Therapeutic efficacy of methylprednisolone sodium succinate via diverse administration routes for mid- to high-frequency sudden sensorineural hearing loss.

BACKGROUND: Sudden sensorineural hearing loss (SSNHL), characterized by a rapid and unexplained loss of hearing, particularly at moderate to high frequencies, presents a significant clinical challenge. The therapeutic use of methylprednisolone sodium succinate (MPSS) via different administration routes, in combination with conventional medications, remains a topic of interest. AIM: To compare the therapeutic efficacy of MPSS administered via different routes in combination with conventional drugs for the treatment of mid- to high-frequency SSNHL. METHODS: The medical records of 109 patients with mid- to high-frequency SSNHL were analyzed. The patients were divided into three groups based on the route of administration: Group A [intratympanic (IT) injection of MPSS combined with mecobalamin and Ginkgo biloba leaf extract injection], Group B (intravenous injection of MPSS combined with mecobalamin and Ginkgo biloba leaf extract injection), and Group C (single IT injection of MPSS). The intervention effects were compared and analyzed. RESULTS: The posttreatment auditory thresholds in Group A (21.23 ± 3 .34) were significantly lower than those in Groups B (28.52 ± 3.36) and C (30.23 ± 4.21; P < 0.05). Group A also exhibited a significantly greater speech recognition rate (92.23 ± 5.34) than Groups B and C. The disappearance time of tinnitus, time to hearing recovery, and disappearance time of vertigo in Group A were significantly shorter than those in Groups B and C (P < 0.05). The total effective rate in Group A (97.56%) was significantly greater than that in Groups B and C (77.14% and 78.79%, χ 2 = 7.898, P = 0.019). Moreover, the incidence of adverse reactions in Groups A and C was significantly lower than that in Group B (4.88%, 3.03% vs 2.57%, χ 2 = 11.443, P = 0.003), and the recurrence rate in Group A was significantly lower than that in Groups B and C (2.44% vs 20.00% vs 21.21%, χ 2 = 7.120, P = 0.028). CONCLUSION: IT injection of MPSS combined with conventional treatment demonstrates superior efficacy and safety compared to systemic administration via intravenous infusion and a single IT injection of MPSS. This approach effectively improves patients' hearing and reduces the risk of disease recurrence.

How the root bacterial community of Ficus tikoua responds to nematode infection: enrichments of nitrogen-fixing and nematode-antagonistic bacteria in the parasitized organs.

Plant-parasitic nematodes (PPNs) are among the most damaging pathogens to host plants. Plants can modulate their associated bacteria to cope with nematode infections. The tritrophic plant-nematode-microbe interactions are highly taxa-dependent, resulting in the effectiveness of nematode agents being variable among different host plants. Ficus tikoua is a versatile plant with high application potential for fruits or medicines. In recent years, a few farmers have attempted to cultivate this species in Sichuan, China, where parasitic nematodes are present. We used 16S rRNA genes to explore the effects of nematode parasitism on root-associated bacteria in this species. Our results revealed that nematode infection had effects on both endophytic bacterial communities and rhizosphere communities in F. tikoua roots, but on different levels. The species richness increased in the rhizosphere bacterial communities of infected individuals, but the community composition remained similar as compared with that of healthy individuals. Nematode infection induces a deterministic assembly process in the endophytic bacterial communities of parasitized organs. Significant taxonomic and functional changes were observed in the endophytic communities of root knots. These changes were characterized by the enrichment of nitrogen-fixing bacteria, including Bradyrhizobium, Allorhizobium-Neorhizobium-Pararhizobium-Rhizobium, and nematode-antagonistic bacteria, such as Pseudonocardia, Pseudomonas, Steroidobacter, Rhizobacter, and Ferrovibrio. Our results would help the understanding of the tritrophic plant-nematode-bacterium interactions in host plants other than dominant crops and vegetables and would provide essential information for successful nematode management when F. tikoua were cultivated on large scales.

A MELET- and IFE-based UV-visible luminescent ratiometric probe for quantization of mercury(II) and nitrofurantoin in environmental sewage.

A novel fluorimetric ratiometric probe of green and eco-friendily nitrogen-enriched, oxygen-doped carbon nanodots (Cnanodots) was prepared for the quantitative analysis of mercury(II) (HgII) and nitrofurantoin (Nit) in the environmental sewage. The Cnanodots exhibits dual-emission peaks respectively at 345 and 445 nm under 285 nm excitation, with excitation-independent properties. Unexpectedly, this Cnanodots displays two obvious ratiometric responses to HgII and Nit through decreasing the signal at 345 nm and remaining invariable at 445 nm. Experimental results confirm that the highly sensitive analysis of HgII and Nit are achieved respectively based on matching energy-level electron transfer and inner filter effect mechanisms. The fluorescence (FL) ratiometric intensity of [FL345nm/FL445nm] expresses a good linear relationship with the concentration of HgII in the scope of 0.01-20 µM, while the logarithm of [Log(FL0345nm-FL345nm)] on the quenching degree of the probe by Nit also shows a good linear correlation within the range of 0.01-100 µM. The detection limits were calculated to be 4.14 nM for HgII, and 7.84 nM for Nit. Moreover, recovery experiments of Cnanodots for HgII and Nit sensing in real sewage samples obtained satisfactory results, comfirming the feasibility of practical application.

Pancreatic STAT5 activation promotes KrasG12D-induced and inflammation-induced acinar-to-ductal metaplasia and pancreatic cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy because it is often diagnosed at a late-stage. Signal transducer and activator of transcription 5 (STAT5) is a transcription factor implicated in the progression of various cancer types. However, its role in KRAS-driven pancreatic tumourigenesis remains unclear. DESIGN: We performed studies with LSL-Kras G12D; Ptf1a-Cre ERT (KCERT) mice or LSL-KrasG12D; LSL-Trp53R172H ; Pdx1-Cre (KPC) mice crossed with conditional disruption of STAT5 or completed deficiency interleukin (IL)-22. Pancreatitis was induced in mice by administration of cerulein. Pharmacological inhibition of STAT5 on PDAC prevention was studied in the orthotopic transplantation and patient-derived xenografts PDAC model, and KPC mice. RESULTS: The expression and phosphorylation of STAT5 were higher in human PDAC samples than control samples and high levels of STAT5 in tumour cells were associated with a poorer prognosis. The loss of STAT5 in pancreatic cells substantially reduces the KRAS mutation and pancreatitis-derived acinar-to-ductal metaplasia (ADM) and PDAC lesions. Mechanistically, we discovered that STAT5 binds directly to the promoters of ADM mediators, hepatocyte nuclear factor (HNF) 1ß and HNF4α. Furthermore, STAT5 plays a crucial role in maintaining energy metabolism in tumour cells during PDAC progression. IL-22 signalling induced by chronic inflammation enhances KRAS-mutant-mediated STAT5 phosphorylation. Deficiency of IL-22 signalling slowed the progression of PDAC and ablated STAT5 activation. CONCLUSION: Collectively, our findings identified pancreatic STAT5 activation as a key downstream effector of oncogenic KRAS signalling that is critical for ADM initiation and PDAC progression, highlighting its potential therapeutic vulnerability.

Corrigendum to 'Predicting post-resection recurrence by integrating imaging-based surrogates of distinct vascular patterns of hepatocellular carcinoma' (JHEP Reports 5 [2023] 100806).

[This corrects the article DOI: 10.1016/j.jhepr.2023.100806.].

A Novel Ultrasound Method of Evaluating Dynamic Extrusion of Lateral Meniscus in Healthy Population: Different Patterns of Dynamic Extrusion Revealed Between Lateral and Medial Meniscus.

OBJECTIVES: To establish a reliable ultrasound (US) method of evaluating dynamic extrusion of lateral meniscus in healthy population, and to investigate the pattern of dynamic meniscus extrusion (ME) in lateral meniscus under loading conditions. METHODS: The lateral ME was examined via US method in unloaded, double-leg standing, and single-leg standing positions. Two different US measurement methods were compared to the magnetic resonance imaging (MRI) results to determine the optimal measurement methods. The US results obtained by different researchers were tested for interobserver consistency and the results obtained by the same researcher on two separate days were tested for intraobserver consistency. The patterns of dynamic extrusion were compared between medial and lateral sides. RESULTS: A total of healthy 44 volunteers were included in the study, with 86 knees assessed by US, and 25 knees evaluated by MRI. The US evaluation of dynamic lateral ME demonstrated excellent interobserver and intraobserver reliability. The US measurements using method A were consistent with the MRI results with no significant difference (P = .861, intraclass correlation coefficient [ICC] = 0.868), while method B underestimated the lateral ME compared to MRI (P = .001, ICC = 0.649). Lateral ME decreased slightly from unloaded (1.0 ± 0.8 mm) to single-leg standing position (0.8 ± 0.8 mm), whereas medial ME increased significantly in both double-leg and single-leg standing positions (2.4 ± 0.7 mm, 2.6 ± 0.7 mm). CONCLUSION: A novel US evaluation method of lateral ME was established with reliable and accurate results compared to the MRI. Lateral ME in healthy populations decreased slightly as the loadings increased, which was different from the pattern of dynamic extrusion in medial meniscus.

Unveiling the role of chronic inflammation in ovarian aging: insights into mechanisms and clinical implications.

Ovarian aging, a natural process in women and various other female mammals as they age, is characterized by a decline in ovarian function and fertility due to a reduction in oocyte reserve and quality. This phenomenon is believed to result from a combination of genetic, hormonal, and environmental factors. While these factors collectively contribute to the shaping of ovarian aging, the substantial impact and intricate interplay of chronic inflammation in this process have been somewhat overlooked in discussions. Chronic inflammation, a prolonged and sustained inflammatory response persisting over an extended period, can exert detrimental effects on tissues and organs. This review delves into the novel hallmark of aging-chronic inflammation-to further emphasize the primary characteristics of ovarian aging. It endeavors to explore not only the clinical symptoms but also the underlying mechanisms associated with this complex process. By shining a spotlight on chronic inflammation, the aim is to broaden our understanding of the multifaceted aspects of ovarian aging and its potential clinical implications.

A Redox-active Phenothiazine-based Pd2L4-type Coordination Cage and Its Isolable Crystalline Polyradical Cations.

Polyradical cages are of great interest because they show very fascinating physical and chemical properties, but many challenges remain, especially for their synthesis and characterization. Herein, we present the synthesis of a polyradical cation cage 14•+ through post-synthetic oxidation of a redox-active phenothiazine-based Pd2L4-type coordination cage 1. It's worth noting that 1 exhibits excellent reversible electrochemical and chemical redox activity due to the introduction of a bulky 3,5-di-tert-butyl-4-methoxyphenyl substituent. The generation of 14•+ through reversible electrochemical oxidation is investigated by in situ UV-vis-NIR and EPR spectroelectrochemistry. Meanwhile, chemical oxidation of 1 can also produce 14•+ which can be reversibly reduced back to the original cage 1, and the process is monitored by EPR and NMR spectroscopies. Eventually, we succeed in the isolation and single crystal X-ray diffraction analysis of 14•+, whose electronic structure and conformation are distinct to original 1. The magnetic susceptibility measurements indicate the predominantly antiferromagnetic interactions between the four phenothiazine radical cations in 14•+. We believe that our study including the facile synthesis methodology and in situ spectroelectrochemistry will shed some light on the synthesis and characterization of novel polyradical systems, opening more perspectives for developing functional supramolecular cages.

Mitochondrial homeostasis in odontoblast: Physiology, pathogenesis and targeting strategies.

Caries and pulpitis remain a major global disease burden and affect the quality of life of patients. Odontoblasts are key players in the progression of caries and pulpitis, not only secreting and mineralizing to form dentin, but also acting as a wall of defense to initiate immune defenses. Mitochondrion is an information processor for numerous cellular activities, and dysregulation of mitochondrion homeostasis not only affects cellular metabolism but also triggers a wide range of diseases. Elucidating mitochondrial homeostasis in odontoblasts can help deepen scholars' understanding of odontoblast-associated diseases. Articles on mitochondrial homeostasis in odontoblasts were evaluated for information pertinent to include in this narrative review. This narrative review focused on understanding the complex interplay between mitochondrial homeostasis in odontoblasts under physiological and pathological conditions. Furthermore, mitochondria-centered therapeutic strategies (including mitochondrial base editing, targeting platforms, and mitochondrial transplantation) were emphasized by resolving key genes that regulate mitochondrial function. Mitochondria are involved in odontoblast differentiation and function, and act as mitochondrial danger-associated molecular patterns (mtDAMPs) to mediate odontoblast pathological progression. Novel mitochondria-centered therapeutic strategies are particularly attractive as emerging therapeutic approaches for the maintenance of mitochondrial homeostasis. It is expected to probe key events of odontoblast differentiation and advance the clinical resolution of dentin formation and mineralization disorders and odontoblast-related diseases.

Have Previous COVID-19 Vaccinations Shaped the Potential Enhancing Infection of Variant Strains?

OBJECTIVE: This study aimed to investigate the infection status of Omicron in the population and the association between COVID-19 vaccination and infection with Omicron. METHODS: We conducted a cross-sectional study to openly recruit participants for a survey of SARS-CoV-2 infection by convenience sampling from 1 January to 15 January 2023 after a COVID-19 pandemic swept across China. Additionally, the binary logistic regression model was adopted to evaluate the association between COVID-19 vaccination and the infection outcomes or symptom severity, respectively. Meanwhile, the relations between the vaccination and duration of the symptoms were estimated via ordinal logistic analysis. RESULTS: Of the 2007 participants, the prevalence of infection with Omicron was 82.9%. Compared with unvaccinated individuals, inactivated COVID-19 vaccination could increase the risk of Omicron infection (OR = 1.942, 95% CI: 1.093-3.448), and the receipt of at least one dose of non-inactivated COVID-19 vaccines was a protective factor against infection (OR = 0.428, 95% CI: 0.226-0.812). By contrast, no relations were observed in COVID-19 vaccination with the symptoms of infection and duration of symptoms (p > 0.05). CONCLUSIONS: This cross-sectional study concluded that inactivated COVID-19 vaccination might increase the risk of Omicron infection, which should be a concern during COVID-19 vaccination and the treatment of variant infections in the future, and the receipt of at least one dose of non-inactivated COVID-19 vaccine was a protective factor against infection.

Systematically Evaluating Cell-Free DNA Fragmentation Patterns for Cancer Diagnosis and Enhanced Cancer Detection via Integrating Multiple Fragmentation Patterns.

Cell-free DNA (cfDNA) fragmentation patterns have immense potential for early cancer detection. However, the definition of fragmentation varies, ranging from the entire genome to specific genomic regions. These patterns have not been systematically compared, impeding broader research and practical implementation. Here, 1382 plasma cfDNA sequencing samples from 8 cancer types are collected. Considering that cfDNA within open chromatin regions is more susceptible to fragmentation, 10 fragmentation patterns within open chromatin regions as features and employed machine learning techniques to evaluate their performance are examined. All fragmentation patterns demonstrated discernible classification capabilities, with the end motif showing the highest diagnostic value for cross-validation. Combining cross and independent validation results revealed that fragmentation patterns that incorporated both fragment length and coverage information exhibited robust predictive capacities. Despite their diagnostic potential, the predictive power of these fragmentation patterns is unstable. To address this limitation, an ensemble classifier via integrating all fragmentation patterns is developed, which demonstrated notable improvements in cancer detection and tissue-of-origin determination. Further functional bioinformatics investigations on significant feature intervals in the model revealed its impressive ability to identify critical regulatory regions involved in cancer pathogenesis.

A Biphasic Strategy to Synergistically Accelerate Activation and CO Spillover in Formic Acid Oxidation Catalysis.

Developing highly efficient and carbon monoxide (CO)-tolerant platinum (Pt) catalysts for the formic acid oxidation reaction (FAOR) is vital for direct formic acid fuel cells (DFAFCs), yet it is challenging due to the high energy barrier of direct intermediates (HCOO* and COOH*) as well as the CO poisoning issues associated with Pt alloy catalysts. Here we present a versatile biphasic strategy by creating a hexagonal/cubic crystalline-phase-synergistic PtPb/C (h/c-PtPb/C) catalyst to tackle the aforementioned issues. Detailed investigations reveal that h/c-PtPb/C can simultaneously facilitate the adsorption of direct intermediates while inhibiting CO adsorption, thereby significantly improving the activation and CO spillover. As a result, h/c-PtPb/C showcases an outstanding FAOR activity of 8.1 A mgPt-1, which is 64.5 times higher than that of commercial Pt/C and significantly surpasses monophasic PtPb. Moreover, the h/c-PtPb/C-based membrane electrode assembly exhibits an exceptional peak power density of 258.7 mW cm-2 for practical DFAFC applications.

Single-cell analyses reveal evolution mimicry during the specification of breast cancer subtype.

Background: The stem or progenitor antecedents confer developmental plasticity and unique cell identities to cancer cells via genetic and epigenetic programs. A comprehensive characterization and mapping of the cell-of-origin of breast cancer using novel technologies to unveil novel subtype-specific therapeutic targets is still absent. Methods: We integrated 195,144 high-quality cells from normal breast tissues and 406,501 high-quality cells from primary breast cancer samples to create a large-scale single-cell atlas of human normal and cancerous breasts. Potential heterogeneous origin of malignant cells was explored by contrasting cancer cells against reference normal epithelial cells. Multi-omics analyses and both in vitro and in vivo experiments were performed to screen and validate potential subtype-specific treatment targets. Novel biomarkers of identified immune and stromal cell subpopulations were validated by immunohistochemistry in our cohort. Results: Tumor stratification based on cancer cell-of-origin patterns correlated with clinical outcomes, genomic aberrations and diverse microenvironment constitutions. We found that the luminal progenitor (LP) subtype was robustly associated with poor prognosis, genomic instability and dysfunctional immune microenvironment. However, the LP subtype patients were sensitive to neoadjuvant chemotherapy (NAC), PARP inhibitors (PARPi) and immunotherapy. The LP subtype-specific target PLK1 was investigated by both in vitro and in vivo experiments. Besides, large-scale single-cell profiling of breast cancer inspired us to identify a range of clinically relevant immune and stromal cell subpopulations, including subsets of innate lymphoid cells (ILCs), macrophages and endothelial cells. Conclusion: The present single-cell study revealed the cellular repertoire and cell-of-origin patterns of breast cancer. Combining single-cell and bulk transcriptome data, we elucidated the evolution mimicry from normal to malignant subtypes and expounded the LP subtype with vital clinical implications. Novel immune and stromal cell subpopulations of breast cancer identified in our study could be potential therapeutic targets. Taken together, Our findings lay the foundation for the precise prognostic and therapeutic stratification of breast cancer.

Discovery of Novel Ortho-Aminophenol Derivatives Targeting Lipid Peroxidation with Potent Antiferroptotic Activities.

The concept of ferroptosis inhibition has gained growing recognition as a promising therapeutic strategy for addressing a wide range of diseases. Here, we present the discovery of four series of ortho-aminophenol derivatives as potential ferroptosis inhibitors beginning with the endogenous substance 3-hydroxyanthranilic acid (3-HA) by employing quantum chemistry techniques, in vitro and in vivo assays. Our findings reveal that these ortho-aminophenol derivatives exhibit unique intra-H bond interactions, compelling ortho-amines to achieve enhanced alignment with the aromatic π-system, thereby expanding their activity. Notably, compounds from all four series display remarkable activity against RSL3-induced ferroptosis, showcasing an activity 100 times more than that of 3-HA. Furthermore, these compounds also demonstrate robust in vivo efficacy in protecting mice from kidney ischemia-reperfusion injury and acetaminophen-induced hepatotoxicity. In summary, we provide four distinct series of active scaffolds that significantly expand the chemical space of ferroptosis inhibitors, serving as valuable insights for future structural modifications.

Histone methyltransferase MLL4 protects against pressure overload-induced heart failure via a THBS4-mediated protection in ER stress.

Pressure overload-induced pathological cardiac hypertrophy eventually leads to heart failure (HF). Unfortunately, lack of effective targeted therapies for HF remains a challenge in clinical management. Mixed-lineage leukemia 4 (MLL4) is a member of the SET family of histone methyltransferase enzymes, which possesses histone H3 lysine 4 (H3K4)-specific methyltransferase activity. However, whether and how MLL4 regulates cardiac function is not reported in adult HF. Here we report that MLL4 is required for endoplasmic reticulum (ER) stress homeostasis of cardiomyocytes and protective against pressure overload-induced cardiac hypertrophy and HF. We observed that MLL4 is increased in the heart tissue of HF mouse model and HF patients. The cardiomyocyte-specific deletion of Mll4 (Mll4-cKO) in mice leads to aggravated ER stress and cardiac dysfunction following pressure overloading. MLL4 knockdown neonatal rat cardiomyocytes (NRCMs) also display accelerated decompensated ER stress and hypertrophy induced by phenylephrine (PE). The combined analysis of Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and RNA sequencing (RNA-seq) data reveals that, silencing of Mll4 alters the chromatin landscape for H3K4me1 modification and gene expression patterns in NRCMs. Interestingly, the deficiency of MLL4 results in a marked reduction of H3K4me1 and H3K27ac occupations on Thrombospondin-4 (Thbs4) gene loci, as well as Thbs4 gene expression. Mechanistically, MLL4 acts as a transcriptional activator of Thbs4 through mono-methylation of H3K4 and further regulates THBS4-dependent ER stress response, ultimately plays a role in HF. Our study indicates that pharmacologically targeting MLL4 and ER stress might be a valid therapeutic approach to protect against cardiac hypertrophy and HF.

Harnessing cerium-based biomaterials for the treatment of bone diseases.

Bone, an actively metabolic organ, undergoes constant remodeling throughout life. Disturbances in the bone microenvironment can be responsible for pathologically bone diseases such as periodontitis, osteoarthritis, rheumatoid arthritis and osteoporosis. Conventional bone tissue biomaterials are not adequately adapted to complex bone microenvironment. Therefore, there is an urgent clinical need to find an effective strategy to improve the status quo. In recent years, nanotechnology has caused a revolution in biomedicine. Cerium(III, IV) oxide, as an important member of metal oxide nanomaterials, has dual redox properties through reversible binding with oxygen atoms, which continuously cycle between Ce(III) and Ce(IV). Due to its special physicochemical properties, cerium(III, IV) oxide has received widespread attention as a versatile nanomaterial, especially in bone diseases. This review describes the characteristics of bone microenvironment. The enzyme-like properties and biosafety of cerium(III, IV) oxide are also emphasized. Meanwhile, we summarizes controllable synthesis of cerium(III, IV) oxide with different nanostructural morphologies. Following resolution of synthetic principles of cerium(III, IV) oxide, a variety of tailored cerium-based biomaterials have been widely developed, including bioactive glasses, scaffolds, nanomembranes, coatings, and nanocomposites. Furthermore, we highlight the latest advances in cerium-based biomaterials for inflammatory and metabolic bone diseases and bone-related tumors. Tailored cerium-based biomaterials have already demonstrated their value in disease prevention, diagnosis (imaging and biosensors) and treatment. Therefore, it is important to assist in bone disease management by clarifying tailored properties of cerium(III, IV) oxide in order to promote the use of cerium-based biomaterials in the future clinical setting. STATEMENT OF SIGNIFICANCE: In this review, we focused on the promising of cerium-based biomaterials for bone diseases. We reviewed the key role of bone microenvironment in bone diseases and the main biological activities of cerium(III, IV) oxide. By setting different synthesis conditions, cerium(III, IV) oxide nanostructures with different morphologies can be controlled. Meanwhile, tailored cerium-based biomaterials can serve as a versatile toolbox (e.g., bioactive glasses, scaffolds, nanofibrous membranes, coatings, and nanocomposites). Then, the latest research advances based on cerium-based biomaterials for the treatment of bone diseases were also highlighted. Most importantly, we analyzed the perspectives and challenges of cerium-based biomaterials. In future perspectives, this insight has given rise to a cascade of cerium-based biomaterial strategies, including disease prevention, diagnosis (imaging and biosensors) and treatment.

Atrimonas thermophila gen. nov., sp. nov., a novel anaerobic thermophilic bacterium of the phylum Atribacterota isolated from deep subsurface gas field and proposal of Atrimonadaceae fam. nov. within the class Atribacteria in the phylum Atribacterota.

A novel anaerobic, thermophilic bacterium of the class Atribacteria, strain M15T, was isolated from a high-temperature gas reservoir, Japan. Cells of strain M15T were gram-negative, short oval-shaped, and lacked flagella. Growth occurred at 45-75 °C (optimum 70-75 °C) and pH 6.5-8.5 (optimum pH 7.5-8.0) and was fast under optimal conditions (doubling time 11.4 h). Yeast extract was required for growth. Fermentative growth with glucose, arabinose, xylose, and cellobiose was observed. The major fermentative end products of glucose were acetate and hydrogen. The major cellular fatty acids were C16:0, iso-C15:0, and C18:0. The genomic G + C content was 46.0 mol%. Fluorescence and electron microscopy observations revealed the intracellular localization of genomic DNA surrounded by a membrane in the cells of strain M15T as reported in a sole validly described species of the class Atribacteria in the phylum Atribacterota, Atribacter laminatus strain RT761T, suggesting that the unique morphological traits are widely shared in this class. Phylogenetic analyses indicated that strain M15T belongs to a distinct family-level lineage in the class Atribacteria and shows low similarities to Atribacter laminatus strain RT761T (16S rRNA gene sequence identity of 90.1 %, average nucleotide identity [ANI] of 66.1 %, average amino acid identity [AAI] of 55.8 %). Phenotypic traits of strain M15T (thermophilic, fast-growing, relatively high G + C content, etc.) were clearly distinct from A. laminatus. Based on these phenotypic and genomic properties, we propose a novel genus and species, Atrimonas thermophila gen. nov., sp. nov. for strain M15T (=JCM39389T, =KCTC25731T) representing a novel family Atrimonadaceae fam., nov. in the class Atribacteria.

Proteomics study the potential targets for Rifampicin-resistant spinal tuberculosis.

Introduction: The escalating global surge in Rifampicin-resistant strains poses a formidable challenge to the worldwide campaign against tuberculosis (TB), particularly in developing countries. The frequent reports of suboptimal treatment outcomes, complications, and the absence of definitive treatment guidelines for Rifampicin-resistant spinal TB (DSTB) contribute significantly to the obstacles in its effective management. Consequently, there is an urgent need for innovative and efficacious drugs to address Rifampicin-resistant spinal tuberculosis, minimizing the duration of therapy sessions. This study aims to investigate potential targets for DSTB through comprehensive proteomic and pharmaco-transcriptomic analyses. Methods: Mass spectrometry-based proteomics analysis was employed to validate potential DSTB-related targets. PPI analysis confirmed by Immunohistochemistry (IHC) and Western blot analysis. Results: The proteomics analysis revealed 373 differentially expressed proteins (DEPs), with 137 upregulated and 236 downregulated proteins. Subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses delved into the DSTB-related pathways associated with these DEPs. In the context of network pharmacology analysis, five key targets-human leukocyte antigen A chain (HLAA), human leukocyte antigen C chain (HLA-C), HLA Class II Histocompatibility Antigen, DRB1 Beta Chain (HLA-DRB1), metalloproteinase 9 (MMP9), and Phospholipase C-like 1 (PLCL1)-were identified as pivotal players in pathways such as "Antigen processing and presentation" and "Phagosome," which are crucially enriched in DSTB. Moreover, pharmaco-transcriptomic analysis can confirm that 58 drug compounds can regulate the expression of the key targets. Discussion: This research confirms the presence of protein alterations during the Rifampicin-resistant process in DSTB patients, offering novel insights into the molecular mechanisms underpinning DSTB. The findings suggest a promising avenue for the development of targeted drugs to enhance the management of Rifampicin-resistant spinal tuberculosis.

In vivo genome editing via CRISPR/Cas9-mediated homology-independent targeted integration for Bietti crystalline corneoretinal dystrophy treatment.

Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive chorioretinal degenerative disease without approved therapeutic drugs. It is caused by mutations in CYP4V2 gene, and about 80% of BCD patients carry mutations in exon 7 to 11. Here, we apply CRISPR/Cas9 mediated homology-independent targeted integration (HITI)-based gene editing therapy in HEK293T cells, BCD patient derived iPSCs, and humanized Cyp4v3 mouse model (h-Cyp4v3mut/mut) using two rAAV2/8 vectors via sub-retinal administration. We find that sgRNA-guided Cas9 generates double-strand cleavage on intron 6 of the CYP4V2 gene, and the HITI donor inserts the carried sequence, part of intron 6, exon 7-11, and a stop codon into the DNA break, achieving precise integration, effective transcription and translation both in vitro and in vivo. HITI-based editing restores the viability of iPSC-RPE cells from BCD patient, improves the morphology, number and metabolism of RPE and photoreceptors in h-Cyp4v3mut/mut mice. These results suggest that HITI-based editing could be a promising therapeutic strategy for those BCD patients carrying mutations in exon 7 to 11, and one injection will achieve lifelong effectiveness.

Potential gap in understanding cyanoHABs: Light-dependent morphological variations in colonial cyanobacterium Microcystis.

Colony formation is a crucial characteristic of Microcystis, a cyanobacterium known for causing cyanobacterial harmful algal blooms (cyanoHABs). It has been observed that as Microcystis colonies grow larger, they often become less densely packed, which correlates with a decrease in light penetration. The objective of this study was to investigate the effects of light limitation on the morphological variations in Microcystis, particularly in relation to the crowded cellular environment. The results indicated that when there was sufficient light (transmittance = 100 %) to support a growth rate of 0.11±0.01 day-1, a significant increase in colony size was found, from 466±15 µm to 1030±111 µm. However, under light limitation (transmittance = 50 % - 1 %) where the growth rate was lower than 0, there was no significant improvement in colony size. Microcystis in the light limitation groups exhibited a loose cell arrangement and even the presence of holes or pores within the colony, confirming the negative correlation between colony size and cell arrangement. This pattern is driven by regional differences in growth within the colony, as internal cells have a significantly lower frequency of division compared to peripheral cells, due to intra-colony self-shading (ICSS). The research demonstrates that Microcystis can adjust its cell arrangement to avoid excessive self-shading, which has implications for predicting and controlling cyanoHABs. These findings also contribute to the understanding of cyanobacterial variations and can potentially inform future research on the diverse phycosphere.