[Characteristics of caries-related oral microorganisms in early childhood caries].

PURPOSE: To study the structural characteristics of oral microorganisms in children with caries by 16S rRNA high-throughput sequencing technology. METHODS: Thirty healthy children aged 3-5 years were enrolled as subjects. According to the index of dmfs, they were divided into caries-free (CF) group (15) and early childhood caries (ECC) group(15). To compare the differences in bacterial community structure, samples of saliva and dental plaque were collected, and high-throughput sequencing was conducted using the Illumina Miseq sequencing platform. Bioinformatics analysis was used to analyze the difference of microbial community structure and diversity with SPSS 23.0 software package. RESULTS: Microbial diversity in ECC group was significantly lower than CF group. At phylum level, Actinobateria was more abundant in saliva samples of ECC group, while Firmicutes was more abundant in plaque samples of CF group. At genus level, the abundance of Lautropia of CF group was higher in saliva samples while Cardiobacterium, Gemella and Granulicatella were abundant in plaque samples. The abundance of Rothia of ECC group was higher in saliva samples and Corynebacterium was abundant of ECC group in plaque samples. CONCLUSIONS: There are significant differences in the species and composition of microbial community in saliva and plaque of children with or without caries. Specific microorganisms are related to the occurrence of ECC, and screening specific microorganisms is helpful for early prediction and prevention of ECC.

Small RNA SmsR1 modulates acidogenicity and cariogenic virulence by affecting protein acetylation in Streptococcus mutans.

Post-transcriptional regulation by small RNAs and post-translational modifications (PTM) such as lysine acetylation play fundamental roles in physiological circuits, offering rapid responses to environmental signals with low energy consumption. Yet, the interplay between these regulatory systems remains underexplored. Here, we unveil the cross-talk between sRNAs and lysine acetylation in Streptococcus mutans, a primary cariogenic pathogen known for its potent acidogenic virulence. Through systematic overexpression of sRNAs in S. mutans, we identified sRNA SmsR1 as a critical player in modulating acidogenicity, a key cariogenic virulence feature in S. mutans. Furthermore, combined with the analysis of predicted target mRNA and transcriptome results, potential target genes were identified and experimentally verified. A direct interaction between SmsR1 and 5'-UTR region of pdhC gene was determined by in vitro binding assays. Importantly, we found that overexpression of SmsR1 reduced the expression of pdhC mRNA and increased the intracellular concentration of acetyl-CoA, resulting in global changes in protein acetylation levels. This was verified by acetyl-proteomics in S. mutans, along with an increase in acetylation level and decreased activity of LDH. Our study unravels a novel regulatory paradigm where sRNA bridges post-transcriptional regulation with post-translational modification, underscoring bacterial adeptness in fine-tuning responses to environmental stress.

Projection domain decomposition denoising algorithm based on low rank and similarity-based regularization.

BACKGROUND: Projection Domain Decomposition (PDD) is a dual energy reconstruction method which implements the decomposition process before image reconstruction. The advantage of PDD is that it can alleviate beam hardening artifacts and metal artifacts effectively as energy spectra estimation is considered in PDD. However, noise amplification occurs during the decomposition process, which significantly impacts the accuracy of effective atomic number and electron density. Therefore, effective noise reduction techniques are required in PDD. OBJECTIVE: This study aims to develop a new algorithm capable of minimizing noise while simultaneously preserving edges and fine details. METHODS: In this study, a denoising algorithm based on low rank and similarity-based regularization (LRSBR) is presented. This algorithm incorporates the low-rank characteristic of tensors into similarity-based regularization (SBR) framework. This method effectively addresses the issue of instability in edge pixels within the SBR algorithm and enhances the structural consistency of dual-energy images. RESULTS: A series of simulation and practical experiments were conducted on a dual-layer dual-energy CT system. Experiments demonstrate that the proposed method outperforms exiting noise removal methods in Peak Signal-to-noise Ratio (PSNR), Root Mean Square Error (RMSE), and Structural Similarity (SSIM). Meanwhile, there has been a notable enhancement in the visual quality of CT images. CONCLUSIONS: The proposed algorithm has a significantly improved noise reduction compared to other competing approach in dual-energy CT. Meanwhile, the LRSBR method exhibits outstanding performance in preserving edges and fine structures, making it practical for PDD applications.

Dual-space high-frequency learning for transformer-based MRI super-resolution.

BACKGROUND AND OBJECTIVE: Magnetic resonance imaging (MRI) can provide rich and detailed high-contrast information of soft tissues, while the scanning of MRI is time-consuming. To accelerate MR imaging, a variety of Transformer-based single image super-resolution methods are proposed in recent years, achieving promising results thanks to their superior capability of capturing long-range dependencies. Nevertheless, most existing works prioritize the design of transformer attention blocks to capture global information. The local high-frequency details, which are pivotal to faithful MRI restoration, are unfortunately neglected. METHODS: In this work, we propose a high-frequency enhanced learning scheme to effectively improve the awareness of high frequency information in current Transformer-based MRI single image super-resolution methods. Specifically, we present two entirely plug-and-play modules designed to equip Transformer-based networks with the ability to recover high-frequency details from dual spaces: 1) in the feature space, we design a high-frequency block (Hi-Fe block) paralleled with Transformer-based attention layers to extract rich high-frequency features; while 2) in the image intensity space, we tailor a high-frequency amplification module (HFA) to further refine the high-frequency details. By fully exploiting the merits of the two modules, our framework can recover abundant and diverse high-frequency information, rendering faithful MRI super-resolved results with fine details. RESULTS: We integrated our modules with six Transformer-based models and conducted experiments across three datasets. The results indicate that our plug-and-play modules can enhance the super-resolution performance of all foundational models to varying degrees, surpassing the capabilities of existing state-of-the-art single image super-resolution networks. CONCLUSION: Comprehensive comparison of super-resolution images and high-frequency maps from various methods, clearly demonstrating that our module possesses the capability to restore high-frequency information, showing huge potential in clinical practice for accelerated MRI reconstruction.

Use of serum KL-6 and chest radiographic severity grade to predict 28-day mortality in COVID-19 patients with pneumonia: a retrospective cohort study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has had a global social and economic impact. An easy assessment procedure to handily identify the mortality risk of inpatients is urgently needed in clinical practice. Therefore, the aim of this study was to develop a simple nomogram model to categorize patients who might have a poor short-term outcome. METHODS: A retrospective cohort study of 189 COVID-19 patients was performed at Shanghai Ren Ji Hospital from December 12, 2022 to February 28, 2023. Chest radiography and biomarkers, including KL-6 were assessed. Risk factors of 28-day mortality were selected by a Cox regression model. A nomogram was developed based on selected variables by SMOTE strategy. The predictive performance of the derived nomogram was evaluated by calibration curve. RESULTS: In total, 173 patients were enrolled in this study. The 28-day mortality event occurred in 41 inpatients (23.7%). Serum KL-6 and radiological severity grade (RSG) were selected as the final risk factors. A nomogram model was developed based on KL-6 and RSG. The calibration curve suggested that the nomogram model might have potential clinical value. The AUCs for serum KL-6, RSG, and the combined score in the development group and validation group were 0.885 (95% CI: 0.804-0.952), 0.818 (95% CI: 0.711-0.899), 0.868 (95% CI: 0.776-0.942) and 0.932 (95% CI: 0.862-0.997), respectively. CONCLUSIONS: Our results suggested that the nomogram based on KL-6 and RSG might be a potential method for evaluating 28-day mortality in COVID-19 patients. A high combined score might indicate a poor outcome in COVID-19 patients with pneumonia.

STADNet: Spatial-Temporal Attention-Guided Dual-Path Network for cardiac cine MRI super-resolution.

Cardiac cine magnetic resonance imaging (MRI) is a commonly used clinical tool for evaluating cardiac function and morphology. However, its diagnostic accuracy may be compromised by the low spatial resolution. Current methods for cine MRI super-resolution reconstruction still have limitations. They typically rely on 3D convolutional neural networks or recurrent neural networks, which may not effectively capture long-range or non-local features due to their limited receptive fields. Optical flow estimators are also commonly used to align neighboring frames, which may cause information loss and inaccurate motion estimation. Additionally, pre-warping strategies may involve interpolation, leading to potential loss of texture details and complicated anatomical structures. To overcome these challenges, we propose a novel Spatial-Temporal Attention-Guided Dual-Path Network (STADNet) for cardiac cine MRI super-resolution. We utilize transformers to model long-range dependencies in cardiac cine MR images and design a cross-frame attention module in the location-aware spatial path, which enhances the spatial details of the current frame by using complementary information from neighboring frames. We also introduce a recurrent flow-enhanced attention module in the motion-aware temporal path that exploits the correlation between cine MRI frames and extracts the motion information of the heart. Experimental results demonstrate that STADNet outperforms SOTA approaches and has significant potential for clinical practice.

Structure modification of anoplin for fighting resistant bacteria.

The emergence of bacterial resistance has posed a significant challenge to clinical antimicrobial treatment, rendering commonly used antibiotics ineffective. The development of novel antimicrobial agents and strategies is imperative for the treatment of resistant bacterial infections. Antimicrobial peptides (AMPs) are considered a promising class of antimicrobial agents due to their low propensity for resistance and broad-spectrum activity. Anoplin is a small linear α-helical natural antimicrobial peptide that was isolated from the venom of the solitary wasp Anplius samariensis. It exhibits rich biological activity, particularly broad-spectrum antimicrobial activity and low hemolytic activity. Over the past three decades, more than 40 research publications on anoplin have been made available online. This review focuses on the advancements of anoplin in antimicrobial research, encompassing its sources, characterization, antimicrobial activity, influencing factors and structural modifications. The aim is to provide assistances for the development of new antimicrobial agents that can combat bacterial resistance.

WNT-inhibitory factor 1-mediated glycolysis protects photoreceptor cells in diabetic retinopathy.

BACKGROUND: In diabetic retinopathy (DR), hypoxia-inducible factor (HIF-1α) induces oxidative stress by upregulating glycolysis. This process leads to neurodegeneration, particularly photoreceptor cell damage, which further contributes to retinal microvascular deterioration. Further, the regulation of Wnt-inhibitory factor 1 (WIF1), a secreted Wnt signaling antagonist, has not been fully characterized in neurodegenerative eye diseases. We aimed to explore the impact of WIF1 on photoreceptor function within the context of DR. METHOD: Twelve-week-old C57BL/KsJ-db/db mice were intravitreally injected with WIF1 overexpression lentivirus. After 4 weeks, optical coherence tomography (OCT), transmission electron microscopy (TEM), H&E staining, and electroretinography (ERG) were used to assess the retinal tissue and function. The potential mechanism of action of WIF1 in photoreceptor cells was explored using single-cell RNA sequencing. Under high-glucose conditions, 661 W cells were used as an in vitro DR model. WIF1-mediated signaling pathway components were assessed using quantitative real-time PCR, immunostaining, and western blotting. RESULT: Typical diabetic manifestations were observed in db/db mice. Notably, the expression of WIF1 was decreased at the mRNA and protein levels. These pathological manifestations and visual function improved after WIF1 overexpression in db/db mice. TEM demonstrated that WIF1 restored damaged mitochondria, the Golgi apparatus, and photoreceptor outer segments. Moreover, ERG indicated the recovery of a-wave potential amplitude. Single-cell RNA sequencing and in vitro experiments suggested that WIF1 overexpression prevented the expression of glycolytic enzymes and lactate production by inhibiting the canonical Wnt signaling pathway, HIF-1α, and Glut1, thereby reducing retinal and cellular reactive oxygen species levels and maintaining 661 W cell viability. CONCLUSIONS: WIF1 exerts an inhibitory effect on the Wnt/ß-catenin-HIF-1α-Glut1 glycolytic pathway, thereby alleviating oxidative stress levels and mitigating pathological structural characteristics in retinal photoreceptor cells. This mechanism helps preserve the function of photoreceptor cells in DR and indicates that WIF1 holds promise as a potential therapeutic candidate for DR and other neurodegenerative ocular disorders.

Design, synthesis and biological evaluation of bakuchiol derivatives as multi-target agents for the treatment of Alzheimer's disease.

The concept of multi-target-directed ligands offers fresh perspectives for the creation of brand-new Alzheimer's disease medications. To explore their potential as multi-targeted anti-Alzheimer's drugs, eighteen new bakuchiol derivatives were designed, synthesized, and evaluated. The structures of the new compounds were elucidated by IR, NMR, and HRMS. Eighteen compounds were assayed for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in vitro using Ellman's method. It was shown that most of the compounds inhibited AChE and BuChE to varying degrees, but the inhibitory effect on AChE was relatively strong, with fourteen compounds showing inhibition of >50% at the concentration of 200 µM. Among them, compound 3g (IC50 = 32.07 ± 2.00 µM) and compound 3n (IC50 = 34.78 ± 0.34 µM) showed potent AChE inhibitory activities. Molecular docking studies and molecular dynamics simulation showed that compound 3g interacts with key amino acids at the catalytically active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase and binds stably to acetylcholinesterase. On the other hand, compounds 3n and 3q significantly reduced the pro-inflammatory cytokines TNF-α and IL-6 released from LPS-induced RAW 264.7 macrophages. Compound 3n possessed both anti-acetylcholinesterase activity and anti-inflammatory properties. Therefore, an in-depth study of compound 3n is expected to be a multi-targeted anti-AD drug.

Association of Head Injury, Neck Injury or Acoustic Trauma on Phenotype of Ménière's Disease.

The aim of the present study was to investigate adverse effects of head injury, neck trauma, and chronic noise exposure on the complaint profile in people with Ménière's disease (MD). The study used a retrospective design. Register data of 912 patients with MD from the Finnish Ménière Federation database were studied. The data comprised case histories of traumatic brain injury (TBI), neck trauma and occupational noise exposure, MD specific complaints, impact related questions, and the E-Qol health-related quality of life instrument. TBI was classified based on mild, moderate, and severe categories of transient loss of consciousness (TLoC). The mean age of the participants was 60.2 years, the mean duration of the disease was 12.6 years, and 78.7% were females. Logistic regression analysis, linear correlation, and pairwise comparisons were used in evaluating the associations. 19.2% of the participants with MD had a history of TBI. The phenotype of participants with TBI was associated with frequent vestibular drop attacks (VDA), presyncope, headache-associated vertigo, and a reduction in the E-QoL. Logistic regression analysis explained the variability of mild TBI in 6.8%. A history of neck trauma was present in 10.8% of the participants. Neck trauma associated with vertigo (NTwV) was seen in 47 and not associated with vertigo in 52 participants. The phenotype of NTwV was associated with balance problems, VDA, physical strain-induced vertigo, and hyperacusia. Logistic regression analysis explained 8.7% of the variability of the complaint profile. Occupational noise exposure was recorded in 25.4% of the participants and correlated with the greater impact of tinnitus, hyperacusis, and hearing loss. Neither the frequency, duration, or severity of vertigo or nausea were significantly different between the baseline group and the TBI, NTwV, or noise-exposure groups. The results indicate that TBI and NTwV are common among MD patients and may cause a confounder effect.

MiR-146a alleviates acute lung injury via inhibiting Notch 1 signaling pathway targeting macrophage.

Acute lung injury (ALI) is associated with the leukocyte infiltration and inflammation. Previous studies have shown that miR-146a is a valid regulator of the macrophage polarization in vitro inflammatory model. However, it is unclear whether miR-146a plays a protective role in ALI via modulating macrophage inflammation. To explore the potential therapeutic effect mechanism of miR-146a on ALI. We analyzed the expression of miR-146a in acute injured lung tissues and differentiated macrophage. Lipopolysaccharide (LPS) and interleukin-4 (IL-4) were employed in provoking the macrophage to polarization. We used miR-146a mimics to improve the overexpression of miR-146a and investigated the effect of increased miR-146a on LPS-induced ALI mice via the target of macrophage polarization. We showed that the expression of miR-146a markedly decreased in injured lung tissue and type M1 macrophage, while increased miR-146a expression exhibited in type M2 macrophage. Moreover, overexpression of miR-146a in LPS-induced macrophage reversed inflammatory M1 phenotype to anti-inflammatory M2 phenotype and mitigated inflammatory level via inhibiting Notch 1 signaling pathway. Hence, inflammation, infiltration, integrity of capillary barrier, and histology in ALI model were corrected after miR-146a overexpression treatment. These results suggested that miR-146a promotes type M2 macrophage polarization via restraining Notch 1 signaling pathway. Overexpression of miR-146a prevents inflammation damage and ameliorates lung damage after LPS induction. Therefore, miR-146a may serve as a promising target for the therapy of ALI in the future.

Safety and Immunogenicity of the Monovalent Omicron XBB.1.5-Adapted BNT162b2 COVID-19 Vaccine in Individuals ≥12 Years Old: A Phase 2/3 Trial.

Vaccination remains an important mitigation tool against COVID-19. We report 1-month safety and preliminary immunogenicity data from a substudy of an ongoing, open-label, phase 2/3 study of monovalent Omicron XBB.1.5-adapted BNT162b2 (single 30-µg dose). Healthy participants ≥12 years old (N = 412 (12-17 years, N = 30; 18-55 years, N = 174; >55 years, N = 208)) who previously received ≥3 doses of a US-authorized mRNA vaccine, the most recent being an Omicron BA.4/BA.5-adapted bivalent vaccine ≥150 days before study vaccination, were vaccinated. Serum 50% neutralizing titers against Omicron XBB.1.5, EG.5.1, and BA.2.86 were measured 7 days and 1 month after vaccination in a subset of ≥18-year-olds (N = 40) who were positive for SARS-CoV-2 at baseline. Seven-day immunogenicity was also evaluated in a matched group who received bivalent BA.4/BA.5-adapted BNT162b2 in a previous study (ClinicalTrials.gov Identifier: NCT05472038). There were no new safety signals; local reactions and systemic events were mostly mild to moderate in severity, adverse events were infrequent, and none led to study withdrawal. The XBB.1.5-adapted BNT162b2 induced numerically higher titers against Omicron XBB.1.5, EG.5.1, and BA.2.86 than BA.4/BA.5-adapted BNT162b2 at 7 days and robust neutralizing responses to all three sublineages at 1 month. These data support a favorable benefit-risk profile of XBB.1.5-adapted BNT162b2 30 µg. ClinicalTrials.gov Identifier: NCT05997290.

Controlled release of dexamethasone from fibrin sealant for intratympanic administration in inner ear therapy.

The aim of the present work was to show the sustainability of fibrin sealant in releasing dexamethasone and adjust the protocol for clinical application of the novel method in the treatment of Meniere's disease (MD) and sudden sensorineural hearing loss (SSHL). Gelation occurred shortly after mixing dexamethasone-containing fibrinogen with thrombin. Dexamethasone was constantly released for at least 16 d at a stable level after 7 d in protocol 1 (low-dose), while it was robustly released within 4 d and slowed afterward until 10 d in protocol 2 (high-dose). There were significant differences among the time points in Protocol 2 (p < 0.01, ANOVA), and the exponential model with the formula y = 15.299 * e-0.483 *t fits the association. The estimated concentration of dexamethasone released on 7 d in protocol 2 was slightly lower than that observed in protocol 1. The fibrin sealant is capable of constantly releasing dexamethasone with adjustable dynamics. Targeted and minimally invasive administration of the material can be achieved in the clinic by sequential injections of the fluids using a soft-tipped catheter.

SMU_1361c regulates the oxidative stress response of Streptococcus mutans.

Dental caries is the most common chronic infectious disease around the world and disproportionately affects the marginalized socioeconomic group. Streptococcus mutans, considered a primary etiological agent of caries, depends on the coordinated physiological response to tolerate the oxidative stress generated by commensal species within dental plaque, which is a critical aspect of its pathogenicity. Here, we identified and characterized a novel tetracycline repressor family regulator, SMU_1361c, which appears to be acquired by the bacteria via horizontal gene transfer. Surprisingly, smu_1361c functions as a negative transcriptional regulator to regulate gene expression outside its operon and is involved in the oxidative stress response of S. mutans. The smu_1361c overexpression strain UA159/pDL278-1361c was more susceptible to oxidative stress and less competitive against hydrogen peroxide generated by commensal species Streptococcus gordonii and Streptococcus sanguinis. Transcriptomics analysis revealed that smu_1361c overexpression resulted in the significant downregulation of 22 genes, mainly belonging to three gene clusters responsible for the oxidative stress response. The conversed DNA binding motif of SMU_1361c was determined by electrophoretic mobility shift and DNase I footprinting assay with purified SMU_1361c protein; therefore, smu_1361c is directly involved in gene transcription related to the oxidative stress response. Crucially, our finding provides a new understanding of how S. mutans deals with the oxidative stress that is required for pathogenesis and will facilitate the development of new and improved therapeutic approaches for dental caries.IMPORTANCEStreptococcus mutans is the major organism associated with the development of dental caries, which globally is the most common chronic disease. To persist and survive in biofilms, S. mutans must compete with commensal species that occupy the same ecological niche. Here, we uncover a novel molecular mechanism of how tetracycline repressor family regulator smu_1361c is involved in the oxidative stress response through transcriptomics analysis, electrophoretic mobility shift assay, and DNase I footprinting assay. Furthermore, we demonstrated that smu_1361c mediates S. mutans sensitivity to oxidative stress and competitiveness with commensal streptococci. Therefore, this study has revealed a previously unknown regulation between smu_1361c and genes outside its operon and demonstrated the importance of smu_1361c in the oxidative stress response and the fitness of S. mutans within the plaque biofilms, which can be exploited as a new therapy to modulate ecological homeostasis and prevent dental caries.

Overlooked Role of Coexistent Hydrogen Peroxide in Activated Peracetic Acid by Cu(II) for Enhanced Oxidation of Organic Contaminants.

Cu(II)-catalyzed peracetic acid (PAA) processes have shown significant potential to remove contaminants in water treatment. Nevertheless, the role of coexistent H2O2 in the transformation from Cu(II) to Cu(I) remained contentious. Herein, with the Cu(II)/PAA process as an example, the respective roles of PAA and H2O2 on the Cu(II)/Cu(I) cycling were comprehensively investigated over the pH range of 7.0-10.5. Contrary to previous studies, it was surprisingly found that the coexistent deprotonated H2O2 (HO2-), instead of PAA, was crucial for accelerating the transformation from Cu(II) to Cu(I) (kHO2-/Cu(II) = (0.17-1) × 106 M-1 s-1, kPAA/Cu(II) < 2.33 ± 0.3 M-1 s-1). Subsequently, the formed Cu(I) preferentially reacted with PAA (kPAA/Cu(I) = (5.84 ± 0.17) × 102 M-1 s-1), rather than H2O2 (kH2O2/Cu(I) = (5.00 ± 0.2) × 101 M-1 s-1), generating reactive species to oxidize organic contaminants. With naproxen as the target pollutant, the proposed synergistic role of H2O2 and PAA was found to be highly dependent on the solution pH with weakly alkaline conditions being more conducive to naproxen degradation. Overall, this study systematically investigated the overlooked but crucial role of coexistent H2O2 in the Cu(II)/PAA process, which might provide valuable insights for better understanding the underlying mechanism in Cu-catalyzed PAA processes.

Metformin inhibits high glucose-induced apoptosis of renal podocyte through regulating miR-34a/SIRT1 axis.

BACKGROUND: Previous studies have reported SIRT1 was inversely modulated by miR-34a, However, mechanism of metformin (MFN)'s renal podocyte protection under high glucose (HG) conditions and the connection between miR-34a and SIRT1 expression in diabetic nephropathy (DN) remain unclear. METHOD: We aimed to further elucidate the role of miR-34a in HG-treated podocytes in DN. A conditionally immortalized human podocyte cell line was cultivated in d-glucose (30 mM). RESULTS: Microarray and RT-qPCR revealed that miR-34a was downregulated in HG-treated podocytes. Additionally, miR-34a levels increased in MFN-treated HG-induced podocytes. CCK-8 assay, colony formation assay, flow cytometry, and Western blot detection showed that HG treatment reduced cell viability and promoted via HG treatment, and MFN treatment reversed this phenotypic change. MiR-34a upregulation caused restored cell viability and suppressed cell apoptosis in HG-treated podocytes, and miR-34a downregulation led to damaged cell survival and induced apoptosis in MFN-administered and HG-treated podocytes. The dual luciferase reporter assay showed that SIRT1 3'-UTR was a direct miR-34a target. Further studies demonstrated an elevation in SIRT1 levels in HG-exposed podocytes, whereas MFN treatment decreased SIRT1 levels. In addition, miR-34a upregulation led to reduced SIRT1 expression, whereas miR-34a inhibition increased SIRT1 levels in cells. MFN-induced miR-34a suppresses podocyte apoptosis under HG conditions by acting on SIRT1. CONCLUSION: This study proposes a promising approach to interpret the mechanisms of action of the MFN-miR-34a axis involved in DN.

CD80-Fc fusion protein as a potential cancer immunotherapy strategy.

The activation of T lymphocytes is a crucial component of the immune response, and the presence of CD80, a membrane antigen, is necessary for T-cell activation. CD80 is usually expressed on antigen-presenting cells (APCs), which can interact with cluster of differentiation 28 (CD28) or programmed cell death ligand 1 (PD-L1) to promote T-cell proliferation, differentiation and function by activating costimulatory signal or blocking inhibitory signal. Simultaneously, CD80 on the APCs also interacts with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of T cells to suppress the response of specific effector T cells, particularly in the context of persistent antigenic stimulation. Due to the pivotal role of CD80 in the immune response, the CD80-Fc fusion protein has emerged as a promising approach for cancer immunotherapy. This review primarily focused on the crucial role of CD80 in the cancer immunotherapy. We also reviewed the current advancements in the research of CD80-Fc fusion proteins. Finally, we deliberated on the challenges encountered by CD80-Fc fusion proteins and proposed the potential strategies that could yield the benefits for patients.

A Murine Model of Post-acute Neurological Sequelae Following SARS-CoV-2 Variant Infection.

Viral variant is one known risk factor associated with post-acute sequelae of COVID-19 (PASC), yet the pathogenesis is largely unknown. Here, we studied SARS-CoV-2 Delta variant-induced PASC in K18-hACE2 mice. The virus replicated productively, induced robust inflammatory responses in lung and brain tissues, and caused weight loss and mortality during the acute infection. Longitudinal behavior studies in surviving mice up to 4 months post-acute infection revealed persistent abnormalities in neuropsychiatric state and motor behaviors, while reflex and sensory functions recovered over time. Surviving mice showed no detectable viral RNA in the brain and minimal neuroinflammation post-acute infection. Transcriptome analysis revealed persistent activation of immune pathways, including humoral responses, complement, and phagocytosis, and reduced levels of genes associated with ataxia telangiectasia, impaired cognitive function and memory recall, and neuronal dysfunction and degeneration. Furthermore, surviving mice maintained potent T helper 1 prone cellular immune responses and high neutralizing antibodies against Delta and Omicron variants in the periphery for months post-acute infection. Overall, infection in K18-hACE2 mice recapitulates the persistent clinical symptoms reported in long COVID patients and may be useful for future assessment of the efficacy of vaccines and therapeutics against SARS-CoV-2 variants.

Response mechanism of soil leachate and disinfection by-product formation to extreme precipitation events under continuous drought scenario.

In this study, a rainfall simulation device was employed to investigate the response mechanism of soil leachate and disinfection by-products formation potential (DBPsFP) to extreme precipitation events. The results revealed that the aromaticity of dissolved organic matter (DOM) and the concentration of hydrophobic DOM containing aromatic carbon groups in leachate decreased with rising temperature. The humification degree of DOM decreased at 25 °C (99 mm/h), while the humification degree and protein-like level of DOM increased under high temperatures droughts (45 °C and 65 °C). Higher temperatures resulted in the leach of more microbial-derived humus and low molecular phenolic compounds from soil and broadened the range of molecular weight distribution. Increasing temperature increased DBPsFP and DBPs species and caused the precursors of haloacetic acids (HAAs) in leachate to become more hydrophobic, while the precursors of trihalomethanes (THMs) became more hydrophilic. Most importantly, the increased temperature attenuated the rainfall-mediated dilution of organic pollutant concentration, and temperature has a more significant effect than extreme rainfall in DOM abundance and the formation potential (or species) of DBPs. The results help to better understand the impact of climate change on the physicochemical processes of water quality.

Integrated multi-omics analyses identify anti-viral host factors and pathways controlling SARS-CoV-2 infection.

Host anti-viral factors are essential for controlling SARS-CoV-2 infection but remain largely unknown due to the biases of previous large-scale studies toward pro-viral host factors. To fill in this knowledge gap, we perform a genome-wide CRISPR dropout screen and integrate analyses of the multi-omics data of the CRISPR screen, genome-wide association studies, single-cell RNA-Seq, and host-virus proteins or protein/RNA interactome. This study uncovers many host factors that are currently underappreciated, including the components of V-ATPases, ESCRT, and N-glycosylation pathways that modulate viral entry and/or replication. The cohesin complex is also identified as an anti-viral pathway, suggesting an important role of three-dimensional chromatin organization in mediating host-viral interaction. Furthermore, we discover another anti-viral regulator KLF5, a transcriptional factor involved in sphingolipid metabolism, which is up-regulated, and harbors genetic variations linked to COVID-19 patients with severe symptoms. Anti-viral effects of three identified candidates (DAZAP2/VTA1/KLF5) are confirmed individually. Molecular characterization of DAZAP2/VTA1/KLF5-knockout cells highlights the involvement of genes related to the coagulation system in determining the severity of COVID-19. Together, our results provide further resources for understanding the host anti-viral network during SARS-CoV-2 infection and may help develop new countermeasure strategies.