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Abstract Purpose To evaluate the utility of apparent diffusion coefficient (ADC) values of extraocular muscles (EOMs) in differentiating activity of thyroid eye disease (TED). Method Forty-two TED patients who underwent diffusion tensor imaging(DTI) were retrospectively enrolled in this study, including 29 patients in analysis group and 13 patients in validation group. The mean, maximum and minimum ADC value of each EOM were regarded as ADCmean, ADCmax and ADCmin. The difference between ADCmax and ADCmin was regarded as △ADC. The correlations between ADCmean or △ADC of each EOM and clinical activity score (CAS) were assessed. Results In analysis group, ADCmean differed between active and inactive eyes and positively correlated with CAS in IR (P 0.05). While △ADC differed between two groups and negatively correlated with CAS in all EOMs (all P

Abstract Extracellular vesicles (EVs) are known to mediate cell communications and shape tumor microenvironment. Compared to the well-studied small EVs, the function of large microvesicles (MVs) during tumorigenesis is poorly understood. Here we show the proteome of MVs in Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC), and identify olfactomedin 4 (OLFM4) is induced by EBV infection and secreted via MVs to promote tumor progression through Hippo signaling. Specifically, OLFM4 is a target gene of the cGAS-STING pathway, and EBV infection activates cGAS-STING pathway and increases OLFM4 expression. Moreover, MV-carried OLFM4 binds with the extracellular cadherin domain of FAT1, thereby impairing its intracellular interaction with MST1 and leading to YAP activation in recipient cells. Together, our study not only reveals a regulatory mechanism though which viral infection is coupled via MVs with intercellular control of the Hippo signaling, but also highlights the OLFM4-Hippo axis as a therapeutic target for EBV-associated cancers.

Abstract This study aimed to evaluate the efficacy and safety of dolutegravir plus lamivudine (DTG/3TC) in antiretroviral treatment (ART)-experienced people living with HIV (PLWH). A total of 303 PLWH in Shanghai, China, who switched from triple ART to DTG/3TC between January 2019 and June 2022, with a minimum ART duration of 6 months, were retrospectively enrolled. More than 95% of PLWH maintained viral suppression with no significant changes in CD4 counts 12 months after switching. Patients transitioning from non-tenofovir (TDF)-based regimens demonstrated more pronounced improvements in lipid profiles, while those previously on TDF-based regimens showed greater enhancements in bone metabolism.

Abstract Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting tens of millions of people globally. The causal relationship between metabolites and AD pathology has not yet been formally indicated, and the mediating mechanism by which metabolites affect AD has not yet been explored. This study aimed to determine the genetic relationship between metabolites and AD and to determine the pathways through which amino acid metabolites affect AD. Meta-analysis integrates the results of multiple GWAS analyses using METAL software. Using bidirectional two-sample Mendelian randomization (MR), we analyzed the causal relationships between metabolites and AD. The principal MR test of causal effects was conducted using inverse-variance weighted regression, and we used reverse MR analysis to exclude reverse causality. We also performed the MR-PRESSO test to detect and correct for possible pleiotropic effects, and used the Cochran Q test to assess heterogeneity. Two-step MR was utilized to analyze the mediating factors between amino acid metabolites and the onset of AD. The correlation between mediating factors (inflammatory protein S100A12) and immune cell infiltration was analyzed using the edgeR and GSVA software packages. Using single-cell sequencing data from skin tissues of patients with AD, we studied the regulatory role of the S100A12 gene in immune cells. Multiple drug databases and macromolecular docking were used to search for S100A12-targeting drugs. Bidirectional two-sample MR analyses indicated that twenty-two metabolites and one inflammatory protein (S100A12) were significantly associated with AD pathogenesis. S100A12 is a mediator of amino acid metabolites (N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine) that are genetically associated with AD. S100A12 was positively correlated with the infiltration of multiple immune cell types in lesional AD skin. The amino acid metabolites N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine influence AD pathogenesis by mediating S100A12 expression.

Abstract Activation and selective oxidation of inert C(sp 3)–H bonds remain one of the most challenging tasks in current synthetic chemistry due to the inherent inertness of C(sp 3)–H bonds. In this study, inspired by natural monooxygenases, we developed a coordination polymer with naphthalenediimide (NDI)-based ligands and binuclear iron nodes. The mixed-valence FeIIIFeII species and chlorine radicals (Cl•) are generated via ligand-to-metal charge transfer (LMCT) between FeIII and chlorine ions. These Cl• radicals abstract a hydrogen atom from the inert C(sp 3)–H bond of alkanes via hydrogen atom transfer (HAT). In addition, NDI converts oxygen to 1O2 via energy transfer (EnT), which then coordinates to FeII, forming an FeIV = O intermediate for the selective oxidation of C(sp 3)–H bonds. This synthetic platform, which combines photoinduced EnT, LMCT and HAT, provides a EnT-mediated parallel multiphoton excitation strategy with kinetic synergy effect for selective C(sp 3)–H oxidation under mild conditions and a blueprint for designing coordination polymer-based photocatalysts for C(sp 3)–H bond oxidation.

Small-scale pumps for controlling microfluidics have promising applications in drug delivery and chemical assays. Liquid metal (LM) demonstrates excellent flow pumping performance due to its simple structure and the electrocapillary effect under an electric field. However, LM droplets risk escaping from constrained structures, which can lead to pump failure. Temperature regulation is also a critical parameter in optimizing chemical reactions in fluidic systems, however, integrating it into a compact system remains challenging. Here, we develop a temperature-triggered gallium-based actuator (TTGA) by introducing a gallium (Ga) droplet wetted on a copper (Cu) plate as the core element for flow actuation. The Cu plate prevents the Ga droplet from escaping the chamber and significantly increases the flow rate. By leveraging the electrochemical method to inhibit the supercooling effect of Ga, the TTGA enables activation/deactivation for flow actuation at different temperatures. We investigate the impact of electrode position, solution concentration, and applied voltage on TTGA’s pumping efficiency. By dynamically tuning the Ga droplet’s temperature to control phase transition, TTGA allows for accurate flow actuation control. Furthermore, placing Ga and eutectic Ga-indium (EGaIn) droplets in different channels enables the expected flow divergence for fluids with different temperatures. The development of TTGA presents new opportunities in microfluidics and biomedical treatment.

BackgroundType 2 diabetes mellitus (T2DM) is a chronic non-infectious disease that seriously endangers human health. This study aimed to determine the main factors influencing the medical expenditure of T2DM patients and provide guidance for the allocation and control of medical expenditure.MethodsThe homepage data of patients with T2DM were retrospectively collected from six tertiary hospitals in southwest China from January 2011 to December 2021. A multiple linear regression model was constructed to examine the factors associated with medical expenses per patient. Furthermore, the trends of medical expenditure according to other important measures and patient subgroups were described, and a proportional breakdown of medical expenditure was generated. All expenditure data were reported in Chinese Yuan (CNY), based on the 2021 value, and adjusted using the year-specific healthcare consumer price index.ResultsA total of 45,237 patients with T2DM were analyzed in this study. Multiple linear regression showed that age, marital status, insurance type, length of stay, number of clinical visits, number of comorbidities, history of disease, history of surgery, smoking history, and the age-adjusted Charlson comorbidity index score were influencing factors of medical expenditure in patients with T2DM. Considering the overall average medical expenditure, diagnosis cost accounted for the largest proportion and was never

Centromere protein H (CENP-H) is an important component of a functional centromere. Studies have demonstrated that CENP-H is overexpressed in renal cell, gastric, hypopharyngeal squamous cell, nasopharyngeal, endometrial, lung, cervical, esophageal, liver, colorectal, oral squamous cell, breast, and tongue carcinomas. CENP-H overexpression is positively correlated with a poor prognosis, pathological stage, T stage, and lymph node metastasis in patients with the above carcinomas. CENP-H can promote cancer growth and metastasis through PI3K/AKT, survivin, and mitochondrial apoptosis signaling mechanisms, and it can be regulated by long non-coding ribonucleic acid (lncRNA) plasmacytoma variant translocation 1 (PVT1)/miR-612, Sp1, or Sp3. This review aims to summarize the expression of CENP-H, the relationship between CENP-H expression and prognostic features, growth and metastasis of cancer in patients, as well as the mechanism of CENP-H in cancer. It also proposes a new candidate molecule for treating patients with cancer.

Atopic dermatitis (AD) is a chronic relapsing disease with complex pathogenesis. Among them, inflammation is one of the primary pathogenesis of AD. AD is characterized by infiltration of lymphocytes into the skin’s dermis, and the skin homing of lymphocytes plays an essential role in the recurrence of AD. Currently, there is more and more evidence to support this view. This article reviews the relevant role of T lymphocyte skin-homing-related molecules in the recurrence of AD to provide a reference for the cure of AD.

BackgroundIntracranial imaging abnormalities are commonly observed in patients suffering from HIV-associated cryptococcal meningitis, both before and during the treatment period. This study aims to analyze the prevalence, origins, radiological characteristics, treatments, and prognosis of intracranial lesions in patients with HIV-associated cryptococcal meningitis, thereby providing references for future clinical decision-making.MethodsThe clinical data of patients diagnosed with HIV-associated cryptococcal meningitis and admitted to the Shanghai Public Health Clinical Centre between 2013 and 2019 were collected. Logistic regression analysis was subsequently conducted to identify potential risk factors associated with the development of intracranial lesions in this patient group.ResultsOf 211 patients analyzed, 64.5% (136/211) had intracranial lesions during treatment and follow-up. Initial cranial imaging showed 60% had lesions pre-treatment. Throughout treatment, 32.7% (52/159) developed new or worsened lesions. Mortality rates at 2 weeks, 8 weeks, and 2 years for those with detected lesions were 3%, 7.6%, and 13.2%, respectively. Lesions were primarily caused by Cryptococcus (70.5%) and Mycobacterium (24.3%). Lacunar infarcts, especially in the basal ganglia, were the most common type. Patients aged 50 years or older, and those presenting with altered mental status upon admission, were found to be more likely to have intracranial lesions at baseline, with adjusted odds ratios of 5.364 (95% CI: 1.468-19.591, P=0.011) and 7.970 (95% CI: 2.241-28.337, P=0.001), respectively. Patients with lesion progression showed higher levels of IFN-γ, IL-4, IL-5, IL-6, IL-1Ra, IL-1β, GM-CSF, Eotaxin, and Basic FGF in cerebrospinal fluid after four weeks of treatment.ConclusionIntracranial lesions in HIV-associated cryptococcal meningitis patients are mostly due to Cryptococcus and Mycobacterium infections. They often appear as lacunar infarcts, predominantly in the basal ganglia, and can worsen with treatment initiation, possibly due to higher baseline cytokine levels in cerebrospinal fluid.

Bisphenol A (BPA) is a ubiquitous environmental pollutant with endocrine-disrupting functions. Identifying protective drugs and exploring the mechanisms against BPA are crucial in healthcare. Natural products exhibiting antioxidant properties are considered to be able to protect against BPA toxicity. Although BPA-modulated targets and miRNAs have been individually reported, their connections to natural products were rarely organized. With the help of a protein–protein interaction database (STRING), the relationship between individual BPA-modulated targets was interconnected to provide a systemic view. In this review, BPA-downregulated and -upregulated targets are classified, and their interactive network was innovatively analyzed using the bioinformatic database (STRING). BPA-modulated miRNAs were also retrieved and ingeniously connected to BPA-modulated targets. Moreover, a novel connection between BPA-countering natural products was integrated into BPA-modulated miRNAs and targets. All these targets-associated natural products and/or miRNAs were incorporated into the STRING network, providing systemic relationships. Overall, the BPA-modulated target–miRNA-protecting natural product axis was innovatively constructed, providing a straightforward direction for exploring the integrated BPA-countering effects and mechanisms of natural products.

BackgroundThe nod-like receptor family pyrin domain-containing 3 (NLRP3) has been implicated in various skin diseases. However, its role in mediating 2, 4-dinitrofluorobenzene (DNFB)-induced chronic itch remains unclear.MethodsWidetype (WT) and Nlrp3 deletion (Nlrp3-/-)mice, the expression of transient receptor potential (TRP) ankyrin 1 (TRPA1) inhibitor or recombinant mice interleukin-18 (IL-18) were used to establish and evaluate the severity of DNFB-mediated chronic itch. Quantitative real-time PCR, western blotting, immunohistochemistry staining, immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA) was used to examine the expression of NLRP3 inflammasome, type 2 immunity and receptors in dorsal root ganglion (DRG) neurons related with chronic itch. Flow cytometry was performed to quantify the frequency of type 2 immune cells.ResultsThis study revealed that the NLRP3 inflammasome was activated in the skin of DNFB-induced chronic itch mice. Surprisingly, the absence of Nlrp3 exacerbated itch behavior. In Nlrp3-/- mice, IL-18 expression was downregulated, whereas markers of type 2 immunity, such as IL-4 and thymic stromal lymphopoietin (TSLP), were significantly upregulated in the skin. Furthermore, TRPA1 and its colocalization with the IL-4 receptor were increased in the DRG. Inhibition of TRPA1 or administration of recombinant IL-18 significantly reduced DNFB-induced itch behavior in Nlrp3-/- mice. Recombinant IL-18 also decreased the expression of TRPA1, IL-4, and TSLP.DiscussionThese findings suggested that the absence of Nlrp3 aggravated DNFB-induced chronic itch by exacerbating type 2 immunity in the skin and enhancing the IL-4/TSLP-TRPA1 axis, potentially driven by reduced IL-18 levels.

Abstract Recent advancements in wearable electrochemical biosensors have opened new avenues for on‐body and continuous detection of biomarkers, enabling personalized, real‐time, and preventive healthcare. While glucose monitoring has set a precedent for wearable biosensors, the field is rapidly expanding to include a wider range of analytes crucial for disease diagnosis, treatment, and management. In this review, recent key innovations are examined in the design and manufacturing underpinning these biosensing platforms including biorecognition elements, signal transduction methods, electrode and substrate materials, and fabrication techniques. The applications of these biosensors are then highlighted in detecting a variety of biochemical markers, such as small molecules, hormones, drugs, and macromolecules, in biofluids including interstitial fluid, sweat, wound exudate, saliva, and tears. Additionally, the review also covers recent advances in wearable electrochemical biosensing platforms, such as multi‐sensory integration, closed‐loop control, and power supply. Furthermore, the challenges associated with critical issues are discussed, such as biocompatibility, biofouling, and sensor degradation, and the opportunities in materials science, nanotechnology, and artificial intelligence to overcome these limitations.

Purpose: This study aims to identify risk factors for vertebral compression fracture and enhance the ability to indicate fracture risk. Methods: A retrospective collection of clinical and imaging data was conducted for patients with vertebral compression fractures and control subjects who underwent quantitative computed tomography scans. Stepwise logistic regression analysis was employed to identify variables associated with fractures, constructing both unadjusted model and adjusted model. Results: Compared with the non-fracture group, the fracture group showed significant differences in weight, body mass index (BMI), bone mineral density (BMD), vertebral cross-sectional area, paraspinal muscle area and right psoas major muscle fat area (all P

Rock abrasiveness is an important factor affecting the tool's lifetime and efficiency in breaking a rock. Characterizing rock abrasiveness helps in the design, optimization, and mean-life prediction of tools. X-ray diffraction, cast thin section analysis, and CERCHAR abrasiveness tests were performed on 18 different sandstones to characterize rock abrasiveness and explore new methods for characterization. The relationship between the mineral composition and microstructure of sandstone and abrasiveness was investigated. The results show that different structural maturities have varying effects on abrasiveness. In addition, the higher the structural maturity, the more the abrasiveness. Furthermore, in sandstones of the same structural maturity, the abrasiveness increases with equivalent quartz content (EQC). The texture coefficient (TC) and CERCHAR abrasiveness index (CAI) of sandstones with the same structural maturity showed a good linear relationship. Moreover, the correlation coefficients considering the combined parameters are above 0.85. Therefore, obtaining the microstructure and mineral composition of sandstone can effectively characterize rock abrasiveness. It also provides a new method for predicting the abrasiveness of the rock in the well.

Abstract The combination of ASC22, an anti-PD-L1 antibody potentially enhancing HIV-specific immunity and chidamide, a HIV latency reversal agent, may serve as a strategy for antiretroviral therapy-free virological control for HIV. People living with HIV, having achieved virological suppression, were enrolled to receive ASC22 and chidamide treatment in addition to their antiretroviral therapy. Participants were monitored over 24 weeks to measure changes in viral dynamics and the function of HIV-specific CD8+ T cells (NCT05129189). 15 participants completed the study. At week 8, CA HIV RNA levels showed a significant increase from baseline, and the values returned to baseline after discontinuing ASC22 and chidamide. The total HIV DNA was only transiently increased at week 4 (P = 0.014). In contrast, integrated HIV DNA did not significantly differ from baseline. Increases in the proportions of effector memory CD4+ and CD8+ T cells (TEM) were observed from baseline to week 24 (P = 0.034 and P = 0.002, respectively). The combination treatment did not succeed in enhancing the function of HIV Gag/Pol- specific CD8+ T cells. Nevertheless, at week 8, a negative correlation was identified between the proportions of HIV Gag-specific TEM cells and alterations in integrated DNA in the T cell function improved group (P = 0.042 and P = 0.034, respectively). Nine adverse events were solicited, all of which were graded 1 and resolved spontaneously. The combined treatment of ASC22 and chidamide was demonstrated to be well-tolerated and effective in activating latent HIV reservoirs. Further investigations are warranted in the context of analytic treatment interruption.

Abstract Bone is a common organ affected by metastasis in various advanced cancers, including lung, breast, prostate, colorectal, and melanoma. Once a patient is diagnosed with bone metastasis, the patient's quality of life and overall survival are significantly reduced owing to a wide range of morbidities and the increasing difficulty of treatment. Many studies have shown that bone metastasis is closely related to bone microenvironment, especially bone immune microenvironment. However, the effects of various immune cells in the bone microenvironment on bone metastasis remain unclear. Here, we described the changes in various immune cells during bone metastasis and discussed their related mechanisms. Osteoblasts, adipocytes, and other non‐immune cells closely related to bone metastasis were also included. This review also summarized the existing treatment methods and potential therapeutic targets, and provided insights for future studies of cancer bone metastasis.

Intestinal stem cells are an important part of maintaining the stability of intestinal barrier function, which is closely related to intestinal homeostasis, intestinal epithelial renewal, and repair of intestinal damage. Normal physiological activities of the human body cannot be separated from energy intake and metabolism, and the differentiation fate of stem cells is affected by energy metabolism, and impaired intestinal barrier is associated with the development of many intestinal diseases. Therefore, this paper focuses on intestinal stem cells, takes energy metabolism and metabolites as the background to investigate how energy metabolism and metabolites regulate the function and activity of stem cells, thus regulating the function of intestinal barrier and providing ideas for the treatment of various intestinal diseases; in addition, with the in-depth research of modern medical science in protecting intestinal barrier, the theory of traditional Chinese medicine (TCM) that cares for spleen and stomach is gradually showing its scientific validity, with the hope of providing ideas for the subsequent research.

Abstract Understanding the mechanical characteristics of rocks when subjected to direct tension is crucial for assessing the stability of rock formations. Within the scope of this research, a series of tests was conducted using Tage tuff to assess the deformation behavior and crack extension of rock under direct tension. The axial, lateral, and shear strain fields as well as crack propagation, localized deformation behavior, and failure mode of the rocks were analyzed using three-dimensional digital image correlation method. The results showed that the axial strain fields on the specimen surface were heterogeneous, with different locations and localization occurring in the pre-peak stage, which was similar to the evolution of shear strain, whereas the lateral strain only showed slight changes. The crack extension direction was inferred, indicating that both tensile and shear stress occurred in the tests. Furthermore, different stress–strain responses were observed for the inside and outside of the localized bands. Then, the surface patterns of specimen failure were scanned and analyzed to assess the failure mode and residual strength of the specimen under direct tensile stress. Finally, the results of direct tension, uniaxial compression, and Brazilian split tests for Tage tuff were compared, and the complete stress–strain curve of uniaxial tension (UT) was simulated using a nonlinear-variable-compliance constitutive equation. This study provides a deeper understanding into the damage behavior of rocks under direct tension.

Abstract Host defense peptide (HDP)-mimicking polymers are promising therapeutic alternatives to antibiotics and have large-scale untapped potential. Artificial intelligence (AI) exhibits promising performance on large-scale chemical-content design, however, existing AI methods face difficulties on scarcity data in each family of HDP-mimicking polymers (105), and multi-constraints on properties and structures when exploring high-dimensional polymer space. Herein, we develop a universal AI-guided few-shot inverse design framework by designing multi-modal representations to enrich polymer information for predictions and creating a graph grammar distillation for chemical space restriction to improve the efficiency of multi-constrained polymer generation with reinforcement learning. Exampled with HDP-mimicking β-amino acid polymers, we successfully simulate predictions of over 105 polymers and identify 83 optimal polymers. Furthermore, we synthesize an optimal polymer DM0.8 iPen0.2 and find that this polymer exhibits broad-spectrum and potent antibacterial activity against multiple clinically isolated antibiotic-resistant pathogens, validating the effectiveness of AI-guided design strategy.

Abstract Skin wound infection has become a notable medical threat. Herein, the polysaccharide-based injectable hydrogels with multifunctionality were developed by a simple and fast gelation process not only to inactivate bacteria but also to accelerate bacteria-infected wound healing. Sodium nitroprusside (SNP) loaded PCN-224 nanoparticles were introduced into the polymer matrix formed by the dynamic and reversible coordinate bonds between Ag+ with carboxyl and amino or hydroxyl groups on carboxymethyl chitosan (CMCS), hydrogen bonds and electrostatic interactions in the polymer to fabricate SNP@PCN@Gel hydrogels. SNP@PCN@Gel displayed interconnected porous structure, excellent self-healing capacity, low cytotoxicity, good blood compatibility, and robust antibacterial activity. SNP@PCN@Gel could produce reactive oxygen species (ROS) and NO along with Fe2+, and showed long-term sustained release of Ag+, thereby effectively killing bacteria by synergistic photothermal (hyperthermia), photodynamic (ROS), chemodynamic (Fenton reaction), gas (NO) and ion (Ag+ and -NH3 + in CMCS) therapy. Remarkably, the hydrogels significantly promoted granulation tissue formation, reepithelization, collagen deposition and angiogenesis as well as wound contraction in bacteria-infected wound healing. Taken together, the strategy represented a general method to engineer the unprecedented photoactivatable “all-in-one” hydrogels with enhanced antibacterial activity and paved a new way for development of antibiotic alternatives and wound dressing. Graphical abstract

Immunogenic cell death (ICD) spatiotemporally regulates damage-associated molecular patterns (DAMPs) derived from dying cancer cells to signal the immune response. Intriguingly, these DAMPs and cytokines also induce cellular responses in non-immune cells, particularly cancer cells. Several ICD-modulating natural products and miRNAs have been reported to regulate the DAMP, cytokine, and cell death responses, but they lack systemic organization and connection. This review summarizes the impacts of natural products and miRNAs on the DAMP and cytokine responses and cancer cell death responses (apoptosis, autophagy, ferroptosis, necroptosis, and pyroptosis). We establish the rationale that ICD inducers of natural products have modulating effects on miRNAs, targeting DAMPs and cytokines for immune and cancer cell death responses. In conclusion, DAMP, cytokine, and cell death responses are intricately linked in cancer cells, and they are influenced by ICD-modulating natural products and miRNAs.

The transgenerational effects of exposing male mice to chronic social instability (CSI) stress are associated with decreased sperm levels of multiple members of the miR-34/449 family that persist after their mating through preimplantation embryo (PIE) development. Here we demonstrate the importance of these miRNA changes by showing that restoring miR-34c levels in PIEs derived from CSI stressed males prevents elevated anxiety and defective sociability normally found specifically in their adult female offspring. It also restores, at least partially, levels of sperm miR-34/449 normally reduced in their male offspring who transmit these sex-specific traits to their offspring. Strikingly, these experiments also revealed that inducing miR-34c levels in PIEs enhances the expression of its own gene and that of miR-449 in these cells. The same induction of embryo miR-34/449 gene expression likely occurs after sperm-derived miR-34c is introduced into oocytes upon fertilization. Thus, suppression of this miRNA amplification system when sperm miR-34c levels are reduced in CSI stressed mice can explain how a comparable fold-suppression of miR-34/449 levels can be found in PIEs derived from them, despite sperm containing ~50-fold lower levels of these miRNAs than those already present in PIEs. We previously found that men exposed to early life trauma also display reduced sperm levels of miR-34/449. And here we show that miR-34c can also increase the expression of its own gene, and that of miR-449 in human embryonic stem cells, suggesting that human PIEs derived from men with low sperm miR-34/449 levels may also contain this potentially harmful defect.

Primary cilia (PC) are essential signaling hubs for proper epithelial formation and the maintenance of skin homeostasis. Found on most cells in the human body, including skin cells, PC facilitate signal transduction that allows ciliated cells to interact with the immune system via multiple pathways, helping to maintain immune system homeostasis. PC can be altered by various microenvironmental stimuli to develop corresponding regulatory functions. Both PC and ciliary signaling pathways have been shown to be involved in the immune processes of various skin lesions. However, the mechanisms by which PC regulate cellular functions and maintain immune homeostasis in tissues are highly complex, and our understanding of them in the skin remains limited. In this paper, we discuss key ciliary signaling pathways and ciliated cells in the skin, with a focus on their immunomodulatory functions. We have compiled evidence from various cells, tissues and disease models to help explore the potential immunomodulatory effects of PC in the skin and their molecular mechanisms.

BackgroundPatients with locally advanced non-small cell lung cancer (LA-NSCLC) usually bear high tumor burden and are not tolerated well to concurrent chemoradiation therapy (CRT) followed by consolidation immunotherapy. We investigated the feasibility of chemoimmunotherapy as induction therapy before CRT for LA-NSCLC.MethodsWe retrospectively analyzed data from 91 patients with unresectable stage III NSCLC treated with either induction chemoimmunotherapy or chemotherapy before CRT. Tumor responses, survival statistics, and toxic effects were compared. The dosimetric parameters of the RT protocol were evaluated. The primary endpoint was progression-free survival (PFS). The overall response (ORR), the depth of response (DpR) were accessed at the end of CRT (ORRinduc+CRT, DpRinduc+CRT) and induction therapy (ORRinduc, DpRinduc).ResultsThe median PFS (mPFS) were significantly longer in the chemoimmunotherapy induction group (13.5 months vs. 11.2 months; HR, 0.56; 95% CI, 0.32–0.97; p=0.036). The ORRinduc+CRT, median DpRinduc+CRT (mDpRinduc+CRT) and mDpRinduc were significantly higher in the chemoimmunotherapy induction group (ORRinduc+CRT, 84.0% vs. 65.9%, p=0.044; mDpRinduc+CRT, 49.5% vs. 39.0%, p = 0.012; mDpRinduc, 38.5% vs. 28.0%, p=0.044). Incidence of treatment-related adverse events (AE) was similar between groups, with myelosuppression being the most common grade ≥ 3 AE. Regarding radiotherapy, adopting a mapping strategy with a 5–8 mm margin for clinical tumor volume resulted in decreased radiation doses to critical organs in the chemoimmunotherapy induction group.ConclusionsChemoimmunotherapy induction therapy before CRT improves efficacy with comparable incidence of AEs compared to chemotherapy induction in LA-NSCLC patients. Further studies are warranted to validate these findings.

Summary: Background: The continuous emergence of multidrug-resistant (MDR) Acinetobacter baumannii (Ab) strains poses further challenges in its control and clinical management. It is necessary to decipher the mechanisms underlying the high mortality of Ab infections to explore unconventional strategies for controlling outbreaks of drug-resistant infections. Methods: The immune responses of Ab sepsis infection were investigated using flow cytometry, RNA-seq, qRT-PCR, and ELISA and scRNA-seq. The detailed pathways mediating Ab immune responses were also depicted and a specific therapy was developed based on the understanding of the mechanisms underlying Ab-induced cytokine storms. Findings: The results highlighted the critical role of alveolar and interstitial macrophages as targets of Ab during the infection process. These cells were found to undergo polarization towards the M1 phenotype, triggering a cytokine storm that eventually caused the death of the host. The polarization and excessive inflammatory response mediated by macrophages were mainly regulated by the TLR2/Myd88/NF-κB signaling pathway. Suppression of Ab-triggered inflammatory responses and M1 polarization by the drug naproxen (NPXS) was shown to confer full protection of mice from lethal infections. Interpretation: The findings in this work depict the major mechanisms underlying the high mortality rate of Ab infections and highlight the clinical potential application of anti-inflammatory drugs or immunosuppressants in reducing the mortality of such infections, including those caused by MDR strains. Funding: Funding sources are described in the acknowledgments section.

Leveraging the unique attributes of functional soft materials to generate force and deformation, significant advancements in soft actuators are driving the evolution of smart robotics. Liquid metals (LMs), known for their high deformability and tunable morphology, demonstrate remarkable actuating capabilities through controllable surface tension. Inspired by the predation method of chameleons, this work introduces a bioinspired LM actuator (BLMA) by modulating the morphology of LM. This BLMA enables high‐strain (up to 170%) actuation by precisely directing LM droplets toward an electrode. Various parameters affecting the BLMA's actuating performance are explored. Notably, the application of a reductive voltage induces rapid solidification of supercooled LM, facilitating phase transition at room temperature. The solidified LM enhances its holding force of BLMA by over 1000 times. To underscore the superior capabilities of the BLMA, diverse applications, such as a complex two‐dimensional plane actuator, a stepper motor with adjustable step intervals, a phase transition‐controlled relay, and a laser code lock actuation gate set, are presented. It is anticipated that the exceptional characteristics of the BLMA will propel advancements in the realms of soft robotics and mechatronics.

Abstract Impulse waves are generated by rapid subaerial mass movements including landslides, avalanches and glacier break-offs, which pose a potential risk to public facilities and residents along the shore of natural lakes or engineered reservoirs. Therefore, the prediction and assessment of impulse waves are of considerable importance to practical engineering. Tsunami Squares, as a meshless numerical method based on a hybrid Eulerian–Lagrangian algorithm, have focused on the simulation of landslide-generated impulse waves. An updated numerical scheme referred to as Tsunami Squares Leapfrog, was developed which contains a new smooth function able to achieve space and time convergence tests as well as the Leapfrog time integration method enabling second-order accuracy. The updated scheme shows improved performance due to a lower wave decay rate per unit propagation distance compared to the original implementation of Tsunami Squares. A systematic benchmark testing of the updated scheme was conducted by simulating the run-up, reflection and overland flow of solitary waves along a slope for various initial wave amplitudes, water depths and slope angles. For run-up, the updated scheme shows good performance when the initial relative wave amplitude is smaller than 0.4. Otherwise, the model tends to underestimate the run-up height for mild slopes, while an overestimation is observed for steeper slopes. With respect to overland flow, the prediction error of the maximum flow height can be limited to ± 50% within a 90% confidence interval. However, the prediction of the front propagation velocity can only be controlled to ± 100% within a 90% confidence interval. Furthermore, a sensitivity analysis of the dynamic friction coefficient of water was performed and a suggested range from 0.01 to 0.1 was given for reference.

Objective: To observe the effects of Danggui Shaoyao powder (DSP) on hepatic lipid metabolism and further explore its mechanism of action by peroxisome proliferator-activated receptor (PPARγ)-liver X receptor (LXRα)-adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) pathway regulation. Methods: Eight C57BL/6J male mice were selected as the control group, and 24 ApoE−/− male mice were randomly divided into the atherosclerosis model (AS) group, atorvastatin calcium (AC) group, and DSP group (n = 8 each group). To establish an AS model, ApoE−/− mice were fed a high-fat diet for 16 weeks. Pathologic changes in the aortic vasculature and liver were identified using Oil Red O staining. Triglyceride (TG), cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels were determined in the livers using a single-reagent GPO-PAP method. Fluorescence quantitative polymerase chain reaction and western blot were used to observe and evaluate the mRNA and protein expression of the PPARγ-LXRα-ABCA1 intermediates in the liver. Results: After 16 weeks of a high-fat diet, ApoE−/− mice showed more Oil Red O staining in the aorta and liver compared to the CONT group. Compared to the AS group, the DSP and AC treatment reduced aortic plaque and hepatic lipid deposition to varying degrees. Furthermore, DSP significantly reduced the hepatic lipid area in ApoE−/− mice (P

Coupled plate structures composed of stiffened plates and sub-plates have been widely used in marine engineering practice. Meanwhile, the low-frequency multi-linear spectrum vibration control of the coupled stiffened plate structures has become necessary and meaningful. However, the design efficiency of the dynamic vibration absorber of the corresponding structure is still low. In the present study, a mathematical model of coupled plate structures and a dynamic vibration absorber is introduced to improve design efficiency. Subsequently, an experiment is designed to verify the effectiveness and advantages of the current method. The reliability of the current mathematical model is verified by comparing it with modal experiment results. Moreover, the equivalent mass solution efficiency is greatly improved by comparing it with FEM. Finally, a comparison experiment of the dynamic vibration absorber has also been conducted to further verify the effectiveness of the current method. The semi-analytical method proposed in the current research may be useful when designing dynamic vibration absorbers for the coupled plate structures of offshore platforms.

The underlying mechanisms and diagnostic biomarkers for the progress of COVID-19 in HIV patients have not been fully elucidated. In this study, the aim is to analyze the metabolomic profiles of HIV/AIDS patients co-infected with SARS-CoV-2 and to identify biomarkers indicative of co-infection. In this study, we conducted a retrospective cohort analysis of peripheral blood samples collected from 30 HIV/AIDS patients co-infected with SARS-CoV-2 (pc group) and 30 patients without SARS-CoV-2 (nc group). In this study, through non-targeted metabolomics and lipidomics analysis, 77 differential metabolites were identified in the plasma of patients co-infected with HIV and SARS-CoV-2 compared to the nc group, with vitamin K1 emerging as a significant feature. Moreover, the plasma of the pc group showed disturbances in lipid metabolism, with elevated triglycerides (TG) and phosphatidylcholine (PC) and decreased phosphatidylglycerol (PG) compared to the control group. Vitamin K1 may be a biomarker for SARS-CoV-2 in HIV/AIDS patients, and changes in the levels of TG, PC, and PG molecules appear to be the main features following HIV co-infection with COVID-19. The emphasis in our study is on the power of using comprehensive metabolomics (lipidomics) approaches to identify metabolic biomarkers and potential mechanisms of COVID-19 in HIV/AIDS patients.