Prostaglandin E2 controls the metabolic adaptation of T cells to the intestinal microenvironment.

Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8+ T cells to the intestinal microenvironment and how this process shapes the establishment of the CD8+ T cell pool. CD8+ T cells progressively remodel their transcriptome and surface phenotype as they enter the gut wall, and downregulate expression of mitochondrial genes. Human and mouse intestinal CD8+ T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We find that the intestinal microenvironment is rich in prostaglandin E2 (PGE2), which drives mitochondrial depolarization in CD8+ T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE2 sensing promotes CD8+ T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell pool. Thus, a PGE2-autophagy-glutathione axis defines the metabolic adaptation of CD8+ T cells to the intestinal microenvironment, to ultimately influence the T cell pool.

Synchronization of Bloch Oscillations in a Strongly Coupled Pair of Small Josephson Junctions: Evidence for a Shapiro-like Current Step.

Bloch oscillations are a fundamental phenomenon linking the adiabatic transport of Cooper pairs to time. Here, we investigate synchronization of the Bloch oscillations in a strongly coupled system of sub-100 nm Al/AlO_{x}/Al Josephson junctions in a high-Ohmic environment composed of highly inductive meanders of granulated aluminum and high-Ohmic titanium microstrips. We observe a pronounced current mirror effect in the coupled junctions and demonstrate current plateaus, akin to the first dual Shapiro step in microwave experiments. These findings suggest that our circuit design holds promise for realizing protected Bloch oscillations and precise Shapiro steps of interest for current metrology.

Prostaglandin E 2 controls the metabolic adaptation of T cells to the intestinal microenvironment.

Immune cells must adapt to different environments during the course of an immune response. We studied the adaptation of CD8 + T cells to the intestinal microenvironment and how this process shapes their residency in the gut. CD8 + T cells progressively remodel their transcriptome and surface phenotype as they acquire gut residency, and downregulate expression of mitochondrial genes. Human and mouse gut-resident CD8 + T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We found that the intestinal microenvironment is rich in prostaglandin E 2 (PGE 2 ), which drives mitochondrial depolarization in CD8 + T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE 2 sensing promotes CD8 + T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell population. Thus, a PGE 2 -autophagy-glutathione axis defines the metabolic adaptation of CD8 + T cells to the intestinal microenvironment, to ultimately influence the T cell pool.

Statistical Majorana Bound State Spectroscopy.

Tunnel spectroscopy data for the detection of Majorana bound states (MBS) is often criticized for its proneness to misinterpretation of genuine MBS with low-lying Andreev bound states. Here, we suggest a protocol removing this ambiguity by extending single shot measurements to sequences performed at varying system parameters. We demonstrate how such sampling, which we argue requires only moderate effort for current experimental platforms, resolves the statistics of Andreev side lobes, thus providing compelling evidence for the presence or absence of a Majorana center peak.

Non-Hermitian Physics without Gain or Loss: The Skin Effect of Reflected Waves.

Physically, one tends to think of non-Hermitian systems in terms of gain and loss: the decay or amplification of a mode is given by the imaginary part of its energy. Here, we introduce an alternative avenue to the realm of non-Hermitian physics, which involves neither gain nor loss. Instead, complex eigenvalues emerge from the amplitudes and phase differences of waves backscattered from the boundary of insulators. We show that for any strong topological insulator in a Wigner-Dyson class, the reflected waves are characterized by a reflection matrix exhibiting the non-Hermitian skin effect. This leads to an unconventional Goos-Hänchen effect: due to non-Hermitian topology, waves undergo a lateral shift upon reflection, even at normal incidence. Going beyond systems with gain and loss vastly expands the set of experimental platforms that can access non-Hermitian physics and show signatures associated with non-Hermitian topology.

Intracellular infection and immune system cues rewire adipocytes to acquire immune function.

Adipose tissue (AT) plays a central role in systemic metabolic homeostasis, but its function during bacterial infection remains unclear. Following subcutaneous bacterial infection, adipocytes surrounding draining lymph nodes initiated a transcriptional response indicative of stimulation with IFN-γ and a shift away from lipid metabolism toward an immunologic function. Natural killer (NK) and invariant NK T (iNKT) cells were identified as sources of infection-induced IFN-γ in perinodal AT (PAT). IFN-γ induced Nos2 expression in adipocytes through a process dependent on nuclear-binding oligomerization domain 1 (NOD1) sensing of live intracellular bacteria. iNOS expression was coupled to metabolic rewiring, inducing increased diversion of extracellular L-arginine through the arginosuccinate shunt and urea cycle to produce nitric oxide (NO), directly mediating bacterial clearance. In vivo, control of infection in adipocytes was dependent on adipocyte-intrinsic sensing of IFN-γ and expression of iNOS. Thus, adipocytes are licensed by innate lymphocytes to acquire anti-bacterial functions during infection.

Period Tripling due to Parametric Down-Conversion in Circuit QED.

Discrete time-translation symmetry breaking can be observed in periodically driven systems oscillating at a fraction of the frequency of the driving force. However, with the exception of the parametric instability in period doubling, multiperiodic driving does not lead to an instability threshold. In this Letter, we point out that quantum vacuum fluctuations can be generically employed to induce period multiplication. In particular, we discuss the period-tripled states in circuit QED and propose a microwave setup. We show that for weak dissipation or strong driving, the system exhibits a nonequilibrium phase transition in the sense that the timescale over which the period-tripled state is generated can be arbitrarily separated from the timescale of the subsequent dephasing.

Plasmacytoid dendritic cell activation is dependent on coordinated expression of distinct amino acid transporters.

Human plasmacytoid dendritic cells (pDCs) are interleukin-3 (IL-3)-dependent cells implicated in autoimmunity, but the role of IL-3 in pDC biology is poorly understood. We found that IL-3-induced Janus kinase 2-dependent expression of SLC7A5 and SLC3A2, which comprise the large neutral amino acid transporter, was required for mammalian target of rapamycin complex 1 (mTORC1) nutrient sensor activation in response to toll-like receptor agonists. mTORC1 facilitated increased anabolic activity resulting in type I interferon, tumor necrosis factor, and chemokine production and the expression of the cystine transporter SLC7A11. Loss of function of these amino acid transporters synergistically blocked cytokine production by pDCs. Comparison of in vitro-activated pDCs with those from lupus nephritis lesions identified not only SLC7A5, SLC3A2, and SLC7A11 but also ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2) as components of a shared transcriptional signature, and ENPP2 inhibition also blocked cytokine production. Our data identify additional therapeutic targets for autoimmune diseases in which pDCs are implicated.

Low-energy in-gap states of vortices in superconductor-semiconductor heterostructures.

The recent interest in the low-energy states in vortices of semiconductor-superconductor heterostructures are mainly fuelled by the prospects of using Majorana zero modes for quantum computation. The knowledge of low-lying states in the vortex core is essential as they pose a limitation on the topological computation with these states. Recently, the low-energy spectra of clean heterostructures, for superconducting-pairing profiles that vary slowly on the scale of the Fermi wavelength of the semiconductor, have been analytically calculated. In this work, we formulate an alternative method based on perturbation theory to obtain concise analytical formulas to predict the low-energy states including explicit magnetic-field and gap profiles. We provide results for both a topological insulator (with a linear spectrum) as well as for a conventional electron gas (with a quadratic spectrum). We discuss the spectra for a wide range of parameters, including both the size of the vortex and the chemical potential of the semiconductor, and thereby provide a tool to guide future experimental efforts. We compare these findings to numerical results.

Triacylglycerol synthesis enhances macrophage inflammatory function.

Foamy macrophages, which have prominent lipid droplets (LDs), are found in a variety of disease states. Toll-like receptor agonists drive triacylglycerol (TG)-rich LD development in macrophages. Here we explore the basis and significance of this process. Our findings indicate that LD development is the result of metabolic commitment to TG synthesis on a background of decreased fatty acid oxidation. TG synthesis is essential for optimal inflammatory macrophage activation as its inhibition, which prevents LD development, has marked effects on the production of inflammatory mediators, including IL-1ß, IL-6 and PGE2, and on phagocytic capacity. The failure of inflammatory macrophages to make PGE2 when TG-synthesis is inhibited is critical for this phenotype, as addition of exogenous PGE2 is able to reverse the anti-inflammatory effects of TG synthesis inhibition. These findings place LDs in a position of central importance in inflammatory macrophage activation.

Metabolic conditioning of CD8+ effector T cells for adoptive cell therapy.

CD8+ effector T (TE) cell proliferation and cytokine production depends on enhanced glucose metabolism. However, circulating T cells continuously adapt to glucose fluctuations caused by diet and inter-organ metabolite exchange. Here we show that transient glucose restriction (TGR) in activated CD8+ TE cells metabolically primes effector functions and enhances tumour clearance in mice. Tumour-specific TGR CD8+ TE cells co-cultured with tumour spheroids in replete conditions display enhanced effector molecule expression, and adoptive transfer of these cells in a murine lymphoma model leads to greater numbers of immunologically functional circulating donor cells and complete tumour clearance. Mechanistically, TE cells treated with TGR undergo metabolic remodelling that, after glucose re-exposure, supports enhanced glucose uptake, increased carbon allocation to the pentose phosphate pathway (PPP) and a cellular redox shift towards a more reduced state-all indicators of a more anabolic programme to support their enhanced functionality. Thus, metabolic conditioning could be used to promote efficiency of T-cell products for adoptive cellular therapy.

Inflammatory macrophage dependence on NAD+ salvage is a consequence of reactive oxygen species-mediated DNA damage.

The adoption of Warburg metabolism is critical for the activation of macrophages in response to lipopolysaccharide. Macrophages stimulated with lipopolysaccharide increase their expression of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD+ salvage, and loss of NAMPT activity alters their inflammatory potential. However, the events that lead to the cells' becoming dependent on NAD+ salvage remain poorly defined. We found that depletion of NAD+ and increased expression of NAMPT occurred rapidly after inflammatory activation and coincided with DNA damage caused by reactive oxygen species (ROS). ROS produced by complex III of the mitochondrial electron-transport chain were required for macrophage activation. DNA damage was associated with activation of poly(ADP-ribose) polymerase, which led to consumption of NAD+. In this setting, increased NAMPT expression allowed the maintenance of NAD+ pools sufficient for glyceraldehyde-3-phosphate dehydrogenase activity and Warburg metabolism. Our findings provide an integrated explanation for the dependence of inflammatory macrophages on the NAD+ salvage pathway.

Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to Prostaglandin E2.

Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here, we show that PGE2 caused mitochondrial membrane potential (Δψm) to dissipate in interleukin-4-activated (M(IL-4)) macrophages. Effects on Δψm were a consequence of PGE2-initiated transcriptional regulation of genes, particularly Got1, in the malate-aspartate shuttle (MAS). Reduced Δψm caused alterations in the expression of 126 voltage-regulated genes (VRGs), including those encoding resistin-like molecule α (RELMα), a key marker of M(IL-4) cells, and genes that regulate the cell cycle. The transcription factor ETS variant 1 (ETV1) played a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Δψm-sensitive transcription factor and Δψm as a mediator of mitochondrial-directed nuclear gene expression.

Quantum transport through MoS2 constrictions defined by photodoping.

We present a device scheme to explore mesoscopic transport through molybdenum disulfide (MoS2) constrictions using photodoping. The devices are based on van-der-Waals heterostructures where few-layer MoS2 flakes are partially encapsulated by hexagonal boron nitride (hBN) and covered by a few-layer graphene flake to fabricate electrical contacts. Since the as-fabricated devices are insulating at low temperatures, we use photo-induced remote doping in the hBN substrate to create free charge carriers in the MoS2 layer. On top of the device, we place additional metal structures, which define the shape of the constriction and act as shadow masks during photodoping of the underlying MoS2/hBN heterostructure. Low temperature two- and four-terminal transport measurements show evidence of quantum confinement effects.

Quantum Phase Transitions of the Majorana Toric Code in the Presence of Finite Cooper-Pair Tunneling.

The toric code based on Majorana fermions on mesoscopic superconducting islands is a promising candidate for quantum information processing. In the limit of vanishing Cooper-pair tunneling, it has been argued that the phase transition separating the topologically ordered phase of the toric code from the trivial one is in the universality class of the (2+1)D XY model. On the other hand, in the limit of infinitely large Cooper-pair tunneling, the phase transition is in the universality class of the (2+1)D Ising model. In this work, we treat the case of finite Cooper-pair tunneling and address the question of how the continuous XY symmetry breaking phase transition turns into a discrete Z_{2} symmetry breaking one when the Cooper-pair tunneling rate is increased. We show that this happens through a couple of tricritical points and first order phase transitions. Using a Jordan-Wigner transformation, we map the problem to that of spins coupled to quantum rotors and subsequently, propose a Landau field theory for this model that matches the known results in the respective limits. We calculate the effective field theories and provide the relevant critical exponents for the different phase transitions. Our results are relevant for predicting the stability of the topological phase in realistic experimental implementations.

Traumatic nonanastomotic axilloprofundal PTFE-bypass rupture: a case report.

A 76-year-old male patient was admitted to our emergency department with painful swelling of the right lateral chest after a fall. Imaging revealed a hematoma, secondary to rupture of a synthetic axilloprofundal bypass. In an emergency surgical procedure, the spelled hematoma was evacuated and the graft legs were successfully ligated. The patient was discharged after an uneventful hospital stay. Traumatic bypass rupture because of blunt trauma is an exceedingly rare event; however, it must be taken into consideration in a patient with bypass surgery in his/her history.

Reconstitution of the peripheral B lymphocyte compartment in patients with ANCA-associated vasculitides treated with rituximab for relapsing or refractory disease.

While in patients with rheumatoid arthritis B-cell repopulation starts within 9 months after rituximab (RTX) therapy, a delayed B-cell repopulation was reported in some RTX-treated patients with ANCA-associated vasculitides (AAV). To date, the frequency of AAV patients with impaired peripheral B-cell regeneration and the mechanisms leading to the constricted regenerative capacity are unknown. We analyzed the B-cell repopulation kinetic in 37 AAV patients treated with RTX followed by maintenance immunosuppressants. We report on serum concentrations of the B-cell-activating factor BAFF, immunoglobulins and B-cell subpopulations in patients that relapsed after RTX. B-cells were re-detectable in only one patient within 9 months after RTX. In 14 patients (41%), B-cell repopulation started later, after a mean observation time of 21 months. Only seven of these patients had detectable B-cells within the first year after RTX. Twenty patients (59%) had no B-cell reconstitution within the observation period. BAFF was increased in RTX-treated AAV patients compared to healthy controls and correlated inversely with peripheral B-cell numbers, IgG- and IgA concentrations. Immunoglobulin concentrations declined significantly after RTX and the IgG concentration correlated with B-cell numbers. Thirteen patients relapsed after RTX. Relapses occurred exclusively either after B-cell reconstitution had started or were accompanied by rising ANCA titres. In relapsed patients, the B-lymphocyte compartment consisted mainly of switched memory B-cells. Our data indicate that RTX treatment can induce secondary immunodeficiency in AAV, with hypogammaglobulinemia and long-lasting B-lymphopenia. Further studies are needed to define the pathophysiology of the impaired B-cell development in RTX-treated AAV patients.

Rituximab in the treatment of refractory or relapsing eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

INTRODUCTION: Eosinophilic granulomatosis with polyangiitis (EGPA) is part of antineutrophil cytoplasmic antibodies (ANCAs)-associated vasculitides. In EGPA small-vessel vasculitis is associated with eosinophilia and asthma. About 40% of EGPA patients are ANCA-positive, suggesting a role for B cells in the pathogenesis of EGPA. B cell-depleting therapy with rituximab (RTX) can be effective in ANCA-positive EGPA, but very few patients have been published to date. The role of RTX in the treatment of ANCA-negative EGPA is unclear. METHODS: We report a single-center cohort of patients with eosinophilic granulomatosis with polyangiitis. Of these patients, nine (six ANCA-positive, three ANCA-negative) had been treated with RTX for relapsing or refractory disease on standard immunosuppressive treatment. In a retrospective analysis, data on treatment response, frequency of relapses, adverse events, and peripheral B-cell reconstitution were evaluated. Furthermore, serum immunoglobulin concentrations, ANCA status, and peripheral B cell subpopulations were assessed after RTX treatment. RESULTS: All patients had high disease activity before RTX treatment. At presentation 3 months after RTX therapy, all ANCA-positive and ANCA-negative patients had responded to RTX, with one patient being in complete remission, and eight patients being in partial remission. After a mean follow-up of 9 months, C-reactive protein concentrations had normalized, eosinophils had significantly decreased, and prednisone had been tapered in all patients. In all patients, RTX therapy was combined with a standard immunosuppressive therapy. Within the 9-month observation period, no relapse was recorded. Three patients were preemptively retreated with RTX, and during the median follow-up time of 3 years, no relapse occurred in these patients. During the follow-up of 13 patient-years, five minor but no major infections were recorded. CONCLUSIONS: In our analysis on nine patients with EGPA resistant to standard therapy, rituximab proved to be an efficient and safe treatment for ANCA-positive and ANCA-negative patients. Preemptive retreatment with RTX, combined with standard maintenance immunosuppressants, resulted in a sustained treatment response. Prospective, randomized trials evaluating the use of RTX in EGPA are warranted.

B cell homeostasis is disturbed by immunosuppressive therapies in patients with ANCA-associated vasculitides.

B-lymphocytes play a pivotal role in ANCA-associated vasculitides (AAV). The homeostasis of peripheral human B-lymphocyte subpopulations is tightly regulated, but may be disturbed in autoimmune disease or following immunosuppressive therapies. To elucidate the effect of immunosuppression and the relevance of B-lymphocyte disturbances, the B-lymphocyte compartment was analysed in 61 AAV patients. After immunosuppressive treatment a general B-lymphocytopenia developed in AAV patients. Within the B-lymphocyte subpopulations transitional B cells are the first maturation stage found in the peripheral blood. Transitional B-lymphocytes were significantly lower in AAV patients after immunosuppressive therapy compared to healthy controls. Furthermore, marginal zone B cells--a B-lymphocyte population protecting against encapsulated bacteria--were markedly lowered after immunosuppressive therapy in AAV patients. AAV patients treated with immunosuppressants had lower numbers of naïve and memory B-lymphocytes. Numbers of marginal zone B cells, memory B cells and plasmablasts correlated with concentrations of immunoglobulins. We evaluated plasmablasts for a potential correlation with disease activity. Different from what has been reported for e.g. large vessel vasculitis, absolute numbers of plasmablasts were not increased in patients with AAV and showed no correlation to disease activity. As low transitional B cells after treatment with immunosuppressants indicated an impaired early B-lymphocyte development, seven patients treated with the B cell depleting agent rituximab (RTX) because of relapsing disease activity were analysed for their B cell repopulation kinetics. In the majority of these patients repopulation of the peripheral B cell compartment by newly formed transitional B cells after RTX treatment was constricted and delayed.

From Majorana fermions to topological order.

We consider a system consisting of a 2D network of links between Majorana fermions on superconducting islands. We show that the fermionic Hamiltonian modeling this system is topologically ordered in a region of parameter space: we show that Kitaev's toric code emerges in fourth-order perturbation theory. By using a Jordan-Wigner transformation we can map the model onto a family of signed 2D Ising models in a transverse field where the signs, ferromagnetic or antiferromagnetic, are determined by additional gauge bits. Our mapping allows an understanding of the nonperturbative regime and the phase transition to a nontopological phase. We discuss the physics behind a possible implementation of this model and argue how it can be used for topological quantum computation by adiabatic changes in the Hamiltonian.