Two-dimensional-lattice-confined single-molecule-like aggregates.

Intermolecular distance largely determines the optoelectronic properties of organic matter. Conventional organic luminescent molecules are commonly used either as aggregates or as single molecules that are diluted in a foreigner matrix. They have garnered great research interest in recent decades for a variety of applications, including light-emitting diodes1,2, lasers3-5 and quantum technologies6,7, among others8-10. However, there is still a knowledge gap on how these molecules behave between the aggregation and dilution states. Here we report an unprecedented phase of molecular aggregate that forms in a two-dimensional hybrid perovskite superlattice with a near-equilibrium distance, which we refer to as a single-molecule-like aggregate (SMA). By implementing two-dimensional superlattices, the organic emitters are held in proximity, but, surprisingly, remain electronically isolated, thereby resulting in a near-unity photoluminescence quantum yield, akin to that of single molecules. Moreover, the emitters within the perovskite superlattices demonstrate strong alignment and dense packing resembling aggregates, allowing for the observation of robust directional emission, substantially enhanced radiative recombination and efficient lasing. Molecular dynamics simulations together with single-crystal structure analysis emphasize the critical role of the internal rotational and vibrational degrees of freedom of the molecules in the two-dimensional lattice for creating the exclusive SMA phase. This two-dimensional superlattice unifies the paradoxical properties of single molecules and aggregates, thus offering exciting possibilities for advanced spectroscopic and photonic applications.

Cemented Constrained Liners Used as an Articulating Hip Spacer for the Treatment of Chronic Prosthetic Joint Infection.

Background: Two-stage exchange arthroplasty remains the gold standard for treating chronic hip periprosthetic joint infections. However, controversy remains regarding the optimal spacer type, particularly among patients with increased dislocation risk. This study reports on the outcomes of articulating hip spacers utilizing a single constrained-liner design. Methods: All patients who underwent treatment for hip periprosthetic joint infection at a single institution were screened. Patients were included if they received an articulating spacer utilizing a constrained liner of a single manufacturer design. Indications for constrained liner, demographic variables, and surgical variables were recorded. Patients were assessed for dislocation and component loosening prior to the second stage or at the final follow-up if the second stage was not undertaken. Comparative analysis was performed. Results: Overall, 26 constrained liners were utilized in 25 patients. Indications for constrained liner included history of dislocation (n = 14), massive proximal femoral bone loss (n = 14), greater trochanteric deficiency (n = 12), and absent abductors (n = 7). Many patients had more than one indication. In total, 9 hips (34.6%) underwent a second stage at an average of 7.4 months, while 17 hips never underwent a second stage with an average follow-up of 27.6 months. One patient experienced failure of their constrained liner prior to the second stage due to pelvic discontinuity and massive acetabular bone loss. Conclusions: Utilization of a constrained liner as an articulating spacer is a viable option for patients at high risk of instability. Meticulous cement technique, appropriate component position, and implant selection are crucial in achieving successful outcomes.

Bacillary hemoglobinuria in beef cattle infected with Fascioloides magna in Missouri.

Bacillary hemoglobinuria (BH) is an infectious disease, mostly affecting cattle, caused by Clostridium haemolyticum (C. novyi type D), with acute hepatic necrosis and intravascular hemolysis. Cattle are typically predisposed to BH by liver injury caused by Fasciola hepatica, although cases have been reported in cattle without evidence of this parasite. Here we describe a cluster of 14 BH cases from 7 counties in north-central to central Missouri submitted to a veterinary diagnostic laboratory between December 2020 and April 2023. Postmortem examination in all cases revealed hemoglobinuria and acute hepatic necrosis with large numbers of gram-positive bacilli with terminal-to-subterminal spores. Flukes, fluke ova, and/or fluke pigment consistent with Fascioloides magna were identified in 12 of 14 cases. Sequences of the nuclear ribosomal internal transcribed spacer 1 (ITS1) from one fluke had 100% identity to F. magna. C. novyi was detected by fluorescent antibody testing of liver impression smears (11 of 12 cases) and by immunohistochemistry of liver sections (7 of 7 cases). PCR on formalin-fixed, paraffin-embedded tissues amplified the C. haemolyticum beta toxin gene in each of the 7 cases tested. To our knowledge, a confirmed cluster of BH associated with F. magna has not been reported previously in cattle.

Intranasal delivery of imaging agents to the brain.

The potential of intranasal administered imaging agents to altogether bypass the blood-brain barrier offers a promising non-invasive approach for delivery directly to the brain. This review provides a comprehensive analysis of the advancements and challenges of delivering neuroimaging agents to the brain by way of the intranasal route, focusing on the various imaging modalities and their applications in central nervous system diagnostics and therapeutics. The various imaging modalities provide distinct insights into the pharmacokinetics, biodistribution, and specific interactions of imaging agents within the brain, facilitated by the use of tailored tracers and contrast agents. Methods: A comprehensive literature search spanned PubMed, Scopus, Embase, and Web of Science, covering publications from 1989 to 2024 inclusive. Starting with advancements in tracer development, we going to explore the rationale for integration of imaging techniques, and the critical role novel formulations such as nanoparticles, nano- and micro-emulsions in enhancing imaging agent delivery and visualisation. Results: The review highlights the use of innovative formulations in improving intranasal administration of neuroimaging agents, showcasing their ability to navigate the complex anatomical and physiological barriers of the nose-to-brain pathway. Various imaging techniques, MRI, PET, SPECT, CT, FUS and OI, were evaluated for their effectiveness in tracking these agents. The findings indicate significant improvements in brain targeting efficiency, rapid uptake, and sustained brain presence using innovative formulations. Conclusion: Future directions involve the development of optimised tracers tailored for intranasal administration, the potential of multimodal imaging approaches, and the implications of these advancements for diagnosing and treating neurological disorders.

Clinical and Neuropathological Correlates of Substance Use in American Football Players.

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy more frequently found in deceased former football players. CTE has heterogeneous clinical presentations with multifactorial causes. Previous literature has shown substance use (alcohol/drug) can contribute to Alzheimer's disease and related tauopathies pathologically and clinically. Objective: To examine the association between substance use and clinical and neuropathological endpoints of CTE. Methods: Our sample included 429 deceased male football players. CTE was neuropathologically diagnosed. Informant interviews assessed features of substance use and history of treatment for substance use to define indicators: history of substance use treatment (yes vs no, primary variable), alcohol severity, and drug severity. Outcomes included scales that were completed by informants to assess cognition (Cognitive Difficulties Scale, BRIEF-A Metacognition Index), mood (Geriatric Depression Scale-15), behavioral regulation (BRIEF-A Behavioral Regulation Index, Barratt Impulsiveness Scale-11), functional ability (Functional Activities Questionnaire), as well as CTE status and cumulative p-tau burden. Regression models tested associations between substance use indicators and outcomes. Results: Of the 429 football players (mean age = 62.07), 313 (73%) had autopsy confirmed CTE and 100 (23%) had substance use treatment history. Substance use treatment and alcohol/drug severity were associated with measures of behavioral regulation (FDR-p-values<0.05, ΔR2 = 0.04-0.18) and depression (FDR-p-values<0.05, ΔR2 = 0.02-0.05). Substance use indicators had minimal associations with cognitive scales, whereas p-tau burden was associated with all cognitive scales (p-values <0.05). Substance use treatment had no associations with neuropathological endpoints (FDR-p-values>0.05). Conclusions: Among deceased football players, substance use was common and associated with clinical symptoms.

CRISPR-directed gene-editing induces genetic rearrangement within the human globin gene locus.

CRISPR-Cas is a revolutionary technology but has already demonstrated significant feasibility for clinical and non-clinical applications. While the efficiency and precision of this remarkable genetic tool is unprecedented, unfortunately, a series of collateral genetic rearrangement have been reported in response to double-stranded DNA breakage. Once these molecular scissions occur, the cascade of DNA repair reactions can lead to genomic rearrangements especially if breakage takes place within a family of sequence related genes. Here, we demonstrate that CRISPR- directed gene editing near the sickle cell mutation site generates a curious genetic outcome; a footprint of the δ globin gene proximal to the CRISPR/Cas cut site(s). This rearrangement is not dependent on the presence of an exogenously added DNA template but is apparently dependent on a double strand break. Our results the highlight recombinational capacity of double strand breaks in human chromosomes where the aim is to edit a human gene.

Sex differences in gray matter, white matter, and regional brain perfusion in young, healthy adults.

Cerebrovascular and neurological diseases exhibit sex-specific patterns in prevalence, severity, and regional specificity, some of which are associated with altered cerebral blood flow (CBF). Females often exhibit higher resting CBF, but understanding the impact of sex per se on CBF is hampered by study variability in age, comorbidities, medications, and control for menstrual cycle or hormone therapies. A majority of studies report whole brain CBF without differentiating between gray and white matter or without assessing regional CBF. Thus fundamental sex differences in regional or whole brain CBF remain unclarified. While controlling for the above confounders, we tested the hypothesis that females will exhibit higher total gray and white matter perfusion as well as regional gray matter perfusion. Adults 18-30 yr old (females = 22 and males = 26) were studied using arterial spin labeling (ASL) magnetic resonance imaging (MRI) scans followed by computational anatomy toolbox (CAT12) analysis in statistical parametric mapping (SPM12) to quantify CBF relative to brain volume. Females displayed 40% higher perfusion globally (females = 62 ± 9 and males = 45 ± 10 mL/100 g/min, P < 0.001), gray matter (females = 75 ± 11 and males = 54 ± 12 mL/100 g/min, P < 0.001), and white matter (females = 44 ± 6 and males = 32 ± 7 mL/100 g/min, P < 0.001). Females exhibited greater perfusion than males in 67 of the 68 regions tested, ranging from 14% to 66% higher. A second MRI approach (4-dimensional flow) focused on large arteries confirmed the sex difference in global CBF. These data indicate strikingly higher basal CBF in females at global, gray, and white matter levels and across dozens of brain regions and offer new clarity into fundamental sex differences in global and regional CBF regulation before aging or pathology.NEW & NOTEWORTHY MRI used to measure cerebral blood flow (CBF) in gray matter, white matter, and 68 regions in healthy men and women. This study demonstrated that CBF is 40% higher in women, the highest sex difference reported, when controlling for numerous important clinical confounders like age, smoking, menstrual cycle, comorbidities, and medications.

The Literature that Commercial Insurance Payers Use to Substantiate Knee Osteochondral Allograft Policies Are of a Low Level of Evidence.

OBJECTIVE: The purpose of this study is to analyze how the largest insurance companies support their medical necessity policies regarding osteochondral allograft transplantation (OCA) and to determine whether the literature they cite in their policies is of a high level of evidence (LOE). DESIGN: The 10 largest national health insurance companies were identified. Each payer was contacted via phone or email to obtain their coverage policy regarding OCA. For each policy, the medical necessity criteria were recorded, and all cited references were screened. For all references applicable to OCA, the LOE was recorded, and each reference was screened to determine whether they mentioned the specific criteria reported in the policies. RESULTS: The medical policies for 6 of the 10 national health insurance companies were identified. These 6 policies cited a collective total of 102 applicable references. Most of these studies were an LOE of IV (n = 58, 56.9%) and an LOE of V (n = 18, 17.6%). There were similarities amongst the medical necessity criteria between different commercial payers; however, most criteria were poorly supported by the cited literature. CONCLUSIONS: Our results demonstrate that commercial insurance companies utilize studies that are of a low LOE when justifying their medical necessity criteria. Moreover, these cited studies infrequently support or mention the commercial payers' criteria. Future studies should continue to explore how well-supported insurance policies are with the goal of potentially increasing access and authorization for well-supported treatment modalities.

Mechanism and regulation of cargo entry into the Commander endosomal recycling pathway.

Commander is a multiprotein complex that orchestrates endosomal recycling of integral cargo proteins and is essential for normal development. While the structure of this complex has recently been described, how cargo proteins are selected for Commander-mediated recycling remains unclear. Here we identify the mechanism through which the unstructured carboxy-terminal tail of the cargo adaptor sorting nexin-17 (SNX17) directly binds to the Retriever sub-complex of Commander. SNX17 adopts an autoinhibited conformation where its carboxy-terminal tail occupies the cargo binding groove. Competitive cargo binding overcomes this autoinhibition, promoting SNX17 endosomal residency and the release of the tail for Retriever association. Furthermore, our study establishes the central importance of SNX17-Retriever association in the handover of integrin and lipoprotein receptor cargoes into pre-existing endosomal retrieval sub-domains. In describing the principal mechanism of cargo entry into the Commander recycling pathway we provide key insight into the function and regulation of this evolutionary conserved sorting pathway.

Structural basis for coupling of the WASH subunit FAM21 with the endosomal SNX27-Retromer complex.

Endosomal membrane trafficking is mediated by specific protein coats and formation of actin-rich membrane domains. The Retromer complex coordinates with sorting nexin (SNX) cargo adaptors including SNX27, and the SNX27-Retromer assembly interacts with the Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex which nucleates actin filaments establishing the endosomal recycling domain. Crystal structures, modeling, biochemical, and cellular validation reveal how the FAM21 subunit of WASH interacts with both Retromer and SNX27. FAM21 binds the FERM domain of SNX27 using acidic-Asp-Leu-Phe (aDLF) motifs similar to those found in the SNX1 and SNX2 subunits of the ESCPE-1 complex. Overlapping FAM21 repeats and a specific Pro-Leu containing motif bind three distinct sites on Retromer involving both the VPS35 and VPS29 subunits. Mutation of the major VPS35-binding site does not prevent cargo recycling; however, it partially reduces endosomal WASH association indicating that a network of redundant interactions promote endosomal activity of the WASH complex. These studies establish the molecular basis for how SNX27-Retromer is coupled to the WASH complex via overlapping and multiplexed motif-based interactions required for the dynamic assembly of endosomal membrane recycling domains.

Elevated Salt or Angiotensin II Levels Induce CD38+ Innate Immune Cells in the Presence of Granulocyte-Macrophage Colony Stimulating Factor.

Hypertension (HTN) impacts almost half of adults, predisposing them to cardiovascular disease and renal damage. Salt-sensitive HTN (SSHTN) and angiotensin II (A2)-induced HTN (A2HTN) both involve immune system activation and renal innate immune cell infiltration. Subpopulations of activated [Cluster of differentiation 38 (CD38)] innate immune cells, such as macrophages and dendritic cells (DCs), play distinct roles in modulating renal function and blood pressure. It is unknown how these cells become CD38+ or which subtypes are pro-hypertensive. When bone marrow-derived monocytes (BMDMs) were grown in granulocyte-macrophage colony stimulating factor (GM-CSF) and treated with salt or A2, CD38+ macrophages and CD38+ DCs increased. The adoptive transfer of GM-CSF-primed BMDMs into mice with either SSHTN or A2HTN increased renal CD38+ macrophages and CD38+ DCs. Flow cytometry revealed increased renal M1 macrophages and type-2 conventional DCs (cDC2s), along with their CD38+ counterparts, in mice with either SSHTN or A2HTN. These results were replicable in vitro. Either salt or A2 treatment of GM-CSF-primed BMDMs significantly increased bone marrow-derived (BMD)-M1 macrophages, CD38+ BMD-M1 macrophages, BMD-cDC2s, and CD38+ BMD-cDC2s. Overall, these data suggest that GM-CSF is necessary for the salt or A2 induction of CD38+ innate immune cells, and that CD38 distinguishes pro-hypertensive immune cells. Further investigation of CD38+ M1 macrophages and CD38+ cDC2s could provide new therapeutic targets for both SSHTN and A2HTN.

Assessing the Readability of Patient Education Materials on Cardiac Catheterization From Artificial Intelligence Chatbots: An Observational Cross-Sectional Study.

BACKGROUND: Artificial intelligence (AI) is a burgeoning new field that has increased in popularity over the past couple of years, coinciding with the public release of large language model (LLM)-driven chatbots. These chatbots, such as ChatGPT, can be engaged directly in conversation, allowing users to ask them questions or issue other commands. Since LLMs are trained on large amounts of text data, they can also answer questions reliably and factually, an ability that has allowed them to serve as a source for medical inquiries. This study seeks to assess the readability of patient education materials on cardiac catheterization across four of the most common chatbots: ChatGPT, Microsoft Copilot, Google Gemini, and Meta AI. METHODOLOGY: A set of 10 questions regarding cardiac catheterization was developed using website-based patient education materials on the topic. We then asked these questions in consecutive order to four of the most common chatbots: ChatGPT, Microsoft Copilot, Google Gemini, and Meta AI. The Flesch Reading Ease Score (FRES) was used to assess the readability score. Readability grade levels were assessed using six tools: Flesch-Kincaid Grade Level (FKGL), Gunning Fog Index (GFI), Coleman-Liau Index (CLI), Simple Measure of Gobbledygook (SMOG) Index, Automated Readability Index (ARI), and FORCAST Grade Level. RESULTS: The mean FRES across all four chatbots was 40.2, while overall mean grade levels for the four chatbots were 11.2, 13.7, 13.7, 13.3, 11.2, and 11.6 across the FKGL, GFI, CLI, SMOG, ARI, and FORCAST indices, respectively. Mean reading grade levels across the six tools were 14.8 for ChatGPT, 12.3 for Microsoft Copilot, 13.1 for Google Gemini, and 9.6 for Meta AI. Further, FRES values for the four chatbots were 31, 35.8, 36.4, and 57.7, respectively. CONCLUSIONS: This study shows that AI chatbots are capable of providing answers to medical questions regarding cardiac catheterization. However, the responses across the four chatbots had overall mean reading grade levels at the 11th-13th-grade level, depending on the tool used. This means that the materials were at the high school and even college reading level, which far exceeds the recommended sixth-grade level for patient education materials. Further, there is significant variability in the readability levels provided by different chatbots as, across all six grade-level assessments, Meta AI had the lowest scores and ChatGPT generally had the highest.

Deductive machine learning models for product identification.

Deductive solution strategies are required in prediction scenarios that are under determined, when contradictory information is available, or more generally wherever one-to-many non-functional mappings occur. In contrast, most contemporary machine learning (ML) in the chemical sciences is inductive learning from example, with a fixed set of features. Chemical workflows are replete with situations requiring deduction, including many aspects of lab automation and spectral interpretation. Here, a general strategy is described for designing and training machine learning models capable of deduction that consists of combining individual inductive models into a larger deductive network. The training and testing of these models is demonstrated on the task of deducing reaction products from a mixture of spectral sources. The resulting models can distinguish between intended and unintended reaction outcomes and identify starting material based on a mixture of spectral sources. The models also perform well on tasks that they were not directly trained on, like performing structural inference using real rather than simulated spectral inputs, predicting minor products from named organic chemistry reactions, identifying reagents and isomers as plausible impurities, and handling missing or conflicting information. A new dataset of 1 124 043 simulated spectra that were generated to train these models is also distributed with this work. These findings demonstrate that deductive bottlenecks for chemical problems are not fundamentally insuperable for ML models.

Remote Patient Monitoring Is Associated with Improved Outcomes in Hypertension: A Large, Retrospective, Cohort Analysis.

Hypertension (HTN) is a chronic condition that requires careful monitoring and management. Blood pressure readings in the clinic and self-reported blood pressure readings are often too intermittent to allow for careful management. Remote patient monitoring is a solution that may have positive impacts on HTN management. Individuals at cardiac and primary care clinics were prescribed a remote patient-monitoring (RPM) program. Patients were sent blood pressure monitors that were enabled to transmit data over cellular networks. We reviewed trends in HTN management retrospectively in patients who had previously been on conventional therapy for a year and participated in RPM for a minimum of 90 days. There were 6595 patients enrolled, and the mean duration on RPM was 289 days. A total of 4370 participants (66.3%) had uncontrolled HTN, and 2476 (37.5%) had stage 2 HTN. After at least 90 days on the RPM program, the number of patients with uncontrolled HTN reduced to 2648 (40.2%, p < 0.01), and the number of patients with stage 2 HTN reduced to 1261 (19.1%, p < 0.01). Systolic blood pressure improved by 7.3 mmHg for all patients and 16.7 mmHg for stage 2 HTN. There was improvement in mean arterial pressure (MAP) in all patients with uncontrolled HTN by 8.5 mmHg (p < 0.0001). RPM is associated with improved HTN control and provides further evidence supporting telehealth programs which can aid in chronic disease management.

PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4.

Mitophagy must be carefully regulated to ensure that cells maintain appropriate numbers of functional mitochondria. The SCFFBXL4 ubiquitin ligase complex suppresses mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors, and FBXL4 mutations result in mitochondrial disease as a consequence of elevated mitophagy. Here, we reveal that the mitochondrial phosphatase PPTC7 is an essential cofactor for SCFFBXL4-mediated destruction of BNIP3 and NIX, suppressing both steady-state and induced mitophagy. Disruption of the phosphatase activity of PPTC7 does not influence BNIP3 and NIX turnover. Rather, a pool of PPTC7 on the mitochondrial outer membrane acts as an adaptor linking BNIP3 and NIX to FBXL4, facilitating the turnover of these mitophagy receptors. PPTC7 accumulates on the outer mitochondrial membrane in response to mitophagy induction or the absence of FBXL4, suggesting a homoeostatic feedback mechanism that attenuates high levels of mitophagy. We mapped critical residues required for PPTC7-BNIP3/NIX and PPTC7-FBXL4 interactions and their disruption interferes with both BNIP3/NIX degradation and mitophagy suppression. Collectively, these findings delineate a complex regulatory mechanism that restricts BNIP3/NIX-induced mitophagy.

Differential changes in end organ immune cells and inflammation in salt-sensitive hypertension: effects of increasing M2 macrophages.

Salt-sensitive hypertension (SSHTN) is associated with M1 macrophage polarization and inflammatory responses, leading to inflammation-associated lymphangiogenesis and functional impairment across multiple organs, including kidneys and gonads. However, it remains unclear whether promoting M2 macrophage polarization can alleviate the hypertension, inflammation, and end organ damage in mice with salt sensitive hypertension (SSHTN). Male and female mice were made hypertensive by administering nitro-L-arginine methyl ester hydrochloride (L-NAME; 0.5 mg/ml) for 2 weeks in the drinking water, followed by a 2-week interval without any treatments, and a subsequent high salt diet for 3 weeks (SSHTN). AVE0991 (AVE) was intraperitoneally administered concurrently with the high salt diet. Control mice were provided standard diet and tap water. AVE treatment significantly attenuated BP and inflammation in mice with SSHTN. Notably, AVE promoted M2 macrophage polarization, decreased pro-inflammatory immune cell populations, and improved function in renal and gonadal tissues of mice with SSHTN. Additionally, AVE decreased lymphangiogenesis in the kidneys and testes of male SSHTN mice and the ovaries of female SSHTN mice. These findings highlight the effectiveness of AVE in mitigating SSHTN-induced elevated BP, inflammation, and end organ damage by promoting M2 macrophage polarization and suppressing pro-inflammatory immune responses. Targeting macrophage polarization emerges as a promising therapeutic approach for alleviating inflammation and organ damage in SSHTN. Further studies are warranted to elucidate the precise mechanisms underlying AVE-mediated effects and to assess its clinical potential in managing SSHTN.

Differential changes in end organ immune cells and inflammation in salt-sensitive hypertension: effects of lowering blood pressure.

We reported that salt-sensitive hypertension (SSHTN) is associated with increased pro-inflammatory immune cells, inflammation, and inflammation-associated lymphangiogenesis in the kidneys and gonads of male and female mice. However, it is unknown whether these adverse end organ effects result from increased blood pressure (BP), elevated levels of salt, or both. We hypothesized that pharmaceutically lowering BP would not fully alleviate the renal and gonadal immune cell accumulation, inflammation, and lymphangiogenesis associated with SSHTN. SSHTN was induced in male and female C57BL6/J mice by administering nitro-L-arginine methyl ester hydrochloride (L-NAME; 0.5 mg/ml) in their drinking water for 2 weeks, followed by a 2-week washout period. Subsequently, the mice received a 3-week 4% high salt diet (SSHTN). The treatment group underwent the same SSHTN induction protocol but received hydralazine (HYD; 250 mg/L) in their drinking water during the diet phase (SSHTN+HYD). Control mice received tap water and a standard diet for 7 weeks. In addition to decreasing systolic BP, HYD treatment generally decreased pro-inflammatory immune cells and inflammation in the kidneys and gonads of SSHTN mice. Furthermore, the decrease in BP partially alleviated elevated renal and gonadal lymphatics and improved renal and gonadal function in mice with SSHTN. These data demonstrate that high systemic pressure and salt differentially act on end organ immune cells, contributing to the broader understanding of how BP and salt intake collectively shape immune responses and highlight implications for targeted therapeutic interventions.