Local Response Research Articles

Modulation effects of pressing manipulation on local inflammatory responses and ERK/NF-κB pathway in trigger point model rats

Modulation effects of pressing manipulation on local inflammatory responses and ERK/NF-κB pathway in trigger point model rats

Spatially Resolved Temperature Response Functions to CO2 Emissions

AbstractCarbon dioxide (CO2) emissions affect local temperature; quantifying that local response is important for learning about the earth system, the impacts of mitigation, and adaptation needs. We assume the climate system can be represented as a time‐dependent linear system, diagnosing Green's Functions for the spatial temperature response to CO2 emissions based on CMIP6 earth system models. This allows us to emulate the linear component of the temperature response to CO2. This approach is sufficient to capture the spatial temperature response of CMIP6 experiments within one standard deviation of the multimodel spread across most regions, though accuracy is lower in the Southern Ocean and the Arctic. Our approach reveals where nonlinear feedbacks are important in current CMIP6 models, and where the local system response is well represented by a time‐dependent linear differential operator. It incorporates emissions path dependency and may be useful for evaluating large ensembles of emission scenarios.

Comparative Genomics Screens Identify a Novel Small Secretory Peptide, SlSolP12, which Activates Both Local and Systemic Immune Response in Tomatoes and Exhibits Broad-Spectrum Activity.

Small secreted peptides (SSPs) are essential for defense mechanisms in plant-microbe interactions, acting as danger-associated molecular patterns (DAMPs). Despite the first discovery of SSPs over three decades ago, only a limited number of SSP families, particularly within Solanaceae plants, have been identified due to inefficient approaches. This study employed comparative genomics screens with Solanaceae proteomes (tomato, tobacco, and pepper) to discover a novel SSP family, SolP. Bioinformatics analysis suggests that SolP may serve as an endogenous signal initiating the plant PTI response. Interestingly, SolP family members from tomato, tobacco, and pepper share an identical sequence (VTSNALALVNRFAD), named SlSolP12 (also referred to as NtSolP15 or CaSolP1). Biochemical and phenotypic analyses revealed that synthetic SlSolP12 peptide triggers multiple defense responses: ROS burst, MAPK activation, callose deposition, stomatal closure, and expression of immune defense genes. Furthermore, SlSolP12 enhances systemic resistance against Botrytis cinerea infection in tomato plants and interferes with classical peptides, flg22 and Systemin, which modulate the immune response. Remarkably, SolP12 activates ROS in diverse plant species, such as Arabidopsis thaliana, soybean, and rice, showing a broad spectrum of biological activities. This study provides valuable approaches for identifying endogenous SSPs and highlights SlSolP12 as a novel DAMP that could serve as a useful target for crop protection.

Mechanisms of Gut-Related Viral Persistence in Long COVID.

Long COVID (post-acute sequelae of COVID-19-PASC) is a consequence of infection by SARS-CoV-2 that continues to disrupt the well-being of millions of affected individuals for many months beyond their first infection. While the exact mechanisms underlying PASC remain to be defined, hypotheses regarding the pathogenesis of long COVID are varied and include (but are not limited to) dysregulated local or systemic inflammatory responses, autoimmune mechanisms, viral-induced hormonal imbalances, skeletal muscle abnormalities, complement dysregulation, novel abzymes, and long-term persistence of virus and/or fragments of viral RNA or proteins. This review article is based on a comprehensive review of the wide range of symptoms most often observed in long COVID and an attempt to integrate that information into a plausible hypothesis for the pathogenesis of PASC. In particular, it is proposed that long-term dysregulation of the gut in response to viral persistence could lead to the myriad of symptoms observed in PASC.

Association between COVID-19 Severity and Expression of Viral Nucleic Acid Sensor Genes in Peripheral Blood Mononuclear Cells and Nasopharyngeal Epithelial Cells.

This study examined expression of key viral nucleic acid sensor genes MDA5, ZBP1, and AIM2 in nasopharyngeal epithelial cells and peripheral blood mononuclear cells (PBMCs) obtained from 153 COVID-19 patients across a spectrum of disease severity (mild, severe, and critical) and 42 healthy controls. Quantitative reverse transcription polymerase chain reaction was used to quantify and compare sensor transcript levels. The COVID-19 cohort had a mean age of 53.6 years. All three sensor genes including MDA5 (3.2-fold), ZBP1 (5.1-fold), and AIM2 (4.7-fold) exhibited significantly higher messenger RNA expression in both nasopharyngeal and PBMC samples from infected patients compared with healthy controls. Furthermore, sensor transcript upregulation positively correlated with escalating disease severity. During early stages, ZBP1 and AIM2 transcripts were selectively elevated within the nasopharyngeal compartment, suggesting a localized antiviral response. Whereas later during critical disease stages, ZBP1 and AIM2 levels became preferentially heightened within circulating PBMCs, indicating systemic immune cell activation. By comparison, MDA5 elevation manifested within nasopharyngeal epithelial cells during both early- and late-phase infection. Intriguingly, males displayed higher ZBP1 and AIM2 expression compared with females, whereas MDA5 transcript levels were conversely higher among females. Overall, escalation of these key viral sensor genes appears closely linked to COVID-19 progression, with initial nasal mucosal upregulation transitioning to widespread blood cell activation in severe systemic disease. These patterns of sensor expression suggest frontline immunological efforts to constrain early viral invasion and combat severe late-stage COVID-19 illness through innate detection of replicating SARS-CoV-2.

Estimating bridge stress histories at remote locations from vibration sparse monitoring

Structural health monitoring with accelerometers provides notable benefits over strain gauges, particularly in installation time and cost efficiency. However, effective local damage assessment necessitates access to local stress histories. This paper proposes a methodology that integrates two distinct approaches to identify and predict stress and strain across various bridge locations from sparse monitoring via acceleration data. The proposed model is validated using strain histories and accelerations collected from the composite railway Bryngeån Bridge in Sweden during its in-service conditions. Initially, a deep learning algorithm for sequence data is employed to forecast strain histories from acceleration data gathered across various bridge locations. Subsequently, the local response function method is implemented, utilizing experimental data collected from the bridge and employing localized models of its substructures, allowing predictions of the bridge’s local strain. By integrating these methods, the approach enables accurate prediction of stress ranges and cycles for critical non-instrumented parts, minimizing the need for extensive direct instrumentation and providing a cost-effective, efficient solution for operational structural health monitoring.

Evaluation study of the urban governance of the COVID-19 crisis in the city of Antwerp

BackgroundThe COVID-19 pandemic has demanded crisis management at all governance levels. While most research has focused on responses of national governments, city-level governance had significant potential to develop tailored approaches. This study explored how the local COVID-19 response was organised and adapted to the specific city population and context in the City of Antwerp, Belgium.MethodsA case study using semi-structured interviews was set up with 20 key informants with a central role in the coordination and implementation of the city-level COVID-19 response in Antwerp. Thematic analysis of transcripts was guided by an adapted version of the OECD risk management cycle.ResultsRespondents’ accounts provide a granular understanding of pandemic preparedness, crisis management, and response and adaptation to the COVID-19 crisis in a mid-size European city. Its size was large enough to have a strong capacity within its government bodies, to utilise the expertise of strong partners in the area and to mobilise a critical mass for action, yet small enough to quickly establish connections and trust. In addition to a universal approach, they developed tailored responses to specific neighbourhoods and groups. Well-established community and organisational ties enhanced the effectiveness of grassroots initiatives. The perceived feeling of joint action contributed to a strong collective agency, but respondents noted the need for a system for monitoring and learning.ConclusionsLocal governments are important to develop tailored strategies and organise a locally relevant crisis response in cities. They need expertise and agency, with enough flexibility to experiment. To harness promising practices and avoid repeating errors in future crises, it is crucial to develop a system that better evaluates and monitors local responses, before, during and after crises.

Mechanically induced M2 macrophages are involved in bone remodeling of the midpalatal suture during palatal expansion

BackgroundPalatal expansion is a common way of treating maxillary transverse deficiency. Under mechanical force, the midpalatal suture is expanded, causing local immune responses. This study aimed to determine whether macrophages participate in bone remodeling of the midpalatal suture during palatal expansion and the effects on bone remodeling.MethodsPalatal expansion model and macrophage depletion model were established. Micro-CT, histological staining, and immunohistochemical staining were used to investigate the changes in the number and phenotype of macrophages during palatal expansion as well as the effects on bone remodeling of the midpalatal suture. Additionally, the effect of mechanically induced M2 macrophages on palatal osteoblasts was also elucidated in vitro.ResultsThe number of macrophages increased significantly and polarized toward M2 phenotype with the increase of the expansion time, which was consistent with the trend of bone remodeling. After macrophage depletion, the function of osteoblasts and bone formation at the midpalatal suture were impaired during palatal expansion. In vitro, conditioned medium derived from M2 macrophages facilitated osteogenic differentiation of osteoblasts and decreased the RANKL/OPG ratio.ConclusionsMacrophages through polarizing toward M2 phenotype participated in midpalatal suture bone remodeling during palatal expansion, which may provide a new idea for promoting bone remodeling from the perspective of regulating macrophage polarization.

Epidemic influenza virus nucleoprotein gene incorporated into vaccine influenza virus strain genome to optimize systemic and local T-cell immune response against live attenuated influenza vaccine

Introduction. Optimization of the vaccine-induced T-cell repertoire is one of the strategies to expand the spectrum of protective potential for live attenuated influenza vaccine (LAIV). LAIV cross-protective properties can be improved by introducing the nucleoprotein (NP) gene derived from epidemic parental virus into vaccine strain genome, i.e. by replacing the classical 6:2 genome formula with 5:3. The main objective of the present study was to detail evaluation for virus-specific systemic and tissue-resident memory T-cells subsets in mice immunized with seasonal H1N1 LAIV of the genome formula 6:2 and 5:3. Materials and methods. Two H1N1 LAIV strains with varying NP genes (LAIV 6:2 and LAIV 5:3) were generated using reverse genetics techniques. C57BL/6J mice were immunized intranasally with the vaccine candidates, twice, 3 weeks apart. Cells from the spleen and lung tissues were isolated 7 days after booster immunization to be stimulated with whole H1N1 influenza virus for assessing cytokine-producing memory CD44+CD62L– T-cells as well as expression of CD69 and CD103 surface markers using flow cytometry. Humoral murine serum immunity against H1N1 virus was assessed by ELISA. Results. The LAIV 5:3 vs classical 6:2 vaccine strain carrying the epidemic parental NP gene induced significantly more pronounced humoral immune response against recent influenza virus. The group of mice immunized with LAIV 5:3 demonstrated higher levels of virus-specific CD4+ and CD8+ effector memory T cells (TEM) in the spleen, including a subset of polyfunctional (IFNγ+TNFα+IL-2+) CD4+ TEM, compared to LAIV 6:2 group. Virus-specific memory T cell levels in lung tissues after immunization with LAIV 5:3 vs LAIV 6:2 also tended to increase, but no significant difference in stimulated tissue-resident CD69+CD103– and CD69+CD103+ T cells between the groups were found. Conclusion. Modification of the seasonal LAIV strain genome for updating its epitope composition allowed to enhance the virus-specific T-cell immune response both at systemic level and in lung tissues, thereby shoeing that the effectiveness of the vaccine against circulating influenza viruses can be potentially increased.

Assessing the Impacts of Falling Ice Radiative Effects on the Seasonal Variation of Land Surface Properties

AbstractThe impacts of falling ice radiative effects (FIREs) on land‐atmosphere feedback processes were examined, with a focus on the fidelity of land surface properties and their variability as inferred by global climate models (GCMs). We conducted a pair of sensitivity experiments using the National Center for Atmospheric Research (NCAR) Community Earth System Model Version 1 (CESM1) in fully coupled modes with FIREs turned on and off. This allowed us to investigate the seasonal response of land surface properties to changes in radiation fluxes and land surface temperature (LST) associated with FIREs across global land areas. Our findings indicate that during boreal winter, excluding FIREs results in less surface downward longwave and net flux (∼5–15 Wm−2), leading to a colder land surface (∼2–4 K) and air temperatures (∼1–4 K) at mid‐ and high latitudes. Consequently, the surface frozen soil layer and snow cover persist through spring, delaying snowmelt and thawing until summer. This delay reduces liquid soil moisture, thereby suppressing vegetation productivity in subsequent seasons. Conversely, tropical regions, exhibit contrasting responses, with a warmer land surface (∼0.5 K) and warmer air temperatures (∼0.1–0.5 K) due to increased surface downward shortwave and net flux (∼2–10 Wm−2). This enhancement in radiation fosters increased vegetation productivity throughout the seasonal cycle. These findings illustrate a local response of land surface properties to changes in the surface energy balance and LST, highlighting the significant role that FIREs play in land surface modeling within GCMs.

Retailer Responses to Public Consultations on the Adoption of Takeaway Management Zones Around Schools: A Longitudinal Qualitative Analysis

Background: Takeaway food is often high in calories and served in portion sizes that exceed public health recommendations for fat, salt and sugar. This food is widely accessible in the neighbourhood food environment. As of 2019, of all local authorities in England (n=325), 41 had adopted urban planning-based interventions that can allow them to manage the opening of new takeaway outlets in ‘takeaway management zones around schools’ (known elsewhere as ‘exclusion zones’). Before adoption, local authorities undertake mandatory public consultation where responses objecting to proposals can be submitted. Evidence on common objections could be insightful for practitioners and policymakers considering this intervention. Methods: We included 41 local authorities that adopted a takeaway management zone around schools between 2009 and 2019. We identified and analysed objections to proposals submitted by or on behalf of food retailers and local authority responses to these. We used reflexive thematic analysis with a commercial determinants of health lens to generate themes, and investigated if and how objections and responses changed over time. Results: We generated four themes: The role of takeaways in obesity, Takeaway management zone adoption, Use and interpretation of evidence, and Managing external opinions. Despite not being implicated by the adoption of takeaway management zones around schools, planning consultants objected to proposals on behalf of transnational food retailers, however, independent takeaways did not respond. Objections attempted to determine the causes of poor diet and obesity, suggest alternative interventions to address them, undermine evidence justifying proposals, and influence perspectives about local authorities and their intervention. Objections consistently raised the same arguments, but over time became less explicit and expressed a willingness to partner with local authorities to develop alternative solutions. Conclusion: Objections to local authority proposals to adopt an urban planning intervention that can stop new takeaways opening near schools featured strategies used by other industries to delay or prevent population health intervention adoption. Practitioners and policymakers can use our findings when developing proposals for new takeaway management zones around schools. By using knowledge about their local context and addressing arguments against specific aspects of the intervention, they can pre-empt common objections.

Investigating grain-resolved evolution of lattice strains during plasticity and creep using 3DXRD and crystal plasticity modelling

Microstructure-informed crystal plasticity finite element models have shown great promise in predicting plastic and creep deformation in polycrystalline materials. These models can provide substantial insight into the design, fabrication and lifetime assessment of critical metallic components during operation, for instance, in thermal power plants. However, to correctly incorporate damage prediction into models, the microstructural strain simulated at the grain level must be accurately predicted with suitable validation. For this reason, a 3D X-ray Diffraction (3DXRD) experiment was carried out on 316H stainless steel, a material commonly used in thermal power plants, to obtain the per-grain strain response during plastic and creep deformation at 550°C. Several hundred grains within a probed X-ray volume were tracked and measured whilst loading in-situ, obtaining per-grain centre-of-mass positions, crystallographic orientations, and average lattice strain over individual grains. These data were used to calibrate a crystal plasticity model to study the plastic and creep deformation using macroscopic stress-strain and stress-relaxation data. Subsequently, the model was used to predict the average elastic strain in different grains during the cyclic creep experiment, which was validated by 3DXRD datasets. The model results reveal that {100} or {311} grain families are strongly sensitive to microstructure, thereby a polycrystal model that describes specific orientation and neighbourhood characteristics is essential to predict the local response of these grain families. Whereas, self-consistent models are suitable for {110} and {111} grain families. This study shows that only with a suitable calibration of subsurface grain behaviour, crystal plasticity models reveal grain characteristic-dependent micromechanical behaviour.

Multimodal mucosal and systemic immune characterization of a non-human primate trachoma model highlights the critical role of local immunity during acute phase disease.

Trachoma is a leading cause of infection-related blindness worldwide. This disease is caused by recurrent Chlamydia trachomatis (Ct) infections of the conjunctiva and develops in two phases: i) active (acute trachoma, characterized by follicular conjunctivitis), then long-term: ii) scarring (chronic trachoma, characterized by conjunctival fibrosis, corneal opacification and eyelid malposition). Scarring trachoma is driven by the number and severity of reinfections. The immune system plays a pivotal role in trachoma including exacerbation of the disease. Hence the immune system may also be key to developing a trachoma vaccine. Therefore, we characterized clinical and local immune response kinetics in a non-human primate model of acute conjunctival Ct infection and disease. The conjunctiva of non-human primate (NHP, Cynomolgus monkeys-Macaca fascicularis-) were inoculated with Ct (B/Tunis-864 strain, B serovar). Clinical ocular monitoring was performed using a standardized photographic grading system, and local immune responses were assessed using multi-parameter flow cytometry of conjunctival cells, tear fluid cytokines, immunoglobulins, and Ct quantification. Clinical findings were similar to those observed during acute trachoma in humans, with the development of typical follicular conjunctivitis from the 4th week post-exposure to the 11th week. Immunologic analysis indicated an early phase influx of T cells in the conjunctiva and elevated interleukins 4, 8, and 5, followed by a late phase monocytic influx accompanied with a decrease in other immune cells, and tear fluid cytokines returning to initial levels. Our NHP model accurately reproduces the clinical signs of acute trachoma, allowing for an accurate assessment of the local immune responses in infected eyes. A progressive immune response occurred for weeks after exposure to Ct, which subsided into a persistent innate immune response. An understanding of these local responses is the first step towards using the model to assess new vaccine and therapeutic strategies for disease prevention.

Safety and reactogenicity of a controlled human infection model of sand fly-transmitted cutaneous leishmaniasis.

The leishmaniases are globally important parasitic diseases for which no human vaccines are currently available. To facilitate vaccine development, we conducted an open-label observational study to establish a controlled human infection model (CHIM) of sand fly-transmitted cutaneous leishmaniasis (CL) caused by Leishmania major. Between 24 January and 12 August 2022, we exposed 14 participants to L. major-infected Phlebotomus duboscqi. The primary objective was to demonstrate effectiveness of lesion development (take rate) and safety (absence of CL lesion at 12 months). Secondary and exploratory objectives included rate of lesion development, parasite load and analysis of local immune responses by immunohistology and spatial transcriptomics. Lesion development was terminated by therapeutic biopsy (between days 14 and 42 after bite) in ten participants with clinically compatible lesions, one of which was not confirmed by parasite detection. We estimated an overall take rate for CL development of 64% (9/14). Two of ten participants had one and one of ten participants had two lesion recurrences 4-8 months after biopsy that were treated successfully with cryotherapy. No severe or serious adverse events were recorded, but as expected, scarring due to a combination of CL and the biopsy procedure was evident. All participants were lesion free at >12-month follow-up. We provide the first comprehensive map of immune cell distribution and cytokine/chemokine expression in human CL lesions, revealing discrete immune niches. This CHIM offers opportunities for vaccine candidate selection based on human efficacy data and for a greater understanding of immune-mediated pathology. ClinicalTrials.gov identifier: NCT04512742 .

Neurturin GF Enhances the Acute Cytokine Response of Inflamed Skin

Epidermal keratinocytes, immune cells and sensory nerves all contribute to immune balance and skin homeostasis. Keratinocyte release of growth factors, neuromodulators and immune activators is particularly important because each can evoke local (skin) and systemic (i.e., immune and neural) responses that can initiate and exacerbate skin pathophysiology. From studies of skin and neural growth factors, we hypothesized that neurturin (Nrtn), a member of the glial cell line-derived neurotrophic factor (GDNF) family that is expressed in skin, has particular importance in this process. Here we examine how elevation of Nrtn in skin keratinocytes impacts early cytokine expression in response to complete Freund's adjuvant (CFA)-mediated inflammation. Mice that overexpress Nrtn in keratinocytes (NrtnOE mice) and WT mice injected with Nrtn exhibit an enhanced level of TNFα and IL-1β cytokines in the skin, a response previously shown to support healing. In vitro assays suggest one source of the Nrtn-induced TNFα increase is from keratinocytes, which are shown to express Nrtn and mRNAs encoding the Nrtn receptors GFRα2, Ret, Itgβ1 and NCAM. These findings support the contribution of keratinocyte-derived Nrtn as an autocrine/paracrine factor that acts as a first line defense molecule that regulates the initial cytokine response to inflammatory challenge.

Long-term quality improvement in radiology specialty training at a tertiary cardiothoracic centre

ObjectivesThis quality improvement project (QIP) aimed to foster radiology training at a regional tertiary cardiothoracic centre that had very low trainee satisfaction rankings. MethodsTo study the problem and intervene timely, multiple methods were applied, including a local feedback survey, placement reorganisation, consultant encouragement to train as accredited supervisors, followed by departmental education portal creation and start of externally funded Visiting Fellowships and salaried Clinical Fellowships. The regional rating was monitored. The local feedback survey was distributed and analysed using descriptive statistics. Alongside the QIP, service expansion occurred. ResultsThe site regionally ranked 9/19 in 2 years. Local survey responses (53) showed continuous improvement; cardiothoracic subspecialty interest (+39%) and audit/academic involvement (+36%) increased. Multiple Fellowships were completed; internationally reputable placements were agreed upon. Most consultants trained as supervisors. Per increased demand, compulsory deanery posts were changed to motivation-based, and an additional salaried position was offered. Five fellows stayed in the region as subspecialist consultants. Unexpected challenges included space and workstation loss with service expansion, lack of regional surveys since 2019, and the global pandemic. Regardless, the results were positive with subspecialty interest and projected reputational effect increase. Local long-term survey provided sustainable data in detecting improvement areas. ConclusionsGiven the national radiologist shortage, this quality improvement project shows a possible positive impact of similar interventions, including workforce retention/recruitment and thus improving patient care. Advances in knowledgeContinuous feedback and quality improvement maintenance are valuable to enhance training quality locally and beyond.

Local intragraft humoral immune responses in chronic lung allograft dysfunction

IntroductionDonor human leukocyte antigen (HLA)-specific antibodies (DSA) and non-HLA antibodies can cause allograft injury, possibly leading to chronic lung allograft dysfunction (CLAD) after lung transplantation (LTx). It remains unclear whether these antibodies are produced locally in the graft or derived solely from circulating plasma cells. We hypothesized that DSA and non-HLA antibodies are produced in CLAD lungs. MethodsLung tissue was prospectively collected from 15 CLAD patients undergoing re-LTx or autopsy. 0.3g of fresh lung tissue was cultured for 4 days without or with lipopolysaccharide or with CD40L: resulting lung culture supernatant (LCS) was sampled. Protein eluate was obtained from 0.3g of frozen lung tissue. Mean fluorescence intensity (MFI) of DSA and non-HLA antibodies was measured by Luminex and antigen microarray, respectively. ResultsLCS from all 4 patients who had serum DSA at lung isolation were positive for DSA, with higher levels measured after lung tissue stimulation with CD40L (CD40L+LCS). Of these, only 2 had detectable DSA in the lung eluate. MFI of non-HLA antibodies from CD40L+LCS correlated with those from lung eluate, but not with those from sera. Flow cytometry showed higher frequencies of activated lung B cells for patients whose CD40L+LCS was positive for DSA (n=4) or high non-HLA antibodies (n=6) compared to those with low local antibodies (n=5). Immunofluorescence staining showed CLAD lung lymphoid aggregates with local antibodies contained larger numbers of IgG+ plasma cells and greater IL-21 expression. ConclusionsWe show that DSA and non-HLA antibodies can be produced within activated B cell-rich lung allografts.

Breaking the chain in organ failure: Role of umbilical cord and bone marrow derived mesenchymal stem cells in treatment of severe acute pancreatitis

BackgroundPrevious studies showed that MSCs could mitigate damage in the pancreas during acute pancreatitis (AP). However, acute mortality associated with AP was more often a result of persistent failure of remote organs, rather than local damage, especially in severe acute pancreatitis (SAP), and the effect of MSCs may vary depending on their origin. MethodsAn SAP model was induced in 8-week C57BL/6 J male mice by retrograde injection of 5 % sodium taurocholate solution through the bile duct. SAP mice were divided into the SAP group, UC-MSCs group, and BMSCs group, which were treated with saline, 1 × 106 UC-MSCs, and 1 × 106 BMSCs respectively, through the tail vein. After treatment, serum markers, inflammation, and morphology were assessed in the pancreas, kidneys, lungs, and hearts. ResultsMSCs infusion ameliorated the systemic inflammatory response in SAP mice. In the MSCs-treated SAP mice, local tissue injury and inflammation response in the pancreas were alleviated. But more importantly, the renal and lung injury were all significantly and drastically mitigated, and the levels of pro-inflammatory factors such as IL-6, MCP-1, IL-1β, and TNF-α in the kidney, lung and heart were sharply decreased. In terms of origin, UC-MSCs exhibited superior efficacy compared with BMSCs. Furthermore, compared to the normal control mice, UC-MSCs showed an earlier appearance, higher distribution densities, and longer duration of presence in the injured tissue. ConclusionsThis study provides compelling evidence supporting the therapeutic potential of MSCs in SAP treatment and particularly their ability to mitigate multi-organ failure. Our results also suggested that UC-MSCs may offer greater advantages over BMSCs in SAP therapy.

An alternative modeling approach to incorporate bond-slip effects in fiber-based elements

Fiber-based elements can provide accurate estimates of the global and local inelastic response of RC members subjected to reversed cyclic loads. However, fiber-based elements per se do not account for the localized deformations that arise from strain penetration or bond-slip effects at the member ends. To account for bond-slip effects, some researchers have suggested the use of modified properties for the steel reinforcement fibers, or that a zero-length element be attached at the element ends. In this study, a modified modeling procedure is proposed to include anchorage-slip effects in reinforced concrete frame members modeled with fiber-based beam-column elements. The proposed modeling approach is based on local bond-slip laws that can be implemented in general-purpose fiber-element software, and it differs from existing approaches in that it does not require the use of a zero-length element (though it could be used), and that it can be used with any local bond-slip relationship representative of a variety of bar embedment conditions. As such, the model can be used to simulate the effects of bond-slip of short or long embedment lengths in confined or unconfined concrete. The proposed modeling procedure is validated by comparing the calculated response with experimental data from four independent investigations. The test data included three columns and two beam specimens with various confinement and reinforcement configurations and included members reinforced with conventional and high-strength steel reinforcement. The results from the analyses show that the proposed modeling procedure provides a very good estimate of both the global and the local responses (anchorage-slip rotation) of the specimens.

Immune checkpoint reprogramming via sequential nucleic acid delivery strategy optimizes systemic immune responses for gastrointestinal cancer immunotherapy

Monoclonal antibodies targeting immune checkpoints have been widely applied in gastrointestinal cancer immunotherapy. However, systemic administration of various monoclonal antibodies does not often result in sustained effects in reversing the immunosuppressive tumor microenvironment (TME), which may be due to the spatiotemporal dynamic changes of immune checkpoints. Herein, we reported a novel immune checkpoint reprogramming strategy for gastrointestinal cancer immunotherapy. It was achieved by the sequential delivery of siPD-L1 (siRNA for programmed cell death ligand 1) and pOX40L (plasmid for OX40 ligand), which were complexed with two cationic polymer brush-grafted carbon nanotubes (dense short (DS) and dense long (DL)) designed based on the structural characteristics of nucleic acids and brush architectures. Upon administrating DL/pOX40L for the first three dosages, then followed by DS/siPD-L1 for the next three dosages to the TME, it upregulated the stimulatory checkpoint OX40L on dendritic cells (DCs) and downregulated inhibitory checkpoint PD-L1 on tumor cells and DCs in a sequential reprogramming manner. Compared with other combination treatments, this sequential strategy drastically boosted the DCs maturation, and CD8+ cytotoxic T lymphocytes infiltration in tumor site. Furthermore, it could augment the local antitumor response and improve the T cell infiltration in tumor-draining lymph nodes to reverse the peripheral immunosuppression. Our study demonstrated that sequential nucleic acid delivery strategy via personalized nanoplatforms effectively reversed the immunosuppression status in both tumor microenvironment and peripheral immune landscape, which significantly enhanced the systemic antitumor immune responses and established an optimal immunotherapy strategy against gastrointestinal cancer.