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We report results of low-temperature heat-capacity, magnetocaloric-effect, and neutron-diffraction measurements of TmVO4, an insulator that undergoes a continuous ferroquadrupolar phase transition associated with local partially filled 4f orbitals of the thulium (Tm[Formula: see text]) ions. The ferroquadrupolar transition, a realization of Ising nematicity, can be tuned to a quantum critical point by using a magnetic field oriented along the c axis of the tetragonal crystal lattice, which acts as an effective transverse field for the Ising-nematic order. In small magnetic fields, the thermal phase transition can be well described by using a semiclassical mean-field treatment of the transverse-field Ising model. However, in higher magnetic fields, closer to the field-tuned quantum phase transition, subtle deviations from this semiclassical behavior are observed, which are consistent with expectations of quantum fluctuations. Although the phase transition is driven by the local 4f degrees of freedom, the crystal lattice still plays a crucial role, both in terms of mediating the interactions between the local quadrupoles and in determining the critical scaling exponents, even though the phase transition itself can be described via mean field. In particular, bilinear coupling of the nematic order parameter to acoustic phonons changes the spatial and temporal fluctuations of the former in a fundamental way, resulting in different critical behavior of the nematic transverse-field Ising model, as compared to the usual case of the magnetic transverse-field Ising model. Our results establish TmVO4 as a model material and electronic nematicity as a paradigmatic example for quantum criticality in insulators.
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Electrostatic gating has emerged as a powerful technique for tailoring the magnetic properties of two-dimensional (2D) magnets, offering exciting prospects including enhancement of magnetic anisotropy, boosting Curie temperature, and strengthening exchange coupling effects. Here, we focus on electrical control of the ferromagnetic resonance of the quasi-2D Kagome magnet Cu(1,3-bdc). By harnessing an electrostatic field through ionic liquid gating, significant shifts are observed in the ferromagnetic resonance field in both out-of-plane and in-plane measurements. Moreover, the effective magnetization and gyromagnetic ratios display voltage-dependent variations. A closer examination reveals that the voltage-induced changes can modulate magnetocrystalline anisotropy by several hundred gauss, while the impact on orbital magnetization remains relatively subtle. Density functional theory (DFT) calculations reveal varying d-orbital hybridizations at different voltages. This research unveils intricate physics within the Kagome lattice magnet and further underscores the potential of electrostatic manipulation in steering magnetism with promising implications for the development of spintronic devices.
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We explore spin dynamics in Cu(1,3-bdc), a quasi-2D topological magnon insulator. The results show that the thermal evolution of the Landé g factor (g) is anisotropic: gin-plane decreases while gout-of-plane increases with increasing temperature T. Moreover, the anisotropy of the g factor (Δg) and the anisotropy of saturation magnetization (ΔMs) are correlated below 4 K, but they diverge above 4 K. We show that the electronic orbital moment contributes to the g anisotropy at lower T, while the topological orbital moment induced by thermally excited spin chirality dictates the g anisotropy at higher T. Our work suggests an interplay among topology, spin chirality, and orbital magnetism in Cu(1,3-bdc).
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Low-dimensional metal halides exhibit strong structural and electronic anisotropies, making them candidates for accessing unusual electronic properties. Here, we demonstrate pressure-induced quasi-one-dimensional (quasi-1D) metallicity in δ-CsSnI3. With the application of pressure up to 40 GPa, the initially insulating δ-CsSnI3 transforms to a metallic state. Synchrotron X-ray diffraction and Raman spectroscopy indicate that the starting 1D chain structure of edge-sharing Sn-I octahedra in δ-CsSnI3 is maintained in the high-pressure metallic phase while the SnI6 octahedral chains are distorted. Our experiments combined with first-principles density functional theory calculations reveal that pressure induces Sn-Sn hybridization and enhances Sn-I coupling within the chain, leading to band gap closure and formation of conductive SnI6 distorted octahedral chains. In contrast, the interchain I...I interactions remain minimal, resulting in a highly anisotropic electronic structure and quasi-1D metallicity. Our study offers a high-pressure approach for achieving diverse electronic platforms in the broad family of low-dimensional metal halides.
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OBJECTIVE: To test whether parents of premature infants less than 37 weeks of gestation provided with a unique smartphone app designed to support parents had greater parenting self-efficacy, a key element in parenting confidence, compared with controls. STUDY DESIGN: Using a quasiexperimental, time-lagged study design, parents were assigned to either usual care (control) or NICU2HOME app (intervention) groups. Both groups completed the validated Parenting Sense of Competence (PSOC) scale at 4 time points (approximately day of life 7, 1 day before discharge, and at 14 and 30 days after discharge) representing the neonatal intensive care unit, discharge, and home contexts. App use was described and categorized. Univariate group differences were assessed, and linear mixed effect regression models were used to assess treatment group effect on PSOC score across time, adjusted for covariates and controlling for overall family effect. RESULTS: We enrolled 298 parents (123 control, 175 intervention) with 256 completing 1 or more PSOC screenings. The intervention group had sustained higher PSOC scores than those of the control group (estimate, 4.3; P = .0042) from the first measurement onward with no significant change in PSOC score across time for either group. Average app use was 15 taps per average day; average and above-average users had significantly higher PSOC scores (estimate, 5.16; P = .0024; estimate, 5.16; P = .014) compared with controls or below-average users. CONCLUSIONS: Compared with controls, parents assigned to use the NICU2HOME app reported greater parenting self-efficacy while in the neonatal intensive care unit and this continued once discharged to home. Novel technologies such as point-of-care smartphone applications may hold promise for supporting parents in difficult and stressful situations. TRIAL REGISTRATION: ClincalTrials.gov: NCT03505424.
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Poder Familiar , Telemedicina , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Pais , AutoeficáciaRESUMO
We use ^{79}Br nuclear quadrupole resonance (NQR) to demonstrate that ultraslow lattice dynamics set in below the temperature scale set by the Cu-Cu superexchange interaction J (≃160 K) in the kagome lattice Heisenberg antiferromagnet Zn-barlowite. The lattice completely freezes below 50 K, and ^{79}Br NQR line shapes become twice broader due to increased lattice distortions. Moreover, the frozen lattice exhibits an oscillatory component in the transverse spin echo decay, a typical signature of pairing of nuclear spins by indirect nuclear spin-spin interaction. This indicates that some Br sites form structural dimers via a pair of kagome Cu sites prior to the gradual emergence of spin singlets below â¼30 K. Our findings underscore the significant roles played by subtle structural distortions in determining the nature of the disordered magnetic ground state of the kagome lattice.
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Fermi surface (FS) topology is a fundamental property of metals and superconductors. In electron-doped cuprate Nd2-x Ce x CuO4 (NCCO), an unexpected FS reconstruction has been observed in optimal- and overdoped regime (x = 0.15-0.17) by quantum oscillation measurements (QOM). This is all the more puzzling because neutron scattering suggests that the antiferromagnetic (AFM) long-range order, which is believed to reconstruct the FS, vanishes before x = 0.14. To reconcile the conflict, a widely discussed external magnetic-field-induced AFM long-range order in QOM explains the FS reconstruction as an extrinsic property. Here, we report angle-resolved photoemission (ARPES) evidence of FS reconstruction in optimal- and overdoped NCCO. The observed FSs are in quantitative agreement with QOM, suggesting an intrinsic FS reconstruction without field. This reconstructed FS, despite its importance as a basis to understand electron-doped cuprates, cannot be explained under the traditional scheme. Furthermore, the energy gap of the reconstruction decreases rapidly near x = 0.17 like an order parameter, echoing the quantum critical doping in transport. The totality of the data points to a mysterious order between x = 0.14 and 0.17, whose appearance favors the FS reconstruction and disappearance defines the quantum critical doping. A recent topological proposal provides an ansatz for its origin.
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Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that expand in inflammatory conditions including transplantation. MDSCs may be capable of controlling rejection. The critical mechanisms underlying MDSC mediated alloregulation remain unexplored. G-CSF potently stimulates MDSC expansion. We hypothesized that G-CSF-induced MDSCs use a novel mechanism to suppress T cell responses. G-CSF promoted expansion of MDSCs and enhanced their suppressive function against T cell proliferation. Gene expression analysis revealed MDSCs expanded with G-CSF upregulated immune-related genes, but downregulated proliferation-related genes when compared to naïve control MDSCs. The KIT oncogene, encoding the c-Kit (CD117) transmembrane tyrosine kinase receptor, was the most significantly increased in MDSCs expanded with G-CSF. c-Kit inhibition with both imatinib and monoclonal blocking antibody reduced expression of ARG-1, iNOS, PD-L1, and SAA3. Further, imatinib also reduced MDSC-mediated T cell suppression in vitro. Modulation of c-Kit activity may represent a therapeutic target for alloregulatory MDSCs.
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Rejeição de Enxerto/imunologia , Fator Estimulador de Colônias de Granulócitos/metabolismo , Inflamação/imunologia , Células Supressoras Mieloides/imunologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Linfócitos T/imunologia , Animais , Antineoplásicos/farmacologia , Proliferação de Células , Células Cultivadas , Feminino , Rejeição de Enxerto/tratamento farmacológico , Humanos , Mesilato de Imatinib/farmacologia , Tolerância Imunológica , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transplante de Órgãos , Proteínas Proto-Oncogênicas c-kit/genética , TranscriptomaRESUMO
Myeloid-derived suppressor cells (MDSCs) expand in an inflammatory microenvironment such as cancer and autoimmunity. To study if transplantation induces MDSCs and these cells regulate allograft survival, C57BL/6 donor hearts were transplanted into BALB/c recipients and endogenous MDSCs were characterized. The effects of adoptive transfer of transplant (tx), tumor (tm), and granulocyte-colony stimulating factor (g-csf)-expanded MDSCs or depletion of MDSC were assessed. MDSCs expanded after transplantation (1.7-4.6-fold) in the absence of immunosuppression, homed to allografts, and suppressed proliferation of CD4 T cells in vitro. Tx-MDSCs differed phenotypically from tm-MDSCs and g-csf-MDSCs. Among various surface markers, Rae-1 expression was notably low and TGF-ß receptor II was high in tx-MDSCs when compared to tm-MDSCs and g-csf-MDSCs. Adoptive transfer of these three MDSCs led to differential graft survival: control (6 days), tx-MDSCs (7.5 days), tm-MDSCs (9.5 days), and g-csf-MDSCs (19.5 days). In combination with anti-CD154 mAb, MDSCs synergistically extended graft survival from 40 days (anti-CD154 alone) to 86 days with tm-MDSCs and 132 days with g-csf-MDSCs. Early MDSC depletion (day 0 or 20), however, abrogated graft survival, but late depletion (day 25) did not. In conclusion, MDSCs expanded following transplantation, migrated to cardiac allografts, prolonged graft survival, and were synergistic with anti-CD154 mAb.
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Transplante de Coração , Células Supressoras Mieloides , Animais , Sobrevivência de Enxerto , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Doadores de TecidosRESUMO
The experimental realization of quantum spin liquids is a long-sought goal in physics, as they represent new states of matter. Quantum spin liquids cannot be described by the broken symmetries associated with conventional ground states. In fact, the interacting magnetic moments in these systems do not order, but are highly entangled with one another over long ranges. Spin liquids have a prominent role in theories describing high-transition-temperature superconductors, and the topological properties of these states may have applications in quantum information. A key feature of spin liquids is that they support exotic spin excitations carrying fractional quantum numbers. However, detailed measurements of these 'fractionalized excitations' have been lacking. Here we report neutron scattering measurements on single-crystal samples of the spin-1/2 kagome-lattice antiferromagnet ZnCu(3)(OD)(6)Cl(2) (also called herbertsmithite), which provide striking evidence for this characteristic feature of spin liquids. At low temperatures, we find that the spin excitations form a continuum, in contrast to the conventional spin waves expected in ordered antiferromagnets. The observation of such a continuum is noteworthy because, so far, this signature of fractional spin excitations has been observed only in one-dimensional systems. The results also serve as a hallmark of the quantum spin-liquid state in herbertsmithite.
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To examine cortisol diurnal rhythms over the transition from the critical care setting to home for fathers and mothers of very low-birth-weight infants, including how cortisol is associated with psychosocial stress and parenting sense of competence. This cohort study in a level III neonatal intensive care unit and the general community had 86 parents complete salivary collection and self-reported psychosocial measures. Salivary samples were collected 3 times a day on the day before discharge, and on 3 subsequent days at home. Self-report measures included the Perceived Stress Scale and the Parenting Sense of Competence Scale, which measure parenting satisfaction. Fathers showed increased physiologic stress over the transition home, reflected by flattening of slopes, lower wakeup, and higher bedtime cortisol. Mothers reporting increases in perceived stress over the transition home had higher bedtime cortisol, suggesting a link between higher perceived stress and higher physiologic stress. Results were significant after controlling for breastfeeding, insurance status, and gestational age. This study examined a physiologic marker of stress in parents with very low-birth-weight infants, finding sex disparities in diurnal cortisol patterns during the transition from neonatal intensive care unit to the community. Fathers may be especially susceptible to stressors during this transition.
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Ritmo Circadiano/fisiologia , Hidrocortisona/análise , Recém-Nascido de muito Baixo Peso/psicologia , Saliva/metabolismo , Estresse Psicológico/metabolismo , Adulto , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Masculino , Adulto JovemRESUMO
Lower testosterone during the transition to new parenthood is considered beneficial to help parents better engage with their infants. No data currently exist studying salivary testosterone of parents with infants in neonatal intensive care units (NICUs) during the transition to home. We examine testosterone levels for parents of very low-birth-weight infants, including links between salivary testosterone and infant factors (such as breast-feeding), psychosocial stress, and changes over time.Testosterone salivary samples were assayed after self-collection by 86 parents (43 fathers and 43 mothers) with NICU infants at wakeup and bedtime prior to discharge and at 3 additional times at home. Self-reported survey measures, including psychosocial reports, were also collected at these times.Using multilevel modeling approaches, we report significant associations between paternal testosterone by time and psychosocial adjustment and between both paternal and maternal testosterone and infant feeding mode (P < .05). Results were significant after accounting for covariates. Our study is the first to examine the time course of diurnal testosterone for parents of premature infants over the transition home; as such, we suggest further research into better understanding parental physiology in this vulnerable parent population.
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Recém-Nascido de muito Baixo Peso , Pais/psicologia , Saliva/metabolismo , Ajustamento Social , Estresse Psicológico , Testosterona , Adulto , Aleitamento Materno/métodos , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro/metabolismo , Recém-Nascido Prematuro/psicologia , Recém-Nascido de muito Baixo Peso/metabolismo , Recém-Nascido de muito Baixo Peso/psicologia , Masculino , Alta do Paciente , Estatística como Assunto , Estresse Psicológico/etiologia , Estresse Psicológico/metabolismo , Estresse Psicológico/reabilitação , Testosterona/análise , Testosterona/metabolismoRESUMO
The cooperative Jahn-Teller effect (CJTE) refers to the correlation of distortions arising from individual Jahn-Teller centres in complex compounds. The effect usually induces strong coupling between the static or dynamic charge, orbital and magnetic ordering, which has been related to many important phenomena such as colossal magnetoresistance and superconductivity. Here we report a Na5/8MnO2 superstructure with a pronounced static CJTE that is coupled to an unusual Na vacancy ordering. We visualize this coupled distortion and Na ordering down to the atomic scale. The Mn planes are periodically distorted by a charge modulation on the Mn stripes, which in turn drives an unusually large displacement of some Na ions through long-ranged Na-O-Mn(3+)-O-Na interactions into a highly distorted octahedral site. At lower temperatures, magnetic order appears, in which Mn atomic stripes with different magnetic couplings are interwoven with each other. Our work demonstrates the strong interaction between alkali ordering, displacement, and electronic and magnetic structure, and underlines the important role that structural details play in determining electronic behaviour.
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At low temperatures, the thermal conductivity of spin excitations in a magnetic insulator can exceed that of phonons. However, because they are charge neutral, the spin waves are not expected to display a thermal Hall effect. However, in the kagome lattice, theory predicts that the Berry curvature leads to a thermal Hall conductivity κ(xy). Here we report observation of a large κ(xy) in the kagome magnet Cu(1-3, bdc) which orders magnetically at 1.8 K. The observed κ(xy) undergoes a remarkable sign reversal with changes in temperature or magnetic field, associated with sign alternation of the Chern flux between magnon bands. The close correlation between κ(xy) and κ(xx) firmly precludes a phonon origin for the thermal Hall effect.
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The response of an oxide crystal to the atmosphere can be personified as breathing-a dynamic equilibrium between O2 gas and O2- anions in the solid. We characterize the analogous defect reaction in an iodide double-perovskite semiconductor, Cs2SnI6. Here, I2 gas is released from the crystal at room temperature, forming iodine vacancies. The iodine vacancy defect is a shallow electron donor and is therefore ionized at room temperature; thus, the loss of I2 is accompanied by spontaneous n-type self-doping. Conversely, at high I2 pressures, I2 gas is resorbed by the perovskite, consuming excess electrons as I2 is converted to 2I-. Halide mobility and irreversible halide loss or exchange reactions have been studied extensively in halide perovskites. However, the reversible exchange equilibrium between iodide and iodine [2I-(s) â I2(g) + 2e-] described here has often been overlooked in prior studies, though it is likely general to halide perovskites and operative near room temperature, even in the dark. An analysis of the 2I-(s)/I2(g) equilibrium thermodynamics and related transport kinetics in single crystals of Cs2SnI6 therefore provides insight toward achieving stable composition and electronic properties in the large family of iodide perovskite semiconductors.
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Material design is increasingly used to realize desired functional properties, and the perovskite structure family is one of the richest and most diverse: perovskites are employed in many applications due to their structural flexibility and compositional diversity. Hexagonal, layered perovskite structures with chains of face-sharing transition metal oxide octahedra have attracted great interest as quantum materials due to their magnetic and electronic properties. Ba4MMn3O12, a member of the "12R" class of hexagonal, layered perovskites, contains trimers of face-sharing MnO6 octahedra that are linked by a corner-sharing, bridging MO6 octahedron. Here, we investigate cluster magnetism in the Mn3O12 trimers and the role of this bridging octahedron on the magnetic properties of two isostructural 12R materials by systematically changing the M4+ cation from nonmagnetic Ce4+ (f0) to magnetic Pr4+ (f1). We synthesized 12R-Ba4MMn3O12 (M= Ce, Pr) with high phase purity and characterized their low-temperature crystal structures and magnetic properties. Using substantially higher purity samples than previously reported, we confirm the frustrated antiferromagnetic ground state of 12R-Ba4PrMn3O12 below TN ≈ 7.75 K and explore the cluster magnetism of its Mn3O12 trimers. Despite being atomically isostructural with 12R-Ba4CeMn3O12, the f1 electron associated with Pr4+ causes much more complex magnetic properties in 12R-Ba4PrMn3O12. In 12R-Ba4PrMn3O12, we observe a sharp, likely antiferromagnetic transition at T2 ≈ 12.15 K and an additional transition at T1 ≈ 200 K, likely in canted antiferromagnetic order. These results suggest that careful variation of composition within the family of hexagonal, layered perovskites can be used to tune material properties using the complex role of the Pr4+ ion in magnetism.
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PURPOSE: Tissue-derived tumor mutation burden (TMB) of ≥10 mutations/Mb is a histology-agnostic biomarker for the immune checkpoint inhibitor (ICI) pembrolizumab. However, the dataset in which this was validated lacked colorectal cancers (CRC), and there is limited evidence for immunotherapy benefits in CRC using this threshold. PATIENTS AND METHODS: CO.26 was a randomized phase II study of 180 patients, comparing durvalumab and tremelimumab (D + T, n = 119 patients) versus best supportive care (BSC; n = 61 patients). ctDNA sequencing was available for 168 patients (n = 118 D + T; n = 50), of whom 165 had evaluable plasma TMB (pTMB). Tissue sequencing was available for 108 patients. Optimal thresholds for stratifying patients based on OS were determined using a minimal P value approach. This report includes the final OS analysis. RESULTS: Tissue TMB ≥10 mutations/Mb was not predictive of benefit from D + T compared with BSC in microsatellite stable (MSS) metastatic CRC [HR, 0.71 (95% CI, 0.28-1.80); P = 0.47]. No tissue TMB threshold could identify a high TMB group that benefited from ICI. By contrast, plasma TMB (pTMB) ≥28 mutations/Mb was predictive of benefit from D + T [HR, 0.34 (95% CI, 0.13-0.85); P = 0.022], as was clonal pTMB ≥10.6 mutations/Mb [HR, 0.10 (95% CI, 0.014-0.79); P = 0.029] and subclonal pTMB ≥25.9/Mb [HR, 0.20 (95% CI, 0.061-0.69); P = 0.010]. Higher pTMB was associated with length of time on cytotoxic agents (P = 0.021) and prior anti-EGFR exposure (P = 2.44 × 10-06). CONCLUSIONS: pTMB derived from either clonal or subclonal mutations may identify a group likely to benefit from immunotherapy, although validation is required. Tissue TMB provided no predictive utility for immunotherapy in this trial.
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Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais , Neoplasias Colorretais , Mutação , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores Tumorais/genética , Feminino , Masculino , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/sangue , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/administração & dosagem , Idoso de 80 Anos ou mais , Metástase NeoplásicaRESUMO
In the underdoped n-type cuprate Nd2-xCexCuO4, long-range antiferromagnetic order reconstructs the Fermi surface, resulting in a putative antiferromagnetic metal with small Fermi pockets. Using angle-resolved photoemission spectroscopy, we observe an anomalous energy gap, an order of magnitude smaller than the antiferromagnetic gap, in a wide portion of the underdoped regime and smoothly connecting to the superconducting gap at optimal doping. After considering all the known ordering tendencies in tandem with the phase diagram, we hypothesize that the normal-state gap in the underdoped n-type cuprates originates from Cooper pairing. The high temperature scale of the normal-state gap raises the prospect of engineering higher transition temperatures in the n-type cuprates comparable to those of the p-type cuprates.
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BACKGROUND: Despite ongoing improvements to regimens preventing allograft rejection, most cardiac and other organ grafts eventually succumb to chronic vasculopathy, interstitial fibrosis, or endothelial changes, and eventually graft failure. The events leading to chronic rejection are still poorly understood and the gut microbiota is a known driving force in immune dysfunction. We previously showed that gut microbiota dysbiosis profoundly influences the outcome of vascularized cardiac allografts and subsequently identified biomarker species associated with these differential graft outcomes. METHODS: In this study, we further detailed the multifaceted immunomodulatory properties of protolerogenic and proinflammatory bacterial species over time, using our clinically relevant model of allogenic heart transplantation. RESULTS: In addition to tracing longitudinal changes in the recipient gut microbiome over time, we observed that Bifidobacterium pseudolongum induced an early anti-inflammatory phenotype within 7 d, whereas Desulfovibrio desulfuricans resulted in a proinflammatory phenotype, defined by alterations in leukocyte distribution and lymph node (LN) structure. Indeed, in vitro results showed that B pseudolongum and D desulfuricans acted directly on primary innate immune cells. However, by 40 d after treatment, these 2 bacterial strains were associated with mixed effects in their impact on LN architecture and immune cell composition and loss of colonization within gut microbiota, despite protection of allografts from inflammation with B pseudolongum treatment. CONCLUSIONS: These dynamic effects suggest a critical role for early microbiota-triggered immunologic events such as innate immune cell engagement, T-cell differentiation, and LN architectural changes in the subsequent modulation of protolerant versus proinflammatory immune responses in organ transplant recipients.
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Bifidobacterium , Microbioma Gastrointestinal , Rejeição de Enxerto , Transplante de Coração , Transplante de Coração/efeitos adversos , Microbioma Gastrointestinal/imunologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/microbiologia , Rejeição de Enxerto/prevenção & controle , Animais , Masculino , Fatores de Tempo , Sobrevivência de Enxerto , Disbiose , Camundongos Endogâmicos C57BL , Imunidade Inata , Imunomodulação , Fenótipo , Probióticos/uso terapêutico , Linfonodos/microbiologia , Linfonodos/imunologiaRESUMO
Immune mediated graft loss still represents a major risk to transplant recipients. Creative approaches to immunosuppression that exploit the recipient's own alloregulatory mechanisms could reduce the need for pharmacologic immunosuppression and potentially induce immune tolerance. In the process of studying recipient derived myeloid derived suppressor cells (MDSCs), we identified key alloregulatory MDSC mechanisms, mediated by isolatable proteins IL-4, IL-34, and IL-10. We sought to purify these proteins and fuse them for subsequent infusion into transplant recipients as a means of inducing an alloregulatory response. In this introductory investigation, we leveraged molecular engineering technology to create a fusion protein (FP) of three cytokine coding sequences of IL-4, IL-34, and IL-10 and demonstrated their expressions by Western Blot analysis. Following purification, we tested whether FP IL-4/IL-34/IL-10 (FP1) can protect heart transplant allografts. Injection of FP1 significantly prolonged allogeneic cardiac graft survival in a dose-dependent fashion and the increase of graft survival time exceeded survival attributable to IL-34 alone. In vitro, MDSCs cells were expanded by FP1 treatment. However, FP1 did not directly inhibit T cell proliferation in vitro. In conclusion, newly developed FP1 improves the graft survival in cardiac transplantation mouse model. Significant additional work to optimize FP1 or include other novel proteins could supplement current treatment options for transplant patients.