Local Response Research Articles

Self-healing propagation of a longitudinally varying vector optical beam for distance measurement.

Based on the longitudinal manipulation of polarization, a special vector optical beam (VOB) with customized polarization variation in propagation direction can be generated, whose properties and applications remain to be studied. Here, the self-healing propagation behaviors of the longitudinally varying VOB after an opaque object are investigated, and the localized polarization responses on the object distance are revealed. On this basis, characteristic parameters are defined to measure the distance of object, achieving a minimum relative error of 0.63% in a longitudinal range of 300 mm. Besides, the correlations and uncoupling methods of object distance and size are discussed. Our studies open new ways to use the structural properties of VOB and may be instructive for laser measurement.

Distinct cytokine profiles in late pregnancy in Ugandan people with HIV

During pregnancy, multiple immune regulatory mechanisms establish an immune-tolerant environment for the allogeneic fetus, including cellular signals called cytokines that modify immune responses. However, the impact of maternal HIV infection on these responses is incompletely characterized. We analyzed paired maternal and umbilical cord plasma collected during labor from 147 people with HIV taking antiretroviral therapy and 142 HIV-uninfected comparators. Though cytokine concentrations were overall similar between groups, using Partial Least Squares Discriminant Analysis we identified distinct cytokine profiles in each group, driven by higher IL-5 and lower IL-8 and MIP-1α levels in pregnant people with HIV and higher RANTES and E-selectin in HIV-unexposed umbilical cord plasma (P-value < 0.01). Furthermore, maternal RANTES, SDF-α, gro α\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathrm{\\alpha }$$\\end{document}-KC, IL-6, and IP-10 levels differed significantly by HIV serostatus (P < 0.01). Although global maternal and umbilical cord cytokine profiles differed significantly (P < 0.01), umbilical cord plasma profiles were similar by maternal HIV serostatus. We demonstrate that HIV infection is associated with a distinct maternal plasma cytokine profile which is not transferred across the placenta, indicating a placental role in coordinating local inflammatory response. Furthermore, maternal cytokine profiles in people with HIV suggest an incomplete shift from Th2 to Th1 immune phenotype at the end of pregnancy.

“We might not have been in hospital, but we were frontline workers in the community”: a qualitative study exploring unmet need and local community-based responses for marginalised groups in Greater Manchester during the COVID-19 pandemic

BackgroundThe response to the COVID-19 pandemic saw a significant increase in demand for the voluntary, community, faith and social enterprise (VCFSE) sector to provide support to local communities. In Greater Manchester (GM), the VCFSE sector and informal networks provided health and wellbeing support in multiple ways, culminating in its crucial supportive role in the provision of the COVID-19 vaccination rollout across the GM city region. However, the support provided by the VCFSE sector during the pandemic remains under-recognised. The aims of the study were to: understand the views and experiences of marginalised communities in GM during the COVID-19 pandemic; explore how community engagement initiatives played a role during the pandemic and vaccine rollout; assess what can be learnt from the work of key stakeholders (community members, VCFSEs, health-system stakeholders) for future health research and service delivery.MethodsThe co-designed study utilised a participatory approach throughout and was co-produced with a Community Research Advisory Group (CRAG). Focus groups and semi-structured interviews were conducted remotely between September-November 2021, with 35 participants from local marginalised communities, health and care system stakeholders and VCFSE representatives. Thematic framework analysis was used to analyse the data.ResultsLocal communities in GM were not supported sufficiently by mainstream services during the course of the COVID-19 pandemic, resulting in increased pressure onto the VCFSE sector to respond to local communities’ need. Community-based approaches were deemed crucial to the success of the vaccination drive and in providing support to local communities more generally during the pandemic, whereby such approaches were in a unique position to reach members of diverse communities to boost uptake of the vaccine. Despite this, the support delivered by the VCFSE sector remains under-recognised and under-valued by the health system and decision-makers.ConclusionsA number of challenges associated with collaborative working were experienced by the VSCE sector and health system in delivering the vaccination programme in partnership with the VCFSE sector. There is a need to create a broader, more inclusive health system which allows and promotes inter-sectoral working. Flexibility and adaptability in ongoing and future service delivery should be championed for greater cross-sector working.

Potential role of IGF-1R in the interaction between orbital fibroblasts and B lymphocytes: an implication for B lymphocyte depletion in the active inflammatory phase of thyroid-associated ophthalmopathy

BackgroundThyroid eye disease (TED) is an inflammatory process involving lymphocyte-mediated immune response and orbital tissue damage. The anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies produced by B lymphocytes are involved in the activation of orbital fibroblasts and the inflammatory process of orbital tissue damage in TED. The purpose of this study was to explore the role of IGF-1R in the mechanistic connection between orbital fibroblasts and B lymphocytes in TED.MethodsOrbital fibroblasts sampled from orbital connective tissues and peripheral B lymphocytes isolated from peripheral blood, which were obtained from 15 patients with TED and 15 control patients, were co-cultured at a ratio of 1:20. The level of IGF-1R expression in orbital fibroblasts was evaluated by flow cytometry and confocal microscopy. Transient B lymphocyte depletion was induced with anti-CD20 monoclonal antibody rituximab, while the IGF-1R pathway was blocked by the IGF-1R binding protein. The expression levels of interleukin-6 (IL-6) and regulated upon activation, normal T cell expressed and secreted (RANTES) in the co-culture model were quantified via ELISA.ResultsIGF-1R expression was significantly elevated in TED orbital fibroblasts compared to that of controls. A 24-h co-culture of orbital fibroblasts with peripheral B lymphocytes induced elevated expression levels of IL-6 and RANTES in each group (TED patients and controls), with the highest levels occurring in TED patients (T + T group). Rituximab and IGF-1R binding protein significantly inhibited increased levels of IL-6 and RANTES in the co-culture model of TED patients.ConclusionsIGF-1R may mediate interaction between orbital fibroblasts and peripheral B lymphocytes; thus, blocking IGF-1R may reduce the local inflammatory response in TED. Rituximab-mediated B lymphocyte depletion played a role in inhibiting inflammatory responses in this in vitro co-culture model, providing a theoretical basis for the clinical application of anti-CD20 monoclonal antibodies in TED.

Immunity in adipose tissues: Cutting through the fat.

Well known functions of adipose tissue include energy storage, regulation of thermogenesis, and glucose homeostasis-each of which are associated with the metabolic functions of fat. However, adipose tissues also have important immune functions. In this issue of Immunological Reviews, we present a series of articles that highlight the immune functions of adipose tissue, including the roles of specialized adipose-resident immune cells and fat-associated lymphoid structures. Importantly, immune cell functions in adipose tissues are often linked to the metabolic functions of adipocytes and vice versa. These reciprocal interactions and how they influence both immune and metabolic functions will be discussed in each article. In the first article, Wang etal.,11 discuss adipose-associated macrophages and how obesity and metabolism impact their phenotype and function. Several articles in this issue discuss T cells as either contributors to, or regulators of, inflammatory responses in adipose tissues. Valentine and Nikolajczyk12 provide insights into the role of T cells in obesity-associated inflammation and their contribution to metabolic dysfunction, whereas an article from Kallies and Vasanthakumar13 and another from Elkins and Li14 describe adipose-associated Tregs and how they help prevent inflammation and maintain metabolic homeostasis. Articles from Okabe35 as well as from Daley and Benezech15 discuss the structure and function of fat-associated lymphoid clusters (FALCs) that are prevalent in some adipose tissues and support local immune responses to pathogens, gut-derived microbes and fat-associated antigens. Finally, an article from Meher and McNamara16 describes how innate-like B1 cells in adipose tissues regulate cardiometabolic disease. Importantly, these articles highlight the physical and functional attributes of adipose tissues that are different between mice and humans, the metabolic and immune differences between various adipose depots in the body and the differences in immune cells, adipose tissues and metabolic functions between the sexes. At the end of this preface, we highlight how these differences are critically important for our understanding of anti-tumor immunity to cancers that metastasize to a specific example of visceral adipose tissue, the omentum. Together, these articles identify some unanswered mechanistic questions that will be important to address for a better understanding of immunity in adipose tissues.

Ciita Regulates Local and Systemic Immune Responses in a Combined rAAV-α-synuclein and Preformed Fibril-Induced Rat Model for Parkinson's Disease.

Parkinson's disease (PD) is characterized by alpha-synuclein (α-Syn) pathology, neurodegeneration and neuroinflammation. Human leukocyte antigen (HLA) variants associated with PD and α-Syn specific CD4+ T lymphocytes in PD patients highlight the importance of antigen presentation in PD etiology. The class II transactivator (CIITA) regulates major histocompatibility complex class II (MHCII) expression. Reduced Ciita levels significantly increase α-Syn pathology, nigrostriatal neurodegeneration and behavioral deficits in α-Syn-induced rat PD models. Characterize immune profiles associated with enhanced PD-like pathology observed in rats expressing lower Ciita levels (DA.VRA4) compared to the background strain (DA). To model PD, we combined rAAV-mediated α-Syn overexpression in the substantia nigra with striatal injection of α-Syn preformed fibrils. Immune profiles in brain and blood were analyzed by flow cytometry and multiplexed ELISA in naïve rats, 4- and 8 weeks post rAAV injection. Flow cytometry showed Ciita-dependent regulation of MHCII on microglia, brain macrophages and circulating myeloid cells. The MHCII-dependent microglial response was highest at 4 weeks post rAAV injection, whereas the MHCII levels in circulating myeloid cells was highest at 8 weeks. There was no major infiltration of macrophages or T lymphocytes into the CNS in response to α-Syn and only subtle Ciita- and/or α-Syn-dependent changes in the T lymphocyte compartment. Lower Ciita levels were consistently associated with higher TNF levels in serum. Ciita regulates susceptibility to PD-like pathology through minor but detectable changes in resident and peripheral immune cells and TNF levels, indicating that mild immunomodulatory therapies could have therapeutic effects in PD.

Ascaris suum infection in juvenile pigs elicits a local Th2 response in a setting of ongoing Th1 expansion

Ascaris spp. undergo extensive migration within the body before establishing patent infections in the small intestinal tract of humans and pigs. However, whether larval migration is critical for inducing efficient type 2 responses remains poorly understood. Therefore, we investigated systemic versus local adaptive immune responses along the hepato-tracheal migration of Ascaris suum during primary, single infections in conventionally raised pigs. Neither the initial invasion of gut tissue nor migration through the liver resulted in discernable Th2 cell responses. In contrast, lung-stage larvae elicited a Th2-biased pulmonary response, which declined after the larvae had left the lungs. In the small intestine, we observed an accumulation of Th2 cells upon the arrival of fourth-stage larvae (L4) to the small intestinal lumen. In parallel, we noticed robust and increasing Th1 responses in circulation, migration-affected organs, and draining lymph nodes. Phenotypic analysis of CD4+ T cells specifically recognizing A. suum antigens in the circulation and lung tissue of infected pigs confirmed that the majority of Ascaris-specific T cells produced IL-4 (Th2) and, to a much lesser extent, IL-4/IFN-g (Th2/1 hybrids) or IFN-g alone (Th1). These data demonstrate that lung-stage but not the early liver-stage larvae lead to a locally restricted Th2 response. Significant Th2 cell accumulation in the small intestine occurs only when L4 complete the body migration. In addition, Th2 immunity seems to be hampered by the concurrent, nonspecific Th1 bias in growing pigs. Together, the late onset of Th2 immunity at the site of infection and the Th1-biased systemic immunity likely enable the establishment of intestinal infections by sufficiently large L4 stages and pre-adult worms, some of which resist expulsion mechanisms.

Manifestation and associated factors of systemic and local allergy among patients with allergic fungal rhinosinusitis: An observational study.

Allergic fungal rhinosinusitis (AFRS) is a subtype of chronic rhinosinusitis, characterized by excessive immune responses to environmental molds or fungi. The diagnosis and classification of AFRS into systemic and local types remain clinically challenging due to overlapping characteristics. This study investigated the prevalence of AFRS, its manifestation and associated factors in systemic and local AFRS. A total of 200 patients diagnosed with fungal rhinosinusitis underwent both skin provocation tests (SPT) and nasal provocation tests (NPT) to confirm AFRS and classify systemic and local types. Patients were considered to have AFRS if either the SPT or NPT was positive. Among these, patients with systemic AFRS were those who had a SPT positive. Local AFRS was when patients had a negative SPT and a positive NPT. Medical history, serum total IgE level, nasal endoscopy examinations, and CT scans were also recorded. Most patients were female (65.8%), with a mean age of 55.6 years (SD = 14.4). Based on the SPT and NPT results, 31% of patients (n = 62) were diagnosed with AFRS. Among these, 54.8% (n = 34) had systemic AFRS, while 45.2% (n = 28) had local AFRS. Patients with AFRS exhibited significantly higher levels of total IgE, eosinophils, and more pronounced signs and symptoms compared to those without AFRS. However, no statistically significant differences were observed between patients with systemic AFRS and those with local AFRS. AFRS was prevalent in our study. Among patients with AFRS, both systemic AFRS and local AFRS were also prevalent. While allergic indicators and clinical presentations can aid in AFRS diagnosis, minimal distinctions were observed between systemic and local AFRS. A comprehensive assessment incorporating both local and systemic allergic responses through provocation tests, such as a combination of skin and nasal tests, is imperative for optimizing AFRS diagnosis and management.

Peer-to-peer multi-period energy market with flexible scheduling on a scalable and cost-effective blockchain

Peer-to-Peer (P2P) electricity trading is an emerging means for allowing communities to share local energy production and demand response through direct trading. It is projected to play an important role in the future energy market by increasing the incentive to own and operate distributed energy resources (DERs) and participate in demand response (DR). A common approach to implementing P2P trading is with blockchain, however, existing solutions feature limitations. Typically, concerns involve either scalability and high transaction costs or projects implementing a permissioned blockchain that does not provide the trust and decentralization desired. In addition, the majority of market designs are simplified and do not capture the distinct complexity of electricity markets. They do not consider the inter-temporal constraints of appliances and DERs that need to run for multiple periods. Complex market designs that address these issues have not been implemented in blockchain based systems due to the computational limitations of such systems. To improve these two aspects, this paper proposes a market formulation that supports products running multiple periods with flexible scheduling, modeled as a mixed integer linear programming problem that optimizes social welfare. The trading platform is then implemented as a side chain of Polkadot, a network of blockchains designed to be secure, scalable, and economically feasible to foster an ecosystem of application-specific sidechains. This design is demonstrated to improve social welfare and achieve scalability by benchmarking the number of transactions that can be included per second, based upon typical assumptions of the market size. The result is a decentralized and performant system that allows for complex market designs to be implemented in a blockchain environment. This approach simplifies the process for participants, allowing them to bid DER or DR devices, directly and easily, even when this requires constraints across periods.

Post-processing of a distributed source method for the localization of somatosensory cortex in a cohort of epilepsy patients

Localizing eloquent cortices is crucial for many neurosurgical applications, such as epilepsy and tumor resections. Clinicians may use non-invasive methods such as magnetoencephalography (MEG) to localize these cortical regions using equivalent current dipoles (ECDs). While dipoles are clinically validated, they provide the estimated strength, location, and orientation of only one or a few sources that best describe the recorded neuromagnetic data, requiring clinicians to make subjective decisions on the spatial extent of the underlying cortical area. More accurate delineation of eloquent cortical areas using distributed source localization methods would provide additional pre-surgical information on these regions’ location and spatial distribution, which could lead to reduced post-surgical complications associated with damage to or removal of eloquent cortices. Our objective in this paper was to present a method to post-process the distributed source localization results to yield a directly interpretable, distributed region of activation. As a test case, we selected somatosensory stimulation in a retrospective cohort of focal and multi-focal epilepsy patients. Our algorithm performs source localization using a distributed method (sLORETA), followed by post-processing and blind source separation to identify the area and boundary of the cortical tissue that primarily activates in response to somatosensory stimulation. We calculated the statistical significance of localization by comparing the identified region to an anatomical atlas and random chance. While examining patients who received left (upper left, UL) and right (upper right, UR) sided median nerve stimulation, the cortical areas identified by the algorithm were in anatomically appropriate areas with a median overlap of 97.6% and 94.7%, respectively. We observe that our algorithm localized somatosensory responses better than random chance in 57/58 (98%) patients who performed the UL task (p < 10 × 10−10, binomial test) and 49/50 (98%) patients who performed the UR task (p < 10 × 10−10, binomial test). We compared the localization of our algorithm to current clinical methods and found that our algorithm is not inferior to dipole localization. The algorithm can successfully localize somatosensory responses on the cortical surface in anatomically appropriate regions while providing the spatial extent of cortical activation, reducing subjectivity associated with dipole localization.

Reperfusion therapies in patients with intermediate- and high-risk pulmonary embolism: insights from a multicenter registry

Abstract Funding Acknowledgements None. Background Most acute pulmonary embolism (PE) patients receive anticoagulation as a sole treatment. Reperfusion therapies are required in high-risk (HR) and in intermediate-risk (IR)-PE patients with clinical deterioration. Systemic thrombolysis (ST) is the first-line reperfusion therapy, but due to contraindications and major bleeding concerns, catheter-directed therapies (CDT) are rising as a suitable alternative. Purpose The main objective of this study was to look for predictors that lead physicians to decide between different PE therapies in a contemporary cohort of patients. Methods This ambispective registry included consecutive IR- and HR-acute PE patients evaluated by local Pulmonary Embolism Response Team in two tertiary centers from 2014 to 2022. The patients were grouped according to the elected therapy: anticoagulation alone, CDT or ST. If more than one reperfusion therapy was used, the patient was assigned to the group of the first administered therapy. Predictors of reperfusion therapy assignment were evaluated using a logistic regression analysis. Also, early safety outcomes and procedural results after CDT were analyzed. Results A total of 274 patients were included. Of them, 112 received only anticoagulation, 96 received ST as primary treatment, and 66 underwent CDT at first. Baseline characteristics are displayed in Picture 1. Patients in the ST group were significantly younger (p&amp;lt;0.01). Comorbidities were higher in the CDT group compared to the other two. Patients undergoing CDT or ST had higher PE severity parameters at hospital admission than the anticoagulation group (e.g. shock index, RV involvement, or lactate levels; p&amp;lt;0.01 for all). The Pulmonary Embolism Severity Index score, which incorporates comorbidities and PE severity parameters, was higher in CDT patients compared to the other two groups (p&amp;lt;0.01). Picture 2 shows the trend in the choice between the two primary reperfusion therapies over the years. After multivariable analysis, the Charlson comorbidity index, recent surgery and bilateral central PE remained independent predictors for the use of CDT instead of ST (p&amp;lt;0.05 for all). A significant decrease in the systolic and mean pulmonary artery pressure and a significant increase in systolic blood pressure after procedure was detected in patients undergoing CDT. Regarding early safety outcomes, intracranial bleeding occurred only in the ST group. In contrast, the incidence of major bleeding, acute kidney injury and 30-day mortality did not differ between CDT and ST groups. Conclusion This contemporary registry used CDT as primary therapy in 24% of IHR and HR patients, mainly in comorbid and post-surgical patients, and increased over time. CDT was a safe and effective alternative to ST, achieving significant and early improvement in right ventricular function and hemodynamics.Baseline characteristicsChoice of reperfusion therapy over time

Monocytes - See One Queuing Local Adaptive Immune Responses to Respiratory Viruses.

Monocytes - See One Queuing Local Adaptive Immune Responses to Respiratory Viruses.

Neoadjuvant treatment of colorectal cancer: comprehensive review.

Neoadjuvant therapy has an established role in the treatment of patients with colorectal cancer. However, its role continues to evolve due to both advances in the available treatment modalities, and refinements in the indications for neoadjuvant treatment and subsequent surgery. A narrative review of the most recent relevant literature was conducted. Short-course radiotherapy and long-course chemoradiotherapy have an established role in improving local but not systemic disease control in patients with rectal cancer. Total neoadjuvant therapy offers advantages over short-course radiotherapy and long-course chemoradiotherapy, not only in terms of increased local response but also in reducing the risk of systemic relapses. Non-operative management is increasingly preferred to surgery in patients with rectal cancer and clinical complete responses but is still associated with some negative impacts on functional outcomes. Neoadjuvant chemotherapy may be of some benefit in patients with locally advanced colon cancer with proficient mismatch repair, although patient selection is a major challenge. Neoadjuvant immunotherapy in patients with deficient mismatch repair cancers in the colon or rectum is altering the treatment paradigm for these patients. Neoadjuvant treatments for patients with colon or rectal cancers continue to evolve, increasing the complexity of decision-making for patients and clinicians alike. This review describes the current guidance and most recent developments.

Airway and Systemic Immunoglobulin Profiling and Immune Response in Adult Asthma.

Immunoglobulins play a vital role in host immune response and in the pathogenesis of conditions like asthma. Therapeutic agents such as monoclonal antibodies target specific elements of the asthmatic inflammatory cascade. Decisions to utilize these medications are often based on systemic inflammatory profiling without direct insight into the airway inflammatory profile. We sought to investigate the relationship between immunoglobulin and cytokine profiles in the airway and systemic immune compartments of adult asthmatics. Blood sampling and bronchoscopy with bronchoalveolar lavage (BAL) were performed in 76 well-defined adult asthmatics. Antibody and cytokine profiles were measured in both BAL and serum using ELISA and quantibody arrays. There was no relationship between BAL and serum levels of IgE. This is of significance in an asthma population. For some analytes, correlation analysis was significant (P < 0.05) indicating representativeness of our cohort and experimental setup in those cases. Nevertheless, the predictive power (r2) of the BAL-to-serum comparisons was mostly low except for TNF-α (r2 = 0.73) when assuming a simple (linear) relationship. This study highlights the importance of sample site when investigating the roles of immunoglobulins and cytokines in disease pathogenesis and suggests that both localized and systemic immune responses are at play. The prescription of asthma monoclonal therapy is generally based on systemic evaluation of cytokine and immunoglobulin levels. Our research suggests that this approach may not fully reflect the pathophysiology of the disease and may provide insight into why some patients respond to these targeted therapies while others do not.

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.

Phosphatidylserine and Tyro3-Axl-Mertk Receptor Tyrosine Kinase level detection in plasma and on plasma-derived extracellular vesicle surface in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder characterized by monoclonal B cell proliferation. Studies carried out in recent years suggest that extracellular vesicles (EVs) may be a potential biomarker in cancer. Tyro3-Axl-Mertk (TAM) Receptor Tyrosine Kinases (RTKs) and Phosphatidylserine (PS) have crucial roles in macrophage-mediated immune response under normal conditions. In the tumor microenvironment, these molecules contribute to immunosuppressive signals and prevent the formation of local and systemic antitumor immune responses. Based on this, we aimed to evaluate the amount of PS and TAM RTK in plasma and on the surface of EVs in CLL patients and healthy volunteers in this study. In this study, 25 CLL (11 F/14 M) patients in the Rai (O-I) stage, newly diagnosed or followed up without treatment, and 15 healthy volunteers (11 F/4 M) as a control group were included. For all samples, PS and TAM RTK levels were examined first in the plasma and then in the EVs obtained from the plasma. We detected a significant decrease in plasma PS, and TAM RTK levels in CLL patients compared to the control. Besides, we determined a significant increase in TAM RTK levels on the EV surface in CLL, except for PS. In conclusion, these receptor levels measured by ELISA in plasma may not be effective for the preliminary detection of CLL. However, especially TAM RTKs on the surface of EVs may be good biomarkers and potential targets for CLL therapies.

Acceptance of offshore wind farm in Southwest Sardinia in Italy. Do regional energy policies matter?

Purpose The social acceptance of wind energy is increasingly conditioning the Italian Government and regions to authorize the construction of these plants. The proposal of offshore wind farm in the south-west of Sardinia has raised many perplexities both from the marine environmental point of view and from concern about increasing the electricity production in a region that already exports electricity to the peninsula. The purpose of this study is to evaluate what are the factors that most affect the coastal residents’ acceptability of an offshore wind farm. Design/methodology/approach The data is based on a Sardinia-wide in-person survey with about 512 participants in the period between May and June 2023. Respondents were selected randomly from five different locations in Carloforte region. Multiple regression analysis investigates the factors that influenced acceptability to construction and development of offshore wind power plant. Four independent variables were selected in the regression models such as (i) interest towards wind energy, (ii) attitude towards renewable energy production, (iii) perceived regional energy policy and (iv) attitude towards offshore wind farm. The dependent variables are the rates of coastal local residents’ acceptance of offshore wind farm for respondents in five coastal towns. Findings Fishermen and summer tourism operators’ respondents expressed significant reluctance to accept the new project because they perceive a strong risk of environmental impact on both tuna fishing and marine recreational activities in the vicinity. The distance between the turbines at sea and local residents along the coast and surrounding small islands does not have an influence to accept wind energy. The energy policy of the Region of Sardinia, which is perceived by respondents as an expansive energy policy in the production of electricity that exceeds their needs, not being accompanied by a scenario of reducing that from fossil fuels, is the variable that led about 70% of respondents to express a negative opinion towards this project. Research limitations/implications A potential problem associated with the survey is that local response produced sample selection bias. The proportion of respondents with secondary education and no school certificate is quite high. It is possible that respondents who provided valid questionnaires were more low-educated and therefore, the sample may be biased towards lower-educated people. While this does not invalidate the results of this study, it is important to note that the sample was on average less educated than the overall population in Italy. In addition, people with lower incomes were more likely to complete the questionnaires; the results are more representative of a portion of the population with incomes below the national average. Practical implications Results showed how coastal communities are in favour of wind energy within their island, but not within a marine protected area that is considered unique for its beauty and marine ecosystem. Wind energy developers should, before submitting a proposal for an offshore wind farm project, consider among other things the long approval time and understand the activities carried out by local communities and their attachment to those places. Politicians and developers should develop a coherent energy transition policy based on a long-term vision of zero emissions, because according to the findings of this study, it was the regional energy policy that is the most controversial reason for residents to reject the project. Originality/value The contribution of this study is to fill a part of the research gap linking to ongoing energy transitions. In particular, this study analysed for the first time in Italy the acceptability level of an offshore renewable energy project considering the environmental implications and risks in the fragile marine ecosystem of Carloforte waters. This study also made it possible to analyse the impact of the regional energy policy on the acceptability of residents towards the development of offshore wind farms, which is scarcely discussed in the literature.

Mast cells and wound healing: Still an open question.

Mast cells, which originate from the bone marrow, possess the ability to secrete a diverse array of active molecules. These molecules include mediators (histamine, heparin), which have been identified for decades and are stored in specific granules, as well as small molecules generated instantaneously in response to stimulation (membrane lipid derivatives, nitric oxide), and a multitude of multifunctional cytokines that are secreted constitutively. Activated mast cells participate in the regulation of the local immune response and exert control over critical events of inflammation and healing with the assistance of a vast array of mediators. The involvement of these cell types in inflammatory states suggests that mast cells may function as sentinels that activate local immune processes in response to various types of stimuli and the entry of antigens. Moreover, due to their proximity to nerve fibers and reactivity to a variety of neurotransmitters, mast cells are among the cells that may facilitate local neuroimmune interactions. With this in mind, it is necessary to consider their participation in the repair of injuries in both acute and chronic conditions.

The local mechanosensitive response of primary cardiac fibroblasts is influenced by the microenvironment mechanics

Cardiac fibroblasts (CFs) are essential for preserving myocardial integrity and function. They can detect variations in cardiac tissue stiffness using various cellular mechanosensors, including the Ca2+ permeable mechanosensitive channel Piezo1. Nevertheless, how CFs adapt the mechanosensitive response to stiffness changes remains unclear. In this work we adopted a multimodal approach, combining the local mechanical stimulation (from 10 pN to 350 nN) with variations of culture substrate stiffness. We found that primary rat CFs cultured on stiff (GPa) substrates showed a broad Piezo1 distribution in the cell with particular accumulation at the mitochondria membrane. CFs displayed a force-dependent behavior in both calcium uptake and channel activation probability, showing a threshold at 300 nN, which involves both cytosolic and mitochondrial Ca2+ mobilization. This trend decreases as the myofibroblast phenotype within the cell population increases, following a possible Piezo1 accumulation at focal adhesion sites. In contrast, the inhibition of fibroblasts to myofibroblasts transition with soft substrates (kPa) considerably reduces both mechanically- and chemically-induced Piezo1 activation and expression. Our findings shed light on how Piezo1 function and expression are regulated by the substrate stiffness and highlight its involvement in the environment-mediated modulation of CFs mechanosensitivity.

Damage to monumental masonry buildings in Hatay and Osmaniye following the 2023 Turkey earthquake sequence: The role of wall geometry, construction quality, and material properties

This article reports on the findings of an investigation on 29 historic stone masonry buildings located in the cities of Hatay and Osmaniye following the 2023 Turkey earthquake sequence. The earthquake couplet on 6 February (with moment magnitudes 7.8 and 7.5) and the following events (including another earthquake which occurred on 20 February with a moment magnitude of 6.3) resulted in significant damage to the buildings. To understand why, the examined buildings were assigned an EMS-98 damage level (ranging from 1 to 5) and descriptive response categories (masonry disaggregation, local mechanism, and global response). Overall damage statistics indicated that masonry disaggregation was common and coterminous with local mechanism response. Wall geometry and construction quality indices were then investigated to explore why these were the dominant damage mechanisms. Wall geometry indices highlighted insufficient amount of walls to resist the local seismic demands, particularly in the transverse (e.g. short) direction of buildings. This deficit promoted the formation of local mechanisms. Construction quality indices suggested that stone layouts did not enable interlocking and that the walls were prone to disaggregation. To further investigate the role of material properties on the observed damage, materials were characterized using three non-destructive testing techniques: ultrasonic pulse velocity (UPV) measurements to estimate the static elastic modulus of stones, Schmidt rebound hammer (SRH) tests to estimate the compressive strength of stones, and the mortar penetrometer (MP) tests to estimate the compressive strength of mortar. The measurements indicated poor mortar quality, which may have expedited failures. Using established correlations, various other important material parameters (e.g. mortar cohesion and homogenized masonry strength) are derived. It is envisioned that the damage observations and the material measurements in this article will inform detailed modeling efforts on the behavior of historic masonry buildings during the earthquakes.