Cross-regional coordination of activity in the human brain during autobiographical self-referential processing.

For the human brain to operate, populations of neurons across anatomical structures must coordinate their activity within milliseconds. To date, our understanding of such interactions has remained limited. We recorded directly from the hippocampus (HPC), posteromedial cortex (PMC), ventromedial/orbital prefrontal cortex (OFC), and the anterior nuclei of the thalamus (ANT) during two experiments of autobiographical memory processing that are known from decades of neuroimaging work to coactivate these regions. In 31 patients implanted with intracranial electrodes, we found that the presentation of memory retrieval cues elicited a significant increase of low frequency (LF < 6 Hz) activity followed by cross-regional phase coherence of this LF activity before select populations of neurons within each of the four regions increased high-frequency (HF > 70 Hz) activity. The power of HF activity was modulated by memory content, and its onset followed a specific temporal order of ANT→HPC/PMC→OFC. Further, we probed cross-regional causal effective interactions with repeated electrical pulses and found that HPC stimulations cause the greatest increase in LF-phase coherence across all regions, whereas the stimulation of any region caused the greatest LF-phase coherence between that particular region and ANT. These observations support the role of the ANT in gating, and the HPC in synchronizing, the activity of cortical midline structures when humans retrieve self-relevant memories of their past. Our findings offer a fresh perspective, with high temporal fidelity, about the dynamic signaling and underlying causal connections among distant regions when the brain is actively involved in retrieving self-referential memories from the past.

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.

Plasma Proteomics to Identify Drug Targets and Potential Drugs for Retinal Artery Occlusion: An Integrated Analysis in the UK Biobank.

Retinal artery occlusion (RAO), which is positively correlated with acute ischemic stroke (IS) and results in severe visual impairment, lacks effective intervention drugs. This study aims to perform integrated analysis using UK Biobank plasma proteome data of RAO and IS to identify potential targets and preventive drugs. A total of 7191 participants (22 RAO patients, 1457 IS patients, 8 individuals with both RAO and IS, and 5704 healthy age-gender-matched controls) were included in this study. Unique 1461 protein expression profiles of RAO, IS, and the combined data set, extracted from UK Biobank Plasma proteomics projects, were analyzed using both differential expression analysis and elastic network regression (Enet) methods to identify shared key proteins. Subsequent analyses, including single cell type expression assessment, pathway enrichment, and druggability analysis, were conducted for verifying shared key proteins and discovery of new drugs. Five proteins were found to be shared among the samples, with all of them showing upregulation. Notably, adhesion G-protein coupled receptor G1 (ADGRG1) exhibited high expression in glial cells of the brain and eye tissues. Gene set enrichment analysis revealed pathways associated with lipid metabolism and vascular regulation and inflammation. Druggability analysis unveiled 15 drug candidates targeting ADGRG1, which demonstrated protective effects against RAO, especially troglitazone (-8.5 kcal/mol). Our study identified novel risk proteins and therapeutic drugs associated with the rare disease RAO, providing valuable insights into potential intervention strategies.

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.

Confining Thiolysis of Dinitrophenyl Ether to a Luminescent Metal-Organic Framework with a Large Stokes Shift for Highly Efficient Detection of Hydrogen Sulfide in Rat Brain.

Hydrogen sulfide (H2S) is a gaseous signaling molecule that regulates various physiological and pathological processes in the central nervous system. It is vital to develop an effective method to detect H2S in vivo to elucidate its critical role. However, current fluorescent probes for accurate quantification of H2S still face big challenges due to complicated fabrication, small Stokes shift, unsatisfactory selectivity, and especially delayed response time. Herein, based on simple postsynthetic modification, we present an innovative strategy by confining H2S-triggered thiolysis of dinitrophenyl (DNP) ether within a luminescent metal-organic framework (MOF) to address those issues. Due to the cleavage of the DNP moiety by H2S, the nanoprobe gives rise to a remarkable fluorescence turn-on signal with a large Stokes shift of 190 nm and also provides high selectivity to H2S against various interferents including competing biothiols. In particular, by virtue of the unique structural property of the MOF, it exhibits an ultrafast sensing ability for H2S (only 5 s). Moreover, the fluorescence enhancement efficiency displays a good linear correlation with H2S concentration in the range of 0-160 µM with a detection limit of 0.29 µM. Importantly, these superior sensing performances enable the nanoprobe to measure the basal value and monitor the change of H2S level in the rat brain.

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 analysed 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. TRIAL REGISTRATION: United States National Library of Medicine clinical trials database www.clinicaltrials.gov; RA-BEYOND; NCT01885078.

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.

Activation of the PERK/eIF2α axis is a pivotal prerequisite of taxanes to cancer cell apoptosis and renders synergism to overcome paclitaxel resistance in breast cancer cells.

BACKGROUND: Microtubule polymerization is usually considered as the upstream of apoptotic cell death induced by taxanes, but recently published studies provide more insights into the mechanisms responsible for the antineoplastic effect of taxanes. In this study, we figure out the role of the stress-related PERK/eIF2α axis in tumor cell death upon taxane treatment along with paclitaxel resistance. METHODS: Utilizing immunoblot assay, the activation status of PERK-eIF2α signaling was detected in a panel of cancer cell lines after the treatment of taxanes. The causal role of PERK-eIF2α signaling in the cancer cell apoptosis induced by taxanes was examined via pharmacological and genetic inhibitions of PERK. The relationship between microtubule polymerization and PERK-eIF2α activation was explored by immunofluorescent and immunoblotting assays. Eventaually, the combined therapeutic effect of paclitaxel (PTX) and CCT020312, a PERK agonist, was investigated in PTX-resistant breast cancer cells in vitro and in vivo. RESULTS: PERK-eIF2α axis was dramatically activated by taxanes in several cancer cell types. Pharmacological or genetic inhibition of PERK efficiently impaired taxane-induced apoptotic cell death, independent of the cellular microtubule polymerization status. Moreover, PTX was able to activate the PERK/eIF2α axis in a very low concentration without triggering microtubule polymerization. In PTX-resistant breast cancer cells, the PERK/eIF2α axis was attenuated in comparison with the PTX-sensitive counterparts. Reactivation of the PERK/eIF2α axis in the PTX-resistant breast cancer cells with PERK agonist sensitized them to PTX in vitro. Combination treatment of the xenografted PTX-resistant breast tumors with PERK agonist and PTX validated the synergic effect of PTX and PERK activation in vivo. CONCLUSION: Activation of the PERK/eIF2α axis is a pivotal prerequisite of taxanes to initiate cancer cell apoptosis, which is independent of the well-known microtubule polymerization-dependent manner. Simultaneous activation of PERK-eIF2α signaling would be a promising therapeutic strategy to overcome PTX resistance in breast cancer or other cancers.

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.

G3BP2 promotes tumor progression and gemcitabine resistance in PDAC via regulating PDIA3-DKC1-hENT in a stress granules-dependent manner.

Pancreatic ductal adenocarcinoma (PDAC) is distinguished by its aggressive malignancy, limited treatment avenues and a tendency towards chemotherapy resistance, underscoring the critical need for advanced research to uncover new therapeutic approaches. Stress granules (SGs) that is implicated in cellular self-protection mechanism, along with its associated family molecules have shown pro-cancer effects and are closely related to tumor chemotherapy resistance. In this study we investigated the relationship between Ras GTPase-activating protein-binding proteins 2 (G3BP2), a core component of SGs, and the malignancy of PDAC as well as its resistance to the chemotherapy drug gemcitabine. Analyzing TCGA dataset revealed that the expression of G3BP1 and G3BP2 was significantly upregulated in PDAC compared with adjacent normal pancreatic tissues, and the high expression of G3BP2 rather than G3BP1 was significantly associated with poorer overall survival (OS) in PDAC patients. We demonstrated that knockdown of G3BP2 inhibited the proliferation and invasion of PANC-1 and CFPAC-1 cells in vitro and in vivo. By analyzing the differentially expressed genes in G3BP2 knockdown and overexpressed PANC-1 cells, we identified DKC1 that was associated with RNA stability and regulation as the target of G3BP2. We demonstrated that G3BP2 bound to PDIA3 mRNA and recruited them into SGs, increasing the stability of PDIA3 mRNA and attenuating its translation efficiency, thereby promoting DKC1 expression. Furthermore, DKC1 could bind to hENT mRNA and inhibited its expression, which enhanced gemcitabine resistance of PDAC. Therefore, we propose a novel mechanism wherein G3BP2 facilitates PDAC's resistance to chemotherapy by modulating PDIA3-DKC1-hENT in a SGs-dependent way, suggesting G3BP2 SGs a protentional therapeutic target for the treatment in PDAC.

Genome-wide profiling of long non-coding RNA following ozone exposure: A randomized, controlled exposure trial.

BACKGROUND: Exposure to ambient ozone has been associated with extrapulmonary health, but the underlying mechanisms remain to be understood. LncRNAs are involved in the regulation of gene expression, but their regulatory mechanisms in ozone-related health effects are scarcely explored. OBJECTIVE: To investigate genome-wide lncRNA changes after short-term ozone exposure and their regulatory roles in ozone exposure and gene expression. METHOD: We conducted a randomized, crossover, controlled exposure trial in 32 healthy college students in Shanghai, China. Each participant received both 200-ppb ozone exposure and filtered air exposure for 2 h in a random order with a 14-day washout period. Blood samples were collected after each exposure and used for lncRNA sequencing. Differentially expressed lncRNAs between the two exposures were identified using orthogonal partial least squares discriminant analysis and linear regression analysis. LncRNAs-targeted mRNAs were mapped and subjected to enrichment analyses. We also constructed lncRNA-miRNA-mRNA networks. RESULTS: A total of 90 lncRNAs were differentially expressed after exposure to ozone, with 49 up-regulated and 41 down-regulated. Enrichment analyses suggested that these dysregulated lncRNAs were involved in a variety of biological processes, including those related to oxidative stress, inflammation response, and cell proliferation, development, and differentiation. Multiple pathways such as IL-17 signaling, NF-kB signaling, and Rho GTPases signaling were also enriched. Furthermore, the lncRNA-miRNA-mRNA network revealed that specific lncRNAs may regulate the expression of inflammation- and angiogenesis-related genes by interacting with miRNAs, such as NEAT1/hsa-miR-500a-3p/SIGLEC8, NEAT1/hsa-miR-6835-3p/SLC16A14, OIP5-AS1/miR-183-5p/EGR1, and SNHG25/hsa-miR-663a/FOSB axes. CONCLUSION: This study characterized a thorough profile of human lncRNAs following short-term ozone exposure and suggested the regulatory roles of these lncRNAs in ozone-induced inflammatory responses and angiogenesis, providing novel epigenetic insights into the mechanisms of the health effects of ozone exposure.

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.