrence rates. Common diagnostic approaches are too invasive or generally inefficient in accuracy and specificity. In this work, a totally non-invasive and cost-effective method is established by investigating urine samples using surface-enhanced Raman spectroscopy (SERS) and multivariate statistical analysis. The comparison of urine SERS spectra shows the intensities of characteristic peaks for DNA/RNA, hypoxanthine, albumin, D-( +)-galactosamine, fatty acids, and some amino acids are distinguishable in BC occurrence and invasion progression. A PLS-LDA-based two-step binary classification scheme is performed on urine SERS spectra and the diagnostic accuracies were 97.7% and 96.3% for healthy individuals versus BC patients and NMIBC versus MIBC patients, respectively. Moreover, the impact of urine SERS spectral lengths in reaching high-precision recognition of BC is investigated. The results show that the Raman peaks at 803, 893, 1139, 1375, and 1466 cm-1 play an essential role in correctly categorizing healthy control, NMIBC, and MIBC patients, and SERS spectra ranges from 400 to 1600 cm-1 are enough for this identification task. These findings provide a sensitive, label-free, rapid, and totally non-invasive way for assessment of invasion depth of BC to its early diagnosis and prognosis monitoring, as well as valuable insights for selecting reasonable spectral range to enhance the measurement efficiency especially in large-scale sample datasets.

Serum-free medium for recombinant protein expression in insect cells.

The baculovirus expression vector system (BEVS) has been widely used to produce recombinant proteins because of several advantages, such as eukaryotic post-translational modifications similar to those in mammalian cells, high expression levels and safety, and large gene capacity. Usually, insect cell culture requires 5%‒10% fetal bovine serum, which has many adverse effects, including high cost, heterogeneity between batches, complex composition, and pollution risks. Therefore, serum-free medium (SFM) is indispensable for the production of recombinant proteins in insect cell culture. Here, the most commonly used insect cell lines and three insect cell media, namely basic medium, SFM, and chemically defined medium, are summarized. The basic components of insect cell SFM are similar to those of other cells but contain special components. The components, functions, and issues of different SFM used for insect cell culture are reviewed. In recent years, some special additives have been demonstrated to increase recombinant protein expression yield and quality in BEVS, and the functions and possible mechanisms of small-molecule additives are reviewed herein. Finally, future perspectives of SFM used in BEVS for recombinant protein production are discussed.

Research on the Remaining Useful Life Prediction Method of Energy Storage Battery Based on Multimodel Integration.

The remaining useful life (RUL) of lithium-ion batteries (LIBs) needs to be accurately predicted to enhance equipment safety and battery management system design. Currently, a single machine learning approach (including an improved machine learning approach) has poor generalization performance due to stochasticity, and the combined prediction approach lacks sufficient theoretical support at the same time. In this paper, we first analyze the prediction principles and applicability of models such as long and short-term memory networks and random forests, and then propose a method for predicting the RUL of batteries based on the integration of multiple-model, and finally validate the proposed model by using experimental data. The experimental results show that (1) for the proposed model, in the best case, the root-mean-square error (RMSE) does not exceed 0.14%, which has a stronger generalization; (2) for the comparison with the single model used, the average RMSE is reduced by 46.2%, 43.7%, and 80.6%, which has a better fitting performance. These results show that the model has good prediction accuracy and application prospects for predicting the RUL of energy storage batteries.

Screening Proteins That Interact With AcHog1 and the Functional Analysis of AcSko1 in Aspergillus cristatus.

Aspergillus cristatus is a dominant fungus formed during the "flowering" process of Fuzhuan brick tea. Previous research has established that the sporulation of Aspergillus nidulans, a model organism of filamentous fungi, is regulated by light. However, the sporulation of A. cristatus is dependent on osmotic stress. In a previous study, we used pull-down and mass spectrometry to identify proteins that interacted with AcHog1 in A. cristatus when cultured under different conditions of osmotic stress. In the present study, we analyzed the proteins we identified previously to investigate their functional role. The AA1E3BER4 protein was located downstream of Hog1 in the HOG branch pathway and was identified that was regulated by AcHog1. Furthermore, yeast two-hybrid analysis showed that AA1E3BER4 interacted with AcHog1. In addition, we knocked out and complemented the Acsko1 gene encoding the AA1E3BER4 protein. We found that the number of sexual and asexual spores were downregulated by 3.81- and 4.57-fold, respectively, in the ΔAcsko1 strain. The sensitivity of the ΔAcsko1 strain to sorbitol and sucrose, as regulators of osmotic stress, increased, and the sensitivity to high sucrose was higher than that of sorbitol. Acsko1 also regulated the response of A. cristatus to oxidative stress, Congo red, and SDS (sodium dodecyl sulfate). In addition, the deletion of Acsko1 significantly increased the pigment of the ΔAcsko1 strain. This is the first study to report the role of the sko1 gene in oxidative stress, stress-induced damage to the cell wall, and pigment in Aspergillus cristatus.

The Role and Function of Secretory Protein Matrix Metalloproteinase-3 (MMP3) in Cervical Cancer.

Background: We started with RNA-seq analysis and aimed to investigate the possibility of secretory protein matrix metalloproteinase-3(MMP3) as a new diagnosis and therapeutic target in cervical cancer. Methods: The study was conducted on Nov 2021 at the Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, China. Through conjoint analysis of gene expression data as well as survival rate data, we explored the potential secretary proteins associated with cervical cancer carcinogenesis. One hundred patients aged 38-72 years with clinical stage I-IV cervical cancer, and 100 age-matched healthy women were included. The expression changes in serum of clinical patients was detected. We knockdown or overexpressed the secretory proteins then explored its influence on biological function of cervical cancer cells. Results: By cross-analysis of The Cancer Genome Atlas (TCGA) database and MetazSecKB database, MMP3 gene was most significantly upregulated in cervical cancer patients (P < 0.05). Furthermore, MMP3 protein was remarkably increased in the serum of clinical cervical cancer patients and decreased after receiving treatment. Overexpression of MMP3 in HT-3 cells or culturing new cells using the supernatant of the medium after MMP3 overexpression could increase cell viability (P < 0.05) as well as proliferation (P < 0.05). Knockdown of MMP3 reduced the phosphorylation of PI3K as well as AKT proteins, while the PI3K phosphorylation inhibitors could suppress the impact of MMP3 on increasing cell proliferation as well as viability. Conclusion: MMP3 could be an underlying target for early diagnosis and treat cervical cancer in the future.

Distribution and associated factors of choroidal thickness in highly myopic eyes-a real-world study based on a Chinese population.

PURPOSE: To measure the subfoveal choroidal thickness (SFCT) in highly myopic eyes at different locations using enhanced depth imaging spectral-domain optical coherence tomography (EDI SD-OCT). To identify the ocular and systemic risk factors associated with choroidal thinning in high myopia. METHODS: Based on the Beijing Eye Study, a detailed ophthalmic examination was performed including EDI SD-OCT for the measurement of SFCT. OCT images were obtained from 103 highly myopic eyes (≥ -6.00 dioptres) and 227 normal eyes randomly selected from the baseline population, matched for age and sex. RESULTS: The mean SFCT was 110.6 ± 85.2 µm in highly myopic eyes (range, 3-395 µm). Mean regional choroidal thickness was lowest on the nasal and inferior sides of the macula, and slightly higher on the temporal and superior sides than at the fovea. On multivariate analysis, SFCT was associated with age (b = -0.48; P < 0.001), axial length (b = -0.44; P < 0.001), gender (b = -0.31; P < 0.05) and staphyloma (b = -0.26; P = 0.05). In highly myopic eyes, SFCT decreased by 5.1 µm/year of age, by 9.2 µm/D of myopia, and by 22.6 µm/mm of axial length. CONCLUSIONS: The SFCT decreases with age and increased axial length in highly myopic eyes. The formation of a posterior staphyloma has been identified as a major contributor to choroidal thinning and is therefore a reliable indicator for risk management. The involvement of choroidal abnormalities may be a significant factor in the development of myopic degeneration.

An artificial intelligence algorithm for the detection of pulmonary ground-glass nodules on spectral detector CT: performance on virtual monochromatic images.

BACKGROUND: This study aims to assess the performance of an established an AI algorithm trained on conventional polychromatic computed tomography (CT) images (CPIs) to detect pulmonary ground-glass nodules (GGNs) on virtual monochromatic images (VMIs), and to screen the optimal virtual monochromatic energy for the clinical evaluation of GGNs. METHODS: Non-enhanced chest SDCT images of patients with pulmonary GGNs in our clinic from January 2022 to December 2022 were continuously collected: adenocarcinoma in situ (AIS, n = 40); minimally invasive adenocarcinoma (MIA, n = 44) and invasive adenocarcinoma (IAC, n = 46). A commercial CAD system based on deep convolutional neural networks (DL-CAD) was used to process the CPIs, 40, 50, 60, 70, and 80 keV monochromatic images of 130 spectral CT images. AI-based histogram parameters by logistic regression analysis. The diagnostic performance was evaluated by the receiver operating characteristic (ROC) curves, and Delong's test was used to compare the CPIs group with the VMIs group. RESULTS: When distinguishing IAC from MIA, the diagnostic efficiency of total mass was obtained at 80 keV, which was superior to those of other energy levels (P < 0.05). And Delong's test indicated that the differences between the area-under-the-curve (AUC) values of the CPIs group and the VMIs group were not statistically significant (P > 0.05). CONCLUSION: The AI algorithm trained on CPIs showed consistent diagnostic performance on VMIs. When pulmonary GGNs are encountered in clinical practice, 80 keV could be the optimal virtual monochromatic energy for the identification of preoperative IAC on a non-enhanced chest CT.

Population-wide DNA methylation polymorphisms at single-nucleotide resolution in 207 cotton accessions reveal epigenomic contributions to complex traits.

DNA methylation plays multiple regulatory roles in crop development. However, the relationships of methylation polymorphisms with genetic polymorphisms, gene expression, and phenotypic variation in natural crop populations remain largely unknown. Here, we surveyed high-quality methylomes, transcriptomes, and genomes obtained from the 20-days-post-anthesis (DPA) cotton fibers of 207 accessions and extended the classical framework of population genetics to epigenetics. Over 287 million single methylation polymorphisms (SMPs) were identified, 100 times more than the number of single nucleotide polymorphisms (SNPs). These SMPs were significantly enriched in intragenic regions while depleted in transposable elements. Association analysis further identified a total of 5,426,782 cis-methylation quantitative trait loci (cis-meQTLs), 5078 cis-expression quantitative trait methylation (cis-eQTMs), and 9157 expression quantitative trait loci (eQTLs). Notably, 36.39% of cis-eQTM genes were not associated with genetic variation, indicating that a large number of SMPs associated with gene expression variation are independent of SNPs. In addition, out of the 1715 epigenetic loci associated with yield and fiber quality traits, only 36 (2.10%) were shared with genome-wide association study (GWAS) loci. The construction of multi-omics regulatory networks revealed 43 cis-eQTM genes potentially involved in fiber development, which cannot be identified by GWAS alone. Among these genes, the role of one encoding CBL-interacting protein kinase 10 in fiber length regulation was successfully validated through gene editing. Taken together, our findings prove that DNA methylation data can serve as an additional resource for breeding purposes and can offer opportunities to enhance and expedite the crop improvement process.

Acptp2,3 participates in the regulation of spore production, stress response, and pigments synthesis in Aspergillus cirstatus.

Background: Aspergillus cristatus was a filamentous fungus that produced sexual spores under hypotonic stress and asexual spores under hypertonic stress. It could be useful for understanding filamentous fungi's sporulation mechanism. Previously, we conducted functional studies on Achog1, which regulated the hyperosmotic glycerol signaling (HOG) pathway and found that SI65_02513 was significantly downregulated in the transcriptomics data of ΔAchog1 knockout strain. This gene was located at multiple locations in the HOG pathway, indicating that it might play an important role in the HOG pathway of A. cristatus. Furthermore, the function of this gene had not been identified in Aspergillus fungi, necessitating further investigation. This gene's conserved domain study revealed that it has the same protein tyrosine phosphatases (PTPs) functional domain as Saccharomyces cerevisiae, hence SI65_02513 was named Acptp2,3. Methods: The function of this gene was mostly validated using gene knockout and gene complementation approaches. Knockout strains exhibited sexual and asexual development, as well as pigments synthesis. Morphological observations of the knockout strain were carried out under several stress conditions (osmotic stress, oxidative stress, Congo Red, and sodium dodecyl sulfate (SDS). Real-time fluorescence polymerase chain reaction (PCR) identified the expression of genes involved in sporulation, stress response, and pigments synthesis. Results: The deletion of Acptp2,3 reduced sexual and asexual spore production by 4.4 and 4.6 times, demonstrating that Acptp2,3 positively regulated the sporulation of A. cristatus. The sensitivity tests to osmotic stress revealed that ΔAcptp2,3 strains did not respond to sorbitol-induced osmotic stress. However, ΔAcptp2.3 strains grew considerably slower than the wild type in high concentration sucrose medium. The ΔAcptp2,3 strains grew slower than the wild type on media containing hydrogen peroxide, Congo red, and SDS. These findings showed that Acptp2,3 favorably controlled osmotic stress, oxidative stress, and cell wall-damaging chemical stress in A. cristatus. Deleting Acptp2,3 resulted in a deeper colony color, demonstrating that Apctp2,3 regulated pigment synthesis in A. cistatus. The expression levels of numerous stress-and pigments-related genes matched the phenotypic data. Conclusion: According to our findings, Acptp2,3 played an important role in the regulation of sporulation, stress response, and pigments synthesis in A. cristatus. This was the first study on the function of PTPs in Aspergillus fungi.

FTSNet: Fundus Tumor Segmentation Network on Multiple Scales Guided by Classification Results and Prompts.

The segmentation of fundus tumors is critical for ophthalmic diagnosis and treatment, yet it presents unique challenges due to the variability in lesion size and shape. Our study introduces Fundus Tumor Segmentation Network (FTSNet), a novel segmentation network designed to address these challenges by leveraging classification results and prompt learning. Our key innovation is the multiscale feature extractor and the dynamic prompt head. Multiscale feature extractors are proficient in eliciting a spectrum of feature information from the original image across disparate scales. This proficiency is fundamental for deciphering the subtle details and patterns embedded in the image at multiple levels of granularity. Meanwhile, a dynamic prompt head is engineered to engender bespoke segmentation heads for each image, customizing the segmentation process to align with the distinctive attributes of the image under consideration. We also present the Fundus Tumor Segmentation (FTS) dataset, comprising 254 pairs of fundus images with tumor lesions and reference segmentations. Experiments demonstrate FTSNet's superior performance over existing methods, achieving a mean Intersection over Union (mIoU) of 0.8254 and mean Dice (mDice) of 0.9042. The results highlight the potential of our approach in advancing the accuracy and efficiency of fundus tumor segmentation.

Omnidirectional anisotropic embedded 3D bioprinting.

Anisotropic microstructures resulting from a well-ordered arrangement of filamentous extracellular matrix (ECM) components or cells can be found throughout the human body, including skeletal muscle, corneal stroma, and meniscus, which play a crucial role in carrying out specialized physiological functions. At present, due to the isotropic characteristics of conventional hydrogels, the construction of freeform cell-laden anisotropic structures with high-bioactive hydrogels is still a great challenge. Here, we proposed a method for direct embedded 3D cell-printing of freeform anisotropic structure with shear-oriented bioink (GelMA/PEO). This study focuses on the establishment of an anisotropic embedded 3D bioprinting system, which effectively utilizes the shear stress generated during the extrusion process to create cells encapsulating tissues with distinct anisotropy. In conjunction with the water-solubility of PEO and the in-situ encapsulation effect provided by the carrageenan support bath, high-precise cell-laden bioprinting of intricate anisotropic and porous bionic artificial tissues can be effectively implemented in one-step. Additionally, anisotropic permeable blood vessel has been taken as a representation to validate the effectiveness of the shear-oriented bioink system in fabricating intricate structures with distinct directional characteristics. Lastly, the successful preparation of muscle patches with anisotropic properties and their guiding role for cell cytoskeleton extension have provided a significant research foundation for the application of the anisotropic embedded 3D bioprinting system in the ex-vivo production and in-vivo application of anisotropic artificial tissues.

Direct 3D printing of freeform anisotropic bioactive structure based on shear-oriented ink system.

Various anisotropic tissue structures exist in organisms, including muscle tissue, skin tissue, and nerve tissue. Replicating anisotropic tissue structuresin vitrohas posed a significant challenge. Three-dimensional (3D) printing technology is often used to fabricate biomimetic structures due to its advantages in manufacturing principle. However, direct 3D printing of freeform anisotropic bioactive structures has not been reported. To tackle this challenge, we developed a ternary F/G/P ink system that integrates the printability of Pluronic F127 (F), the robust bioactivity and photocrosslinking properties of gelatin methacryloyl (G), and the shear-induced alignment functionality of high-molecular-weight polyethylene glycol (P). And through this strategic ternary system combination, freeform anisotropic tissue structures can be 3D printed directly. Moreover, these anisotropic structures exhibit excellent bioactivity, and promote orientational growth of different cells. This advancement holds promise for the repair and replacement of anisotropic tissues within the human body.

Redox Concomitant Formation Method for Fabrication of Cu(I)-MOF/Polymer Composites with Antifouling Properties.

Marine biofouling, which is one of the technical challenges hindering the growth of the marine economy, has been controlled using cuprous oxide (Cu2O) nanoparticles due to the exceptional antifouling properties of Cu(I) ions. However, Cu2O nanoparticles have encountered bottlenecks due to explosive releases of Cu+ ions, high toxicity at elevated doses, and long-term instability. Here, we present a novel method called Redox Concomitant Formation (RCF) for fabricating a hierarchical Cu(I) metal-organic framework polypyrrole (Cu(I)-MOF/PPy) composite. This method enables in situ phase transition via successive redox reactions that change the chemical valence state and coordination mode of Cu(II)-MOF, resulting in a new structure of Cu(I)-MOF while creating a PPy layer surrounded by the hierarchical structure. Owing to the steady release of Cu+ ions from the Cu(I) sites and photothermal properties of PPy, Cu(I)-MOF/PPy exhibits superior and broad-spectrum resistance to marine bacteria, algae, and surface-adhered biofilms in complex biological environments, as well as long-term stability, resulting in 100 % eradication efficiency under solar-driven heating. Mechanistic insights into successive structural redox reactions and formation using the RCF method are provided in detail, enabling the fabrication of novel MOFs with the desired composition and structure for a wide range of potential applications.

Superlong Metal-Organic Framework Nanowire Fabricated via Steam-Assisted Conversion.

1D nanomaterials have attracted great attention due to their outstanding anisotropic and linear structures. A facile method is developed to fabricate 1D copper metal-organic framework nanowires (Cu-MOF-NW) through steam-assisted conversion from Cu-MOF precursors. During the steam-assisted conversion, Cu-MOF precursor gradually dissolves in methanol steam, and then recrystallized into Cu-MOF-NW, which shows high aspect ratio of about 600 and identical crystal structure of MOF-74. As-prepared Cu-MOF-NW with multiscale porous structure can effectively remove cationic dyes even in dye mixture. Moreover, Cu-MOF-NW, as an ideal template, is calcined to form Cu nanoparticle-doped carbon nanofiber with maintaining its 1D morphology, which shows excellent electrocatalytic activity for the non-enzymatic sensing of glucose.

Dynamic imaging of micro-vibrations with an ultra-wide bandwidth and a femtometer noise using switchable pulsed laser interferometry.

Imaging the complex dynamics of micro-vibrations plays a fundamental role in the investigation of microelectromechanical systems (MEMS). However, it remains a challenge for achieving both a wide bandwidth and a low noise due to the high photodetector noise and electromagnetic interference at GHz frequencies. Here, we propose a pulsed laser interferometry system with an adaptable switch to image GHz vibrations based on stroboscopic mixing, while measuring lower-frequency vibrations based on the homodyne scheme. The noise power spectral density is shown in both regions from DC to 10 GHz with an average noise down to 30.8 fm/√Hz at GHz frequencies, which holds the highest resolution to the best of our knowledge. Vibrational amplitude and phase mappings of a kHz comb-drive resonator, a GHz piezoelectric transducer, and a GHz film bulk acoustic resonator are presented with animated visualizations and k-space analysis, paving a new paradigm for the first time to image and analyze various MEMS devices of a bandwidth spanning 10 orders of magnitude.

An intelligent spinal soft robot with self-sensing adaptability.

Self-sensing adaptability is a high-level intelligence in living creatures and is highly desired for their biomimetic soft robots for efficient interaction with the surroundings. Self-sensing adaptability can be achieved in soft robots by the integration of sensors and actuators. However, current strategies simply assemble discrete sensors and actuators into one robotic system and, thus, dilute their synergistic and complementary connections, causing low-level adaptability and poor decision-making capability. Here, inspired by vertebrate animals supported by highly evolved backbones, we propose a concept of a bionic spine that integrates sensing and actuation into one shared body based on the reversible piezoelectric effect and a decoupling mechanism to extract the environmental feedback. We demonstrate that the soft robots equipped with the bionic spines feature locomotion speed improvements between 39.5% and 80% for various environmental terrains. More importantly, it can also enable the robots to accurately recognize and actively adapt to changing environments with obstacle avoidance capability by learning-based gait adjustments. We envision that the proposed bionic spine could serve as a building block for locomotive soft robots toward more intelligent machine-environment interactions in the future.

Olgotrelvir as a Single-Agent Treatment of Nonhospitalized Patients with Covid-19.

BACKGROUND: Olgotrelvir is an oral antiviral with dual mechanisms of action targeting severe acute respiratory syndrome coronavirus 2 main protease (i.e., Mpro) and human cathepsin L. It has potential to serve as a single-agent treatment of coronavirus disease 2019 (Covid-19). METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of olgotrelvir in 1212 nonhospitalized adult participants with mild to moderate Covid-19, irrespective of risk factors, who were randomly assigned to receive orally either 600 mg of olgotrelvir or placebo twice daily for 5 days. The primary and key secondary end points were time to sustained recovery of a panel of 11 Covid-19-related symptoms and the viral ribonucleic acid (RNA) load. The safety end point was incidence of treatment-emergent adverse events. RESULTS: The baseline characteristics of 1212 participants were similar in the two groups. In the modified intention-to-treat population (567 patients in the placebo group and 558 in the olgotrelvir group), the median time to symptom recovery was 205 hours in the olgotrelvir group versus 264 hours in the placebo group (hazard ratio, 1.29; 95% confidence interval [CI], 1.13 to 1.46; P<0.001). The least squares mean (95% CI) changes of viral RNA load from baseline were -2.20 (-2.59 to -1.81) log10 copies/ml in olgotrelvir-treated participants and -1.40 (-1.79 to -1.01) in participants receiving placebo at day 4. Skin rash (3.3%) and nausea (1.5%) were more frequent in the olgotrelvir group than in the placebo group; there were no treatment-related serious adverse events, and no deaths were reported. CONCLUSIONS: Olgotrelvir as a single-agent treatment significantly improved symptom recovery. Adverse effects were not dose limiting. (Funded by Sorrento Therapeutics, a parent company of ACEA Therapeutics; ClinicalTrials.gov number, NCT05716425.).

GhWER controls fiber initiation and early elongation by regulating ethylene signaling pathway in cotton (Gossypium hirsutum).

Cotton fibers are specialized single-cell trichomes derived from epidermal cells, similar to root hairs and trichomes in Arabidopsis. While the MYB-bHLH-WD40 (MBW) complex has been shown to regulate initiation of both root hairs and trichomes in Arabidopsis, the role of their homologous gene in cotton fiber initiation remains unknown. In this study, we identified a R2R3 MYB transcription factor (TF), GhWER, which exhibited a significant increase in expression within the outer integument of ovule at -1.5 DPA (days post anthesis). Its expression peaked at -1 DPA and then gradually decreased. Knockout of GhWER using CRISPR technology inhibited the initiation and early elongation of fiber initials, resulting in the shorter mature fiber length. Additionally, GhWER interacted with two bHLH TF, GhDEL65 and GhbHLH121, suggesting a potential regulatory complex for fiber development. RNA-seq analysis of the outer integument of the ovule at -1.5 DPA revealed that the signal transduction pathways of ethylene, auxin and gibberellin were affected in the GhWER knockout lines. Further examination demonstrated that GhWER directly activated ethylene signaling genes, including ACS1 and ETR2. These findings highlighted the biological function of GhWER in regulating cotton fiber initiation and early elongation, which has practical significance for improving fiber quality and yield. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01477-6.