The SARS-CoV-2 Spike is a virulence determinant and plays a major role on the attenuated phenotype of Omicron virus in a feline model of infection.

The role of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.1 Spike (S) on disease pathogenesis was investigated. For this, we generated recombinant viruses harboring the S D614G mutation (rWA1-D614G) and the Omicron BA.1 S gene (rWA1-Omi-S) in the backbone of the ancestral SARS-CoV-2 WA1 strain genome. The recombinant viruses were characterized in vitro and in vivo. Viral entry, cell-cell fusion, plaque size, and the replication kinetics of the rWA1-Omi-S virus were markedly impaired when compared to the rWA1-D614G virus, demonstrating a lower fusogenicity and ability to spread cell-to-cell of rWA1-Omi-S. To assess the contribution of the Omicron BA.1 S protein to SARS-CoV-2 pathogenesis, the pathogenicity of rWA1-D614G and rWA1-Omi-S viruses was compared in a feline model. While the rWA1-D614G-inoculated cats were lethargic and showed increased body temperatures on days 2 and 3 post-infection (pi), rWA1-Omi-S-inoculated cats remained subclinical and gained weight throughout the 14-day experimental period. Animals inoculated with rWA1-D614G presented higher infectious virus shedding in nasal secretions, when compared to rWA1-Omi-S-inoculated animals. In addition, tissue replication of the rWA1-Omi-S was markedly reduced compared to the rWA1-D614G, as evidenced by lower viral load in tissues on days 3 and 5 pi. Histologic examination of the nasal turbinate and lungs revealed intense inflammatory infiltration in rWA1-D614G-inoculated animals, whereas rWA1-Omi-S-inoculated cats presented only mild to modest inflammation. Together, these results demonstrate that the S protein is a major virulence determinant for SARS-CoV-2 playing a major role for the attenuated phenotype of the Omicron virus. IMPORTANCE: We have demonstrated that the Omicron BA.1.1 variant presents lower pathogenicity when compared to D614G (B.1) lineage in a feline model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There are over 50 mutations across the Omicron genome, of which more than two-thirds are present in the Spike (S) protein. To assess the role of the Omicron BA.1 S on virus pathogenesis, recombinant viruses harboring the S D614G mutation (rWA1-D614G) and the Omicron BA.1 Spike gene (rWA1-Omi-S) in the backbone of the ancestral SARS-CoV-2 WA1 were generated. While the Omicron BA.1 S promoted early entry into cells, it led to impaired fusogenic activity and cell-cell spread. Infection studies with the recombinant viruses in a relevant naturally susceptible feline model of SARS-CoV-2 infection here revealed an attenuated phenotype of rWA1-Omi-S, demonstrating that the Omi-S is a major determinant of the attenuated disease phenotype of Omicron strains.

Subtilisin-like proteases from Fusarium graminearum induce plant cell death and contribute to virulence.

Fusarium head blight (FHB), caused by Fusarium graminearum, causes huge annual economic losses in cereal production. To successfully colonize host plants, pathogens secrete hundreds of effectors that interfere with plant immunity and facilitate infection. However, the roles of most secreted effectors of F. graminearum in pathogenesis remain unclear. We analyzed the secreted proteins of F. graminearum and identified 255 candidate effector proteins by liquid chromatography-mass spectrometry (LC-MS). Five subtilisin-like family proteases (FgSLPs) were identified that can induce cell death in Nicotiana benthamiana leaves. Further experiments showed that these FgSLPs induced cell death in cotton (Gossypium barbadense) and Arabidopsis (Arabidopsis thaliana). A signal peptide and light were not essential for the cell death-inducing activity of FgSLPs. The I9 inhibitor domain and the entire C-terminus of FgSLPs were indispensable for their self-processing and cell death-inducing activity. FgSLP-induced cell death occurred independent of the plant signal transduction components BRI-ASSOCIATED KINASE 1 (BAK1), SUPPRESSOR OF BIR1 1 (SOBIR1), ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1), and PHYTOALEXIN DEFICIENT 4 (PAD4). Reduced virulence was observed when FgSLP1 and FgSLP2 were simultaneously knocked out. This study reveals a class of secreted toxic proteins essential for F. graminearum virulence.

Engineering allorejection-resistant CAR-NKT cells from hematopoietic stem cells for off-the-shelf cancer immunotherapy.

The clinical potential of current FDA-approved chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy is encumbered by its autologous nature, which presents notable challenges related to manufacturing complexities, heightened costs, and limitations in patient selection. Therefore, there is a growing demand for off-the-shelf universal cell therapies. In this study, we have generated universal CAR-engineered NKT (UCAR-NKT) cells by integrating iNKT TCR engineering and HLA gene editing on hematopoietic stem cells (HSCs), along with an ex vivo, feeder-free HSC differentiation culture. The UCAR-NKT cells are produced with high yield, purity, and robustness, and they display a stable HLA-ablated phenotype that enables resistance to host cell-mediated allorejection. These UCAR-NKT cells exhibit potent antitumor efficacy to blood cancers and solid tumors, both in vitro and in vivo, employing a multifaceted array of tumor-targeting mechanisms. These cells are further capable of altering the tumor microenvironment by selectively depleting immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells. In addition, UCAR-NKT cells demonstrate a favorable safety profile with low risks of graft-versus-host disease and cytokine release syndrome. Collectively, these preclinical studies underscore the feasibility and significant therapeutic potential of UCAR-NKT cell products and lay a foundation for their translational and clinical development.

Free-Standing Carbon Nanotube Embroidered Graphene Film Electrode Array for Stable Neural Interfacing.

Implantable neural probes that are mechanically flexible yet robust are attractive candidates for achieving stable neural interfacing in the brain. Current flexible neural probes consist mainly of metal thin-film electrodes integrated on micrometer-thick polymer substrates, making it challenging to achieve electrode-tissue interfacing on the cellular scale. Here, we describe implantable neural probes that consist of robust carbon nanotube network embroidered graphene (CeG) films as free-standing recording microelectrodes. Our CeG film microelectrode arrays (CeG_MEAs) are ultraflexible yet mechanically robust, thus enabling cellular-scale electrode-tissue interfacing. Chronically implanted CeG_MEAs can stably track the activities of the same population of neurons over two months. Our results highlight the potential of ultraflexible and free-standing carbon nanofilms for stable neural interfacing in the brain.

Superior Attentional Efficiency of Auditory Cue via the Ventral Auditory-thalamic Pathway.

Auditory commands are often executed more efficiently than visual commands. However, empirical evidence on the underlying behavioral and neural mechanisms remains scarce. In two experiments, we manipulated the delivery modality of informative cues and the prediction violation effect and found consistently enhanced RT benefits for the matched auditory cues compared with the matched visual cues. At the neural level, when the bottom-up perceptual input matched the prior prediction induced by the auditory cue, the auditory-thalamic pathway was significantly activated. Moreover, the stronger the auditory-thalamic connectivity, the higher the behavioral benefits of the matched auditory cue. When the bottom-up input violated the prior prediction induced by the auditory cue, the ventral auditory pathway was specifically involved. Moreover, the stronger the ventral auditory-prefrontal connectivity, the larger the behavioral costs caused by the violation of the auditory cue. In addition, the dorsal frontoparietal network showed a supramodal function in reacting to the violation of informative cues irrespective of the delivery modality of the cue. Taken together, the results reveal novel behavioral and neural evidence that the superior efficiency of the auditory cue is twofold: The auditory-thalamic pathway is associated with improvements in task performance when the bottom-up input matches the auditory cue, whereas the ventral auditory-prefrontal pathway is involved when the auditory cue is violated.

A Novel Frameshift Variant of the ELF4 Gene in a Patient with Autoinflammatory Disease: Clinical Features, Transcriptomic Profiling and Functional Studies.

We described the diagnosis and treatment of a patient with autoinflammatory disease, named "Deficiency in ELF4, X-linked (DEX)". A novel ELF4 variant was discovered and its pathogenic mechanism was elucidated. The data about clinical, laboratory and endoscopic features, treatment, and follow-up of a patient with DEX were analyzed. Whole exome sequencing and Sanger sequencing were performed to identify potential pathogenic variants. The mRNA and protein levels of ELF4 were analyzed by qPCR and Western blotting, respectively. The association of ELF4 frameshift variant with nonsense-mediated mRNA decay (NMD) in the pathogenesis DEX was examined. Moreover, RNA-seq was performed to identify the key molecular events triggered by ELF4 variant. The relationship between ELF4 and IFN-ß activity was validated using a dual-luciferase reporter assay and a ChIP-qPCR assay. An 11-year-old boy presented with a Behçet's-like phenotype. The laboratory abnormality was the most obvious in elevated inflammatory indicators. Endoscopy revealed multiple ileocecal ulcers. Intestinal histopathology showed inflammatory cell infiltrations. The patient was treated with long-term immunosuppressant and TNF-α blocker (adalimumab), which reaped an excellent response over 16 months of follow-up. Genetic analysis identified a maternal hemizygote frameshift variant (c.1022del, p.Q341Rfs*30) in ELF4 gene in the proband. The novel variant decreased the mRNA level of ELF4 via the NMD pathway. Mechanistically, insufficient expression of ELF4 disturbed the immune system, leading to immunological disorders and pathogen susceptibility, and disrupted ELF4-activating IFN-ß responses. This analysis detailed the clinical characteristics of a Chinese patient with DEX who harbored a novel ELF4 frameshift variant. For the first time, we used patient-derived cells and carried out transcriptomic analysis to delve into the mechanism of ELF4 variant in DEX.

Sleep deprivation reduced LPS-induced IgG2b production by up-regulating BMAL1 and CLOCK expression.

Sleep deprivation (SD) weakens the immune system and leads to increased susceptibility to infectious or inflammatory diseases. However, it is still unclear how SD affects humoral immunity. In the present study, sleep disturbance was conducted using an sleep deprivation instrument, and the bacterial endotoxin lipopolysaccharide (LPS) was used to activate the immune response. It was found that SD-pretreatment reduced LPS-induced IgG2b+ B cells and IgG2b isotype antibody production in lymphocytes of spleen. And, SD-pretreatment decreased the proportion of CD4+T cells, production of CD4+T cells derived TGF-ß1 and its contribution in helping IgG2b production. Additionally, BMAL1 and CLOCK were selectively up-regulated in lymphocytes after SD. Importantly, BMAL1 and CLOCK deficiency contributed to TGF-ß1 expression and production of IgG2b+ B cells. Thus, our results provide a novel insight to explain the involvement of BMAL1 and CLOCK under SD stress condition, and their roles in inhibiting TGF-ß1 expression and contributing to reduction of LPS induced IgG2b production.

Development and validation of a simple and practical model for early detection of diabetic macular edema in patients with type 2 diabetes mellitus using easily accessible systemic variables.

OBJECTIVE: Diabetic macular edema (DME) is the leading cause of visual impairment in patients with diabetes mellitus (DM). The goal of early detection has not yet achieved due to a lack of fast and convenient methods. Therefore, we aim to develop and validate a prediction model to identify DME in patients with type 2 diabetes mellitus (T2DM) using easily accessible systemic variables, which can be applied to an ophthalmologist-independent scenario. METHODS: In this four-center, observational study, a total of 1994 T2DM patients who underwent routine diabetic retinopathy screening were enrolled, and their information on ophthalmic and systemic conditions was collected. Forward stepwise multivariable logistic regression was performed to identify risk factors of DME. Machine learning and MLR (multivariable logistic regression) were both used to establish prediction models. The prediction models were trained with 1300 patients and prospectively validated with 104 patients from Guangdong Provincial People's Hospital (GDPH). A total of 175 patients from Zhujiang Hospital (ZJH), 115 patients from the First Affiliated Hospital of Kunming Medical University (FAHKMU), and 100 patients from People's Hospital of JiangMen (PHJM) were used as external validation sets. Area under the receiver operating characteristic curve (AUC), accuracy (ACC), sensitivity, and specificity were used to evaluate the performance in DME prediction. RESULTS: The risk of DME was significantly associated with duration of DM, diastolic blood pressure, hematocrit, glycosylated hemoglobin, and urine albumin-to-creatinine ratio stage. The MLR model using these five risk factors was selected as the final prediction model due to its better performance than the machine learning models using all variables. The AUC, ACC, sensitivity, and specificity were 0.80, 0.69, 0.80, and 0.67 in the internal validation, and 0.82, 0.54, 1.00, and 0.48 in prospective validation, respectively. In external validation, the AUC, ACC, sensitivity and specificity were 0.84, 0.68, 0.90 and 0.60 in ZJH, 0.89, 0.77, 1.00 and 0.72 in FAHKMU, and 0.80, 0.67, 0.75, and 0.65 in PHJM, respectively. CONCLUSION: The MLR model is a simple, rapid, and reliable tool for early detection of DME in individuals with T2DM without the needs of specialized ophthalmologic examinations.

Efficacy Of Baricitinib in Patients With Moderate-To-Severe Rheumatoid Arthritis Up to 6.5 Years Of Treatment: Results Of A Long-Term Study.

OBJECTIVES: To evaluate the long-term efficacy of once-daily baricitinib 4 mg or 2 mg in patients with active rheumatoid arthritis who had inadequate response (IR) to MTX, csDMARDs, or bDMARDs. METHODS: Data from three completed phase III studies, RA-BEAM (MTX-IR), RA-BUILD (csDMARD-IR), and RA-BEACON (bDMARD-IR), and one completed long-term extension study (RA-BEYOND) were analyzed up to 6.5 years (340 weeks [RA-BEAM] and 336 weeks [RA-BUILD and RA-BEACON]). Low disease activity (LDA) (Simplified Disease Activity Index [SDAI] ≤11), clinical remission (SDAI ≤3.3), and physical function (Health Assessment Questionnaire Disability Index [HAQ-DI] ≤0.5) were the main outcomes assessed. Completer and non-responder imputation (NRI) analyses were conducted on each population. RESULTS: At week 340 or 336, LDA was achieved in 37%/83% of MTX-IR, 35%/83% of csDMARD-IR, and 23%/73% of bDMARD-IR patients treated with baricitinib 4 mg, assessed by NRI/completer analyses, respectively. Remission was achieved in 20%/40% of MTX-IR, 13%/32% of csDMARD-IR, and 9%/30% of bDMARD-IR patients treated with baricitinib 4 mg, assessed by NRI/completer analyses, respectively. HAQ-DI ≤0.5 was reached in 31%/51% of MTX-IR, 25%/46% of csDMARD-IR, and 24%/38% of bDMARD-IR patients treated with baricitinib 4 mg, assessed by NRI/completer analyses, respectively. CONCLUSION: Treatment with baricitinib 4 mg or 2 mg demonstrated efficacy up to 6.5 years with maintained LDA/remission results across SDAI, CDAI and DAS28-hsCRP consistent with previously reported data, and was well tolerated.

Sucrose phosphate synthase 8 is required for the remobilization of carbon reserves in rice stems during grain filling.

Carbon reserve remobilization in stems is closely related to rice grain filling. Sucrose phosphate synthase (SPS) is highly associated with carbon reserve remobilization. In this study, we investigated the expression pattern of SPS genes in various rice tissues, and found that SPS8 is the major SPS isoform in rice stems during the grain-filling stage. We then constructed sps8 mutants using the CRISPR/Cas9 system. The SPS activity of the sps8 mutants was markedly reduced in the stems. In addition, the sps8 mutants exhibited significant starch accumulation in stems. 14C-labelling experiments revealed that the remobilization of non-structural carbohydrates from rice stems to grains was impaired in the sps8 mutants. In the sps8 mutants, grain filling was delayed and yield decreased by 15% due to a reduced percentage of ripened grains. RNA sequencing and quantitative PCR analyses indicated that the genes involved in starch synthesis and degradation were up-regulated in the sps8 mutant stems. In addition, the activity of the enzymes involved in starch synthesis and degradation was increased in the sps8 stems. These results demonstrate that SPS8 is required for carbon reserve remobilization from rice stems to grains, and that its absence may enhance 'futile cycles' of starch synthesis and degradation in rice stems.

Reduced-toxicity conditioning regimen with low dose post-transplantation cyclophosphamide and low-dose anti-thymocyte globulin as graft-versus-host disease prophylaxis for haploidentical stem cell transplantation in older patients.

Reduced-toxicity conditioning (RIC) regimens are used for allogeneic hematopoietic stem cell transplantation in older patients. However, successful outcomes are hindered by graft-versus-host disease (GVHD), treatment-related mortality, and relapse, particularly after haploidentical donor hematopoietic stem cell transplantation (HID-HSCT). The aim of this study was to evaluate the effectiveness of an RIC conditioning regimen that included a combination of cyclosporin A, methotrexate (on day + 1), mycophenolate, lower doses of post-transplantation PTCy (40 mg/kg on day + 3), and ATG (7.5 mg/kg) as GVHD prophylaxis prior to haplo-stem cell transplantation (haplo-SCT) in older patients. METHODS: We retrospectively analyzed outcomes in 55 patients ≥ 55 years of age with hematologic malignancies treated with fludarabine, cytarabine, busulfan, and low-dose cyclophosphamide as the conditioning regimen between January 1, 2019, and November 30, 2023. RESULTS: Neutrophil engraftment was successful in all patients within 28 days, with 54 patients (98.2%) achieving complete donor chimerism. The cumulative incidence of non-relapse mortality was 0% at 30 days, 7.5% at 100 days, and 19% at 1 year. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 25% (95%CI, 15-38%), whereas that of grade III-IV aGVHD was 9.1% (95% CI, 3.3-19%). The cumulative incidence of extensive chronic graft-versus-host disease at 1 year was 3.6% (95%CI, 0.66-11%). The cumulative incidences of relapse, overall survival, and GVHD-free/relapse-free survival at 1 year were 9.0%, 71.6%, and 67.1%, respectively. CONCLUSIONS: An RIC conditioning regimen, including a combination of lower PTCy/ATG as GVHD prophylaxis, followed by haplo-SCT, might be a promising option for appropriately selected older patients.

Efficacy of microwave ablation in the treatment of large benign thyroid nodules: a multi-center study.

OBJECTIVE: To evaluate the efficacy, safety, and improvement of symptoms by ultrasound-guided microwave ablation (MWA) for patients with large benign thyroid nodules (BTNs). METHODS: Eighty-seven patients with 87 BTNs (≥ 4 cm) treated with MWA between April 2015 and March 2021 were enrolled in this retrospective multicenter study, with clinical and ultrasound examinations performed at the 1st, 3rd, 6th, and 12th months. A multivariable linear mixed effects model was employed to explore the alterations in volume and volume reduction ratio (VRR), as well as the potential factors associated with VRR. RESULTS: The mean age of the 87 patients was 45.69 ± 14.21 years (range 18-76 years), and the ratio of men to women was 1:4.8. The mean volumes were much decreased at the 12th month after ablation compared to the initial volumes (p < .001). The mean VRR was 76.09% at the 12th month. The technique efficacy (VRR > 50%) was 90.80% at the 12th month. A multivariate analysis revealed that VRR was related to the initial volume (p = .015), annular flow (p = .010), and nodule composition (p = .024). The mean symptomatic score decreased from 4.40 ± 0.28 to 0.26 ± 0.06 at the 12th month (p < .001). At the same time, the mean cosmetic score decreased from 3.22 ± 0.10 to 1.31 ± 0.08 (p < .001). CONCLUSION: MWA could serve as a safe and effective therapy for large BTNs, significantly reducing the volume of BTNs and significantly improving compressive symptoms and appearance problems. CLINICAL RELEVANCE STATEMENT: Microwave ablation could serve as a safe and effective therapy for large benign thyroid nodules, leading to significant volume reduction and satisfied symptom and cosmetic alleviation period. KEY POINTS: • This multicenter study investigated the feasibility and safety of microwave ablation for large benign thyroid nodules. • After ablation, the nodule volume was significantly reduced, and patients' symptoms and appearance problems were significantly improved. • Microwave ablation is feasible for large benign thyroid nodules and has been a supplement treatment.

Ultra-Tough and Highly Stretchable Dual-Crosslinked Eutectogel Based on Coordinated and Non-Coordinated Two Types Deep Eutectic Solvent Mixture.

Eutectogels are gaining attention in flexible device applications for their superior ionic conductivity, stability, biocompatibility, and cost-effectiveness. However, most existing eutectogels suffer from low strength and toughness. Herein, ultra-tough and highly stretchable polyacrylamide (PAM) eutectogels featuring a dual-crosslinked network comprising chemical cross-linking and physical cross-linking facilitated by metal coordination bonds and hydrogen bonds are developed. This is achieved through a controlled strategy involving polymerization of acrylamide in a coordinated metal salt-type deep eutectic solvent (DES) combined with a non-coordinated choline chloride (ChCl)-type DES mixture. By varying the molar ratio of these two types of DES, exceptional and adjustable mechanical properties of the resulting eutectogel are achieved, including a high tensile strength ranging from 2.9 to 8.2 MPa and elongation at break ranging from 1725 to 747%, at a 70 wt% DES content. Furthermore, the reversible non-covalent crosslinking in these eutectogels enables self-recovery and self-healing capabilities of eutectogels. The prepared eutectogels also exhibit outstanding ionic conductivity (3.56 mS cm-1 ), making them well-suited for use as strain sensors in human motion detection. The toughening strategy is universally effective for creating tough eutectogels using coordinated metal salt-type DES with various metal ions, as well as a diverse range of coordinatable polymers.

Alterations of outer retinal reflectivity in diabetic patients without clinically detectable retinopathy.

PURPOSE: This study aimed to investigate alterations of outer retinal reflectivity on spectral-domain optical coherence tomography (OCT) in diabetic patients without clinically detectable retinopathy (NDR). METHODS: In this retrospective study, 64 NDR patients and 71 controls were included. Relative reflectivity (RR) of the ellipsoid zone (EZ), photoreceptor outer segment (OS) and inner segment (IS), and outer nuclear layer (ONL) at the foveola and at 500 µm, 1000 µm, and 2000 µm nasal (N), temporal (T), superior (S), and inferior (I) to the foveola was measured by cross-line OCT and ImageJ. Retinal vessel densities (VD) in fovea, parafovea, and perifovea areas were detected by OCT angiography (OCTA). RESULTS: EZ RR in most retinal locations was significantly lower in NDR eyes compared to controls (all P < 0.05), except the foveola. Compared with controls, NDR eyes also displayed lower RR at N2000, T2000, S1000, and I1000 of OS, at S500 and I500 of IS, and at I500 of ONL (all P < 0.05). Negative correlations could be observed between retinal RR and diabetes duration, HbA1c, and best-corrected visual acuity (BCVA) (r = - 0.303 to - 0.452). Compared to controls, EZ, OS, and IS RR of the NDR eyes showed lower correlation coefficients with whole image SCP and DCP VD of parafovea and perifovea regions. CONCLUSION: Outer retinal reflectivity, along with the coefficients between retinal reflectivity and VD, is reduced in NDR patients and is correlated with diabetes duration, HbA1c, and BCVA. The reduction of outer retinal reflectivity may be a potential biomarker of early retinal alterations in diabetic patients.

NGEF is a potential prognostic biomarker and could serve as an indicator for immunotherapy and chemotherapy in lung adenocarcinoma.

BACKGROUND: Neuronal guanine nucleotide exchange factor (NGEF) plays a key role in several cancers; however, its role in lung adenocarcinoma (LUAD) remains unclear. The aim of this study was to evaluate the efficacy of NGEF as a prognostic biomarker and potential therapeutic target for LUAD. METHODS: NGEF expression data for multiple cancers and LUAD were downloaded from multiple databases. The high- and low-NGEF expression groups were constructed based on median NGEF expression in LUAD samples, and then performed Kaplan-Meier survival analysis. Differentially expressed genes (DEGs) from the two NGEF expression groups were screened and applied to construct a protein-protein interaction network. The primary pathways were obtained using gene set enrichment analysis. The associations between NGEF expression and clinical characteristics, immune infiltration, immune checkpoint inhibitors (ICIs), sensitivity to chemotherapy, and tumor mutation burden (TMB) were investigated using R. Levels of NGEF expression in the lung tissue was validated using single-cell RNA sequencing, quantitative polymerase chain reaction (qPCR), immunohistochemical staining, and western blot analysis. RESULTS: The expression of NGEF mRNA was upregulated in multiple cancers. mRNA and protein expression levels of NGEF were higher in patients with LUAD than in controls, as validated using qPCR and western blot. High NGEF expression was an independent prognostic factor for LUAD and was associated with advanced tumor stage, large tumor size, more lymph node metastasis, and worse overall survival (OS). A total of 182 overlapping DEGs were screened between The Cancer Genome Atlas and GSE31210, among which the top 20 hub genes were identified. NGEF expression was mainly enriched in the pathways of apoptosis, cell cycle, and DNA replication. Moreover, elevated NGEF expression were associated with a high fraction of activated memory CD4+ T cells and M0 macrophages; elevated expression levels of the ICIs: programmed cell death 1 and programmed cell death 1 ligand 1 expression; higher TMB; and better sensitivity to bortezomib, docetaxel, paclitaxel, and parthenolide, but less sensitivity to axitinib and metformin. CONCLUSION: NGEF expression is upregulated in LUAD and is significantly associated with tumor stages, OS probability, immune infiltration, immunotherapy response, and chemotherapy response. NGEF may be a potential diagnostic and prognostic biomarker and therapeutic target in LUAD.

PDTC improves cognitive impairment in LPS-induced ARDS by regulating miR-181c/NF-κB axis-mediated neuroinflammation.

BACKGROUND: Cognitive impairment is a severe complication of acute respiratory distress syndrome (ARDS). Emerging studies have revealed the effects of pyrrolidine dithiocarbamate (PDTC) on improving surgery-induced cognitive impairment. The major aim of the study was to investigate whether PDTC protected against ARDS-induced cognitive dysfunction and to identify the underlying mechanisms involved. METHODS: The rat model of ARDS was established by intratracheal instillation of lipopolysaccharide (LPS), followed by treatment with PDTC. The cognitive function of rats was analyzed by the Morris Water Maze, and pro-inflammatory cytokines were assessed by quantitative real-time PCR, enzyme-linked immunosorbent assay, and western blot assays. A dual-luciferase reporter gene assay was performed to identify the relationship between miR-181c and its target gene, TAK1 binding protein 2 (TAB2). RESULTS: The results showed that PDTC improved cognitive impairment and alleviated neuroinflammation in the hippocampus in LPS-induced ARDS model. Furthermore, we demonstrated that miR-181c expression was downregulated in the hippocampus of the ARDS rats, which was restored by PDTC treatment. In vitro studies showed that miR-181c alleviated LPS-induced pro-inflammatory response by inhibiting TAB2, a critical molecule in the nuclear factor (NF)-κB signaling pathway. CONCLUSION: PDTC improves cognitive impairment in LPS-induced ARDS by regulating miR-181c/NF-κB axis-mediated neuroinflammation, providing a potential opportunity for the treatment of this disease.

Ultraflexible Neural Probes for Multidirectional Neuronal Activity Recordings over Large Spatial and Temporal Scales.

The widespread dissemination of ultraflexible neural probes depends on the development of advanced materials and implementation strategies that can allow reliable implantation of ultraflexible neural probes into targeted brain regions, especially deep and difficult-to-access brain regions. Here, we report ultraflexible and multidirectional probes that are encapsulated in a biocompatible polymer alloy with controllable dissolution kinetics. Our probes can be reliably implanted into targeted brain regions over large spatial scales, including deep hindbrain regions that are anatomically difficult-to-access in vivo. Chronically implanted probes can enable long-term, multidirectional recordings from several hundreds of neurons across distributed brain regions. In particular, our results show that 87.0% of chronically recorded neurons in the hindbrain are interneurons, whereas only 41.9% of chronically recorded neurons in the cortex are interneurons. These results demonstrate that our ultraflexible neural probes are a promising tool for large-scale, long-term neural circuit dissection in the brain.

Highly Selective Electrochemical Nitrate to Ammonia Conversion by Dispersed Ru in a Multielement Alloy Catalyst.

Electrochemical reduction of nitrate to ammonia (NH3) converts an environmental pollutant to a critical nutrient. However, current electrochemical nitrate reduction operations based on monometallic and bimetallic catalysts are limited in NH3 selectivity and catalyst stability, especially in acidic environments. Meanwhile, catalysts with dispersed active sites generally exhibit a higher atomic utilization and distinct activity. Herein, we report a multielement alloy nanoparticle catalyst with dispersed Ru (Ru-MEA) with other synergistic components (Cu, Pd, Pt). Density functional theory elucidated the synergy effect of Ru-MEA than Ru, where a better reactivity (NH3 partial current density of -50.8 mA cm-2) and high NH3 faradaic efficiency (93.5%) is achieved in industrially relevant acidic wastewater. In addition, the Ru-MEA catalyst showed good stability (e.g., 19.0% decay in FENH3 in three hours). This work provides a potential systematic and efficient catalyst discovery process that integrates a data-guided catalyst design and novel catalyst synthesis for a range of applications.

Comparison of Twin Block appliance and Herbst appliance in the treatment of Class II malocclusion among children: a meta-analysis.

BACKGROUND: Our meta-analysis aimed to evaluate the efficacy of applying Herbst and Twin Block appliances in the treatment of Class II malocclusion among children. METHODS: Databases, including PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), China VIP Database (VIP), and Wanfang were thoroughly searched from inception to August 9, 2023. The outcomes included skeletal, dental, and soft tissue changes. The weighted mean difference (WMD) was used as the effect indicator, and the effect size was expressed with a 95% confidence interval (CI). The heterogeneity of each outcome effect size was tested, and the heterogeneity statistic I2 ≥ 50% was analyzed by the random-effect model, otherwise, the fixed-effect model was conducted. Sensitivity analysis was performed. RESULTS: A total of 12 studies involving 574 patients were included in this meta-analysis. Herbst appliance had a statistically significant increase in mandibular body length (WMD: 1.44, 95% CI: 0.93 to 1.96, P < 0.001) compared with the Twin Block appliance. More increases in angle and distance of L1 to mandibular plane (MP) were found in the Herbst appliance compared with the Twin Block appliance. Significant and greater improvements in molar relationship (WMD: 0.79, 95% CI: 0.28 to 1.29, P = 0.002), posterior facial height (WMD: -1.23, 95% CI: -2.08 to -0.38, P = 0.005), convexity angle (WMD: -1.89, 95% CI: -3.12 to -0.66, P = 0.003), and Sella-Nasion plane angle (U1 to SN) (WMD: 3.34, 95% CI: 2.25 to 4.43, P < 0.001) were achieved in the Twin Block appliance. Herbst and Twin Block appliances produced similar effects in the skeletal and dentoalveolar changes including Sella-Nasion-point A (SNA), Sella-Nasion-point B, point A-Nasion-point B (ANB), overjet, and overbite. CONCLUSION: As the findings revealed both Herbst and Twin Block appliances contributed successfully to the correction of Class II malocclusion. Compared with the Twin Block appliance, the Herbst appliance may have more advantages in mandibular bone movement. Twin Block therapy resulted in more improvement in the aesthetics of the face.

Axial length, more than aging, decreases the thickness and superficial vessel density of retinal nerve fiber layer in non-glaucomatous eyes.

PURPOSE: This study seeks to build a normative database for the vessel density of the superficial retina (SVD) and evaluate how changes and trends in the retinal microvasculature may be influenced by age and axial length (AL) in non-glaucomatous eyes, as measured with optical coherence tomography angiography (OCTA). METHODS: We included 500 eyes of 290 healthy subjects visiting a county hospital. Each participant underwent comprehensive ophthalmological examinations and OCTA to measure the SVD and thickness of the macular and peripapillary areas. To analyze correlations between SVD and age or AL, multivariable linear regression models with generalized estimating equations were applied. RESULTS: Age was negatively correlated with the SVD of the superior, central, and inferior macular areas and the superior peripapillary area, with a decrease rate of 1.06%, 1.36%, 0.84%, and 0.66% per decade, respectively. However, inferior peripapillary SVD showed no significant correlation with age. AL was negatively correlated with the SVD of the inferior macular area and the superior and inferior peripapillary areas, with coefficients of -0.522%/mm, -0.733%/mm, and -0.664%/mm, respectively. AL was also negatively correlated with the thickness of the retinal nerve fiber layer and inferior ganglion cell complex (p = 0.004). CONCLUSION: Age and AL were the two main factors affecting changes in SVD. Furthermore, AL, a relative term to represent the degree of myopia, had a greater effect than age and showed a more significant effect on thickness than on SVD. This relationship has important implications because myopia is a significant issue in modern cities.