Antisense Oligonucleotide Therapy for Calmodulinopathy.

BACKGROUND: Calmodulinopathies are rare inherited arrhythmia syndromes caused by dominant heterozygous variants in CALM1, CALM2, or CALM3, which each encode the identical CaM (calmodulin) protein. We hypothesized that antisense oligonucleotide (ASO)-mediated depletion of an affected calmodulin gene would ameliorate disease manifestations, whereas the other 2 calmodulin genes would preserve CaM level and function. METHODS: We tested this hypothesis using human induced pluripotent stem cell-derived cardiomyocyte and mouse models of CALM1 pathogenic variants. RESULTS: Human CALM1F142L/+ induced pluripotent stem cell-derived cardiomyocytes exhibited prolonged action potentials, modeling congenital long QT syndrome. CALM1 knockout or CALM1-depleting ASOs did not alter CaM protein level and normalized repolarization duration of CALM1F142L/+ induced pluripotent stem cell-derived cardiomyocytes. Similarly, an ASO targeting murine Calm1 depleted Calm1 transcript without affecting CaM protein level. This ASO alleviated drug-induced bidirectional ventricular tachycardia in Calm1N98S/+ mice without a deleterious effect on cardiac electrical or contractile function. CONCLUSIONS: These results provide proof of concept that ASOs targeting individual calmodulin genes are potentially effective and safe therapies for calmodulinopathies.

Comparative Proteomics Elucidates the Potential Mechanism of Sperm Capacitation of Chinese Mitten Crabs (Eriocheir sinensis).

Sperm capacitation is broadly defined as a suite of biochemical and biophysical changes resulting from the acquisition of fertilization ability. To gain insights into the regulation mechanism of crustacean sperm capacitation, 4D label-free quantitative proteomics was first applied to analyze the changes of sperm in Eriocheir sinensis under three sequential physiological conditions: seminal vesicles (X2), hatched with the seminal receptacle content (X3), and incubated with egg water (X5). In total, 1536 proteins were identified, among which 880 proteins were quantified, with 82 and 224 proteins significantly altered after incubation with the seminal receptacle contents and egg water. Most differentially expressed proteins were attributed to biological processes by Gene Ontology annotation analysis. As the fundamental bioenergetic metabolism of sperm, the oxidative phosphorylation, glycolysis, and the pentose phosphate pathway presented significant changes under the treatment of seminal receptacle contents, indicating intensive regulation for sperm in the seminal receptacle. Additionally, the seminal receptacle contents also significantly increased the oxidation level of sperm, whereas the enhancement of abundance in superoxide dismutase, peroxiredoxin 1, and glutathione S-transferase after incubation with egg water significantly improved the resistance against oxidation. These results provided a new perspective for reproduction studies in crustaceans.

Identification of a druggable pocket of the calcium-activated chloride channel TMEM16A in its open state.

The calcium-activated chloride channel TMEM16A is a potential drug target to treat hypertension, secretory diarrhea, and several cancers. However, all reported TMEM16A structures are either closed or desensitized, and direct inhibition of the open state by drug molecules lacks a reliable structural basis. Therefore, revealing the druggable pocket of TMEM16A exposed in the open state is important for understanding protein-ligand interactions and facilitating rational drug design. Here, we reconstructed the calcium-activated open conformation of TMEM16A using an enhanced sampling algorithm and segmental modeling. Furthermore, we identified an open-state druggable pocket and screened a potent TMEM16A inhibitor, etoposide, which is a derivative of a traditional herbal monomer. Molecular simulations and site-directed mutagenesis showed that etoposide binds to the open state of TMEM16A, thereby blocking the ion conductance pore of the channel. Finally, we demonstrated that etoposide can target TMEM16A to inhibit the proliferation of prostate cancer PC-3 cells. Together, these findings provide a deep understanding of the TMEM16A open state at an atomic level and identify pockets for the design of novel inhibitors with broad applications in chloride channel biology, biophysics, and medicinal chemistry.

Polarity-Driven Fluorescence Monitoring of Lipid Droplet Dynamics in Dry Eye Disease.

The emergence of lipid droplets (LDs) has been recognized as cellular markers of ocular surface hyperosmosis, which is recognized as a fundamental mechanism driving dry eye disease (DED), while their dynamics during DED progression and therapy remains unlocked. For this purpose, an LD-specific fluorescent probe P1 is presented in this work that exhibits highly selective and sensitive emission enhancement in response to a decreased ambient polarity (Δf) from 0.209 to 0.021. The hydrophobic nature of P1 enables specific staining of LDs, facilitating visualization of changes in polarity within these cellular structures. Utilizing P1, we observe a decrease in polarity accompanied by an increase in the size and number of LDs in hyperosmotic human corneal epithelial cells (HCECs). Furthermore, interplays between LDs and cellular organelles such as mitochondria and the Golgi apparatus are visualized, suggesting the underlying pathogenesis in DED. Notably, the variations of LDs are observed after the inhibition of ferroptosis or activation of autophagy in hyperosmotic HCECs, implying the great potential of LDs as indicators for the design and efficacy evaluation of DED drugs regarding ferroptosis or autophagy as targets. Finally, LDs are confirmed to be overproduced in corneal tissues from DED mice, and the application of clinical eye drops effectively impedes these changes. This detailed exploration underscores the significant roles of LDs as an indicator for the deep insight into DED advancement and therapy.

Novel Strategy for Human Deep Vein Thrombosis Diagnosis Based on Metabolomics and Stacking Machine Learning.

Deep vein thrombosis (DVT) is a serious health issue that often leads to considerable morbidity and mortality. Diagnosis of DVT in a clinical setting, however, presents considerable challenges. The fusion of metabolomics techniques and machine learning methods has led to high diagnostic and prognostic accuracy for various pathological conditions. This study explored the synergistic potential of dual-platform metabolomics (specifically, gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS)) to expand the detection of metabolites and improve the precision of DVT diagnosis. Sixty-one differential metabolites were identified in serum from DVT patients: 22 from GC-MS and 39 from LC-MS. Among these, five key metabolites were highlighted by SHapley Additive exPlanations (SHAP)-guided feature engineering and then used to develop a stacking diagnostic model. Additionally, a user-friendly interface application system was developed to streamline and automate the application of the diagnostic model, enhancing its practicality and accessibility for clinical use. This work showed that the integration of dual-platform metabolomics with a stacking machine learning model enables faster and more accurate diagnosis of DVT in clinical environments.

Serum lipidome reveals lipid metabolic dysregulation in severe fever with thrombocytopenia syndrome.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a rapidly progressing infectious disease with a high fatality rate caused by a novel bunyavirus (SFTSV). The role of lipids in viral infections is well-documented; however, the specific alterations in lipid metabolism during SFTSV infection remain elusive. This study aims to elucidate the lipid metabolic dysregulations in the early stages of SFTS patients. METHODS: This study prospectively collected peripheral blood sera from 11 critical SFTS patients, 37 mild SFTS patients, and 23 healthy controls during the early stages of infection for lipidomics analysis. A systematic bioinformatics analysis was conducted from three aspects integrating lipid differential expressions, lipid differential correlations, and lipid-clinical indices correlations to reveal the serum lipid metabolic dysregulation in SFTSV-infected individuals. RESULTS: Our findings reveal significant lipid metabolic dysregulation in SFTS patients. Specifically, compared to healthy controls, SFTS patients exhibited three distinct modes of lipid differential expression: increased levels of lipids including phosphatidylserine (PS), hexosylceramide (HexCer), and triglycerides (TG); decreased levels of lipids including lysophosphatidylcholine (LPC), acylcarnitine (AcCa), and cholesterol esters (ChE); and lipids showing "dual changes" including phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Finally, based on lipid metabolic pathways and literature analysis, we systematically elucidated the potential mechanisms underlying lipid metabolic dysregulation in the early stage of SFTSV infection. CONCLUSIONS: Our study presents the first global serum lipidome profile and reveals the lipid metabolic dysregulation patterns in the early stage of SFTSV infection. These findings provide a new basis for the diagnosis, treatment, and further investigation of the disease.

Multifunctional Sandwich-Structured Super-Hygroscopic Zinc-Based MOF-Overlayed Cooling Wearables for Special Personal Thermal Management.

Personal protective equipment pays attention exclusively to external safety protection and ignores the internal thermoregulation of physiological state in association with sweating. Herein, a super-hygroscopic calcium-doped poly(sodium 4-styrenesulfonate) and superhydrophobic metal-organic-framework-overlayed wearables (Ca-PSS/MOF) integrated cooling wearable is proposed for special personal thermal management (PTM). Compared to the pristine fabric, the superhydrophobic MOF wearables exhibit anti-fouling and antibacterial capabilities, and the antibacterial efficiency is up to 99.99% and 98.99% against E. coli and S. aureus, respectively. More importantly, Ca-PSS/MOF demonstrate significant heat index changes up to 25.5 °C by reducing relative humidity dramatically from 91.0% to 60.0% and temperature from 36.5 to 31.6 °C during the running test. The practical feasibility of the Ca-PSS/MOF cooling wearables is well proved with the protective suit of the fireman. Owing to these multifunctional merits, the sandwich-structured cooling Ca-PSS/MOF are expected to provide new insights for designing the next-generation multifunctional apparel for PTM.

Kilogram-Scale Synthesis of Extremely Small Gadolinium Oxide Nanoparticles as a T1-Weighted Contrast Agent for Magnetic Resonance Imaging.

Magnetic resonance imaging contrast agents are frequently used in clinics to enhance the contrast between diseased and normal tissues. The previously reported poly(acrylic acid) stabilized exceedingly small gadolinium oxide nanoparticles (ES-GdON-PAA) overcame the problems of commercial Gd chelates, but limitations still exist, i.e., high r2/r1 ratio, long blood circulation half-life, and no data for large scale synthesis and formulation optimization. In this study, polymaleic acid (PMA) is found to be an ideal stabilizer to synthesize ES-GdONs. Compared with ES-GdON-PAA, the PMA-stabilized ES-GdON (ES-GdON-PMA) has a lower r2/r1 ratio (2.05, 7.0 T) and a lower blood circulation half-life (37.51 min). The optimized ES-GdON-PMA-9 has an exceedingly small particle size (2.1 nm), excellent water dispersibility, and stability. A facile, efficient, and environmental friendly synthetic method is developed for large-scale synthesis of the ES-GdONs-PMA. The weight of the optimized freeze-dried ES-GdON-PMA-26 synthesized in a 20 L of reactor reaches the kilogram level. The formulation optimization is also finished, and the concentrated ES-GdON-PMA-26 formulation (CGd = 100 mm) after high-pressure steam sterilization possesses eligible physicochemical properties (i.e., pH value, osmolality, viscosity, and density) for investigational new drug application.

MRI-Guided Tumor Therapy Based on Synergy of Ferroptosis, Immunosuppression Reversal and Disulfidptosis.

Triple negative breast cancer (TNBC) cells have a high demand for oxygen and glucose to fuel their growth and spread, shaping the tumor microenvironment (TME) that can lead to a weakened immune system by hypoxia and increased risk of metastasis. To disrupt this vicious circle and improve cancer therapeutic efficacy, a strategy is proposed with the synergy of ferroptosis, immunosuppression reversal and disulfidptosis. An intelligent nanomedicine GOx-IA@HMON@IO is successfully developed to realize this strategy. The Fe release behaviors indicate the glutathione (GSH)-responsive degradation of HMON. The results of titanium sulfate assay, electron spin resonance (ESR) spectra, 5,5'-Dithiobis-(2-nitrobenzoic acid (DTNB) assay and T1-weighted magnetic resonance imaging (MRI) demonstrate the mechanism of the intelligent iron atom (IA)-based cascade reactions for GOx-IA@HMON@IO, generating robust reactive oxygen species (ROS). The results on cells and mice reinforce the synergistic mechanisms of ferroptosis, immunosuppression reversal and disulfidptosis triggered by the GOx-IA@HMON@IO with the following steps: 1) GSH peroxidase 4 (GPX4) depletion by disulfidptosis; 2) IA-based cascade reactions; 3) tumor hypoxia reversal; 4) immunosuppression reversal; 5) GPX4 depletion by immunotherapy. Based on the synergistic mechanisms of ferroptosis, immunosuppression reversal and disulfidptosis, the intelligent nanomedicine GOx-IA@HMON@IO can be used for MRI-guided tumor therapy with excellent biocompatibility and safety.

Effects of toothpaste containing inactivated Lacticaseibacillus paracasei Probio-01 on plaque-induced gingivitis and dental plaque microbiota.

Plaque-induced gingivitis is an inflammatory response in gingival tissues resulting from bacterial plaque accumulation at the gingival margin. Postbiotics can promote the proliferation of beneficial bacteria and optimise the state of microbiota in the oral cavity. In this study, we investigated the effect of inactivated Lacticaseibacillus paracasei Probio-01 on plaque-induced gingivitis and the dental plaque microbiota. A total of 32 healthy gingival participants (Group N, using blank toothpaste for 3 months) and 60 patients with plaque-induced gingivitis (30 in Group F, using inactivated Probio-01 toothpaste for 3 months, and 30 in Group B, using blank toothpaste for 3 months, respectively) were recruited. Clinical indices, which included bleeding on probing (BOP), gingival index (GI), and plaque index (PI), were used to assess the severity of gingivitis. Furthermore, 16SrDNA amplicon sequencing was used to explore changes in the gingival state and dental plaque microbiota in patients with plaque-induced gingivitis. The results showed that inactivated Probio-01 significantly reduced clinical indices of gingivitis, including BOP, GI, and PI, in participants with plaque-induced gingivitis and effectively relieved gingival inflammation, compared with that observed in the control group (group B). Inactivated Probio-01 did not significantly influence the diversity of dental plaque microbiota, but increased the relative abundance of dental plaque core bacteria, such as Leptotrichia and Fusobacterium (P < 0.05). Strong correlations were observed between the indices and abundance of dental plaque microbiota. Overall, the inactivated Probio-01 significantly reduced the clinical indices of gingivitis and effectively improved gingival inflammation in patients with plaque-induced gingivitis. The activity of inactivated Probio-01 against plaque-induced gingivitis was possibly mediated by its ability to regulate the dental plaque microbiota, as indicated by the close correlation between the plaque microbiota and clinical indices of gingivitis.

Omics research in atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory disease characterized by lipid deposition within the arterial intima, as well as fibrous tissue proliferation and calcification. AS has long been recognized as one of the primary pathological foundations of cardiovascular diseases in humans. Its pathogenesis is intricate and not yet fully elucidated. Studies have shown that AS is associated with oxidative stress, inflammatory response, lipid deposition, and changes in cell phenotype. Unfortunately, there is currently no effective prevention or targeted treatment for AS. The rapid advancement of omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, has opened up novel avenues to elucidate the fundamental pathophysiology and associated mechanisms of AS. Here, we review articles published over the past decade and focus on the current status, challenges, limitations, and prospects of omics in AS research and clinical practice. Emphasizing potential targets based on omics technologies will improve our understanding of this pathological condition and assist in the development of potential therapeutic approaches for AS-related diseases.

A pattern recognition receptor interleukin-1 receptor is involved in reproductive immunity in Macrobrachium nipponense ovary.

The family of TIR domain-containing receptors includes numerous proteins involved in innate immunity. In this study, a member of this family was characterized from the ovary of the oriental river prawn Macrobrachium nipponense and identified as interleukin-1 receptor (MnIL-1R). Meanwhile, to elucidate the conservation of IL-1R, its orthologous were identified in several crustacean species as well. In addition, the expression pattern of MnIL-1R in various adult tissues and post different pathogen-associated molecular patterns (PAMPs) challenge in ovary was analyzed with qRT-PCR technology. Finally, the roles of MnIL-1R in the ovary were analyzed by RNAi technology. The main results are as follows: (1) MnIL-1R comprises a 1785 bp ORF encoding 594 amino acids and is structurally composed of five domains: a signal peptide, two immunoglobulin (IG) domains, a transmembrane region, and a TIR-2 domain; (2) the TIR domain showed a high conservation among analyzed crustacean species; (3) MnIL-1R is widely detected in all tested tissues including ovary; (4) MnIL-1R showed a positive response to challenges with LPS, PGN, and polyI:C in the ovary; (5) its IG domain showed strong binding ability to LPS and PGN, confirming its role as a pattern recognition receptor; (6) the expression patterns of several members of the Toll signaling pathway (Myd88, TRAF-6, Dorsal, and Relish) was similar to that of MnIL-1R after challenges with LPS, PGN, and polyI:C in the ovary; (7) the silencing of MnIL-1R resulted in down-regulation of theses gene' (Myd88, TRAF-6, Dorsal, and Relish) expression level in the ovary. These results suggest that MnIL-1R can activate the Toll signaling pathway in the ovary by directly recognizing LPS and PGN through its IG domain, thereby contributing to the immune response in the ovary of M. nipponense.

Glycolysis and de novo fatty acid synthesis cooperatively regulate pathological vascular smooth muscle cell phenotypic switching and neointimal hyperplasia.

Switching of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a dedifferentiated (proliferative) phenotype contributes to neointima formation, which has been demonstrated to possess a tumor-like nature. Dysregulated glucose and lipid metabolism is recognized as a hallmark of tumors but has not thoroughly been elucidated in neointima formation. Here, we investigated the cooperative role of glycolysis and fatty acid synthesis in vascular injury-induced VSMC dedifferentiation and neointima formation. We found that the expression of hypoxia-inducible factor-1α (HIF-1α) and its target 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), a critical glycolytic enzyme, were induced in the neointimal VSMCs of human stenotic carotid arteries and wire-injured mouse carotid arteries. HIF-1α overexpression led to elevated glycolysis and resulted in a decreased contractile phenotype while promoting VSMC proliferation and activation of the mechanistic target of rapamycin complex 1 (mTORC1). Conversely, silencing Pfkfb3 had the opposite effects. Mechanistic studies demonstrated that glycolysis generates acetyl coenzyme A to fuel de novo fatty acid synthesis and mTORC1 activation. Whole-transcriptome sequencing analysis confirmed the increased expression of PFKFB3 and fatty acid synthetase (FASN) in dedifferentiated VSMCs. More importantly, FASN upregulation was observed in neointimal VSMCs of human stenotic carotid arteries. Finally, interfering with PFKFB3 or FASN suppressed vascular injury-induced mTORC1 activation, VSMC dedifferentiation, and neointima formation. Together, this study demonstrated that PFKFB3-mediated glycolytic reprogramming and FASN-mediated lipid metabolic reprogramming are distinctive features of VSMC phenotypic switching and could be potential therapeutic targets for treating vascular diseases with neointima formation. © 2023 The Pathological Society of Great Britain and Ireland.

Novel CCR3-targeted cyclic peptides as potential therapeutic agents for age-related macular degeneration via inhibiting angiogenesis and reducing retinal photoreceptor damage.

The prolonged intravitreal administration of anti-vascular endothelial growth factor (VEGF) drugs is prone to inducing aberrant retinal vascular development and causing damage to retinal neurons. Hence, we have taken an alternative approach by designing and synthesizing a series of cyclic peptides targeting CC motif chemokine receptor 3 (CCR3). Based on the binding mode of the N-terminal region in CCR3 protein to CCL11, we used computer-aided identification of key amino acid sequence, conformational restriction through different cyclization methods, designed and synthesized a series of target cyclic peptides, and screened the preferred compound IB-2 through affinity. IB-2 exhibits excellent anti-angiogenic activity in HRECs. The apoptosis level of 661W cells demonstrated a significant decrease with the escalating concentration of IB-2. This suggests that IB-2 may have a protective effect on photoreceptor cells. In vivo experiments have shown that IB-2 significantly reduces retinal vascular leakage and choroidal neovascularization (CNV) area in a laser-induced mouse model of CNV. These findings indicate the potential of IB-2 as a safe and effective therapeutic agent for AMD, warranting further development.

Decreasing mitochondrial fission ameliorates HIF-1α-dependent pathological retinal angiogenesis.

Angiogenesis plays a critical role in many pathological processes, including irreversible blindness in eye diseases such as retinopathy of prematurity. Endothelial mitochondria are dynamic organelles that undergo constant fusion and fission and are critical signalling hubs that modulate angiogenesis by coordinating reactive oxygen species (ROS) production and calcium signalling and metabolism. In this study, we investigated the role of mitochondrial dynamics in pathological retinal angiogenesis. We showed that treatment with vascular endothelial growth factor (VEGF; 20 ng/ml) induced mitochondrial fission in HUVECs by promoting the phosphorylation of dynamin-related protein 1 (DRP1). DRP1 knockdown or pretreatment with the DRP1 inhibitor Mdivi-1 (5 µM) blocked VEGF-induced cell migration, proliferation, and tube formation in HUVECs. We demonstrated that VEGF treatment increased mitochondrial ROS production in HUVECs, which was necessary for HIF-1α-dependent glycolysis, as well as proliferation, migration, and tube formation, and the inhibition of mitochondrial fission prevented VEGF-induced mitochondrial ROS production. In an oxygen-induced retinopathy (OIR) mouse model, we found that active DRP1 was highly expressed in endothelial cells in neovascular tufts. The administration of Mdivi-1 (10 mg·kg-1·d-1, i.p.) for three days from postnatal day (P) 13 until P15 significantly alleviated pathological angiogenesis in the retina. Our results suggest that targeting mitochondrial fission may be a therapeutic strategy for proliferative retinopathies and other diseases that are dependent on pathological angiogenesis.

H*ads dynamics engineering via bimetallic Pd-Cu@MXene catalyst for enhanced electrocatalytic hydrodechlorination.

Electrocatalytic hydrodechlorination (EHDC) is a promising approach to safely remove halogenated emerging contaminants (HECs) pollutants. However, sluggish production dynamics of adsorbed atomic H (H*ads) limit the applicability of this green process. In this study, bimetallic Pd-Cu@MXene catalysts were synthesized to achieve highly efficient removal of HECs. The alloy electrode (Pd-Cu@MX/CC) exhibited better EHDC performance in comparison to Pd@MX/CC electrode, resulting in diclofenac degradation efficiency of 93.3 ± 0.1%. The characterization analysis revealed that the Pd0/PdII ratio decreased by forming bimetallic Pd-Cu alloy. Density functional theory calculations further demonstrated the electronic configuration modulation of the Pd-Cu@MXene catalysts, optimizing binging energies for H* and thereby facilitating H*ads production and tuning the reduction capability of H*ads. Noteably, the amounts and reduction potential of H*ads for Pd-Cu@MXene catalysts were 1.5 times higher and 0.37 eV lower than those observed for the mono Pd electrode. Hence, the introduction of Cu into the Pd catalyst optimized the dynamics of H*ads production, thereby conferring significant advantages to EHDC reactions. This augmentation was underscored by the successful application of the alloy catalysts supported by MXene in EHDC experiments involving other HECs, which represented a new paradigm for EHDC for efficient recalcitrant pollutant removal by H*ads.

Application of Blood Lymphocyte Immunophenotype and TCR Gene Rearrangement in the Diagnosis of CTCL.

BACKGROUND: The immunophenotype of peripheral blood lymphocytes and T-cell receptor (TCR) gene rearrangement of cutaneous T cell lymphoma (CTCL) patients were retrospectively analyzed to explore their value in the diagnosis of CTCL. METHODS: A total of fifty patients' results were enrolled from 2013 to 2021, including 29 malignant skin disorders and 21 benign skin disorders. The immunophenotype of peripheral blood lymphocytes were analyzed by flow cytometry and TCR gene rearrangement was detected by capillary electrophoresis. Lymphocyte subsets, CD4/CD8 ratio, the percentage of CD3+CD4+CD7- cells and CD45RA/CD45RO ratio was calculated between malignant and benign skin disorders. Peripheral blood lymphocyte immunophenotype and TCR gene rearrangement was compared with skin biopsy to evaluate their sensitivity and specificity. RESULTS: Lymphocyte subsets between malignant and benign groups have no significant difference in percentage of T cell (p > 0.05). The CD4/CD8 ratio is higher in patients with malignant lymphoma than the healthy range. The percentage of CD3+CD4+CD7- cells in malignant groups is higher than that in benign groups and CD45RA/ CD45RO ratio has significant difference between malignant and benign groups (p < 0.05). The sensitivity and specificity of TCR rearrangement for CTCL were 51.7% and 42.9%. The sensitivity and specificity of peripheral blood lymphocyte immunophenotype for CTCL were 44.8% and 33.3%. Combining the two methods, the sensitivity and specificity reached 69.0% and 38.1%, respectively. CONCLUSIONS: CD4/CD8 ratio of lymphocyte subsets, the proportion of CD4+CD7-T cells and CD45RA/CD45RO ratio can effectively distinguish benign and malignant dermatosis. TCR rearrangement method combined with lymphocyte immunophenotype can improve the sensitivity and specificity of CTCL diagnosis.

Conformal thyroidectomy is a feasible option in papillary thyroid microcarcinoma: a retrospective cohort study with 10-year follow-up results.

BACKGROUND: In recent years, there has been an increasing prevalence of patients with papillary thyroid microcarcinoma (PTMC) without lymph node involvement in medical centers worldwide. For patients who are unable to undergo active surveillance (AS) and are afraid of postoperative complications, conformal thyroidectomy may be a suitable option to ensure both preservation of function and complete removal of the tumor. METHODS: The patients in the cohort during 2010 to 2015 were retrospectively enrolled strictly following the inclusion and exclusion criteria. The observation and control groups were defined based on the surgical approach, with patients in the observation group undergoing conformal thyroidectomy and patients in the control group undergoing lobectomy. Event-free survival (EFS), the interval from initial surgery to the detection of recurrent or metastatic disease, was defined as the primary observation endpoint. RESULTS: A total of 319 patients were included in the study, with 124 patients undergoing conformal thyroidectomy and 195 patients undergoing lobectomy. When compared to lobectomy, conformal thyroidectomy demonstrated reduced hospital stays, shorter operative times, and lower rates of vocal cord paralysis and hypoparathyroidism. Furthermore, the mean bleeding volume during the operation and the rate of permanent hypothyroidism were also lower in the conformal thyroidectomy group than in the lobectomy group. However, there was no statistically significant difference observed in the 5- and 10-year EFS between the two groups. CONCLUSIONS: Conformal thyroidectomy had advantages in perioperative management and short-term complication rates, with an EFS that was not inferior to that of lobectomy. Thus, conformal thyroidectomy is a feasible option for low-risk PTMC patients.

Changes in gender disparities of depressive symptoms among middle-aged and older adults in China: an age-period-cohort analysis.

PURPOSE: Depression is one of the most common mental disorders and substantially decreases socioemotional well-being and health-related quality of life. Analyzing temporal patterns in depressive symptoms can reveal emerging risks that require attention and have implications for mental health promotion. The present study disentangled age, period, and cohort (APC) effects on trends in depressive symptoms and their gender disparities among China's nationally representative samples of middle-aged and older adults. METHODS: Using four-wave data (2011, 2013, 2015, and 2018) from the China Health and Retirement Longitudinal Study (N = 65455), APC effects were quantified based on the hierarchical APC model. The 10-item Center for Epidemiologic Studies Depression Scale (CES-D-10) was used to measure depressive symptoms. RESULTS: Depressive symptoms increased during late life and stabilized after reaching an advanced age. After further adjusting for individual characteristics, depressive symptoms exhibited a negative trend with advancing age. The mean levels of depressive symptoms remained stable during the study period. Depressive symptoms varied significantly across cohorts, with those born in 1949-1951 having the most severe depressive symptoms. Significant life-course and cohort variations existed in the gender gaps in depressive symptoms. Although women had higher mean scores on the CES-D-10 scale throughout the life course, the gender gaps in depressive symptoms gradually narrowed with age, as depressive symptoms decreased more rapidly among women. A widening trend in gender gaps in depressive symptoms was found among those born after the mid-1950s, mainly driven by a notable decline in depressive symptoms among men CONCLUSIONS: The convergence of living conditions between genders in late life, as a result of traditional Chinese culture, may have narrowed the gender gap in depressive symptoms. However, given the widening gender disparities in depressive symptoms among younger cohorts, more attention should be paid to women's mental health in the context of China's rapid socioeconomic development.

Down-regulation of miR-29 improves lipid metabolism in fatty liver of dairy cows.

In this study, we conducted a thorough investigation into the mechanisms by which miR-29 influences lipid metabolism. Thirty-two cows were selected and categorized into distinct groups based on their liver triglyceride (TG) content: healthy, mild fatty liver, and moderate fatty liver groups. Dairy cows with moderate fatty liver showed higher levels of hepatic lipid accumulation, MDA content and serum AST, ALT and ALP contents and lower hepatic catalase CAT and SOD activities. Subsequently, hepatocytes isolated from healthy calves were exposed to sodium oleate (SO) in the presence or absence of pre-incubation with miR-29 inhibitor or inhibitor NC. Pre-transfection with miR-29 inhibitor resulted in reduced hepatocyte lipid accumulation and MDA levels, as well as decreased levels of AST, ALT, and ALP in the supernatant. In the miR-29 inhibitor + SO group, there was an increase in the expression of SREBP-1, FAS, SCD1, and Sirt1. Meanwhile, the expression of PPARα, CPT1, CPT2, PGC-1α, NRF-1, UCP2, and miR-29 were observed to be decreased. In comparison to the miR-29 inhibitor + SO group, some of the measured indicators showed partial reversal in the miR-29 inhibitor + siSirt1 + SO group. Collectively, these findings provide evidence that miR-29 may play a crucial role in the pathogenesis of fatty liver in dairy cows.