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Abstract Highly sensitive airborne virus monitoring is critical for preventing and containing epidemics. However, the detection of airborne viruses at ultra-low concentrations remains challenging due to the lack of ultra-sensitive methods and easy-to-deployment equipment. Here, we present an integrated microfluidic cartridge that can accurately detect SARS-COV-2, Influenza A, B, and respiratory syncytial virus with a sensitivity of 10 copies/mL. When integrated with a high-flow aerosol sampler, our microdevice can achieve a sub-single-copy spatial resolution of 0.83 copies/m3 for airborne virus surveillance with an air flow rate of 400 L/min and a sampling time of 30 minutes. We then designed a series of virus-in-aerosols monitoring systems (RIAMs), including versions of a multi-site sampling RIAMs (M-RIAMs), a stationary real-time RIAMs (S-RIAMs), and a roaming real-time RIAMs (R-RIAMs) for different application scenarios. Using M-RIAMs, we performed a comprehensive evaluation of 210 environmental samples from COVID-19 patient wards, including 30 aerosol samples. The highest positive detection rate of aerosol samples (60%) proved the aerosol-based SARS-CoV-2 monitoring represents an effective method for spatial risk assessment. The detection of 78 aerosol samples in real-world settings via S-RIAMs confirmed its reliability for ultra-sensitive and continuous airborne virus monitoring. Therefore, RIAMs shows the potential as an effective solution for mitigating the risk of airborne virus transmission.

Earthquakes are major catastrophes that cause great life and economic losses to human society and environment. This paper reviews and synthesizes relevant studies, drawing from a systematic examination of 4229 articles from the Web of Science core collection (1982–2023). Employing the CiteSpace visualization and analysis tool, current research and emerging trends in seismic risk assessment are discussed and analyzed. This paper provides a holistic overview of principal contributions, knowledge sources, interdisciplinary characteristics, and principal research topics in this field. Additionally, we propose key technologies that are in urgent need of enhancement, including data availability, quantity and quality of data, interpretability of machine learning models, performance improvement of machine learning methods and application of foundation models, as well as real-time risk assessment techniques. These insights support both theoretical understanding and practical applications of seismic risk assessment and damage analysis.

Abstract Emerging diagnostic scenarios, such as population surveillance by pooled testing and on‐site rapid diagnosis, highlight the importance of advanced microfluidic systems for in vitro diagnostics. However, the widespread adoption of microfluidic technology faces challenges due to the lack of standardized design paradigms, posing difficulties in managing macro‐micro fluidic interfaces, reagent storage, and complex macrofluidic operations. This paper introduces a novel modular‐based mesoscopic design paradigm, featuring a core “needle‐plug/piston” structure with versatile variants for complex fluidic operations. These structures can be easily coupled with various microfluidic platforms to achieve truly self‐contained microsystems. Incorporated into a “3D extensible” design architecture, the mesoscopic design meets the demands of function integration, macrofluid manipulations, and flexible throughputs for point‐of‐care nucleic acid testing. Using this approach, an ultra‐sensitive nucleic acid detection system is developed with a limit of detection of ten copies of SARS‐CoV‐2 per mL. This system efficiently conducts large‐scale pooled testing from 50 pharyngeal swabs in a tube with an uncompromised sensitivity, enabling a truly “sample‐in‐answer‐out” microsystem with exceptional performance.

ABSTRACT The continuous emergence of highly infectious SARS-CoV-2 variants with the capability of immune evasion demands more effective risk assessment and management approaches for infection prevention and control. Controlling nosocomial transmission is critical in response to the COVID-19 pandemic upon the resumption of day-to-day activities. Here, we systematically analyzed the presence of airborne SARS-CoV-2 in the isolation ward and within the contaminant, emergency, and clean zones of a designated COVID-19 hospital. A total of 359 air samples collected in the clean and emergency zones tested negative for SARS-CoV-2, demonstrating the interruption of airborne transmission in a designated COVID-19 hospital by combining the closed-loop management, unidirectional airflow, and negative pressure of isolation wards. In contrast, some air samples in the corridor outside the isolation wards tested positive for SARS-CoV-2. The leakage of virus-containing air from patient rooms to adjoining areas during rounds and meal delivery sheds light on the need for intensive and widespread virus monitoring in designated COVID-19 hospitals. In conclusion, by systematically monitoring viruses in the air, the study provides a starting point for the standardization of transmission risk management in designated hospitals for the future pandemic of a newly emerged respiratory infectious disease. IMPORTANCE Risk management and control of airborne transmission in hospitals is crucial in response to a respiratory virus pandemic. However, the formulation of these infection control measures is often based on epidemiological investigations, which are an indirect way of analyzing the transmission route of viruses. This can lead to careless omissions in infection prevention and control or excessively restrictive measures that increase the burden on healthcare workers. The study provides a starting point for standardizing transmission risk management in designated hospitals by systemically monitoring viruses in the air of typical spaces in COVID-19 hospitals. The negative results of 359 air samples in the clean and emergency zones demonstrated the existing measures to interrupt airborne transmission in a designated COVID-19 hospital. Some positive cases in the corridor of the contaminant zone during rounds and meal delivery highlighted the importance of monitoring airborne viruses for interrupting nosocomial infection.

This study investigates the structural performance of assembled rib-plate bridge abutments (ARBAs) with two different connection methods: bull leg bolt and flange connections. In addition, we explored the bending and shear performance of the connection parts and related areas to assess the damage characteristics and modes of these ARBAs. Utilizing model testing, a numerical analysis was conducted to define the force performance of the ARBA, with reference to a cast-in-place rib-plate abutment. The research results indicate that the bearing capacity and deformation capacity of the cap part of the assembled ribbed slab abutment model with cow leg connections are lower than those of the cast-in-place structure. When the structure fails, a 45° diagonal crack develops from the cross-section at the mid-span joint to the connection between the rib slab and the cap, until the concrete protective layer at the joint is crushed, exhibiting a shear failure mode. The bearing capacity of the assembly rib plate type abutment cap connected by the flange plate is basically the same as that of the cast-in-place structure, and the deformation capacity is weaker than that of the cast-in-place rib plate type abutment. The expansion of structural cracks is consistent with that of the rib plate type abutment connected by the cow leg. When the flange plate at the mid span is damaged, the contact surface between the flange plate and the concrete is pried off, resulting in the inability of the structure to continue bearing, exhibiting a shear failure mode. Through numerical simulation, taking the stress performance of the integral cast-in-place ribbed slab abutment as a reference, the assembled ribbed slab abutment connected by the flange plate is basically consistent with the integral cast-in-place ribbed slab abutment in terms of ultimate load, concrete damage, and steel reinforcement skeleton stress, and the connection device has not yet reached the yield state. The ultimate displacement is slightly weaker than that of the integral cast-in-place ribbed slab abutment. By comparison, it can be seen that the ultimate bearing capacity of the assembled ribbed slab abutment connected by the flange is basically the same as that of the cast-in-place ribbed slab abutment, and the stress performance can reach an “equivalent cast-in-place”, making it the preferred solution for the assembled abutment structure. The finite element parameter analysis of the flanged ARBA revealed that the thickness of the stiffening ribs, the number of bolts, and length of the flange plate anchoring steel plate were proportional to the ultimate load-bearing capacity of the prefabricated ARBA. In the case of no change in the structural damage mode, considering the economic benefits and load-bearing capacity of the structure, the following parameter combinations of the flanged ARBA are recommended: a thickness of 30 mm of the stiffening ribs, the number of bolts is 12, and a length of 50 cm of the length of flange plate anchoring steel plate.

With the increasing construction of undersea tunnels in seismic-prone areas, accurately assessing their response to seismic conditions is crucial. To grasp the dynamic response of undersea tunnel structures to seismic waves, the shaking table test of water–sea–sea submarine tunnel is designed and carried out based on the methods of orthogonal design and fuzzy method. A comprehensive time-domain model is developed to capture the nonlinear dynamic interaction of ocean engineering structures, taking into account seismic waves, seawater, and saturated soil. The research results show that as the burial depth at each measurement point of the submarine tunnel increases, the acceleration response decreases and the horizontal displacement relative to the seabed surface increases. Comparing test and finite element simulation results reveals that under seismic loading, the strain distribution pattern of the tunnel section is mainly in the arch shoulder, waist, and foot with larger strain peaks, whereas the strain peaks at the arch top and the superelevation arch are smaller. Simultaneously, doubling the water pressure induces a slight increase in the overall strain response peak of the tunnel, with an indistinct relative displacement change rule. When a vertically polarized shear wave (SV wave) is vertically incident, different dynamic response indices will have different trends with the change in water level. This study may provide a reference for shaking table tests for saturated soil–submarine tunnels at complex sites.

With the convenient and fast requirements for construction in bridge engineering, prefabricated assembly technology is widely applied in engineering construction. Typically, prefabricated bridge decks are connected through cast-in-place wet joints. Wet joints, as the primary load-bearing parts of bridge decks, undergo complex stress and are prone to cracking and damage. Particularly in the negative bending moment region of bridges, the influence of tensile stress on wet joints is more severe, thus enhancing the mechanical performance and crack resistance of joints becomes crucial. This paper investigates the mechanical behavior of prefabricated reinforced concrete bridge deck panels with variable cross-sections under negative bending moments, focusing on the performance of Ultra High-Performance Concrete (UHPC) wet joints. Full-scale experimental tests were conducted on a 176 m steel truss composite continuous rigid bridge, employing C50 concrete panels with UHPC wet joints. Results show three distinct stages: elastic, crack initiation and propagation, and failure. The maximum failure load reached 822 kN, with a maximum displacement of 21.64 mm. Concrete strains indicate compressive stress near the wet joint and tensile stress near the loading positions. Cracks primarily develop at the wet joint interface and propagate under increasing load, ultimately leading to flexural–shear failure near the variable cross-section of the wet joint. Numerical simulations using ABAQUS/CAE (2020) corroborate experimental findings, closely matching load-displacement curves and identifying damage locations. The study demonstrates that UHPC wet joints significantly enhance crack resistance, meeting design requirements for improved mechanical performance in bridge structures subjected to negative bending moments.

Offshore bridges may suffer from chloride ion corrosion, tsunami wave impact, and earthquake. However, the coupling effects of multiple factors have not been fully considered. This paper studied multiple degradation effects on the seismic performance of offshore piers considering tsunami wave impact, chloride ion corrosion, and their interaction. Firstly, through the scale model test of tsunami wave flume, the wave force of box girder structures and piers under different tsunami wave conditions is measured. Then, according to the corrosion characteristics of coastal chloride salts on reinforced concrete bridge piers, the corrosion parameters is selected by Latin hypercube sampling, and the influence of corrosion expansion and cracking of bridge pier cover on the chloride ion corrosion process is considered to modify the degradation model of corroded reinforced concrete materials. Finally, the wave load measured by the test is converted by the similarity criterion of the fluid mechanic test and loaded into the ABAQUS full-bridge model, and the pier after the tsunami wave is evaluated by the pushover analysis. The bearing capacity and lateral stiffness of the corroded pier before and after different tsunami waves are compared. The results show that the lateral bearing capacity and stiffness of bridge piers are, respectively, decreased by 27.6% and 6.2% after 30 years of service. Without corrosion, the lateral bearing capacity and stiffness of piers were, respectively, reduced by 11.45% and 10.6% after HXB-5 wave impact. After 30 years of service, the lateral bearing capacity and stiffness of bridge piers are, respectively, reduced by 41.8% and 22.5% under the combined action of corrosion and HXB-5 wave impact. It is found that the coupling effects of multiple degradation factors were more significant than the simple superposition ones. Therefore, the coupling effect of multiple factors should be considered in practical engineering.

The genus Acinetobacter has recently emerged as bacterial pathogens associated with mass mortalities in aquaculture. Yet scarce information is available on Acinetobacter venetianus as a potential pathogen of whiteleg shrimp Penaeus vannamei. In the present study, an A. venetianus pathogen (SHF1) was confirmed as a causative agent of red leg disease in freshwater-cultured whiteleg shrimp. It showed a mean lethal dose (LD50) value of 3.8 × 105 CFU mL−1 and developed multiple resistances to phenicols, quinolones and tetracycline drugs used in aquaculture. In addition, the pathogenic A. venetianus could be effectively controlled by Bdellovibrio powder at 0.8 mg L−1, which exhibited significant antibacterial effect and displayed good protection against A. venetianus challenge in P. vannamei for six days. As far as we know, this is the first study to identify A. venetianus as a potential bacterial pathogen of red leg disease in freshwater-farmed whiteleg shrimp.

Abstract The chemokine receptor CXCR4 mediates cell anchorage in the bone marrow (BM) microenvironment and is overexpressed in 25–30% of patients with acute myeloid leukemia (AML). Here we have shown that a new CXCR4 receptor antagonist IgG1 antibody (PF-06747143) binds strongly to AML cell lines and to AML primary cells inhibiting their chemotaxis in response to CXCL12. PF-06747143 also induced cytotoxicity in AML cells via Fc-effector function. To characterize the effects of PF-06747143 on leukemia progression, we used two different patient-derived xenograft (PDX) models: Patient 17CXCR4-low and P15CXCR4-high models, characterized by relatively low and high CXCR4 expression, respectively. Weekly administration of PF-06747143 to leukemic mice significantly reduced leukemia development in both models. Secondary transplantation of BM cells from PF-06747143-treated or IgG1 control-treated animals showed that leukemic progenitors were also targeted by PF-06747143. Administration of a single dose of PF-06747143 to PDX models induced rapid malignant cell mobilization into the peripheral blood (PB). These findings support evaluation of this antibody in AML therapy, with particular appeal to patients resistant to chemotherapy and to unfit patients, unable to tolerate intensive chemotherapy.

Abstract: The chemokine receptor CXCR4 is highly expressed and associated with poor prognosis in multiple malignancies. Upon engagement by its ligand, CXCL12, CXCR4 triggers intracellular signaling pathways that control trafficking of cells to tissues where the ligand is expressed, such as the bone marrow (BM). In hematologic cancers, CXCR4-driven homing of malignant cells to the BM protective niche is a key mechanism driving disease and therapy resistance. We developed a humanized CXCR4 immunoglobulin G1 (IgG1) antibody (Ab), PF-06747143, which binds to CXCR4 and inhibits CXCL12-mediated signaling pathways, as well as cell migration. In in vivo preclinical studies, PF-06747143 monotherapy rapidly and transiently mobilized cells from the BM into the peripheral blood. In addition, PF-06747143 effectively induced tumor cell death via its Fc constant region–mediated effector function. This Fc-mediated cell killing mechanism not only enhanced antitumor efficacy, but also played a role in reducing the duration of cell mobilization, when compared with an IgG4 version of the Ab, which does not have Fc-effector function. PF-06747143 treatment showed strong antitumor effect in multiple hematologic tumor models including non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), and multiple myeloma (MM). Importantly, PF-06747143 synergized with standard-of-care agents in a chemoresistant AML patient-derived xenograft model and in an MM model. These findings suggest that PF-06747143 is a potential best-in-class anti-CXCR4 antagonist for the treatment of hematologic malignancies, including in the resistant setting. PF-06747143 is currently in phase 1 clinical trial evaluation (registered at www.clinicaltrials.gov as #NCT02954653).

Abstract Background The CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow. Therefore, we hypothesized that targeting CXCR4 with an IgG1 antibody, PF-06747143, may constitute an effective therapeutic approach for CLL. Methods Patient-derived primary CLL-B cells were assessed for cytotoxicity in an in vitro model of CLL microenvironment. PF-06747143 was analyzed for cell death induction and for its potential to interfere with the chemokine CXCL12-induced mechanisms, including migration and F-actin polymerization. PF-06747143 in vivo efficacy was determined in a CLL murine xenograft tumor model. Results PF-06747143, a novel-humanized IgG1 CXCR4 antagonist antibody, induced cell death of patient-derived primary CLL-B cells, in presence or absence of stromal cells. Moreover, cell death induction by the antibody was independent of CLL high-risk prognostic markers. The cell death mechanism was dependent on CXCR4 expression, required antibody bivalency, involved reactive oxygen species production, and did not require caspase activation, all characteristics reminiscent of programmed cell death (PCD). PF-06747143 also induced potent B-CLL cytotoxicity via Fc-driven antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity activity (CDC). PF-06747143 had significant combinatorial effect with standard of care (SOC) agents in B-CLL treatment, including rituximab, fludarabine (F-ara-A), ibrutinib, and bendamustine. In a CLL xenograft model, PF-06747143 decreased tumor burden and improved survival as a monotherapy, and in combination with bendamustine. Conclusions We show evidence that PF-06747143 has biological activity in CLL primary cells, supporting a rationale for evaluation of PF-06747143 for the treatment of CLL patients.

A separated foundation model was proposed in order to reduce the calculation scale of the numerical model for analyzing soil-bridge structure dynamics. The essence of the wave input analysis model considering soil-structure interaction was analyzed. Based on the large mass method, a one-dimensional time-domain algorithm of the free field was derived. This algorithm could simulate the specified ground motion input well. The displacement expansion solution of the free wave field was solved based on the propagation law of waves in a medium. By separating the soil foundations around the pile foundations of the bridge, the ground motion was transformed into an equivalent load applied on an artificial boundary. The separated foundation model could consider the incoherence effect and soil-structure interaction simultaneously; the number of model elements were reduced, and the computational efficiency was improved. In order to investigate the seismic response of a curved bridge considering soil-structure interaction under spatially varied earthquakes, a curved bridge with small radius was adopted in practical engineering. Spatially correlated multi-point ground motion time histories were generated, and the nonuniform ground motion field was simulated based on the wave input method on an artificial viscoelastic boundary. The effects of different apparent wave velocities, coherence values, and site conditions on the seismic response of the bridge were analyzed. The results showed that the spatial variation of seismic ground motion had a considerable effect on the bending moment and the torsion of the girder. The site effect had great influence on the bending moment of the pier bottom. When considering soil-structure interaction, the spatial variation of ground motion should be fully considered to avoid underestimating the structural response.

PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) mutations can help predict the antitumor activity of phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway inhibitors in both preclinical and clinical settings. In light of the recent discovery of tumor-initiating cancer stem cells (CSCs) in various tumor types, we developed an in vitro CSC model from xenograft tumors established in mice from a colorectal cancer patient tumor in which the CD133+/EpCAM+ population represented tumor-initiating cells. CD133+/EpCAM+ CSCs were enriched under stem cell culture conditions and formed 3-dimensional tumor spheroids. Tumor spheroid cells exhibited CSC properties, including the capability for differentiation and self-renewal, higher tumorigenic potential and chemo-resistance. Genetic analysis using an OncoCarta™ panel revealed a PIK3CA (H1047R) mutation in these cells. Using a dual PI3K/mTOR inhibitor, PF-04691502, we then showed that blockage of the PI3K/mTOR pathway inhibited the in vitro proliferation of CSCs and in vivo xenograft tumor growth with manageable toxicity. Tumor growth inhibition in mice was accompanied by a significant reduction of phosphorylated Akt (pAKT) (S473), a well-established surrogate biomarker of PI3K/mTOR signaling pathway inhibition. Collectively, our data suggest that PF-04691502 exhibits potent anticancer activity in colorectal cancer by targeting both PIK3CA (H1047R) mutant CSCs and their derivatives. These results may assist in the clinical development of PF-04691502 for the treatment of a subpopulation of colorectal cancer patients with poor outcomes.

PURPOSE Non-invasive methods for predicting pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) can provide distinct leverage in the management of patients with locally advanced rectal cancer (LARC). This study aimed to investigate whether including the golden- angle radial sparse parallel (GRASP) dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion parameter (Ktrans), in addition to tumor regression grading (TRG) and apparent diffusion coefficient (ADC) values, can improve the predictive ability for pCR. METHODS Patients with LARC who underwent nCRT and subsequent surgery were included. The imaging parameters were compared between patients with and without pCR. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive ability of these parameters for pCR. RESULTS A total of 111 patients were included in the study. A pCR was obtained in 32 patients (28.8%). MRIbased TRG (mrTRG) showed a negative correlation with pCR (r = -0.61, P < 0.001), and the average ADC value showed a positive correlation with pCR (r = 0.62, P < 0.001). Before nCRT, Ktrans in the pCR group was significantly higher than in the non-pCR group (1.30 ± 0.24 vs. 0.88 ± 0.34, P < 0.001), but no difference was identified after nCRT. Following ROC curve analysis, the area under the curve (AUC) of mrTRG (level 1-2), average ADC value, and Ktrans value for predicting pCR were 0.738 [95% confidence interval (CI): 0.65-0.82], 0.78 (95% CI: 0.69-0.86), and 0.84 (95% CI: 0.77-0.92), respectively. The model combining the three parameters had significantly higher predictive ability for pCR (AUC: 0.94, 95% CI: 0.88-0.98). CONCLUSION The use of a combination of the GRASP DCE-MRI Ktrans with mrTRG and ADC can lead to a better pCR predictive performance. [ABSTRACT FROM AUTHOR]

Background: Childhood obesity tends to persist into adulthood, predisposing individuals to cardiometabolic risk (CMR). This study aims to investigate the mediating role of cardiorespiratory fitness (CRF) in the associations between multiple fatness indicators and individual CMR markers and clustered CMRscore, and explore sex differences. Methods: We recruited 1,557 children (age: 8 to 10, male/female: 52.7%/ 47.3%) in September 2022 in Ningbo, China. Physical examinations, overnight fasting blood test, and CRF was evaluated. The CMR-score was calculated by summing age- and sex-specific z scores of four CMRmarkers, including mean arterial blood pressure, triglycerides, the total cholesterol to high-density lipoprotein cholesterol ratio, and homeostatic model assessment for insulin resistance. Generalized linear mixed models were used to identify the associations, mediation analyses were performed to dissect the function of CRF. Results: Partial correlation analyses revealed positive associations between high fatness indicators (including body mass index [BMI], BMI z score, body fat mass index [BFMI] and waist-to-height ratio [WHtR]) and increased CMR markers, whereas high CRF was associated with decreased CMR markers (all P < 0.05). In the mediation analyses, CRF emerged as a partial mediator, attenuating the relationship between four fatness indicators and CMR-score. Specifically, CRF mediated 6.5%, 7.7%, 5.3%, and 12.5% of the association between BMI, BMI z score, BFMI, WHtR and CMR-score (all P < 0.001). And the mediating effects of CRF between WHtR and four individual CMR markers was particularly robust, ranging from 10.4% to 21.1% (all P < 0.05). What's more, CRF mediates the associations between WHtR and CMR-score more pronounced in girls than boys with a mediation effect size of 17.3% (P < 0.001). Conclusion: In Chinese children, CRF partially mitigates the adverse effects of fatness on CMR, underscoring the significance of enhancing CRF in children. [ABSTRACT FROM AUTHOR]

ERK1/2 is a key protein that mediates cell signal transduction, and it is involved in regulating biological processes such as chromatin remodeling, nuclear disintegration, proliferation, survival, metabolism, and cell migration and differentiation. Its overactivation is closely related to the occurrence and progression of cancer, and the mechanism is manifested as the overactivation of ERK1/2 by gene mutations of upstream pathway molecules or regulators and the reactivation of ERK1/2 after inhibition against the above targets. ERK1/2 is a potentially valuable target. In this review, the mechanism of post-translational modification and spatial regulation of ERK1/2 and the application status of corresponding small-molecule inhibitors were discussed. The current antitumor strategy of targeting and regulating ERK1/2 was summarized, and the possibility of exploring potential targets was elucidated, thus providing new insights into the developmental research of ERK1/2 as an ideal anticancer target.

Background: Primary Sjogren's syndrome (pSS) is a common chronic autoimmune disease that presents limited treatment options and poses significant challenges for patients. Maidong Dishao Decoction (MDDST), a traditional Chinese medicine compound, has demonstrated potential in alleviating dryness symptoms associated with pSS. Therefore, it is important to study the specific mechanism of its therapeutic effect. Objective: This study aims to investigate the effects of MDDST on gut microbiota, short-chain fatty acids (SCFAs), and the Th17/Treg immune balance in non-obese diabetes (NOD) mice. Methods: The study employed ultrahigh-performance liquid chromatography coupled with quadrupole-exactive mass spectrometry (UHPLC-QE-MS) to identify the primary components of MDDST. Subsequently, hematoxylin and eosin (HE) staining, enzyme-linked immunosorbent assays (ELISA), and flow cytometry analyses were conducted to evaluate the therapeutic effects of MDDST in NOD mice. Additionally, 16S rDNA sequencing and gas chromatography-mass spectrometry (GC-MS) were utilized to assess the influence of MDDST on gut microbiota and SCFAs. Finally, fecal microbiota transplantation (FMT) and SCFA-based interventions were performed to elucidate the mechanisms through which MDDST exerts its effects. Results: The research findings demonstrate that MDDST exerts therapeutic effects on NOD mice, primarily manifested as reduced inflammation, decreased water intake, ameliorated pathological changes and lowered levels of Sjogren's syndrome antigen A (SSA) and immunoglobulin G (IgG). Additionally, MDDST significantly decreased serum levels of interleukin-6 (IL-6) and interleukin-17 (IL-17), while enhancing levels of interleukin-10 (IL-10) and transforming growth factor beta (TGF-β), thereby regulating the Th17/Treg immune balance. Further investigations revealed that MDDST treatment induces alterations in gut microbiota composition and elevates SCFA levels in the gut. Subsequent FMT and SCFA intervention experiments demonstrated a downregulation of pSS-related phenotypes. Conclusion: In summary, MDDST demonstrates protective effects against pSS by restoring the balance between Th17 and Treg cells. The therapeutic effects can be partially attributed to its regulation of gut microbiota and SCFAs. Our finding provides a new option for treating pSS.

BackgroundLow levels of physical activity (PA) are prevalent among children with intellectual and developmental disabilities (IDD). Implementing family-based physical activities as extracurricular interventions offers a promising approach to enhancing their PA levels and promoting overall health.PurposeThis study aims to explore a novel integrative strategy by combining family-based activities with school physical education classes, with the objective of enhancing PA levels and improving the quality of life (QoL) for children with IDD. Methods: A total of 36 children with IDD (mean age = 16.4 years) were randomly assigned to a 6-month intervention group (IG) or a control group (CG). Both groups received adjusted adaptive physical education, while the IG received additional family support. Assessments of PA, QoL, and the Physical Activity Enjoyment Scale (PACES) were conducted at baseline, after 6 months, and at a 2-month follow-up post-intervention.ResultsThe 6-month intervention results showed that the IG had a significant increase in moderate to vigorous physical activity (MVPA) compared to the CG (p

PurposeSleep disturbances are prevalent in autistic children. The emergence of telehealth offers new possibilities for remote professional intervention. By combining telehealth with parental support, this study aims to explore a novel family-based model to enhance moderate-to-vigorous physical activity (MVPA) and improve sleep quality in children with autism.MethodsThirty-four autistic children (mean age = 15.7 years) were randomly assigned to either a 6-month intervention group or a control group. Both groups received standard physical education classes at school. The intervention group received additional after-school telehealth support. MVPA and sleep quality were assessed 1 week before the intervention and at the 6-month follow-up.ResultsAfter 6 months, children in the intervention group nearly doubled their daily MVPA compared to the control group (Cohen's d = 8.34, CI95% = 6.17–10.52). Actigraphy-assessed sleep efficiency was notably higher (d = 2.35, CI95% = 1.44–3.26), and there were reductions in wake time (d = 1.65, CI95% = 0.84–2.46), sleep fragmentation (d = 0.80, CI95% = 0.07–1.52), and sleep latency (d = 0.82, CI95% = 0.09–1.54) were all reduced. These improvements in objective sleep metrics were corroborated by subjective assessments using the Sleep Disturbance Scale for Children (d = 0.86, CI95% = 0.13–1.59).ConclusionsTelehealth combined with parental support addresses barriers to enhancing health behaviors at home. This innovative model not only improves after-school MVPA and sleep quality in autistic children but also holds significant potential for benefiting other populations requiring remote support.Clinical Trial Registrationhttps://clinicaltrials.gov/study/NCT06444659?id=NCT06444659&rank=1 (NCT06444659).

Abstract Background Breast cancer is the most prevalent malignant tumor among women, with hormone receptor-positive cases constituting 70%. Fulvestrant, an antagonist for these receptors, is utilized for advanced metastatic hormone receptor-positive breast cancer. Yet, its inhibitory effect on tumor cells is not strong, and it lacks direct cytotoxicity. Consequently, there's a significant challenge in preventing recurrence and metastasis once cancer cells develop resistance to fulvestrant. Method To address these challenges, we engineered tumor-targeting nanoparticles termed 131I-fulvestrant-ALA-PFP-FA-NPs. This involved labeling fulvestrant with 131I to create 131I-fulvestrant. Subsequently, we incorporated the 131I-fulvestrant and 5-aminolevulinic acid (ALA) into fluorocarbon nanoparticles with folate as the targeting agent. This design facilitates a tri-modal therapeutic approach—endocrine therapy, radiotherapy, and PDT for estrogen receptor-positive breast cancer. Results Our in vivo and in vitro tests showed that the drug-laden nanoparticles effectively zeroed in on tumors. This targeting efficiency was corroborated using SPECT-CT imaging, confocal microscopy, and small animal fluorescence imaging. The 131I-fulvestrant-ALA-PFP-FA-NPs maintained stability and showcased potent antitumor capabilities due to the synergism of endocrine therapy, radiotherapy, and CR-PDT. Throughout the treatment duration, we detected no notable irregularities in hematological, biochemical, or histological evaluations. Conclusion We've pioneered a nanoparticle system loaded with radioactive isotope 131I, endocrine therapeutic agents, and a photosensitizer precursor. This system offers a combined modality of radiotherapy, endocrine treatment, and PDT for breast cancer. Graphical Abstract

Abstract Objective Rheumatoid arthritis (RA) is a chronic inflammatory arthritis. This study aimed to identify potential biomarkers and possible pathogenesis of RA using various bioinformatics analysis tools. Methods The GMrepo database provided a visual representation of the analysis of intestinal flora. We selected the GSE55235 and GSE55457 datasets from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) separately. With the intersection of these DEGs with the target genes associated with RA found in the GeneCards database, we obtained the DEGs targeted by RA (DERATGs). Subsequently, Disease Ontology, Gene Ontology, and the Kyoto Encyclopedia of Genes and Genomes were used to analyze DERATGs functionally. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were performed on the data from the gene expression matrix. Additionally, the protein-protein interaction network, transcription factor (TF)-targets, target-drug, microRNA (miRNA)-mRNA networks, and RNA-binding proteins (RBPs)-DERATGs correlation analyses were built. The CIBERSORT was used to evaluate the inflammatory immune state. The single-sample GSEA (ssGSEA) algorithm and differential analysis of DERATGs were used among the infiltration degree subtypes. Results There were some correlations between the abundance of gut flora and the prevalence of RA. A total of 54 DERATGs were identified, mainly related to immune and inflammatory responses and immunodeficiency diseases. Through GSEA and GSVA analysis, we found pathway alterations related to metabolic regulations, autoimmune diseases, and immunodeficiency-related disorders. We obtained 20 hub genes and 2 subnetworks. Additionally, we found that 39 TFs, 174 drugs, 2310 miRNAs, and several RBPs were related to DERATGs. Mast, plasma, and naive B cells differed during immune infiltration. We discovered DERATGs’ differences among subtypes using the ssGSEA algorithm and subtype grouping. Conclusions The findings of this study could help with RA diagnosis, prognosis, and targeted molecular treatment.

Abstract Background To investigate the regulatory role of microRNA (miR)-148a-3p in mouse corpus cavernous pericyte (MCPs)-derived extracellular vesicles (EVs) in the treatment of diabetes-induced erectile dysfunction (ED). Methods Mouse corpus cavernous tissue was used for MCP primary culture and EV isolation. Small-RNA sequencing analysis was performed to assess the type and content of miRs in MCPs-EVs. Four groups of mice were used: control nondiabetic mice and streptozotocin-induced diabetic mice receiving two intracavernous injections (days − 3 and 0) of phosphate buffered saline, MCPs-EVs transfected with reagent control, or MCPs-EVs transfected with a miR-148a-3p inhibitor. miR-148a-3p function in MCPs-EVs was evaluated by tube-formation assay, migration assay, TUNEL assay, intracavernous pressure, immunofluorescence staining, and Western blotting. Results We extracted EVs from MCPs, and small-RNA sequencing analysis showed miR-148a-3p enrichment in MCPs-EVs. Exogenous MCPs-EV administration effectively promoted mouse cavernous endothelial cell (MCECs) tube formation, migration, and proliferation, and reduced MCECs apoptosis under high-glucose conditions. These effects were significantly attenuated in miR-148a-3p-depleted MCPs-EVs, which were extracted after inhibiting miR-148a-3p expression in MCPs. Repetitive intracavernous injections of MCPs-EVs improved erectile function by inducing cavernous neurovascular regeneration in diabetic mice. Using online bioinformatics databases and luciferase report assays, we predicted that pyruvate dehydrogenase kinase-4 (PDK4) is a potential target gene of miR-148a-3p. Conclusions Our findings provide new and reliable evidence that miR-148a-3p in MCPs-EVs significantly enhances cavernous neurovascular regeneration by inhibiting PDK4 expression in diabetic mice.

The International Classification of Functioning, Disability, and Health (ICF) offers a comprehensive bio-psycho-social model for evaluating the multifaceted needs of individuals with disabilities. While its adoption in healthcare settings is widespread, its utilization within the domain of physical activity interventions, particularly for adolescents with intellectual disabilities (IDs), remains insufficiently explored. This study rigorously examines the efficacy of a 6-month ICF-based Adaptive Physical Activity (APA) intervention on the development of fundamental motor skills (FMSs), improvements in physical fitness (PF), and enhancements in quality of life (QoL) among adolescents with ID. A total of thirty-eight adolescents were randomly allocated into either an intervention group (IG), which participated in the tailored APA program, or a control group (CG), which received standard physical education. The findings demonstrated statistically significant improvements in the IG’s test of gross motor development (TGMD) total, locomotor, object control, and QOL scores relative to the CG (p < 0.001, η² = 0.330, 0.249, 0.224, and 0.439, respectively). Furthermore, substantial gains were observed in PF measures, including upper and lower limb strength as well as cardiorespiratory fitness (p < 0.001, η² = 0.254, 0.351, 0.176). Strong positive correlations were noted between FMS, PF, and QoL (r = 0.34–0.71, p < 0.05). This study underscores the importance of tailoring physical activity programs for adolescents with ID, offering insights into the relationships between FMS, PF, and QoL, and guidance for future interventions aimed at improving health outcomes in this population.

The popularization of recycled concrete (RC) is an important way to achieve efficient resource utilization of construction solid waste (CSW), which can coordinate the sustainable economic development with environmental protection. In this paper, CiteSpace software is used to quantitatively analyze the literatures on RC field, identifying its research hotspots and recent developments. Based on the Web of Science database, we screened published literatures in the field of RC from 2004 to 2023, and obtained 2011 articles. CiteSpace software and knowledge graph technology are adopted to visually analyze the literature information, including the collaborators, keywords and citation status. The results show that, Xiao JZ from Tongji University, Poon CS from Hong Kong Polytechnic University and Tam VWY from University of Western Sydney publish a large number of articles and are frequently cited. It indicates that their researches are widely recognized in academic circles. There is a research team with a large size formed in the Chinese mainland, and the core members include Xiao JZ, Li WG, Chen ZP. At present, the research interest gradually shifts from recycled coarse aggregate to recycled fine aggregate, mainly focusing on microscale research of pore structure and interfacial transition zone. In addition, 8 co-citation clusters of selected references and the potential development trends are detailly analyzed. This study is helpful for researchers to fully understand the current hotspots and future research trends in the field of RC.

In the process of developing clinical practice guidelines, consensus method is essential to determine clinical problems and recommendations, among which Delphi method and modified Delphi method are the most common. Therefore, scientific and standardized application of Delphi method to reach a consensus (such as expert selection, process design) has become an important topic in urgent need of study. In the process of using Delphi method, it is necessary to refer to mature methodological suggestions to make theconsensus process structured and transparent. This article focuses on the key elements of Delphi method in the development of clinical practice guidelines, and elaborates its basic methods and processes, including the number, composition, standards and selection methods of the 'expert group', as well as the key points of patients' participation. In terms of technical points, anonymity, consensus threshold and time control are described. Furthermore, the limitations of Delphi method and the highlights of the report are presented, in order to promote the standardized application of Delphi method in the development of the guidelines.