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1.
Nat Rev Cancer ; 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38969810

RESUMO

The tumour immune microenvironment is shaped by the crosstalk between cancer cells, immune cells, fibroblasts, endothelial cells and other stromal components. Although the immune tumour microenvironment (TME) serves as a source of therapeutic targets, it is also considered a friend or foe to tumour-directed therapies. This is readily illustrated by the importance of T cells in triple-negative breast cancer (TNBC), culminating in the advent of immune checkpoint therapy in combination with cytotoxic chemotherapy as standard of care for both early and advanced-stage TNBC, as well as recent promising signs of efficacy in a subset of hormone receptor-positive disease. In this Review, we discuss the various components of the immune TME in breast cancer and therapies that target or impact the immune TME, as well as the complexity of host physiology.

2.
J Neuroophthalmol ; 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38965655

RESUMO

BACKGROUND: Neuro-ophthalmology frequently requires a complex and multi-faceted clinical assessment supported by sophisticated imaging techniques in order to assess disease status. The current approach to diagnosis requires substantial expertise and time. The emergence of AI has brought forth innovative solutions to streamline and enhance this diagnostic process, which is especially valuable given the shortage of neuro-ophthalmologists. Machine learning algorithms, in particular, have demonstrated significant potential in interpreting imaging data, identifying subtle patterns, and aiding clinicians in making more accurate and timely diagnosis while also supplementing nonspecialist evaluations of neuro-ophthalmic disease. EVIDENCE ACQUISITION: Electronic searches of published literature were conducted using PubMed and Google Scholar. A comprehensive search of the following terms was conducted within the Journal of Neuro-Ophthalmology: AI, artificial intelligence, machine learning, deep learning, natural language processing, computer vision, large language models, and generative AI. RESULTS: This review aims to provide a comprehensive overview of the evolving landscape of AI applications in neuro-ophthalmology. It will delve into the diverse applications of AI, optical coherence tomography (OCT), and fundus photography to the development of predictive models for disease progression. Additionally, the review will explore the integration of generative AI into neuro-ophthalmic education and clinical practice. CONCLUSIONS: We review the current state of AI in neuro-ophthalmology and its potentially transformative impact. The inclusion of AI in neuro-ophthalmic practice and research not only holds promise for improving diagnostic accuracy but also opens avenues for novel therapeutic interventions. We emphasize its potential to improve access to scarce subspecialty resources while examining the current challenges associated with the integration of AI into clinical practice and research.

3.
J Hand Surg Am ; 2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38970601

RESUMO

PURPOSE: To determine whether preservation of blood supply to the index metacarpophalangeal joint decreases the rate of physeal arrest. METHODS: A retrospective review of 41 pollicized digits in 35 patients with 2-year minimum radiographic follow-up was conducted at a single institution. Other complications evaluated included nonunion at the pollicized digit base and clinical instability at the new carpometacarpal joint. Findings were compared to historical controls, which were performed by our group prior to routine identification and sparing of the metacarpophalangeal joint blood supply. No other modifications to surgical technique were made between the previous and current patient cohorts. RESULTS: Two pollicized digits in two different patients had radiographic evidence of physeal arrest, one of which was partial and the other complete, for an arrest rate of 4.9%. This was significantly less than the arrest rate in our historical cohort of 24.7% (21 of 85 patients). Five patients did not have radiographic bony union at the base of the index metacarpal, but only one patient had clinical instability at the new carpometacarpal joint. CONCLUSIONS: Significantly fewer patients who underwent index finger pollicization with preservation of the metacarpophalangeal joint blood supply went on to develop physeal arrest when compared to patients who underwent pollicization prior to adoption of this technique. This finding suggests that sparing of the physeal blood supply is preventative against proximal phalanx physeal arrest. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

4.
Artigo em Inglês | MEDLINE | ID: mdl-38976153

RESUMO

In tic disorders (TD), tic expression varies across the lifespan and as a function of contextual factors. This study explored connections between tic expression and contextual triggers across life periods in 74 adults (Mage = 23.2) with TDs. The Tic History and Coping Strategies form assessed retrospective self-reports of contextual antecedents, consequences, and tic severity during four life periods (middle school; 9th/10th grade; 11th/12th grade; college/work) and past month. Tics reportedly worsened during and after school in school-aged years and worsened in the evening during college/work years. Stress and anxiety were reported to consistently trigger tics across time. The impact of activities, places, and emotions did not differ across life periods. Attention-based consequences, most prevalent during middle school, were more common than escape- or avoidance-related consequences across all periods. Findings illuminate how contextual factors may influence tics across life periods and underscore the consistent impact of tic-triggering emotions and attention-related consequences.

5.
Immunity ; 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38876098

RESUMO

Allogeneic T cell expansion is the primary determinant of graft-versus-host disease (GVHD), and current dogma dictates that this is driven by histocompatibility antigen disparities between donor and recipient. This paradigm represents a closed genetic system within which donor T cells interact with peptide-major histocompatibility complexes (MHCs), though clonal interrogation remains challenging due to the sparseness of the T cell repertoire. We developed a Bayesian model using donor and recipient T cell receptor (TCR) frequencies in murine stem cell transplant systems to define limited common expansion of T cell clones across genetically identical donor-recipient pairs. A subset of donor CD4+ T cell clonotypes differentially expanded in identical recipients and were microbiota dependent. Microbiota-specific T cells augmented GVHD lethality and could target microbial antigens presented by gastrointestinal epithelium during an alloreactive response. The microbiota serves as a source of cognate antigens that contribute to clonotypic T cell expansion and the induction of GVHD independent of donor-recipient genetics.

6.
Sci Rep ; 14(1): 13751, 2024 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-38877112

RESUMO

While spot spraying has gained increasing popularity in recent years, spot application of granule agrochemical has seen little development. Despite the potential for the technology, there currently exists no commercially available granular applicators capable of spot application. Therefore, the goal of this study was to design, build, and lab evaluate a precision applicator for spot applying granular agrochemical in wild blueberry. The design incorporated a John Deere RC2000 with a custom control box, recirculation system, and electrically actuated valves. All components were modified to fit a Valmar 1255 Twin-Roller. The system receives inputs from a predeveloped prescription map and can actuate each of the twelve valves separately to provide individual orifice control. Casoron® G4 was used as the testing agrochemical and in cycling the product pneumatically for 1 hour incurred no significant product degradation (p = 0.110). In lab evaluations, the applicator encountered zero errors in reading prescription maps and actuating the correct valves accordingly. Further, the granule recycling system had zero instances where product built up in the lines or jammed the valves. In all, this project represents the first successful development of a precision granular spot applicator for any cropping system.


Assuntos
Agroquímicos , Mirtilos Azuis (Planta) , Agroquímicos/farmacologia
7.
Neurol Clin Pract ; 14(5): e200328, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38895642

RESUMO

Background and Objectives: We determined inter-modality (in-person vs telemedicine examination) and inter-rater agreement for telemedicine assessments (2 different examiners) using the Telemedicine Buffalo Concussion Physical Examination (Tele-BCPE), a standardized concussion examination designed for remote use. Methods: Patients referred for an initial evaluation for concussion were invited to participate. Participants had a brief initial assessment by the treating neurologist. After a patient granted informed consent to participate in the study, the treating neurologist obtained a concussion-related history before leaving the examination room. Using the Tele-BCPE, 2 virtual examinations in no specific sequence were then performed from nearby rooms by the treating neurologist and another neurologist. After the 2 telemedicine examinations, the treating physician returned to the examination room to perform the in-person examination. Intraclass correlation coefficients (ICC) determined inter-modality validity (in-person vs remote examination by the same examiner) and inter-rater reliability (between remote examinations done by 2 examiners) of overall scores of the Tele-BCPE within the comparison datasets. Cohen's kappa, κ, measured levels of agreement of dichotomous ratings (abnormality present vs absent) on individual components of the Tele-BCPE to determine inter-modality and inter-rater agreement. Results: For total scores of the Tele-BCPE, both inter-modality agreement (ICC = 0.95 [95% CI 0.86-0.98, p < 0.001]) and inter-rater agreement (ICC = 0.88 [95% CI 0.71-0.95, p < 0.001]) were reliable (ICC >0.70). There was at least substantial inter-modality agreement (κ ≥ 0.61) for 25 of 29 examination elements. For inter-rater agreement (2 telemedicine examinations), there was at least substantial agreement for 8 of 29 examination elements. Discussion: Our study demonstrates that the Tele-BCPE yielded consistent clinical results, whether conducted in-person or virtually by the same examiner, or when performed virtually by 2 different examiners. The Tele-BCPE is a valid indicator of neurologic examination findings as determined by an in-person concussion assessment. The Tele-BCPE may also be performed with excellent levels of reliability by neurologists with different training and backgrounds in the virtual setting. These findings suggest that a combination of in-person and telemedicine modalities, or involvement of 2 telemedicine examiners for the same patient, can provide consistent concussion assessments across the continuum of care.

8.
J Clin Child Adolesc Psychol ; : 1-12, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38900723

RESUMO

OBJECTIVE: Cognitive Disengagement Syndrome (CDS; previously called Sluggish Cognitive Tempo) refers to a constellation of cognitive and motor behaviors characterized by a predisposition toward mind wandering (cognitive subdomain) and slowed motor behavior (hypoactive). While there are a number of studies linking CDS traits to greater global impairment in children with attention-deficit/hyperactivity disorder (ADHD) and autistic children, there are few studies examining the prevalence and impact of CDS traits in autistic children with co-occurring ADHD (Autistic+ADHD). The current study explored CDS traits in autistic children with and without co-occurring ADHD, children with ADHD, and neurotypical children. METHODS: Participants were 196 children between 3- and 7-years-of-age comprising four groups: Neurotypical (N = 44), ADHD (N = 51), Autistic (N = 55), and Autistic+ADHD (N = 46). CDS traits, social and communication skills, repetitive behaviors, and sensory processing were all assessed via parent report. RESULTS: Children diagnosed with ADHD, autistic children, and Autistic+ADHD children exhibited similar levels of overall CDS traits. However, when explored separately, Autistic+ADHD children had higher cognitive CDS trait scores compared to children with ADHD alone. Both overall CDS traits and the cognitive subdomain were associated with greater social difficulties, particularly social withdrawal, higher levels of repetitive behaviors, and more sensory sensitivities, regardless of diagnosis. CONCLUSIONS: Findings suggest that CDS traits may be an additional factor directly impact functional outcomes in both autistic and ADHD children. As such, clinicians should be assessing CDS traits in addition to other clinical domains associated with ADHD and autism when developing intervention plans for young neurodiverse children.

9.
J Clin Invest ; 134(11)2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38828727

RESUMO

Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A-secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific TCM, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones.


Assuntos
Inibidores de Calcineurina , Doença Enxerto-Hospedeiro , Isoantígenos , Células T de Memória , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/patologia , Animais , Camundongos , Isoantígenos/imunologia , Inibidores de Calcineurina/farmacologia , Doença Crônica , Células T de Memória/imunologia , Tacrolimo/farmacologia , Linfócitos T CD4-Positivos/imunologia , Ciclosporina/farmacologia , Feminino , Linfócitos T CD8-Positivos/imunologia , Subpopulações de Linfócitos T/imunologia
10.
Cognition ; 250: 105863, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38924875

RESUMO

The human capacity to imagine possible future events unintentionally, with minimal cognitive effort, is termed spontaneous future thought (SFT). This paper addresses an important theoretical question for cognitive science: What are the possible cognitive mechanisms underlying such SFT experiences? We contrasted three hypotheses present in the literature: the online construction hypothesis, the recasting hypothesis, and the memories of future thoughts hypothesis. Study 1 (N = 41) used novel subjective ratings which challenged the recasting mechanism: SFTs were mostly rated as dissimilar to autobiographical memories, suggesting they are not simply past experiences 'recast' as future events. Study 2 (N = 90) used a novel experimental paradigm, comparing effects of voluntary episodic future constructions and non-personal narratives upon subsequent spontaneous thought sampling. Results suggested that voluntary future constructions remain accessible to spontaneous retrieval, supporting the memories of future thoughts hypothesis. This finding, and other data presented across the two studies, still indicates a role for online construction processes in SFT, but further empirical work is needed to clarify how and when constructive processes are engaged in SFT. Taken together, these two studies represent initial efforts to elucidate the mechanisms underlying SFT, providing the first proof-of-principle that deliberately envisioned future events can reappear, without intention, in consciousness at some later time, and further supporting the dual process account of future thinking. These methods and findings provide a firm basis for subsequent experimental and longitudinal research on SFT.

11.
Annu Rev Immunol ; 42(1): 317-345, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38941605

RESUMO

Regionalized immune surveillance relies on the concerted efforts of diverse memory T cell populations. Of these, tissue-resident memory T (TRM) cells are strategically positioned in barrier tissues, where they enable efficient frontline defense against infections and cancer. However, the long-term persistence of these cells has been implicated in a variety of immune-mediated pathologies. Consequently, modulating TRM cell populations represents an attractive strategy for novel vaccination and therapeutic interventions against tissue-based diseases. Here, we provide an updated overview of TRM cell heterogeneity and function across tissues and disease states. We discuss mechanisms of TRM cell-mediated immune protection and their potential contributions to autoimmune disorders. Finally, we examine how TRM cell responses might be durably boosted or dampened for therapeutic gain.


Assuntos
Memória Imunológica , Células T de Memória , Humanos , Animais , Células T de Memória/imunologia , Células T de Memória/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Especificidade de Órgãos/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Vigilância Imunológica
12.
Cell Rep ; 43(6): 114317, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38848213

RESUMO

Naive CD4+ T cells must differentiate in order to orchestrate immunity to Plasmodium, yet understanding of their emerging phenotypes, clonality, spatial distributions, and cellular interactions remains incomplete. Here, we observe that splenic polyclonal CD4+ T cells differentiate toward T helper 1 (Th1) and T follicular helper (Tfh)-like states and exhibit rarer phenotypes not elicited among T cell receptor (TCR) transgenic counterparts. TCR clones present at higher frequencies exhibit Th1 skewing, suggesting that variation in major histocompatibility complex class II (MHC-II) interaction influences proliferation and Th1 differentiation. To characterize CD4+ T cell interactions, we map splenic microarchitecture, cellular locations, and molecular interactions using spatial transcriptomics at near single-cell resolution. Tfh-like cells co-locate with stromal cells in B cell follicles, while Th1 cells in red pulp co-locate with activated monocytes expressing multiple chemokines and MHC-II. Spatial mapping of individual transcriptomes suggests that proximity to chemokine-expressing monocytes correlates with stronger effector phenotypes in Th1 cells. Finally, CRISPR-Cas9 gene disruption reveals a role for CCR5 in promoting clonal expansion and Th1 differentiation. A database of cellular locations and interactions is presented: https://haquelab.mdhs.unimelb.edu.au/spatial_gui/.


Assuntos
Linfócitos T CD4-Positivos , Diferenciação Celular , Malária , Fenótipo , Animais , Malária/imunologia , Malária/parasitologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Th1/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores CCR5/metabolismo , Receptores CCR5/genética , Baço/imunologia
13.
Ophthalmology ; 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38703795

RESUMO

PURPOSE: Defining how the in vivo immune status of peripheral tissues is shaped by the external environment has remained a technical challenge. We recently developed Functional in vivo confocal microscopy (Fun-IVCM) for dynamic, longitudinal imaging of corneal immune cells in living humans. This study investigated the effect of seasonal-driven environmental factors on the morphodynamic features of human corneal immune cell subsets. DESIGN: Longitudinal, observational clinical study. PARTICIPANTS: Sixteen healthy participants (aged 18-40 years) attended 2 visits in distinct seasons in Melbourne, Australia (Visit 1, November-December 2021 [spring-summer]; Visit 2, April-June 2022 [autumn-winter]). METHODS: Environmental data were collected over each period. Participants underwent ocular surface examinations and corneal Fun-IVCM (Heidelberg Engineering). Corneal scans were acquired at 5.5 ± 1.5-minute intervals for up to 5 time points. Time-lapse Fun-IVCM videos were created to analyze corneal immune cells, comprising epithelial T cells and dendritic cells (DCs), and stromal macrophages. Tear cytokines were analyzed using a multiplex bead-based immunoassay. MAIN OUTCOME MEASURES: Difference in the density, morphology, and dynamic parameters of corneal immune cell subsets over the study periods. RESULTS: Visit 1 was characterized by higher temperature, lower humidity, and higher air particulate and pollen levels compared with Visit 2. Clinical ocular surface parameters and the density of immune cell subsets were similar across visits. At Visit 1 , corneal epithelial DCs were larger, with a lower dendrite probing speed (0.38 ± 0.21 vs. 0.68 ± 0.33 µm/min; P < 0.001) relative to Visit 2; stromal macrophages were more circular and had less dynamic activity (Visit 1, 7.2 ± 1.9 vs. Visit 2, 10.3 ± 3.7 dancing index; P < 0.001). Corneal T cell morphodynamics were unchanged across periods. Basal tear levels of interleukin 2 and CXCL10 were relatively lower during spring-summer. CONCLUSIONS: This study identifies that the in vivo morphodynamics of innate corneal immune cells (DCs, macrophages) are modified by environmental factors, but such effects are not evident for adaptive immune cells (T cells). The cornea is a potential in vivo window to investigate season-dependent environmental influences on the human immune system. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

14.
Behav Res Ther ; 179: 104556, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38761558

RESUMO

Trichotillomania (TTM) is associated with impairments in response inhibition and cognitive flexibility, but it is unclear how such impairments relate to treatment outcome. The present study examined pre-treatment response inhibition and cognitive flexibility as predictors of treatment outcome, change in these domains from pre-to post-treatment, and associations with TTM severity. Participants were drawn from a randomized controlled trial comparing acceptance-enhanced behavior therapy (AEBT) to psychoeducation and supportive therapy (PST) for TTM. Adults completed assessments at pre-treatment (n = 88) and following 12 weeks of treatment (n = 68). Response inhibition and cognitive flexibility were assessed using the Stop Signal Task and Object Alternation Task, respectively. Participants completed the MGH-Hairpulling Scale. Independent evaluators administered the NIMH-Trichotillomania Severity Scale and Clinical Global Impressions-Improvement Scale. Higher pre-treatment TTM severity was associated with poorer pre-treatment cognitive flexibility, but not response inhibition. Better pre-treatment response inhibition performance predicted positive treatment response and lower post-treatment TTM symptom severity, irrespective of treatment assignment. Cognitive flexibility did not predict treatment response. After controlling for age, neither neurocognitive variable changed during treatment. Response inhibition and cognitive flexibility appear uniquely related to hair pulling severity and treatment response in adults with TTM. Implications for treatment delivery and development are discussed.


Assuntos
Índice de Gravidade de Doença , Tricotilomania , Humanos , Tricotilomania/terapia , Tricotilomania/psicologia , Tricotilomania/complicações , Feminino , Adulto , Masculino , Resultado do Tratamento , Inibição Psicológica , Pessoa de Meia-Idade , Adulto Jovem , Cognição , Função Executiva/fisiologia , Terapia de Aceitação e Compromisso/métodos , Adolescente
15.
Anal Chem ; 96(22): 9177-9184, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38780285

RESUMO

We describe micro- and nanoelectrode array analysis with an automated version of the array microcell method (AMCM). Characterization of hundreds of electrodes, with diameters ranging from 100 nm to 2 µm, was carried out by using AMCM voltammetry and chronoamperometry. The influence of solvent evaporation on mass transport in the AMCM pipette and the resultant electrochemical response were investigated, with experimental results supported by finite element method simulations. We also describe the application of AMCM to high-throughput single-entity electrochemistry in measurements of stochastic nanoparticle impacts. Collision experiments recorded 3270 single-particle events from 671 electrodes. Data collection parameters were optimized to enable these experiments to be completed in a few hours, and the collision transient sizes were analyzed with a U-Net deep learning model. Elucidation of collision transient sizes by histograms from these experiments was enhanced due to the large sample size possible with AMCM.

16.
J Environ Manage ; 360: 121070, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38744210

RESUMO

Countries' circularity performance and CO2 emissions should be addressed as a part of the UN net-zero Sustainable Development Goals (SDGs) 2030. Macro-scale circularity assessment is regarded as a helpful tool for tracking and adjusting nations' progress toward the sustainable Circular Economy (CE) and SDGs. However, practical frameworks are required to address the shortage of real-world circularity assessments at the macro level. The establishment of CE benchmarks is also essential to enhance circularity in less sustainable nations. Further, monitoring the extent to which nations' circularity activities are sustainable and in line with the SDGs is an area that lacks sufficient practical research. The current research aims to develop a macro-level framework and benchmarks for national sustainable circularity assessments. Methodologically, we develop a dynamic network data envelopment analysis (DN-DEA) framework for multi-period circularity and eco-efficiency assessment of OECD countries. To do so, we incorporate dual-role and bidirectional carryovers in our macro-scale framework. From a managerial perspective, we conduct a novel comparative analysis of the circularity and eco-efficiency of the nations to monitor macro-scale sustainable CE trends. Research results reveal a significant performance disparity in circularity, eco-efficiency, and benchmarking patterns. Accordingly, circularly efficient nations cannot necessarily be considered eco-friendly and sustainable. Although Germany (as a superior circular nation) can be regarded as a circularity benchmark, it cannot serve as an eco-efficiency benchmark for less eco-efficient nations. Hence, the new method allows decision-makers not only to identify the nations' circularity outcome but also to distinguish sustainable nations from less sustainable ones. This, on the one hand, provides policymakers with a multi-faceted sustainability analysis, beyond the previous unidimensional analysis. On the other, it proposes improvement benchmarks for planning and regulating nations' future circularity in line with real sustainability goals. The capabilities of our innovative approach are demonstrated in the case study.


Assuntos
Organização para a Cooperação e Desenvolvimento Econômico , Desenvolvimento Sustentável , Conservação dos Recursos Naturais/métodos , Benchmarking , Dióxido de Carbono/análise
17.
Sci Immunol ; 9(94): eadg1094, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38640253

RESUMO

Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here, we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (TPHEX), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with BATF expression and motif accessibility. IFN-γ+ TPHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ+ TPHEX. We also observed IFN-γ+ TPHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19+ leukemia cells. An IFN-γ+ TPHEX gene signature was recapitulated in TEX cells from human cancers, including myeloma and lymphoma. Here, we characterize a TEX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional TEX found in chronic viral infections. Thus, IFN-γ+ TPHEX represent a potential target for immunotherapy of blood cancers.


Assuntos
Neoplasias Hematológicas , Mieloma Múltiplo , Humanos , Receptor Celular 2 do Vírus da Hepatite A , Mieloma Múltiplo/metabolismo , Linfócitos T CD8-Positivos , Fenótipo , Microambiente Tumoral
18.
J Clin Invest ; 134(7)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38557487

RESUMO

Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT), but how this affects immune responses broadly remains unknown. Using a preclinical model of CMV reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells, resulting in sustained IFN-γ secretion, which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for IgG recycling, and rapid IgG loss. T cell-specific deletion of IL-6R led to persistence of recipient-derived, CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN-γ in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invoked IFN-γ-dependent EC injury and consequent IgG loss, leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury, thereby preserving humoral immunity after immunotherapy.


Assuntos
Transplante de Medula Óssea , Infecções por Citomegalovirus , Imunidade Humoral , Interleucina-6 , Antivirais , Transplante de Medula Óssea/efeitos adversos , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/metabolismo , Imunoglobulina G , Interleucina-6/metabolismo , Animais , Camundongos
19.
STAR Protoc ; 5(2): 103036, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38676927

RESUMO

Neurons that originate from pre-vertebral sympathetic ganglia, the splanchnic-celiac-superior mesenteric ganglion complex (SCSMG) in mouse, have important roles in control of organs of the upper abdomen. Here, we present a protocol for the isolation of the mouse sympathetic SCSMG. We describe steps for surgical incision, ganglia isolation, ganglia fine dissection, and whole-mount SCSMG after clearing-enhanced 3D (Ce3D) clearing method and immunohistochemistry. Given the importance of mice in studies of that control, this protocol aims to assist biomedical researchers in the dissection of the mouse SCSMG.


Assuntos
Gânglios Simpáticos , Nervos Esplâncnicos , Animais , Camundongos , Gânglios Simpáticos/citologia , Gânglios Simpáticos/cirurgia , Nervos Esplâncnicos/cirurgia , Imuno-Histoquímica , Dissecação/métodos , Neurônios/citologia
20.
Sci Rep ; 14(1): 9114, 2024 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-38643228

RESUMO

Homeowners in coastal environments often augment their access to estuarine ecosystems by building private docks on their personal property. Despite the commonality of docks, particularly in the Southeastern United States, few works have investigated their historical development, their distribution across the landscape, or the environmental justice dimensions of this distribution. In this study, we used historic aerial photography to track the abundance and size of docks across six South Carolina counties from the 1950s to 2016. Across our roughly 60-year study period, dock abundance grew by two orders of magnitude, mean length of newly constructed docks doubled, and the cumulative length of docks ballooned from 34 to 560 km. Additionally, we drew on census data interpolated into consistent 2010 tract boundaries to analyze the racial and economic distribution of docks in 1994, 1999, 2011, and 2016. Racial composition, measured as the percentage of a tract's population that was White, positively correlated with dock abundance in each year. Median household income and dock abundance were only correlated in 2011. Taken together, these metrics indicate the growing desire for direct estuary access, however, that access does not appear to be equally spread across racial groups. Because docks enhance estuarine access and demarcate private property, our study provides longitudinal insights into environmental justice concerns related to disparate private property ownership. We found a persistent correlation between the racial characteristics of an area and dock abundance, strongly indicating that White South Carolinians have had disproportionately greater private water access for the past two decades.


Assuntos
Ecossistema , Meio Ambiente , Geografia , South Carolina/epidemiologia , Brancos
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