IL-1 is a critical regulator of group 2 innate lymphoid cell function and plasticity.

Group 2 innate lymphoid cells (ILC2 cells) are important for type 2 immune responses and are activated by the epithelial cytokines interleukin 33 (IL-33), IL-25 and thymic stromal lymphopoietin (TSLP). Here we demonstrated that IL-1ß was a critical activator of ILC2 cells, inducing proliferation and cytokine production and regulating the expression of epithelial cytokine receptors. IL-1ß also governed ILC2 plasticity by inducing low expression of the transcription factor T-bet and the cytokine receptor chain IL-12Rß2, which enabled the conversion of these cells into an ILC1 phenotype in response to IL-12. This transition was marked by an atypical chromatin landscape characterized by the simultaneous transcriptional accessibility of the locus encoding interferon-γ (IFN-γ) and the loci encoding IL-5 and IL-13. Finally, IL-1ß potentiated ILC2 activation and plasticity in vivo, and IL-12 acted as the switch that determined an ILC2-versus-ILC1 response. Thus, we have identified a previously unknown role for IL-1ß in facilitating ILC2 maturation and plasticity.

Inflammatory triggers associated with exacerbations of COPD orchestrate plasticity of group 2 innate lymphoid cells in the lungs.

Innate lymphoid cells (ILCs) are critical mediators of mucosal immunity, and group 1 ILCs (ILC1 cells) and group 3 ILCs (ILC3 cells) have been shown to be functionally plastic. Here we found that group 2 ILCs (ILC2 cells) also exhibited phenotypic plasticity in response to infectious or noxious agents, characterized by substantially lower expression of the transcription factor GATA-3 and a concomitant switch to being ILC1 cells that produced interferon-γ (IFN-γ). Interleukin 12 (IL-12) and IL-18 regulated this conversion, and during viral infection, ILC2 cells clustered within inflamed areas and acquired an ILC1-like phenotype. Mechanistically, these ILC1 cells augmented virus-induced inflammation in a manner dependent on the transcription factor T-bet. Notably, IL-12 converted human ILC2 cells into ILC1 cells, and the frequency of ILC1 cells in patients with chronic obstructive pulmonary disease (COPD) correlated with disease severity and susceptibility to exacerbations. Thus, functional plasticity of ILC2 cells exacerbates anti-viral immunity, which may have adverse consequences in respiratory diseases such as COPD.

Cholesterol in the cargo membrane amplifies tau inhibition of kinesin-1-based transport.

Intracellular cargos are often membrane-enclosed and transported by microtubule-based motors in the presence of microtubule-associated proteins (MAPs). Whereas increasing evidence reveals how MAPs impact the interactions between motors and microtubules, critical questions remain about the impact of the cargo membrane on transport. Here we combined in vitro optical trapping with theoretical approaches to determine the effect of a lipid cargo membrane on kinesin-based transport in the presence of MAP tau. Our results demonstrate that attaching kinesin to a fluid lipid membrane reduces the inhibitory effect of tau on kinesin. Moreover, adding cholesterol, which reduces kinesin diffusion in the cargo membrane, amplifies the inhibitory effect of tau on kinesin binding in a dosage-dependent manner. We propose that reduction of kinesin diffusion in the cargo membrane underlies the effect of cholesterol on kinesin binding in the presence of tau, and we provide a simple model for this proposed mechanism. Our study establishes a direct link between cargo membrane cholesterol and MAP-based regulation of kinesin-1. The cholesterol effects uncovered here may more broadly extend to other lipid alterations that impact motor diffusion in the cargo membrane, including those associated with aging and neurological diseases.

Assessing the impact of atrial fibrillation on symptoms and quality of life in hypertrophic cardiomyopathy.

INTRODUCTION: In hypertrophic cardiomyopathy (HCM), atrial fibrillation (AF) has historically been regarded to have a deleterious impact on clinical course, strongly associated with progressive heart failure (HF) symptoms. However, there is a paucity of information regarding the impact of AF on HCM employing validated quality of life (QoL) surveys. Therefore, we evaluated the impact of AF on QoL utilizing patient reported outcome measures (PROMs). METHODS: 218 consecutive HCM patients with or without AF at the Lahey HCM center in 2022 completed PROMs at their most recent visit evaluating HF (Kansas City Cardiomyopathy Questionnaire [KCCQ]) and AF symptoms (AF Effect on QoL [AFEQT]). RESULTS: Among the 218 patients, 50 (23%) had a history of AF and comprise the primary study cohort. AF was diagnosed at 55 ± 10 years of age, median of 5.5 years before PROM, with 66% of patients treated with a rhythm control strategy with antiarrhythmic drug and/or AF ablation. AFEQT indicated that 52% of patients experienced no or minimal AF-related disability, mild to moderate in 22%, and severe in 26%. There was no substantial difference in HCM phenotype in patients with no or minimal AF disability compared to those with severe disability. HF symptoms for most HCM patients with prior AF history was consistent with no or minimal (59%) or only mild (27%) disability as measured by KCCQ overall summary scores. In addition, with multivariate analysis, AF history was associated with less HF symptoms and improved QoL (OR 0.4, p = 0.02). CONCLUSION: In contrast to prior perceptions, HCM patients with prior AF history were less likely to incur HF symptoms impairing QoL compared to HCM patients without AF. After treatment, prior history of AF did not substantially impact current QoL. These data provide a realistic appraisal for the impact that AF has on HCM patients and also offers a measure of reassurance for this patient subgroup.

Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection.

Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease and is presumed to be central to the altered responsiveness to recurrent infection in these patients. We examined the effects of smoke priming underlying the exacerbated response to viral infection in mice. Lack of interleukin-33 (IL-33) signaling conferred complete protection during exacerbation and prevented enhanced inflammation and exaggerated weight loss. Mechanistically, smoke was required to upregulate epithelial-derived IL-33 and simultaneously alter the distribution of the IL-33 receptor ST2. Specifically, smoke decreased ST2 expression on group 2 innate lymphoid cells (ILC2s) while elevating ST2 expression on macrophages and natural killer (NK) cells, thus altering IL-33 responsiveness within the lung. Consequently, upon infection and release, increased local IL-33 significantly amplified type I proinflammatory responses via synergistic modulation of macrophage and NK cell function. Therefore, in COPD, smoke alters the lung microenvironment to facilitate an alternative IL-33-dependent exaggerated proinflammatory response to infection, exacerbating disease.

T1 and T2 quantification using magnetic resonance fingerprinting in mild traumatic brain injury.

OBJECTIVES: To assess whether MR fingerprinting (MRF)-based relaxation properties exhibit cross-sectional and prospective correlations with patient outcome and compare the results with those from DTI. METHODS: Clinical imaging, MRF, and DTI were acquired in patients (24 ± 10 days after injury (timepoint 1) and 90 ± 17 days after injury (timepoint 2)) and once in controls. Patient outcome was assessed with global functioning, symptom profile, and neuropsychological testing. ADC and fractional anisotropy (FA) from DTI and T1 and T2 from MRF were compared in 12 gray and white matter regions with Mann-Whitney tests. Bivariate associations between MR measures and outcome were assessed using the Spearman correlation and logistic regression. RESULTS: Data from 22 patients (38 ± 12 years; 17 women) and 18 controls (32 ± 8 years; 12 women) were analyzed. Fourteen patients (37 ± 12 years; 11 women) returned for timepoint 2, while two patients provided only timepoint 2 clinical outcome data. At timepoint 1, there were no differences between patients and controls in T1, T2, and ADC, while FA was lower in mTBI frontal white matter. T1 at timepoint 1 and the change in T1 exhibited more (n = 18) moderate to strong correlations (|r|= 0.6-0.85) with clinical outcome at timepoint 2 than T2 (n = 3), FA (n = 7), and ADC (n = 2). High T1 at timepoint 1, and serially increasing T1, accounted for five of the six MR measures with the highest utility for identification of non-recovered patients at timepoint 2 (AUC > 0.80). CONCLUSION: T1 derived from MRF was found to have higher utility than T2, FA, and ADC for predicting 3-month outcome after mTBI. KEY POINTS: • In a region-of-interest approach, FA, ADC, and T1 and T2 all showed limited utility in differentiating patients from controls at an average of 24 and 90 days post-mild traumatic brain injury. • T1 at 24 days, and the serial change in T1, revealed more and stronger predictive correlations with clinical outcome at 90 days than did T2, ADC, or FA. • T1 showed better prospective identification of non-recovered patients at 90 days than ADC, T2, and FA.

The cytokines interleukin 27 and interferon-γ promote distinct Treg cell populations required to limit infection-induced pathology.

Interferon-γ (IFN-γ) promotes a population of T-bet(+) CXCR3(+) regulatory T (Treg) cells that limit T helper 1 (Th1) cell-mediated pathology. Our studies demonstrate that interleukin-27 (IL-27) also promoted expression of T-bet and CXCR3 in Treg cells. During infection with Toxoplasma gondii, a similar population emerged that limited T cell responses and was dependent on IFN-γ in the periphery but on IL-27 at mucosal sites. Transfer of Treg cells ameliorated the infection-induced pathology observed in Il27(-/-) mice, and this was dependent on their ability to produce IL-10. Microarray analysis revealed that Treg cells exposed to either IFN-γ or IL-27 have distinct transcriptional profiles. Thus, IFN-γ and IL-27 have different roles in Treg cell biology and IL-27 is a key cytokine that promotes the development of Treg cells specialized to control Th1 cell-mediated immunity at local sites of inflammation.

Microbial burden and viral exacerbations in a longitudinal multicenter COPD cohort.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by frequent exacerbation phenotypes independent of disease stage. Increasing evidence shows that the microbiota plays a role in disease progression and severity, but long-term and international multicenter assessment of the variations in viral and bacterial communities as drivers of exacerbations are lacking. METHODS: Two-hundred severe COPD patients from Europe and North America were followed longitudinally for 3 years. We performed nucleic acid detection for 20 respiratory viruses and 16S ribosomal RNA gene sequencing to evaluate the bacterial microbiota in 1179 sputum samples collected at stable, acute exacerbation and follow-up visits. RESULTS: Similar viral and bacterial taxa were found in patients from the USA compared to Bulgaria and Czech Republic but their microbiome diversity was significantly different (P < 0.001) and did not impact exacerbation rates. Virus infection was strongly associated with exacerbation events (P < 5E-20). Human rhinovirus (13.1%), coronavirus (5.1%) and influenza virus (3.6%) constitute the top viral pathogens in triggering exacerbation. Moraxella and Haemophilus were 5-fold and 1.6-fold more likely to be the dominating microbiota during an exacerbation event. Presence of Proteobacteria such as Pseudomonas or Staphylococcus amongst others, were associated with exacerbation events (OR > 0.17; P < 0.02) but more strongly associated with exacerbation frequency (OR > 0.39; P < 4E-10), as confirmed by longitudinal variations and biotyping of the bacterial microbiota, and suggesting a role of the microbiota in sensitizing the lung. CONCLUSIONS: This study highlights bacterial taxa in lung sensitization and viral triggers in COPD exacerbations. It provides a global overview of the diverse targets for drug development and explores new microbiome analysis methods to guide future patient management applications.

Kerr-Nonlinearity-Induced Mode-Splitting in Optical Microresonators.

The Kerr effect in optical microresonators plays an important role for integrated photonic devices and enables third harmonic generation, four-wave mixing, and the generation of microresonator-based frequency combs. Here we experimentally demonstrate that the Kerr nonlinearity can split ultra-high-Q microresonator resonances for two continuous-wave lasers. The resonance splitting is induced by self- and cross-phase modulation and counterintuitively enables two lasers at different wavelengths to be simultaneously resonant in the same microresonator mode. We develop a pump-probe spectroscopy scheme that allows us to measure power dependent resonance splittings of up to 35 cavity linewidths (corresponding to 52 MHz) at 10 mW of pump power. The required power to split the resonance by one cavity linewidth is only 286 µW. In addition, we demonstrate threefold resonance splitting when taking into account four-wave mixing and two counterpropagating probe lasers. These Kerr splittings are of interest for applications that require two resonances at optically controlled offsets, e.g., for optomechanical coupling to phonon modes, optical memories, and precisely adjustable spectral filters.

Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10.

Interleukin 10 (IL-10) has a prominent function in regulating the balance between protective and pathological T cell responses. Consistent with that activity, many sources of this cytokine are found in vivo, including from myeloid cells and a variety of T cell subsets. However, although there are many pathways that regulate innate production of IL-10, the factors that govern its synthesis by the adaptive response are poorly understood. Here we report that IL-27 and IL-6 induced T helper type 1 and type 2 cells, as well as T helper cells that produce IL-17, to secrete IL-10. This effect was dependent on the transcription factors STAT1 and STAT3 for IL-27 and on STAT3 for IL-6. Our studies identify a previously unknown pathway that allows the immune system to temper inflammatory responses.

Terahertz wave generation using a soliton microcomb.

The Terahertz or millimeter wave frequency band (300 GHz - 3 THz) is spectrally located between microwaves and infrared light and has attracted significant interest for applications in broadband wireless communications, space-borne radiometers for Earth remote sensing, astrophysics, and imaging. In particular optically generated THz waves are of high interest for low-noise signal generation. Here, we propose and demonstrate stabilized terahertz wave generation using a microresonator-based frequency comb (microcomb). A unitravelling-carrier photodiode (UTC-PD) converts low-noise optical soliton pulses from the microcomb to a terahertz wave at the soliton's repetition rate (331 GHz). With a free-running microcomb, the Allan deviation of the Terahertz signal is 4.5×10-9 at 1 s measurement time with a phase noise of -72 dBc/Hz (-118 dBc/Hz) at 10 kHz (10 MHz) offset frequency. By locking the repetition rate to an in-house hydrogen maser, in-loop fractional frequency stabilities of 9.6×10-15 and 1.9×10-17 are obtained at averaging times of 1 s and 2000 s respectively, indicating that the stability of the generated THz wave is limited by the maser reference signal. Moreover, the terahertz signal is successfully used to perform a proof-of-principle demonstration of terahertz imaging of peanuts. Combining the monolithically integrated UTC-PD with an on-chip microcomb, the demonstrated technique could provide a route towards highly stable continuous terahertz wave generation in chip-scale packages for out-of-the-lab applications. In particular, such systems would be useful as compact tools for high-capacity wireless communication, spectroscopy, imaging, remote sensing, and astrophysical applications.

Thermo-optical pulsing in a microresonator filtered fiber-laser: a route towards all-optical control and synchronization.

We report on 'slow' pulsing dynamics in a silica resonator-based laser system: by nesting a high-Q rod-resonator inside an amplifying fiber cavity, we demonstrate that trains of microsecond pulses can be generated with repetition rates in the hundreds of kilohertz. We show that such pulses are produced with a period equivalent to several hundreds of laser cavity roundtrips via the interaction between the gain dynamics in the fiber cavity and the thermo-optical effects in the high-Q resonator. Experiments reveal that the pulsing properties can be controlled by adjusting the amplifying fiber cavity parameters. Our results, confirmed by numerical simulations, provide useful insights on the dynamical onset of complex self-organization phenomena in resonator-based laser systems where thermo-optical effects play an active role. In addition, we show how the thermal state of the resonator can be probed and even modified by an external, counter-propagating optical field, thus hinting towards novel approaches for all-optical control and sensing applications.

Interplay of Polarization and Time-Reversal Symmetry Breaking in Synchronously Pumped Ring Resonators.

Optically induced breaking of symmetries plays an important role in nonlinear photonics, with applications ranging from optical switching in integrated photonic circuits to soliton generation in ring lasers. In this work we study for the first time the interplay of two types of spontaneous symmetry breaking that can occur simultaneously in optical ring resonators. Specifically we investigate a ring resonator that is synchronously pumped with short pulses of light. In this system we numerically study the interplay and transition between regimes of temporal symmetry breaking (in which pulses in the resonator either run ahead or behind the seed pulses) and polarization symmetry breaking (in which the resonator spontaneously generates elliptically polarized light out of linearly polarized seed pulses). We find ranges of pump parameters for which each symmetry breaking can be independently observed, but also a regime in which a dynamical interplay takes place. Besides the fundamentally interesting physics of the interplay of different types of symmetry breaking, our work contributes to a better understanding of the nonlinear dynamics of optical ring cavities which are of interest for future applications including all-optical logic gates, synchronously pumped optical frequency comb generation, and resonator-based sensor technologies.

Internal strain drives spontaneous periodic buckling in collagen and regulates remodeling.

Fibrillar collagen, an essential structural component of the extracellular matrix, is remarkably resistant to proteolysis, requiring specialized matrix metalloproteinases (MMPs) to initiate its remodeling. In the context of native fibrils, remodeling is poorly understood; MMPs have limited access to cleavage sites and are inhibited by tension on the fibril. Here, single-molecule recordings of fluorescently labeled MMPs reveal cleavage-vulnerable binding regions arrayed periodically at ∼1-µm intervals along collagen fibrils. Binding regions remain periodic even as they migrate on the fibril, indicating a collective process of thermally activated and self-healing defect formation. An internal strain relief model involving reversible structural rearrangements quantitatively reproduces the observed spatial patterning and fluctuations of defects and provides a mechanism for tension-dependent stabilization of fibrillar collagen. This work identifies internal-strain-driven defects that may have general and widespread regulatory functions in self-assembled biological filaments.

With a little help from their friends: interleukin-21, T cells, and B cells.

T follicular cells help B cells generate high-affinity antibodies. Two papers in this issue of Immunity (Nurieva et al., 2008, and Vogelzang et al., 2008) have identified a role for interleukin-21 in the development of these specialized cells and highlight questions about how this dedicated population is generated.

Adverse structural remodeling of the left ventricle and ventricular arrhythmias in patients with depressed ejection fraction.

BACKGROUND: The relationship of life-threatening ventricular arrhythmias to specific patterns of adverse LV remodeling has not been reported. We examined the relationship of ventricular tachycardia and/or fibrillation (VT/VF) to the pattern of left ventricular (LV) structural remodeling and to the degree of LV dysfunction in patients with a low ejection fraction (EF). METHODS AND RESULTS: Data from 127 patients with a low EF (≤0.45) and an implantable cardioverter-defibrillator (ICD) were examined and VT/VF identified by means of ICD device interrogation. Echocardiographic data were used to define LV structural remodeling (eccentric hypertrophy, concentric remodeling/hypertrophy, and normal geometry). VT/VF occurred in 26% of the 127 patients. VT/VF was more common in the 60 patients with LV hypertrophy versus the 67 with normal LV mass (40% vs 13%; P = .001) and in the 61 patients with LV enlargement versus the 66 with a normal chamber size (34% vs 18%; P = .04). When LV chamber size, wall mass, and geometry were assessed in a combinatorial fashion, a Kaplan-Meier analysis indicated that the occurrence of VT/VF was highest in the patients with eccentric hypertrophy (43%), intermediate in those with concentric remodeling/hypertrophy (30%), and lowest (12%) in those with normal geometry (all P < .02). The EFs were similar (P = ns) in these 3 groups of distinctly different patterns of remodeling. CONCLUSIONS: Life-threatening ventricular arrhythmias in patients with a low EF are related to the pattern of LV remodeling, not the degree of LV dysfunction. Risk stratification of such patients might be improved by a consideration of the pattern of LV remodeling.

Longitudinal changes in sodium concentration and in clinical outcome in mild traumatic brain injury.

Ionic imbalances and sodium channel dysfunction, well-known sequelae of traumatic brain injury (TBI), promote functional impairment in affected subjects. Therefore, non-invasive measurement of sodium concentrations using 23Na MRI has the potential to detect clinically relevant injury and predict persistent symptoms. Recently, we reported diffusely lower apparent total sodium concentrations (aTSC) in mild TBI patients compared to controls, as well as correlations between lower aTSC and worse clinical outcomes. The main goal of this study was to determine whether these aTSC findings, and their changes over time, predict outcomes at 3- and 12-month from injury. Twenty-seven patients previously studied with 23Na MRI and outcome measures at 22 ± 10 days (average ± standard deviation) after injury (visit-1, v1) were contacted at 3- (visit-2, v2) and 12-month after injury (visit-3, v3) to complete the Rivermead post-concussion symptoms questionnaire (RPQ), the extended Glasgow outcome scale (GOSE), and the brief test of adult cognition by telephone (BTACT). Follow-up 1H and 23Na MRI were additionally scheduled at v2. Linear regression was used to calculate aTSC in global grey and white matters. Six hypotheses were tested in relation to the serial changes in outcome measures and in aTSC, and in relation to the cross-sectional and serial relationships between aTSC and outcome. Twenty patients contributed data at v2 and fifteen at v3. Total RPQ and composite BTACT z-scores differed significantly for v2 and v3 in comparison to v1 (each P < 0.01), reflecting longitudinally reduced symptomatology and improved performance on cognitive testing. No associations between aTSC and outcome were observed at v2. Previously lower grey and white matter aTSC normalized at v2 in comparison to controls, in line with a statistically detectable longitudinal increase in grey matter aTSC between v1 and v2 (P = 0.0004). aTSC values at v1 predicted a subset of future BTACT subtest scores, but not future RPQ scores nor GOSE-defined recovery status. Similarly, aTSC rates of change correlated with BTACT rates of change, but not with those of RPQ. Tissue aTSC, previously shown to be diffusely decreased compared to controls at v1, was no longer reduced by v2, suggesting normalization of the sodium ionic equilibrium. These changes were accompanied by marked improvement in outcome. The results support the notion that early aTSC from 23Na MRI predicts future BTACT, but not RPQ scores, nor future GOSE status.