Emergence of large-scale cell death through ferroptotic trigger waves.

Large-scale cell death is commonly observed during organismal development and in human pathologies1-5. These cell death events extend over great distances to eliminate large populations of cells, raising the question of how cell death can be coordinated in space and time. One mechanism that enables long-range signal transmission is trigger waves6, but how this mechanism might be used for death events in cell populations remains unclear. Here we demonstrate that ferroptosis, an iron- and lipid-peroxidation-dependent form of cell death, can propagate across human cells over long distances (≥5 mm) at constant speeds (around 5.5 µm min-1) through trigger waves of reactive oxygen species (ROS). Chemical and genetic perturbations indicate a primary role of ROS feedback loops (Fenton reaction, NADPH oxidase signalling and glutathione synthesis) in controlling the progression of ferroptotic trigger waves. We show that introducing ferroptotic stress through suppression of cystine uptake activates these ROS feedback loops, converting cellular redox systems from being monostable to being bistable and thereby priming cell populations to become bistable media over which ROS propagate. Furthermore, we demonstrate that ferroptosis and its propagation accompany the massive, yet spatially restricted, cell death events during muscle remodelling of the embryonic avian limb, substantiating its use as a tissue-sculpting strategy during embryogenesis. Our findings highlight the role of ferroptosis in coordinating global cell death events, providing a paradigm for investigating large-scale cell death in embryonic development and human pathologies.

DNA hypomethylation ameliorates erosive inflammatory arthritis by modulating interferon regulatory factor-8.

Epigenetic regulation plays a crucial role in the pathogenesis of autoimmune diseases such as inflammatory arthritis. DNA hypomethylating agents, such as decitabine (DAC), have been shown to dampen inflammation and restore immune homeostasis. In the present study, we demonstrate that DAC elicits potent anti-inflammatory effects and attenuates disease symptoms in several animal models of arthritis. Transcriptomic and epigenomic profiling show that DAC-mediated hypomethylation regulates a wide range of cell types in arthritis, altering the differentiation trajectories of anti-inflammatory macrophage populations, regulatory T cells, and tissue-protective synovial fibroblasts (SFs). Mechanistically, DAC-mediated demethylation of intragenic 5'-Cytosine phosphate Guanine-3' (CpG) islands of the transcription factor Irf8 (interferon regulatory factor 8) induced its re-expression and promoted its repressor activity. As a result, DAC restored joint homeostasis by resetting the transcriptomic signature of negative regulators of inflammation in synovial macrophages (MerTK, Trem2, and Cx3cr1), TREGs (Foxp3), and SFs (Pdpn and Fapα). In conclusion, we found that Irf8 is necessary for the inhibitory effect of DAC in murine arthritis and that direct expression of Irf8 is sufficient to significantly mitigate arthritis.

Independent insulin signaling modulators govern hot avoidance under different feeding states.

Thermosensation is critical for the survival of animals. However, mechanisms through which nutritional status modulates thermosensation remain unclear. Herein, we showed that hungry Drosophila exhibit a strong hot avoidance behavior (HAB) compared to food-sated flies. We identified that hot stimulus increases the activity of α'ß' mushroom body neurons (MBns), with weak activity in the sated state and strong activity in the hungry state. Furthermore, we showed that α'ß' MBn receives the same level of hot input from the mALT projection neurons via cholinergic transmission in sated and hungry states. Differences in α'ß' MBn activity between food-sated and hungry flies following heat stimuli are regulated by distinct Drosophila insulin-like peptides (Dilps). Dilp2 is secreted by insulin-producing cells (IPCs) and regulates HAB during satiety, whereas Dilp6 is secreted by the fat body and regulates HAB during the hungry state. We observed that Dilp2 induces PI3K/AKT signaling, whereas Dilp6 induces Ras/ERK signaling in α'ß' MBn to regulate HAB in different feeding conditions. Finally, we showed that the 2 α'ß'-related MB output neurons (MBONs), MBON-α'3 and MBON-ß'1, are necessary for the output of integrated hot avoidance information from α'ß' MBn. Our results demonstrate the presence of dual insulin modulation pathways in α'ß' MBn, which are important for suitable behavioral responses in Drosophila during thermoregulation under different feeding states.

Degeneration of the Olfactory System in a Murid Rodent that Evolved Diurnalism.

In mammalian research, it has been debated what can initiate an evolutionary tradeoff between different senses, and the phenomenon of sensory tradeoff in rodents, the most abundant mammalian clade, is not evident. The Nile rat (Arvicanthis niloticus), a murid rodent, recently adapted to a diurnal niche through an evolutionary acquisition of daylight vision with enhanced visual acuity. As such, this model provides an opportunity for a cross-species investigation where comparative morphological and multi-omic analyses of the Nile rat are made with its closely related nocturnal species, e.g. the mouse (Mus musculus) and the rat (Rattus norvegicus). Thus, morphological examinations were performed, and evolutionary reductions in relative sizes of turbinal bone surfaces, the cribriform plate, and the olfactory bulb were discovered in Nile rats. Subsequently, we compared multiple murid genomes, and profiled olfactory epithelium transcriptomes of mice and Nile rats at various ages with RNA sequencing. The results further demonstrate that, in comparison with mouse olfactory receptor (OR) genes, Nile rat OR genes have experienced less frequent gain, more frequent loss, and more frequent expression reduction during their evolution. Furthermore, functional degeneration of coding sequences in the Nile rat lineage was found in OR genes, yet not in other genes. Taken together, these results suggest that acquisition of improved vision in the Nile rat has been accompanied by degeneration of both olfaction-related anatomical structures and OR gene repertoires, consistent with the hypothesis of an olfaction-vision tradeoff initiated by the switch from a nocturnal to a diurnal lifestyle in mammals.

Hepatocellular carcinoma reduced, HBsAg loss increased, and survival improved after finite therapy in hepatitis B patients with cirrhosis.

BACKGROUND AND AIMS: Long-term nucleos(t)ide analog (Nuc) treatment can reduce HCC in patients with HBV-related liver cirrhosis (HBV-LC). Earlier small cohort studies showed a comparable 5-year incidence of HCC in HBeAg-negative patients with HBV-LC who stopped and those continued Nuc therapy. This study aimed to validate these findings using a large cohort with 10-year follow-up. APPROACH AND RESULTS: From 2 centers, 494 HBeAg-negative patients with HBV-LC who stopped (finite group) and 593 who continued (continuous group) Nuc therapy were recruited. HCC, HBsAg loss, liver-related mortality/transplantation, and overall survival rates were compared between 2 groups with 1:1 propensity score matching of sex, treatment history, types of Nuc, age, transaminases, platelet count, and HBsAg levels at end of therapy in finite group or 3-year on-therapy in continuous groups. During a median follow-up of 6.2 (3.4-8.9) years, the annual and 10-year HCC incidence were lower in finite group (1.6 vs. 3.3%/y and 10-y 15.7% vs. 26.8%, respectively; log-rank test, p <0.0001). The finite group showed greater HBsAg decline/year (-0.116 vs. -0.095 log 10 IU/mL, p =0.0026) and 7.6 times higher 10-year incidence of HBsAg loss (22.7% vs. 3%, p <0.0001). Multivariate Cox regression showed finite therapy an independent factor for HBsAg loss (adjusted HR: 11.79) but protective against HCC (adjusted HR: 0.593), liver-related mortality/transplantation (adjusted HR: 0.312), and overall mortality (adjusted HR: 0.382). CONCLUSIONS: Finite Nuc therapy in HBeAg-negative HBV-LC may reduce HCC incidence, increase HBsAg loss, and improve survival. Greater HBsAg decline/loss may reflect enhanced immunity and contribute to the reduction of hepatic carcinogenesis.

Impaired Glymphatic and Meningeal Lymphatic Functions in Patients with Chronic Migraine.

OBJECTIVE: This study was undertaken to investigate migraine glymphatic and meningeal lymphatic vessel (mLV) functions. METHODS: Migraine patients and healthy controls (HCs) were prospectively recruited between 2020 and 2023. Diffusion tensor image analysis along the perivascular space (DTI-ALPS) index for glymphatics and dynamic contrast-enhanced magnetic resonance imaging parameters (time to peak [TTP]/enhancement integral [EI]/mean time to enhance [MTE]) for para-superior sagittal (paraSSS)-mLV or paratransverse sinus (paraTS)-mLV in episodic migraine (EM), chronic migraine (CM), and CM with and without medication-overuse headache (MOH) were analyzed. DTI-ALPS correlations with clinical parameters (migraine severity [numeric rating scale]/disability [Migraine Disability Assessment (MIDAS)]/bodily pain [Widespread Pain Index]/sleep quality [Pittsburgh Sleep Quality Index (PSQI)]) were examined. RESULTS: In total, 175 subjects (112 migraine + 63 HCs) were investigated. DTI-ALPS values were lower in CM (median [interquartile range] = 0.64 [0.12]) than in EM (0.71 [0.13], p = 0.005) and HCs (0.71 [0.09], p = 0.004). CM with MOH (0.63 [0.07]) had lower DTI-ALPS values than CM without MOH (0.73 [0.12], p < 0.001). Furthermore, CM had longer TTP (paraSSS-mLV: 55.8 [12.9] vs 40.0 [7.6], p < 0.001; paraTS-mLV: 51.2 [8.1] vs 44.0 [3.3], p = 0.002), EI (paraSSS-mLV: 45.5 [42.0] vs 16.1 [9.2], p < 0.001), and MTE (paraSSS-mLV: 253.7 [6.7] vs 248.4 [13.8], p < 0.001; paraTS-mLV: 252.0 [6.2] vs 249.7 [1.2], p < 0.001) than EM patients. The MIDAS (p = 0.002) and PSQI (p = 0.002) were negatively correlated with DTI-ALPS index after Bonferroni corrections (p < q = 0.01). INTERPRETATION: CM patients, particularly those with MOH, have glymphatic and meningeal lymphatic dysfunctions, which are highly clinically relevant and may implicate pathogenesis for migraine chronification. ANN NEUROL 2024;95:583-595.

Molecular insight into the specific enzymatic properties of TREX1 revealing the diverse functions in processing RNA and DNA/RNA hybrids.

In various autoimmune diseases, dysfunctional TREX1 (Three prime Repair Exonuclease 1) leads to accumulation of endogenous single-stranded DNA (ssDNA), double-stranded DNA (dsDNA) and DNA/RNA hybrids in the cytoplasm and triggers immune activation through the cGAS-STING pathway. Although inhibition of TREX1 could be a useful strategy for cancer immunotherapy, profiling cellular functions in terms of its potential substrates is a key step. Particularly important is the functionality of processing DNA/RNA hybrids and RNA substrates. The exonuclease activity measurements conducted here establish that TREX1 can digest both ssRNA and DNA/RNA hybrids but not dsRNA. The newly solved structures of TREX1-RNA product and TREX1-nucleotide complexes show that 2'-OH does not impose steric hindrance or specific interactions for the recognition of RNA. Through all-atom molecular dynamics simulations, we illustrate that the 2'-OH-mediated intra-chain hydrogen bonding in RNA would affect the binding with TREX1 and thereby reduce the exonuclease activity. This notion of higher conformational rigidity in RNA leading TREX1 to exhibit weaker catalytic cleavage is further validated by the binding affinity measurements with various synthetic DNA-RNA junctions. The results of this work thus provide new insights into the mechanism by which TREX1 processes RNA and DNA/RNA hybrids and contribute to the molecular-level understanding of the complex cellular functions of TREX1 as an exonuclease.

Syphilis and cardiovascular risk: a Taiwanese registry.

BACKGROUND AND AIMS: Studies on the impact of syphilis on the cardiovascular system in large populations are limited. This study investigated the effects of syphilis on cardiovascular outcomes. METHODS: Medical records from 2010 to 2015 were retrieved from the Taiwan National Health Insurance Research Database, linked to the Notifiable Infectious Diseases database from the Taiwan Centers for Disease Control. Patients with syphilis were identified, excluding those with missing information, under 20 years of age, or with a history of human immunodeficiency virus infection, acute myocardial infarction, heart failure, aortic regurgitation, replacement of the aortic valve, aneurysm and/or dissection of the aorta, atrial fibrillation, ischaemic stroke, haemorrhagic stroke, and venous thromboembolism. Primary outcomes included new-onset acute myocardial infarction, heart failure, aortic regurgitation, aneurysm and dissection of the aorta, atrial fibrillation, ischaemic stroke, haemorrhagic stroke, venous thromboembolism, cardiovascular death, and all-cause mortality. RESULTS: A total of 28 796 patients with syphilis were identified from 2010 to 2015. After exclusions and frequency matching, 20 601 syphilis patients and 20 601 non-syphilis patients were analysed. The relative rate (RR) was utilized in the analysis, as the competing risk of death was not considered. Compared with patients without syphilis, patients with syphilis had increased risks of acute myocardial infarction (RR 38%, 95% confidence interval [CI] 1.19-1.60, P < .001), heart failure (RR 88%, 95% CI 1.64-2.14, P < .001), aortic regurgitation (RR 81%, 95% CI 1.18-2.75, P = .006), atrial fibrillation (RR 45%, 95% CI 1.20-1.76, P < .001), ischaemic stroke (RR 68%, 95% CI 1.52-1.87, P < .001), haemorrhagic stroke (RR 114%, 95% CI 1.74-2.64, P < .001), venous thromboembolism (RR 67%, 95% CI 1.23-2.26, P = .001), cardiovascular death (RR 155%, 95% CI 2.11-3.08, P < .001), and all-cause death (RR 196%, 95% CI 2.74-3.19, P < .001) but not for aneurysm and dissection of the aorta. CONCLUSIONS: This study demonstrates that patients with syphilis have a higher risk of cardiovascular events and all-cause mortality compared with those without syphilis.

Bone marrow stromal cell antigen-1 deficiency protects from acute kidney injury.

This study aimed to investigate the role of bone marrow stromal cell antigen-1 (Bst1; also known as CD157) in acute kidney injury (AKI). Bst1 is a cell surface molecule with various enzymatic activities and downstream intracellular signaling pathways that modulate the immune response. Previous research has linked Bst1 to diseases such as ovarian cancer, Parkinson's disease, and rheumatoid arthritis. We used bilateral ischemia-reperfusion injury (IRI) as an AKI model and created bone marrow chimeric mice to evaluate the role of Bst1 in bone marrow-derived cells. We also used flow cytometry to identify Bst1/CD157 expression in hematopoietic cells and evaluate immune cell dynamics in the kidney. The findings showed that Bst1-deficient (Bst1-/-) mice were protected against renal bilateral IRI. Bone marrow chimera experiments revealed that Bst1 expression on hematopoietic cells, but not parenchymal cells, induced renal IRI. Bst1 was mainly found in B cells and neutrophils by flow cytometry of the spleen and bone marrow. In vitro, migration of neutrophils from Bst1-/- mice was suppressed, and adoptive transfer of neutrophils from wild-type Bst1+/+ mice abolished the renal protective effect in Bst1 knockout mice. In conclusion, the study demonstrated that Bst1-/- mice are protected against renal IRI and that Bst1 expression in neutrophils plays a crucial role in inducing renal IRI. These findings suggest that targeting Bst1 in neutrophils could be a potential therapeutic strategy for AKI.NEW & NOTEWORTHY Acute kidney injury (AKI), a serious disease for which there is no effective Federal Drug Administration-approved treatment, is associated with high mortality rates. Bone marrow stromal cell antigen-1 (Bst1) is a cell surface molecule that can cause kidney fibrosis, but its role in AKI is largely unknown. Our study showed that Bst1-/- mice revealed a protective effect against renal bilateral ischemia-reperfusion injury (IRI). Adoptive transfer studies confirmed that Bst1 expression in hematopoietic cells, especially neutrophils, contributed to renal bilateral IRI.

ELIXCYTE®, an Allogenic Adipose-Derived Stem Cell Product, Mitigates Osteoarthritis by Reducing Inflammation and Preventing Cartilage Degradation In Vitro.

Adipose-derived stem cells (ADSCs) comprise a promising therapy for osteoarthritis (OA). The therapeutic potential of ELIXCYTE®, an allogeneic human ADSC (hADSC) product, was demonstrated in a phase I/II OA clinical trial. However, the exact mechanism underlying such effects is not clear. Moreover, studies suggest that interleukin-11 (IL-11) has anti-inflammatory, tissue-regenerative, and immune-regulatory functions. Our aim was to unravel the mechanism associated with the therapeutic effects of ELIXCYTE® on OA and its relationship with IL-11. We cocultured ELIXCYTE® with normal human articular chondrocytes (NHACs) in synovial fluid obtained from individuals with OA (OA-SF) to investigate its effect on chondrocyte matrix synthesis and degradation and inflammation by assessing gene expression and cytokine levels. NHACs exposed to OA-SF exhibited increased MMP13 expression. However, coculturing ELIXCYTE® with chondrocytes in OA-SF reduced MMP13 expression in chondrocytes and downregulated PTGS2 and FGF2 expression in ELIXCYTE®. ELIXCYTE® treatment elevated anti-inflammatory cytokine (IL-1RA, IL-10, and IL-13) levels, and the reduction in MMP13 was positively correlated with IL-11 concentrations in OA-SF. These findings indicate that IL-11 in OA-SF might serve as a predictive biomarker for the ELIXCYTE® treatment response in OA, emphasizing the therapeutic potential of ELIXCYTE® to mitigate OA progression and provide insights into its immunomodulatory effects.

Galectin-3 contributes to pathogenesis of IgA nephropathy.

IgA nephropathy (IgAN) is the most common type of glomerulonephritis that frequently progresses to kidney failure. However, the molecular pathogenesis underlying IgAN remains largely unknown. Here, we investigated the role of galectin-3 (Gal-3), a galactoside-binding protein in IgAN pathogenesis, and showed that Gal-3 expression by the kidney was significantly enhanced in patients with IgAN. In both TEPC-15 hybridoma-derived IgA-induced, passive, and spontaneous "grouped" ddY IgAN models, Gal-3 expression was clearly increased with disease severity in the glomeruli, peri-glomerular regions, and some kidney tubules. Gal-3 knockout (KO) in the passive IgAN model had significantly improved proteinuria, kidney function and reduced severity of kidney pathology, including neutrophil infiltration and decreased differentiation of Th17 cells from kidney-draining lymph nodes, despite increased percentages of regulatory T cells. Gal-3 KO also inhibited the NLRP3 inflammasome, yet it enhanced autophagy and improved kidney inflammation and fibrosis. Moreover, administration of 6-de-O-sulfated, N-acetylated low-molecular-weight heparin, a competitive Gal-3 binding inhibitor, restored kidney function and improved kidney lesions in passive IgAN mice. Thus, our results suggest that Gal-3 is critically involved in IgAN pathogenesis by activating the NLRP3 inflammasome and promoting Th17 cell differentiation. Hence, targeting Gal-3 action may represent a new therapeutic strategy for treatment of this kidney disease.

Immune-related adverse events requiring hospitalization in patients with lung cancer: implications and insights.

BACKGROUND: Immune checkpoint inhibitors (ICI) are associated with a distinct spectrum of toxicities. Data on irAE hospitalization rates and clinical course of patients with thoracic malignancies are lacking. METHODS: Patients with advanced thoracic malignancy treated with ICI (2/2016 to 6/2021) were retrospectively identified. Demographic and clinical data of confirmed irAE hospitalizations were extracted from the medical record and a descriptive analysis was performed. RESULTS: From February 2016 to June 2021, 1312 patients with thoracic malignancy received ICI (monotherapy, combination with 2nd ICI or other agents) with 102 patients (7.7%) hospitalized for irAEs. Treatment intent was first-line therapy in most patients (N = 50, 49%) with 9% (n = 9) receiving adjuvant ICI (N = 9). Sixty patients (59%) received ICI alone, 32% (N = 33) chemo plus immunotherapy, and 7% (N = 7) dual ICI. The median age on admission was 68 years. The median time between ICI initiation and admission was 64 days (1-935 days). Pneumonitis (32.3%; 33/102) was the most frequent indication for admission followed by gastroenterocolitis (19.6%; 20/102), hepatitis (12.7%; 13/102), myo/pericarditis (9.8%; 10/102), and endocrinopathies (9.8%; 10/102). Multi-organ toxicity occurred in 36% (N = 37) of patients. Overall, 85.2% (87/102) of patients received systemic corticosteroids and 17.6% (18/102) required additional lines of immunosuppression. The median length of hospitalization stay was 7 days (2-28 days) with a 25.5% (n = 26) readmission rate within 60 days and an 11.8% (n = 12) in house mortality rate. CONCLUSIONS: Severe irAE requiring inpatient admission, although infrequent, results in considerable morbidity, mortality, and healthcare utilization. Pneumonitis was the most common irAE requiring inpatient management in our patient population with a significant risk of mortality despite the use of guideline-directed systemic immunosuppression. This study highlights the continued need for collaborative efforts amongst medical specialties for improving the diagnostic and therapeutic management of patients with irAEs.

Renal macrophages induce hypertension and kidney fibrosis in Angiotensin II salt mice model.

The immune system is involved in hypertension development with different immune cells reported to have either pro or anti-hypertensive effects. In hypertension, immune cells have been thought to infiltrate blood pressure-regulating organs, resulting in either elevation or reduction of blood pressure. There is controversy over whether macrophages play a detrimental or beneficial role in the development of hypertension, and the few existing studies have yielded conflicting results. This study aimed to determine the effects of angiotensin II (Ang II) salt-induced hypertension on renal immune cells and to determine whether renal macrophages are involved in the induction of hypertension. Hypertension was induced by administration of Ang II and saline for two weeks. The effects of hypertension on kidney immune cells were assessed using flow cytometry. Macrophage infiltration in the kidney was assessed by immunohistochemistry and kidney fibrosis was assessed using trichrome stain and kidney real time-qPCR. Liposome encapsulated clodronate was used to deplete macrophages in C57BL/6J mice and investigate the direct role of macrophages in hypertension induction. Ang II saline mice group developed hypertension, had increased renal macrophages, and had increased expression of Acta2 and Col1a1 and kidney fibrotic areas. Macrophage depletion blunted hypertension development and reduced the expression of Acta2 and Col1a1 in the kidney and kidney fibrotic areas in Ang II saline group. The results of this study demonstrate that macrophages infiltrate the kidneys and increase kidney fibrosis in Ang II salt-induced hypertension, and depletion of macrophages suppresses the development of hypertension and decreases kidney fibrosis. This indicates that macrophages play a direct role in hypertension development. Hence macrophages have a potential to be considered as therapeutic target in hypertension management.

Alkaline-Responsive, Self-Healable, and Conductive Copolymer Composites with Enhanced Mechanical Properties Tailored for Wearable Tech.

Despite significant advancements, current self-healing materials often suffer from a compromise between mechanical robustness and functional performance, particularly in terms of conductivity and responsiveness to environmental stimuli. Addressing this issue, the research introduces a self-healable and conductive copolymer, poly(ionic liquid-co-acrylic acid) (PIL-co-PAA), synthesized through free radical polymerization, and further optimized by incorporating thermoplastic polyurethane (TPU). This combination leverages the unique properties of each component, especially ion-dipole interactions and hydrogen bonds, resulting in a material that exhibits exceptional self-healing abilities and demonstrates enhanced mechanical properties and electrical conductivity. Moreover, the PIL-co-PAA/TPU films showcase alkaline-responsive behavior, a feature that broadens their applicability in dynamic environments. Through systematic characterization, including thermogravimetric analysis, tensile testing, and electrical properties measurements, the mechanisms behind the improved performance and functionality of these films are elucidated. The conductivities and ultimate tensile strength (σuts) of the PIL-co-PAA/TPU films regain 80% under 8 h healing process. To extend the applications for wearable devices, the self-healing properties of commercial cotton fabrics coated with the self-healable PIL-co-PAA are also investigated, demonstrating both self-healing and electrical properties. This study advances the understanding of self-healable conductive polymers and opens new avenues for their application in wearable technology.

Reversible Sensing Technologies Using Upcycled TPEE: Crafting pH and Light Responsive Materials towards Sustainable Monitoring.

Multiresponsive materials with reversible and durable characteristics are indispensable because of their promising applications in environmental change detections. To fabricate multiresponsive materials in mass production, however, complex reactions and impractical situations are often involved. Herein, a dual responsive (light and pH) spiropyran-based smart sensor fabricated by a simple layer-by-layer (LbL) assembly process from upcycled thermoplastic polyester elastomer (TPEE) materials derived from recycled polyethylene terephthalate (r-PET) is proposed. Positively charged chitosan solutions and negatively charged merocyanine-COOH (MC-COOH) solutions are employed in the LbL assembly technique, forming the chitosan-spiropyran deposited TPEE (TPEE-CH-SP) film. Upon UV irradiation, the spiropyran-COOH (SP-COOH) molecules on the TPEE-CH-SP film undergo the ring-opening isomerization, along with an apparent color change from colorless to purple, to transform into the MC-COOH molecules. By further exposing the TPEE-CH-MC film to hydrogen chloride (HCl) and nitric acid (HNO3) vapors, the MC-COOH molecules can be transformed into protonated merocyanine-COOH (MCH-COOH) with the simultaneous color change from purple to yellow.

Velocity selective spin labeling using parallel transmission.

PURPOSE: Ultra-high field (UHF) provides improved SNR which greatly benefits SNR starved imaging techniques such as perfusion imaging. However, transmit field (B1 + ) inhomogeneities commonly observed at UHF hinders the excitation uniformity. Here we show how replacing standard excitation pulses with parallel transmit pulses can improve efficiency of velocity selective labeling. METHODS: The standard tip-down and tip-up excitation pulses found in a velocity selective preparation module were replaced with tailored non-selective kT -points pulse solutions. Bloch simulations and experimental validation on a custom-built flow phantom and in vivo was performed to evaluate different pulse configurations in circularly polarized mode (CP-mode) and parallel transmit (pTx) mode. RESULTS: Tailored pTx pulses significantly improved velocity selective labeling fidelity and signal uniformity. The transverse magnetization normalized RMS error was reduced from 0.489 to 0.047 when compared to standard rectangular pulses played in CP-mode. Simulations showed that manipulation of time symmetry in the tailored pTx pulses is vital in minimizing residual magnetization. In addition, in vivo experiments achieved a 44% lower RF power output and a shorter pulse duration when compared to using adiabatic pulses in CP-mode. CONCLUSION: Using tailored pTx pulses for excitation within a velocity selective labeling preparation mitigated transmit field artifacts and improved SNR and contrast fidelity. The improvement in labeling efficiency highlights the potential of using pTx to improve robustness and accessibility of flow-based sequences such as velocity selective spin labeling at ultra-high field.

Specific long-term changes in anti-SARS-CoV-2 IgG modifications and antibody functions in mRNA, adenovector, and protein subunit vaccines.

Various vaccine platforms were developed and deployed against the COVID-19 disease. The Fc-mediated functions of IgG antibodies are essential in the adaptive immune response elicited by vaccines. However, the long-term changes of protein subunit vaccines and their combinations with messenger RNA (mRNA) vaccines are unknown. A total of 272 serum and plasma samples were collected from individuals who received first to third doses of the protein subunit Medigen, the mRNA (BNT, Moderna), or the adenovector AstraZeneca vaccines. The IgG subclass level was measured using enzyme-linked immunosorbent assay, and Fc-N glycosylation was measured using liquid chromatography coupled to tandem mass spectrometry. Antibody-dependent-cellular-phagocytosis (ADCP) and complement deposition (ADCD) of anti-spike (S) IgG antibodies were measured by flow cytometry. IgG1 and 3 reached the highest anti-S IgG subclass level. IgG1, 2, and 4 subclass levels significantly increased in mRNA- and Medigen-vaccinated individuals. Fc-glycosylation was stable, except in female BNT vaccinees, who showed increased bisection and decreased galactosylation. Female BNT vaccinees had a higher anti-S IgG titer than that of males. ADCP declined in all groups. ADCD was significantly lower in AstraZeneca-vaccinated individuals. Each vaccine produced specific long-term changes in Fc structure and function. This finding is critical when selecting a vaccine platform or combination to achieve the desired immune response.

Quantification, Exchange, and Removal of Surface Ligands on Noble-Metal Nanocrystals.

ConspectusSurface ligands are vital to the colloidal synthesis of noble-metal nanocrystals with well-controlled sizes and shapes for various applications. The surface ligands not only dictate the formation of nanocrystals with diverse shapes but also serve as a colloidal stabilizer to prevent the suspended nanocrystals from aggregation during their synthesis or storage. By leveraging the facet selectivity of some surface ligands, one can further control the sites for growth or galvanic replacement to transform presynthesized nanocrystals into complex structures that are otherwise difficult to fabricate using conventional methods. Furthermore, the presence of surface ligands on nanocrystals also facilitates their applications in areas such as sensing, imaging, nanomedicine, and self-assembly. Despite their popular use in enhancing the properties of nanocrystals and thus optimizing their performance in a wide variety of applications, it remains a major challenge to quantitatively determine the coverage density of ligand molecules, not to mention the difficulty of substituting or removing them without compromising the surface structure and aggregation state of the nanocrystals.In this Account, we recapitulate our efforts in developing methods capable of qualitatively or quantitatively measuring, exchanging, and removing the surface ligands adsorbed on noble-metal nanocrystals. We begin with an introduction to the typical interactions between ligand molecules and surface atoms, followed by a discussion of the Langmuir model that can be used to describe the adsorption of surface ligands. It is also emphasized that the adsorption process may become very complex in the case of a polymeric ligand due to the variations in binding configuration and chain conformation. We then highlight the capabilities of various spectroscopy methods to analyze the adsorbed ligands qualitatively or quantitatively. Specifically, surface-enhanced Raman scattering, Fourier transform infrared, and X-ray photoelectron spectroscopy are three examples of qualitative methods that can be used to confirm the absence or presence of a surface ligand. On the other hand, ultraviolet-visible spectroscopy and inductively coupled plasma mass spectrometry can be used for quantitative measurements. Additionally, the coverage density of a ligand can be derived by analyzing the morphological changes during nanocrystal growth. We then discuss how the ligands present on the surface of metal nanocrystals can be exchanged directly or indirectly to meet the requirements of different applications. The former can be done using a ligand with stronger binding, whereas the latter is achieved by introducing a sacrificial shell to the surface of the nanocrystals. Furthermore, we highlight three additional strategies besides simple washing to remove the surface ligands, including calcination, heating in a solution, and UV-ozone treatment. Finally, we showcase three applications of metal nanocrystals in nanomedicine, tumor targeting, and self-assembly by taking advantage of the diversity of surface ligands bearing different functional groups. We also offer perspectives on the challenges and opportunities in realizing the full potential of surface ligands.

Disrupted Brain Functional Status in Patients with Reversible Cerebral Vasoconstriction Syndrome.

OBJECTIVES: The aim of this study was to investigate the functional networks in subjects with reversible cerebral vasoconstriction syndrome (RCVS) using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: We prospectively recruited patients with RCVS and healthy controls (HCs) between February 2017 and April 2021. The rs-fMRI data were analyzed using graph theory methods. We compared node-based global and regional topological metrics (Bundle 1) and network-based intranetwork and internetwork connectivity (Bundle 2) between RCVS patients and HCs. We also explored the associations of clinical and vascular (ie, the Lindegaard index, LI) parameters with significant rs-fMRI metrics. RESULTS: A total of 104 RCVS patients and 93 HCs were included in the final analysis. We identified significantly decreased local efficiency of the left dorsal anterior insula (dAI; p = 0.0005) in RCVS patients within 30 days after disease onset as compared to HCs, which improved 1 month later. RCVS patients also had increased global efficiency (p = 0.009) and decreased average degree centrality (p = 0.045), clustering coefficient (p = 0.033), and assortativity values (p = 0.003) in node-based analysis. In addition, patients with RCVS had increased internetwork connectivity of the default mode network (DMN) with the salience (p = 0.027) and dorsal attention (p = 0.016) networks. Significant correlations between LI and regional local efficiency in left dAI (rs = -0.418, p = 0.042) was demonstrated. INTERPRETATION: The significantly lower local efficiency of the left dAI, suggestive of impaired central autonomic modulation, was negatively correlated with vasoconstriction severity, which is highly plausible for the pathogenesis of RCVS. ANN NEUROL 2023;94:772-784.

Reducing femoral flow artefacts in radial magnetic resonance fingerprinting of the prostate using region-optimised virtual coils.

High acceleration factors in radial magnetic resonance fingerprinting (MRF) of the prostate lead to strong streak-like artefacts from flow in the femoral blood vessels, possibly concealing important anatomical information. Region-optimised virtual (ROVir) coils is a beamforming-based framework to create virtual coils that maximise signal in a region of interest while minimising signal in a region of interference. In this study, the potential of removing femoral flow streak artefacts in prostate MRF using ROVir coils is demonstrated in silico and in vivo. The ROVir framework was applied to radial MRF k-space data in an automated pipeline designed to maximise prostate signal while minimising signal from the femoral vessels. The method was tested in 15 asymptomatic volunteers at 3 T. The presence of streaks was visually assessed and measurements of whole prostate T1, T2 and signal-to-noise ratio (SNR) with and without streak correction were examined. In addition, a purpose-built simulation framework in which blood flow through the femoral vessels can be turned on and off was used to quantitatively evaluate ROVir's ability to suppress streaks in radial prostate MRF. In vivo it was shown that removing selected ROVir coils visibly reduces streak-like artefacts from the femoral blood flow, without increasing the reconstruction time. On average, 80% of the prostate SNR was retained. A similar reduction of streaks was also observed in silico, while the quantitative accuracy of T1 and T2 mapping was retained. In conclusion, ROVir coils efficiently suppress streaking artefacts from blood flow in radial MRF of the prostate, thereby improving the visual clarity of the images, without significant sacrifices to acquisition time, reconstruction time and accuracy of quantitative values. This is expected to help enable T1 and T2 mapping of prostate cancer in clinically viable times, aiding differentiation between prostate cancer from noncancer and healthy prostate tissue.