Peripheral differentiation patterns of human T cells

Long-term T-cell memory is dependent on the maintenance of memory T cells in the lymphoid tissues, and at the surface interfaces that provide entry routes for pathogens. However, much of the current information on human T-cell memory is based on analyzing circulating T cells. Here, we have studied the distribution and age-related changes of memory T-cell subsets in samples from blood, mesenteric LNs, spleen, and ileum, obtained from donors ranging in age from 5 days to 67 years of age. Our data show that the main reservoir of polyclonal naive cells is found in the LNs, and the resting memory subsets capable of self-renewal are also prominent there. In contrast, nondividing but functionally active memory subsets dominate the spleen, and especially the ileum. In general, the replacement of naive cells with memory subsets continues throughout our period of observation, with no apparent plateau. In conclusion, the analysis of lymphoid and nonlymphoid tissues reveals a dynamic pattern of changes distinct to each tissue, and with substantial differences between CD4(+) and CD8(+) compartments.Peer reviewe

Electron Energy Loss Spectroscopy of Bright and Dark Modes in Hyperbolic Metamaterial Nanostructures

Layered metal/dielectric hyperbolic metamaterials (HMMs) support a wide landscape of plasmon polariton excitations. In addition to surface plasmon polaritons, coupled Bloch‐like gap‐plasmon polaritons with high modal confinement inside the multilayer are supported. Photons can excite only a subset of these polaritonic modes, typically with a limited energy and momentum range in respect to the wide set of high‐K modes supported by hyperbolic dispersion media, and coupling with gratings or local excitation is necessary. Strikingly, electron energy loss spectroscopy (EELS) in a scanning transmission electron microscope allows nm‐scale local excitation and mapping of the spatial field distribution of all the modes supported by a photonic or plasmonic structure, both bright and dark, and also all other inelastic interactions of the beam, including phonons and interband transitions. Herein, experimental evidence of the spatial distribution of plasmon polaritons in multilayered type II HMM nanostructures is acquired with an aloof electron beam adjacent to structures of current interest. HMM pillars are useful for their separation and adjustability of optical scattering and absorption, while HMM slot cavities can be used as waveguides with high field confinement. The nature of the modes is confirmed with corresponding simulations of EEL and optical spectra and near‐field intensities

Modification of carbonic anhydrase II with acetaldehyde, the first metabolite of ethanol, leads to decreased enzyme activity

<p>Abstract</p> <p>Background</p> <p>Acetaldehyde, the first metabolite of ethanol, can generate covalent modifications of proteins and cellular constituents. However, functional consequences of such modification remain poorly defined. In the present study, we examined acetaldehyde reaction with human carbonic anhydrase (CA) isozyme II, which has several features that make it a suitable target protein: It is widely expressed, its enzymatic activity can be monitored, its structural and catalytic properties are known, and it contains 24 lysine residues, which are accessible sites for aldehyde reaction.</p> <p>Results</p> <p>Acetaldehyde treatment in the absence and presence of a reducing agent (NaBH₃(CN)) caused shifts in the pI values of CA II. SDS-PAGE indicated a shift toward a slightly higher molecular mass. High-resolution mass spectra of CA II, measured with and without NaBH₃(CN), indicated the presence of an unmodified protein, as expected. Mass spectra of CA II treated with acetaldehyde revealed a modified protein form (+26 Da), consistent with a "Schiff base" formation between acetaldehyde and one of the primary NH₂groups (e.g., in lysine side chain) in the protein structure. This reaction was highly specific, given the relative abundance of over 90% of the modified protein. In reducing conditions, each CA II molecule had reacted with 9–19 (14 on average) acetaldehyde molecules (+28 Da), consistent with further reduction of the "Schiff bases" to substituted amines (N-ethyllysine residues). The acetaldehyde-modified protein showed decreased CA enzymatic activity.</p> <p>Conclusion</p> <p>The acetaldehyde-derived modifications in CA II molecule may have physiological consequences in alcoholic patients.</p

Enhanced nonlinear emission from single multilayered metal–dielectric nanocavities resonating in the near-infrared

Harmonic generation mechanisms are of great interest in nanoscience and nanotechnology, since they allow generating visible light by using near-infrared radiation, which is particularly suitable for its countless applications in bionanophotonics and optoelectronics. In this context, multilayer metal–dielectric nanocavities are widely used for light confinement and waveguiding at the nanoscale. They exhibit intense and localized resonances that can be conveniently tuned in the near-infrared and are therefore ideal for enhancing nonlinear effects in this spectral range. In this work, we experimentally investigate the nonlinear emission properties of multilayer metal–dielectric nanocavities. By engineering their absorption efficiency and exploiting their intrinsic interface-induced symmetry breaking, we achieve an almost 2 orders of magnitude higher second-harmonic generation efficiency compared to gold nanostructures featuring the same geometry and optical resonant behavior. In particular, while both the third-order nonlinear susceptibility and conversion efficiency are comparable with those of the Au nanoresonators, we estimate a second-order nonlinear susceptibility of the order of 1 pm/V, which is comparable with that of typical nonlinear crystals. We envision that our system, which combines the advantages of both plasmonic and dielectric materials, might enable the realization of composite and multifunctional nanosystems for the efficient manipulation of nonlinear optical processes at the nanoscale

Centralized repeated resectability assessment of patients with colorectalliver metastases during first-line treatment : prospective study

Y Background: Metastasectomy is probably underused in metastatic colorectal cancer. The aim of this study was to investigate the effect of centralized repeated assessment on resectability rate of liver metastases. Methods: The prospective RAXO study was a nationwide study in Finland. Patients with treatable metastatic colorectal cancer at any site were eligible. This planned substudy included patients with baseline liver metastases between 2012 and 2018. Resectability was reassessed by the multidisciplinary team at Helsinki tertiary referral centre upfront and twice during first-line systemic therapy. Outcomes were resectability rates, management changes, and survival. Results: Of 812 patients included, 301 (37.1 per cent) had liver-only metastases. Of these, tumours were categorized as upfront resectable in 161 (53.5 per cent), and became amenable to surgery during systemic treatment in 63 (20.9 per cent). Some 207 patients (68.7 per cent) eventually underwent liver resection or ablation. At baseline, a discrepancy in resectability between central and local judgement was noted for 102 patients (33.9 per cent). Median disease-free survival (DFS) after first resection was 20 months and overall survival (OS) 79 months. Median OS after diagnosis of metastatic colorectal cancer was 80, 32, and 21 months in R0-1 resection, R2/ablation, and non-resected groups, and 5-year OS rates were 68, 37, and 9 per cent, respectively. Liver and extrahepatic metastases were present in 511 patients. Of these, tumours in 72 patients (14.1 per cent) were categorized as upfront resectable, and 53 patients (10.4 per cent) became eligible for surgery. Eventually 110 patients (21.5 per cent) underwent liver resection or ablation. At baseline, a discrepancy between local and central resectability was noted for 116 patients (22.7 per cent). Median DFS from first resection was 7 months and median OS 55 months. Median OS after diagnosis of metastatic colorectal cancer was 79, 42, and 17 months in R0-1 resection, R2/ablation, and non-resected groups, with 5-year OS rates of 65, 39, and 2 per cent, respectively. Conclusion: Repeated centralized resectability assessment in patients with colorectal liver metastases improved resection and survival rates.Peer reviewe

Polariton lasing in AlGaN microring with GaN/AlGaN quantum wells

Microcavity polaritons are strongly interacting hybrid light–matter quasiparticles, which are promising for the development of novel light sources and active photonic devices. Here, we report polariton lasing in the UV spectral range in microring resonators based on GaN/AlGaN slab waveguides, with experiments carried out from 4 K up to room temperature. Stimulated polariton relaxation into multiple ring resonator modes is observed, which exhibit threshold-like dependence of the emission intensity with pulse energy. The strong exciton-photon coupling regime is confirmed by the significant reduction of the free spectral range with energy and the blueshift of the exciton–like modes with increasing pulse energy. Importantly, the exciton emission shows no broadening with power, further confirming that lasing is observed at electron–hole densities well below the Mott transition. Overall, our work paves the way toward the development of novel UV devices based on the high-speed slab waveguide polariton geometry operating up to room temperature with the potential to be integrated into complex photonic circuits

Exciton–polaritons in GaAs-based slab waveguide photonic crystals

We report the observation of bandgaps for low loss exciton-polaritons propagating outside the light cone in GaAs-based planar waveguides patterned into two-dimensional photonic crystals. By etching square lattice arrays of shallow holes into the uppermost layer of our structure, we open gaps on the order of 10 meV in the photonic mode dispersion, whose size and light-matter composition can be tuned by proximity to the strongly coupled exciton resonance. We demonstrate gaps ranging from almost fully photonic to highly excitonic. Opening a gap in the exciton-dominated part of the polariton spectrum is a promising first step toward the realization of quantum-Hall-like states arising from topologically nontrivial hybridization of excitons and photons

Treatment response of colorectal cancer liver metastases to neoadjuvant or conversion therapy : a prospective multicentre follow-up study using MRI, diffusion-weighted imaging and H-1-MR spectroscopy compared with histology (subgroup in the RAXO trial)

Background: Colorectal cancer liver metastases respond to chemotherapy and targeted agents not only by shrinking, but also by morphologic and metabolic changes. The aim of this study was to evaluate the value of advanced magnetic resonance imaging (MRI) methods in predicting treatment response and survival. Patients and methods: We investigated contrast-enhanced MRI, apparent diffusion coefficient (ADC) in diffusionweighted imaging and H-1-magnetic resonance spectroscopy (1H-MRS) in detecting early morphologic and metabolic changes in borderline or resectable liver metastases, as a response to first-line neoadjuvant or conversion therapy in a prospective substudy of the RAXO trial (NCT01531621, EudraCT2011-003158-24). MRI findings were compared with histology of resected liver metastases and KaplaneMeier estimates of overall survival (OS). Results: In 2012-2018, 52 patients at four Finnish university hospitals were recruited. Forty-seven patients received neoadjuvant or conversion chemotherapy and 40 liver resections were carried out. Low ADC values (below median) of the representative liver metastases, at baseline and after systemic therapy, were associated with partial response according to RECIST criteria, but not with morphologic MRI changes or histology. Decreasing ADC values following systemic therapy were associated with improved OS compared to unchanged or increasing ADC, both in the liver resected subgroup (5-year OS rate 100% and 34%, respectively, P = 0.022) and systemic therapy subgroup (5-year OS rate 62% and 23%, P = 0.049). H-1-MRS revealed steatohepatosis induced by systemic therapy. Conclusions: Low ADC values at baseline or during systemic therapy were associated with treatment response by RECIST but not with histology, morphologic or detectable metabolic changes. A decreasing ADC during systemic therapy is associated with improved OS both in all patients receiving systemic therapy and in the resected subgroup.Peer reviewe

Treatment response of colorectal cancer liver metastases to neoadjuvant or conversion therapy : a prospective multicentre follow-up study using MRI, diffusion-weighted imaging and H-1-MR spectroscopy compared with histology (subgroup in the RAXO trial)

Background: Colorectal cancer liver metastases respond to chemotherapy and targeted agents not only by shrinking, but also by morphologic and metabolic changes. The aim of this study was to evaluate the value of advanced magnetic resonance imaging (MRI) methods in predicting treatment response and survival. Patients and methods: We investigated contrast-enhanced MRI, apparent diffusion coefficient (ADC) in diffusionweighted imaging and H-1-magnetic resonance spectroscopy (1H-MRS) in detecting early morphologic and metabolic changes in borderline or resectable liver metastases, as a response to first-line neoadjuvant or conversion therapy in a prospective substudy of the RAXO trial (NCT01531621, EudraCT2011-003158-24). MRI findings were compared with histology of resected liver metastases and KaplaneMeier estimates of overall survival (OS). Results: In 2012-2018, 52 patients at four Finnish university hospitals were recruited. Forty-seven patients received neoadjuvant or conversion chemotherapy and 40 liver resections were carried out. Low ADC values (below median) of the representative liver metastases, at baseline and after systemic therapy, were associated with partial response according to RECIST criteria, but not with morphologic MRI changes or histology. Decreasing ADC values following systemic therapy were associated with improved OS compared to unchanged or increasing ADC, both in the liver resected subgroup (5-year OS rate 100% and 34%, respectively, P = 0.022) and systemic therapy subgroup (5-year OS rate 62% and 23%, P = 0.049). H-1-MRS revealed steatohepatosis induced by systemic therapy. Conclusions: Low ADC values at baseline or during systemic therapy were associated with treatment response by RECIST but not with histology, morphologic or detectable metabolic changes. A decreasing ADC during systemic therapy is associated with improved OS both in all patients receiving systemic therapy and in the resected subgroup.Peer reviewe