Insights into the Interaction Mechanism of DTP3 with MKK7 by Using STD-NMR and Computational Approaches

GADD45β/MKK7 complex is a non-redundant, cancer cell-restricted survival module downstream of the NF-kB survival pathway, and it has a pathogenically critical role in multiple myeloma, an incurable malignancy of plasma cells. The first-in-class GADD45β/MKK7 inhibitor DTP3 effectively kills MM cells expressing its molecular target, both in vitro and in vivo, by inducing MKK7/JNK-dependent apoptosis with no apparent toxicity to normal cells. DTP3 combines favorable drug-like properties, with on-target-specific pharmacology, resulting in a safe and cancer-selective therapeutic effect; however, its mode of action is only partially understood. In this work, we have investigated the molecular determinants underlying the MKK7 interaction with DTP3 by combining computational, NMR, and spectroscopic methods. Data gathered by fluorescence quenching and computational approaches consistently indicate that the N-terminal region of MKK7 is the optimal binding site explored by DTP3. These findings further the understanding of the selective mode of action of GADD45β/MKK7 inhibitors and inform potential mechanisms of drug resistance. Notably, upon validation of the safety and efficacy of DTP3 in human trials, our results could also facilitate the development of novel DTP3-like therapeutics with improved bioavailability or the capacity to bypass drug resistance

The glycosaminoglycan-binding domain of PRELP acts as a cell type–specific NF-κB inhibitor that impairs osteoclastogenesis

The PRELP heparin sulfate–binding protein translocates to the nucleus, where it impairs NF-κB transcriptional activity, which in turn regulates bone homeostasis

GADD45β loss ablates innate immunosuppression in cancer

T cell exclusion from the tumour microenvironment (TME) is a major barrier to overcoming immune escape. Here we identify a myeloid-intrinsic mechanism governed by the NF-κB effector molecule GADD45β that restricts tumour-associated inflammation and T cell trafficking into tumours. In various models of solid cancers refractory to immunotherapies, including hepatocellular carcinoma (HCC) and ovarian adenocarcinoma, Gadd45b inhibition in myeloid cells restored activation of pro-inflammatory tumour-associated macrophages (TAM) and intratumoural immune infiltration, thereby diminishing oncogenesis. Our results provide a basis to interpret clinical evidence that elevated expression of GADD45B confers poor clinical outcomes in most human cancers. Further, they suggest a therapeutic target in GADD45β for re-programming TAM to overcome immunosuppression and T cell exclusion from the TME

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

Light Hadron Production measurement with LHCb fixed-target data and LHCb RICH system commissioning for Run3

The LHCb experiment located at CERN is one of the major experiments at the LHC accelerator. The LHCb detector is unique among the other detectors due to its single-arm spectrometer design. An excellent Particle Identification (PID) is among the necessary requirements to achieve the precision needed for CP violation studies and b-quarks decays, which constitute the main original physics cases of the experiment. Provided with a Ring Imaging Cherenkov (RICH) system, LHCb is optimized to identify and discriminate light hadrons (π, K and p). Throughout its lifetime, the LHCb physics reach has extended substantially beyond what was originally planned, and the detector is currently operating also in a fixed-target mode exploiting collisions of the LHC beams with gas targets. The gas is injected into the beam pipe by means of the SMOG system, providing a unique fixed-target facility at the highest available beam energy. The combination of an excellent PID with the collection of proton-nucleus collision data in an unexplored energy range opens the possibility to perform light-hadron production measurements with distinctive target systems. Charged particle production in hadronic collisions is a fundamental observable for studying the properties of the strong interaction, described by quantum chromodynamics (QCD), giving the possibility to probe and study the so-called Cold Nuclear Matter (CNM) effects. By studying the medium-induced modifications of light-hadron production in proton-nucleus collisions (p-A) relative to the naive proton-proton collisions (p-p), information on the nontrivial QCD dynamics can be retrieved. These CNM effects can cause the suppression of the production cross sections and the modification of the particle spectra in a regime where the quark-gluon-plasma (QGP) formation is not expected. In recent years, the LHCb detector has undergone a major upgrade to better exploit the luminosity delivered by the LHC with the goal to operate safely and efficiently at the luminosity of 2×10^33 cm^−2 s^−1, five times higher than the past run conditions. This required an upgrade of most of the LHCb subdetectors and of the read-out system to cope with the 40MHz rate and the higher level of radiation foreseen for the incoming Run3, started in 2022. In particular, the RICH detectors have been completely renewed after long and successful upgrade and commissioning activities. For the RICH upgrade, the former Hybrid Photon Detectors (HPDs) have been replaced by Multi Anode Photon Multipliers (MaPMTs), the optics of the RICH nearest to the beam collision have been modified, and the electronics replaced. The new front-end electronics are based on the CLARO chip, FPGAs digital board, and Giga Bit Transceiver (GBT) chip for data transmission and front-end configuration. The modifications to the RICH system aim to maintain and improve excellent PID performance. The RICH system has been almost fully commissioned and has been operated during stable beam collisions delivered by LHC throughout 2022. In this thesis, I present my contribution to the Run2 LHCb fixed-target program, which involves the development of a novel PID tool designed as a Neural Network-based Gaussian Mixture Model making use of the RICH system variables, and a light hadron production analysis using the data collected with He and Ar targets in Run2. Additionally, my activities related to the RICH system Upgrade for Run3 are also described. They comprehend the validation of the opto-electronic chain and the quality assurance of the photomultipliers and Front-End electronics. Also, the work of my last year of PhD in the LHCb control room for the RICH system commissioning is covered in which I've contributed to achieve a stable and reliable RICH system able to operate and collect data in Run3.L'esperimento LHCb situato presso il CERN è uno dei principali esperimenti presso l'acceleratore LHC. Un'eccellente Identificazione delle Particelle (PID) è uno dei requisiti necessari per raggiungere la precisione richiesta negli studi di violazione di CP e decadimenti dei quark b, che costituiscono i principali studi di fisica dell'esperimento. Dotato di un sistema Ring Imaging Cherenkov (RICH), LHCb è ottimizzato per identificare e discriminare adroni leggeri (π, K e p). Nel corso della sua vita, la portata fisica di LHCb si è estesa notevolmente rispetto a quanto originariamente pianificato e il rivelatore è attualmente in funzione anche in modalità fixed-target sfruttando le collisioni dei fasci di LHC con bersagli gassosi. Il gas viene iniettato nel tubo del fascio tramite il sistema SMOG, fornendo un'installazione fixed-target unica con la massima energia di fascio disponibile. La combinazione di un'eccellente PID con la raccolta di dati di collisione protone-nucleo in un intervallo di energia inesplorato apre la possibilità di effettuare misurazioni sulla produzione di adroni leggeri con distintivi sistemi bersaglio. La produzione di particelle cariche nelle collisioni adroniche è una grandezza fondamentale per lo studio delle proprietà dell'interazione forte, descritta dalla cromodinamica quantistica (QCD), offrendo la possibilità di indagare e studiare gli effetti del cosiddetto Cold Nuclear Matter (CNM). Studiando le modifiche indotte dal mezzo alla produzione di adroni leggeri nelle collisioni protone-nucleo (p-A) rispetto alle collisioni protone-protone (p-p), è possibile ottenere informazioni sulla dinamica non banale della QCD. Questi effetti di CNM possono causare la soppressione delle sezioni d'urto di produzione e la modifica degli spettri di particelle in un regime in cui non ci si aspetta la formazione del plasma di quark e gluoni (QGP). Negli ultimi anni, il rivelatore LHCb ha subito una grande aggiornamento per sfruttare al meglio la luminosità fornita dal LHC, con l'obiettivo di operare in modo sicuro ed efficiente alla luminosità di 2×10^33cm−2s−1, cinque volte superiore alle condizioni di funzionamento precedenti. Ciò ha richiesto un aggiornamento della maggior parte dei sotto-rivelatori di LHCb e del sistema di lettura per far fronte al rate di 40MHz e al livello superiore di radiazioni previste per il prossimo Run3, iniziato nel 2022. In particolare, i rivelatori RICH sono stati completamente rinnovati dopo lunghe e riuscite attività di aggiornamento e messa in servizio. Per l'aggiornamento dei RICH, i precedenti rivelatori ibridi a fotoni (HPD) sono stati sostituiti dai fotomoltiplicatori multi anodo (MaPMT), l'ottica del RICH più vicino alla collisione del fascio è stata modificata e l'elettronica è stata sostituita. La nuova elettronica di front-end si basa sul chip CLARO, una scheda digitale FPGA e il chip Giga Bit Transceiver (GBT) per la trasmissione dei dati e la configurazione del front-end. Le modifiche al sistema RICH mirano a mantenere e migliorare le eccellenti prestazioni del PID. In questa tesi, presento il mio contributo al programma LHCb fixed-target del Run2, che coinvolge lo sviluppo di un nuovo strumento PID progettato come un gaussian mixture model basato su una rete neurale che fa uso delle variabili del sistema RICH, e un'analisi sulla produzione di adroni leggeri utilizzando i dati raccolti con bersagli di elio e argon nel Run2. Inoltre, vengono descritte anche le mie attività legate all'aggiornamento del sistema RICH per il Run3. Queste comprendono la convalida della catena opto-elettronica e il controllo di qualità dei fotomoltiplicatori e dell'elettronica di front-end. Inoltre, il lavoro del mio ultimo anno di dottorato nella sala di controllo di LHCb per la messa in servizio del sistema RICH è descritto, a cui ho contribuito per ottenere un sistema RICH stabile e affidabile in grado di operare e raccogliere dati nel Run3

Fixed-target program upgrade and prospects at LHCb

LHCb has the unique capability to operate in fixed-target mode to study collisions of the LHC beams on fixed targets. In Run3, the internal gas target is going to be upgraded to allow for a wider selection of target gas species and a significant increase of the rates of fixed-target collisions by up to two orders of magnitude. Along with significant data acquisition and tracking upgrades, the SMOG2 system greatly enhances the reach of LHCb’s heavy ion program

Light Hadron Production measurement with LHCb fixed-target data and LHCb RICH system commissioning for Run3

The LHCb experiment located at CERN is one of the major experiments at the LHC accelerator. The LHCb detector is unique among the other detectors due to its single-arm spectrometer design. An excellent Particle Identification (PID) is among the necessary requirements to achieve the precision needed for CP violation studies and b-quarks decays, which constitute the main original physics cases of the experiment. Provided with a Ring Imaging Cherenkov (RICH) system, LHCb is optimized to identify and discriminate light hadrons (π, K and p). Throughout its lifetime, the LHCb physics reach has extended substantially beyond what was originally planned, and the detector is currently operating also in a fixed-target mode exploiting collisions of the LHC beams with gas targets. The gas is injected into the beam pipe by means of the SMOG system, providing a unique fixed-target facility at the highest available beam energy. The combination of an excellent PID with the collection of proton-nucleus collision data in an unexplored energy range opens the possibility to perform light-hadron production measurements with distinctive target systems. Charged particle production in hadronic collisions is a fundamental observable for studying the properties of the strong interaction, described by quantum chromodynamics (QCD), giving the possibility to probe and study the so-called Cold Nuclear Matter (CNM) effects. By studying the medium-induced modifications of light-hadron production in proton-nucleus collisions (p-A) relative to the naive proton-proton collisions (p-p), information on the nontrivial QCD dynamics can be retrieved. These CNM effects can cause the suppression of the production cross sections and the modification of the particle spectra in a regime where the quark-gluon-plasma (QGP) formation is not expected. In recent years, the LHCb detector has undergone a major upgrade to better exploit the luminosity delivered by the LHC with the goal to operate safely and efficiently at the luminosity of 2×10^33 cm^−2 s^−1, five times higher than the past run conditions. This required an upgrade of most of the LHCb subdetectors and of the read-out system to cope with the 40MHz rate and the higher level of radiation foreseen for the incoming Run3, started in 2022. In particular, the RICH detectors have been completely renewed after long and successful upgrade and commissioning activities. For the RICH upgrade, the former Hybrid Photon Detectors (HPDs) have been replaced by Multi Anode Photon Multipliers (MaPMTs), the optics of the RICH nearest to the beam collision have been modified, and the electronics replaced. The new front-end electronics are based on the CLARO chip, FPGAs digital board, and Giga Bit Transceiver (GBT) chip for data transmission and front-end configuration. The modifications to the RICH system aim to maintain and improve excellent PID performance. The RICH system has been almost fully commissioned and has been operated during stable beam collisions delivered by LHC throughout 2022. In this thesis, I present my contribution to the Run2 LHCb fixed-target program, which involves the development of a novel PID tool designed as a Neural Network-based Gaussian Mixture Model making use of the RICH system variables, and a light hadron production analysis using the data collected with He and Ar targets in Run2. Additionally, my activities related to the RICH system Upgrade for Run3 are also described. They comprehend the validation of the opto-electronic chain and the quality assurance of the photomultipliers and Front-End electronics. Also, the work of my last year of PhD in the LHCb control room for the RICH system commissioning is covered in which I've contributed to achieve a stable and reliable RICH system able to operate and collect data in Run3.L'esperimento LHCb situato presso il CERN è uno dei principali esperimenti presso l'acceleratore LHC. Un'eccellente Identificazione delle Particelle (PID) è uno dei requisiti necessari per raggiungere la precisione richiesta negli studi di violazione di CP e decadimenti dei quark b, che costituiscono i principali studi di fisica dell'esperimento. Dotato di un sistema Ring Imaging Cherenkov (RICH), LHCb è ottimizzato per identificare e discriminare adroni leggeri (π, K e p). Nel corso della sua vita, la portata fisica di LHCb si è estesa notevolmente rispetto a quanto originariamente pianificato e il rivelatore è attualmente in funzione anche in modalità fixed-target sfruttando le collisioni dei fasci di LHC con bersagli gassosi. Il gas viene iniettato nel tubo del fascio tramite il sistema SMOG, fornendo un'installazione fixed-target unica con la massima energia di fascio disponibile. La combinazione di un'eccellente PID con la raccolta di dati di collisione protone-nucleo in un intervallo di energia inesplorato apre la possibilità di effettuare misurazioni sulla produzione di adroni leggeri con distintivi sistemi bersaglio. La produzione di particelle cariche nelle collisioni adroniche è una grandezza fondamentale per lo studio delle proprietà dell'interazione forte, descritta dalla cromodinamica quantistica (QCD), offrendo la possibilità di indagare e studiare gli effetti del cosiddetto Cold Nuclear Matter (CNM). Studiando le modifiche indotte dal mezzo alla produzione di adroni leggeri nelle collisioni protone-nucleo (p-A) rispetto alle collisioni protone-protone (p-p), è possibile ottenere informazioni sulla dinamica non banale della QCD. Questi effetti di CNM possono causare la soppressione delle sezioni d'urto di produzione e la modifica degli spettri di particelle in un regime in cui non ci si aspetta la formazione del plasma di quark e gluoni (QGP). Negli ultimi anni, il rivelatore LHCb ha subito una grande aggiornamento per sfruttare al meglio la luminosità fornita dal LHC, con l'obiettivo di operare in modo sicuro ed efficiente alla luminosità di 2×10^33cm−2s−1, cinque volte superiore alle condizioni di funzionamento precedenti. Ciò ha richiesto un aggiornamento della maggior parte dei sotto-rivelatori di LHCb e del sistema di lettura per far fronte al rate di 40MHz e al livello superiore di radiazioni previste per il prossimo Run3, iniziato nel 2022. In particolare, i rivelatori RICH sono stati completamente rinnovati dopo lunghe e riuscite attività di aggiornamento e messa in servizio. Per l'aggiornamento dei RICH, i precedenti rivelatori ibridi a fotoni (HPD) sono stati sostituiti dai fotomoltiplicatori multi anodo (MaPMT), l'ottica del RICH più vicino alla collisione del fascio è stata modificata e l'elettronica è stata sostituita. La nuova elettronica di front-end si basa sul chip CLARO, una scheda digitale FPGA e il chip Giga Bit Transceiver (GBT) per la trasmissione dei dati e la configurazione del front-end. Le modifiche al sistema RICH mirano a mantenere e migliorare le eccellenti prestazioni del PID. In questa tesi, presento il mio contributo al programma LHCb fixed-target del Run2, che coinvolge lo sviluppo di un nuovo strumento PID progettato come un gaussian mixture model basato su una rete neurale che fa uso delle variabili del sistema RICH, e un'analisi sulla produzione di adroni leggeri utilizzando i dati raccolti con bersagli di elio e argon nel Run2. Inoltre, vengono descritte anche le mie attività legate all'aggiornamento del sistema RICH per il Run3. Queste comprendono la convalida della catena opto-elettronica e il controllo di qualità dei fotomoltiplicatori e dell'elettronica di front-end. Inoltre, il lavoro del mio ultimo anno di dottorato nella sala di controllo di LHCb per la messa in servizio del sistema RICH è descritto, a cui ho contribuito per ottenere un sistema RICH stabile e affidabile in grado di operare e raccogliere dati nel Run3