The early expansion of anergic NKG2Apos/CD56dim/CD16neg natural killer cells represents a therapeutic target in haploidentical haematopoietic stem cell transplantation

Natural Killer cells are the first lymphocyte population to reconstitute early after non myelo-ablative and T cell-replete haploidentical hematopoietic stem cell transplantation with post-transplant infusion of cyclophosphamide. The present study characterizes the transient and predominant expansion starting from the 2nd week after haploidentical hematopoietic stem cell transplantation of a donor-derived unconventional subset of NKp46neg-low/CD56dim/CD16neg natural killer cells expressing remarkable high levels of CD94/NKG2A. Both transcription and phenotypic profiles indicated that unconventional NKp46neg-low/CD56dim/CD16neg natural killer cells are a distinct natural killer cell subpopulation with features of late stage differentiation, yet retaining proliferative capability and functional plasticity to generate conventional NKp46pos/CD56bright/CD16pos natural killer cells in response to interleukin-15 plus interleukin-18. While present at low frequency in healthy donors, unconventional NKp46neg-low/CD56dim/CD16neg natural killer cells are greatly expanded in the following 7 weeks after haploidentical hematopoietic stem cell transplantation and express high levels of the activating receptors NKGD and NKp30 as well as of the lytic granules Granzyme-B and Perforin. Nonetheless, NKp46neg-low/CD56dim/CD16neg natural killer cells displayed a markedly defective cytotoxicity that could be reversed by blocking the inhibitory receptor CD94/NKG2A. These data open new important perspectives to better understand the ontogenesis/homeostasis of human natural killer cells and to develop a novel immune-therapeutic approach that targets the inhibitory NKG2A check point, thus unleashing natural killer cell alloreactivity early after haploidentical hematopoietic stem cell transplantation

CSF β-amyloid and white matter damage: a new perspective on Alzheimer's disease

Objective: To assess the connection between amyloid pathology and white matter (WM) macro- and micro-structural damage in demented patients compared with controls. Methods: Eighty-five participants were recruited: 65 with newly diagnosed Alzheimer’s disease (AD), non-AD dementia or mild cognitive impairment (MCI), and 20 age- and sex-matched heatlhy controls. β-amyloid1-42 (Aβ) levels were determined in cerebrospinal fluid (CSF) samples from all patients and 5 controls. Among patients, 42 had pathological CSF Aβ levels (Aβ+), while 23 had normal CSF Aβ levels (Aβ-). All participants underwent neurological examination, neuropsychological testing and brain magnetic resonance imaging (MRI). We used T2-weighted scans to quantify white matter (WM) lesion loads (LL), and diffusion weighted images (DWI) to assess their microstructural substrate. Non-parametric statistical tests were used for between-group comparisons and multiple regression analyses. Results: We found an increased WM-LL in Aβ(+) compared to both, healthy controls (p=0.003) and Aβ(-) patients (p=0.02). Interestingly, CSF Aβ concentration was the best predictor patients’ WM-LL (r=-0.30, p<0.05) when using age as a covariate. Lesion apparent diffusion coefficient (ADC) value was higher in all patients than in controls (p=0.0001), and correlated with WM-LL (r=0.41, p=0.001). In Aβ(+), WM-LL correlated with WM microstructural damage in the left peritrigonal WM (p<0.0001). Conclusions: WM damage is crucial in Alzheimer’s disease (AD) pathogenesis. The correlation between CSF Aβ levels and WM-LL suggests a direct link between amyloid pathology and WM macro- and microstructural damage

Terminologia e interculturalità. Problematiche e prospettive

La terminologia contribuisce al consolidamento di patrimoni linguistici e culturali mentre la sua diffusione intra- e interlinguistica favorisce la costruzione di dialoghi interdisciplinari, evolvendo in parallelo a nuovi bisogni e contesti. Queste dinamiche si innestano nelle problematiche della comunicazione interculturale, tanto nelle pratiche dell’espressione quanto in quelle della traduzione interlinguistica. In questo volume, studiose e studiosi, specialiste e specialisti di terminologia presentano le loro riflessioni su queste tematiche, indagando la dimensione culturale e interculturale della ricerca terminologica e delle sue pratiche, interrogando tutti i fenomeni relativi all’incontro fra culture in atto nella realizzazione discorsiva di ambito specialistico. Tali riflessioni considerano ogni dimensione della testualità, fino agli spazi digitali, che offrono strumenti di analisi oltre i limiti della materialità, offrendo così un panorama ampio nel dibattito in corso, un terreno fertile per la verifica teorica alle questioni di ricerca in ambito terminologico

Multidifferential study of identified charged hadron distributions in ZZ-tagged jets in proton-proton collisions at s=\sqrt{s}=13 TeV

Jet fragmentation functions are measured for the first time in proton-proton collisions for charged pions, kaons, and protons within jets recoiling against a $Z$ boson. The charged-hadron distributions are studied longitudinally and transversely to the jet direction for jets with transverse momentum 20 $< p_{\textrm{T}} < 100$ GeV and in the pseudorapidity range $2.5 < \eta < 4$. The data sample was collected with the LHCb experiment at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 1.64 fb$^{-1}$. Triple differential distributions as a function of the hadron longitudinal momentum fraction, hadron transverse momentum, and jet transverse momentum are also measured for the first time. This helps constrain transverse-momentum-dependent fragmentation functions. Differences in the shapes and magnitudes of the measured distributions for the different hadron species provide insights into the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb public pages

Study of the B−→Λc+Λˉc−K−B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-} decay

The decay $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ is studied in proton-proton collisions at a center-of-mass energy of $\sqrt{s}=13$ TeV using data corresponding to an integrated luminosity of 5 $\mathrm{fb}^{-1}$ collected by the LHCb experiment. In the $\Lambda_{c}^+ K^{-}$ system, the $\Xi_{c}(2930)^{0}$ state observed at the BaBar and Belle experiments is resolved into two narrower states, $\Xi_{c}(2923)^{0}$ and $\Xi_{c}(2939)^{0}$, whose masses and widths are measured to be $$m(\Xi_{c}(2923)^{0}) = 2924.5 \pm 0.4 \pm 1.1 \,\mathrm{MeV}, \\ m(\Xi_{c}(2939)^{0}) = 2938.5 \pm 0.9 \pm 2.3 \,\mathrm{MeV}, \\ \Gamma(\Xi_{c}(2923)^{0}) = \phantom{000}4.8 \pm 0.9 \pm 1.5 \,\mathrm{MeV},\\ \Gamma(\Xi_{c}(2939)^{0}) = \phantom{00}11.0 \pm 1.9 \pm 7.5 \,\mathrm{MeV},$$ where the first uncertainties are statistical and the second systematic. The results are consistent with a previous LHCb measurement using a prompt $\Lambda_{c}^{+} K^{-}$ sample. Evidence of a new $\Xi_{c}(2880)^{0}$ state is found with a local significance of $3.8\,\sigma$, whose mass and width are measured to be $2881.8 \pm 3.1 \pm 8.5\,\mathrm{MeV}$ and $12.4 \pm 5.3 \pm 5.8 \,\mathrm{MeV}$, respectively. In addition, evidence of a new decay mode $\Xi_{c}(2790)^{0} \to \Lambda_{c}^{+} K^{-}$ is found with a significance of $3.7\,\sigma$. The relative branching fraction of $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ with respect to the $B^{-} \to D^{+} D^{-} K^{-}$ decay is measured to be $2.36 \pm 0.11 \pm 0.22 \pm 0.25$, where the first uncertainty is statistical, the second systematic and the third originates from the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb public pages

Measurement of the ratios of branching fractions R(D∗)\mathcal{R}(D^{*}) and R(D0)\mathcal{R}(D^{0})

The ratios of branching fractions $\mathcal{R}(D^{*})\equiv\mathcal{B}(\bar{B}\to D^{*}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(\bar{B}\to D^{*}\mu^{-}\bar{\nu}_{\mu})$ and $\mathcal{R}(D^{0})\equiv\mathcal{B}(B^{-}\to D^{0}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(B^{-}\to D^{0}\mu^{-}\bar{\nu}_{\mu})$ are measured, assuming isospin symmetry, using a sample of proton-proton collision data corresponding to 3.0 fb${ }^{-1}$ of integrated luminosity recorded by the LHCb experiment during 2011 and 2012. The tau lepton is identified in the decay mode $\tau^{-}\to\mu^{-}\nu_{\tau}\bar{\nu}_{\mu}$. The measured values are $\mathcal{R}(D^{*})=0.281\pm0.018\pm0.024$ and $\mathcal{R}(D^{0})=0.441\pm0.060\pm0.066$, where the first uncertainty is statistical and the second is systematic. The correlation between these measurements is $\rho=-0.43$. Results are consistent with the current average of these quantities and are at a combined 1.9 standard deviations from the predictions based on lepton flavor universality in the Standard Model.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-039.html (LHCb public pages

Targeting NKG2A to elucidate natural killer cell ontogenesis and to develop novel immune-therapeutic strategies in cancer therapy

Natural Killer (NK) cells are innate immune cells with a primary role in the immune surveillance against non-self-cells. NK cell recognition of "self" relies on the surface expression on autologous cells of MHC class I (MHC-I) molecules. Either the absence or the down-modulation of MHC-I on target cells "license" NK cells to kill threatening tumor-transformed or virally infected cells. This phenomenon is controlled by a limited repertoire of activating and inhibitory NK receptors (aNKRs and iNKRs) that tunes NK cell activation and effector functions. Hence, the calibration of NK cell alloreactivity depends on the ability of iNKRs to bind MHC-I complex and these interactions are key in regulating both NK cell differentiation and effector functions. Indeed, the presence of iNKRs specific for self-MHC haplotypes (i) plays a role in the "licensing/education" process that controls the responsiveness of mature NK cells and prevents their activation against the "self" and (ii) is exploited by tumor cells to escape from NK cell cytotoxicity. Herein, we review our current knowledge on function and clinical application of NKG2A, a C-type lectin iNKR that binds specific haplotypes of human leukocyte antigens early during the NK cell maturation process, thus contributing to modulate the terminal maturation of NK cells as potent effectors against cancers cells. These NKG2A-mediated mechanisms are currently being exploited for developing promising immune-therapeutic strategies to improve the prognosis of solid and blood tumors and to ameliorate the clinical outcome of patients undergone allogeneic hematopoietic stem cell transplantation to treat high-risk hematologic malignancies