Search

Scintillators have been widely used for high‐energy radiation imaging. It is in great demand and challenge to develop scintillator materials with fast decay time, high scintillation light yield, and low detection limit for high‐resolution imaging applications such as time‐of‐flight positron emission tomography. However, it is still a challenge to develop the ultrafast carrier dynamics to achieve 100% ultrafast decay time with high scintillation light yield. To meet the demand, a series of component‐tunable Cs2ZnCl4: x%Zr single crystals as promising ultrafast scintillators is successfully developed. With 8% of Zr‐dopant (Cs2ZnCl4: 8%Zr), the single crystal exhibits high light yield (28000 photons MeV−1) and low detection limit (51 nGy s−1) under X‐ray excitation. Photo‐induced transient absorption signals on sub‐nanosecond and nanosecond scales ensure almost 100% fast decay time (≈3 ns) in nanoseconds under γ‐ray excitation. In particular, the different radiative transition processes are achieved under ultraviolet and high‐energy radiation due to the tunable carrier dynamics from the shallow trapped state to the self‐trapped exciton (STE) state. [ABSTRACT FROM AUTHOR]

In this work, Cs 2 LiLaBr 6 :1%Ce (CLLB:Ce) single crystal with the size of Ф26 mm × 80 mm were successfully grown by the Bridgman method. The optimal conditions of application were presented by coupling with R6231-100 PMT. The pulse spectra are recorded by the 4-channel digital converter DT5751 at a sampling rate of 1 GS/s. The energy spectra of the CLLB:Ce crystal were recorded under different PMT gain voltage. The best energy resolution is obtained (up to 3.8%) when the gain voltage of PMT is 3.65V. The non-proportionality of CLLB:Ce crystal was measured under varied radioactive sources while the background radioactive was discussed. Besides, the energy spectra of CLLB:Ce crystal were recorded when the temperature was varied from −30 °C to 50 °C. Finally, the discriminating ability of neutron and gamma was evaluated under 252Cf source and AmBe source, the FOM value is 1.4 and 1.2, respectively, which has a greatly potential application in the nuclear radiation detection. • Cs 2 LiLaBr 6 :1%Ce single crystal with the size of Ф26mm × 50 mm were successfully grown. • Cs 2 LiLaBr 6 :1%Ce has a good non-proportionality (3%). • CLLB:Ce crystal has a best scintillation properties at the temperature of 30 °C. • The FOM value of CLLB:Ce crystal is estimated about 1.4 under 252Cf source. [ABSTRACT FROM AUTHOR]

• A serial of Eu2+-doped CLLB single crystals were successfully grown. • The Eu2+ activated CLLB matrix strategy increases the Stokes shift. • The light yields of CLLB: 2% Eu is 18700ph/MeV under 137Cs source at 662 keV. • CLLB: Eu crystal has the application potential of long afterglow X-ray imaging. In this work, a novel single crystal scintillator, Eu2+-doped Cs 2 LiLaBr 6 (CLLB: Eu) with Ф12 mm × 50 mm, was successfully grown by the Bridgman method. The effects of substitution amount of europium ions on the crystal structure, luminescent properties and scintillation properties were systematically studied by fluorescence spectroscopy, XEL, decay kinetics, and temperature-dependent emission spectra. The Cs 2 LiLaBr 6 :2%Eu sample presents the highest light yield under X-ray excitation, which is about 235 times that of commercial BGO single crystals. The nanosecond decay lifetime of Eu2+ was observed in Cs 2 LiLaBr 6 :Eu crystal. The afterglow result indicates that the Cs 2 LiLaBr 6 : Eu crystal has a long afterglow and the afterglow mechanism of Cs 2 LiLaBr 6 : Eu crystal was proposed and constructed. It has a potent application in nuclear radiation detection and imaging as a scintillation long afterglow material. [ABSTRACT FROM AUTHOR]

• A serial of Ce3+-doped CLLBC single crystals were successfully grown. • Two different lattice positions of Ce3+ in the CLLBC crystal were proposed. • The scintillation properties depend on the structure and the concentration of Ce3+. • Energy resolution of 3.70 %(FWHM) at 662 keV was measured. In this work, a strategy of controlling the doping concentration of cerium is adopted to improve the gamma response performance of cutting-edge Cs 2 LiLa(Br,Cl) 6 :Ce (CLLBC:Ce) single crystal scintillators. A serial of Ce3+-doped Cs 2 LiLaBr 5.4 Cl 0.6 single crystals with a size of Ф12 mm × 50 mm were successfully grown by the Bridgman method. Two different lattice positions of Ce3+ in the CLLBC crystal were identified by using spectral and decay kinetics, Raman spectra, X-ray photoelectron spectroscopy, refined XRD. The effects of cerium substitution amount on local structure, crystal structure, luminescence properties and the scintillation properties were systematically investigated. As the Ce3+ content increased, the light yield and energy resolution of CLLBC:Ce were first improved and then deteriorated. The Cs 2 LiLaBr 5.4 Cl 0.6 :2 mol% Ce crystal has a highest light yield and optimal energy resolution of 3.70 % under 137Cs@662 keV excitation. [ABSTRACT FROM AUTHOR]

In this work, an anion-alloying strategy using chloride substitution is used to improve the gamma response performance of cutting-edge Cs 2 LiLaBr 6 :Ce single crystal scintillators. Single crystals of Cs 2 LiLa(Br , Cl) 6 :Ce (CLLBC:Ce) with a size of Ф12 mm × 50 mm were successfully grown by the Bridgman method. The effects of chloride substitution amount on crystal structure, band structure, luminescence properties and the scintillation properties were systematically investigated. The light yield and energy resolution of CLLB:Ce were enhanced as the increase of Cl− content. The highest light yield and optimal energy resolution were achieved on the Cs 2 LiLaBr 4 Cl 2 :Ce, about 86% of the commercial LaBr 3 :Ce single crystal and 4.1% at 662 keV. On a basis of the results of first-principle calculation and pure optical method, the band structures of Cs 2 LiLa(Br,Cl):Ce were constructed, indicating a tendency of band-gap to increase as the Cl− content increases. The origin of light yield improvement was also proposed. • The strategy of chloride substitution is used to improve the performance of Cs 2 LiLaBr 6 :Ce single crystal scintillators. • The results of first-principle calculation and pure optical method indicate that the band-gap becomes bigger as the Cl− content increases. • Cs 2 LiLaBr 4 Cl 2 :Ce shows the highest light yield and optimal energy resolution, about 86% of the commercial LaBr 3 :Ce single crystal and 4.1% at 662 keV. • The origin of light yield improvement was also proposed. [ABSTRACT FROM AUTHOR]

The expansive family of metazoan ADP-ribosylation factor and ADP-ribosylation factor-like small GTPases is known to play essential roles in modulating membrane trafficking and cytoskeletal functions. Here, we present the crystal structure of ARL6, mutations in which cause Bardet-Biedl syndrome (BBS3), and reveal its unique ring-like localization at the distal end of basal bodies, in proximity to the so-called ciliary gate where vesicles carrying ciliary cargo fuse with the membrane. Over-production of GDP- or GTP-locked variants of ARL6/BBS3 in vivo influences primary cilium length and abundance. ARL6/BBS3 also modulates Wnt signaling, a signal transduction path-way whose association with cilia in vertebrates is just emerging. Importantly, this signaling function is lost in ARL6 variants containing BBS-associated point mutations. By determining the structure of GTP-bound ARL6/BBS3, coupled with functional assays, we provide a mechanistic explanation for such pathogenic alterations, namely altered nucleotide binding. Our findings therefore establish a previously unknown role for ARL6/BBS3 in mammalian ciliary (dis)assembly and Wnt signaling and provide the first structural information for a BBS protein. [ABSTRACT FROM AUTHOR]

Members of the plexin family are unique transmembrane receptors in that they interact directly with Rho family small GTPases; moreover, they contain a GTPase-activating protein (GAP) domain for R-Ras, which is crucial for plexin-mediated regulation of cell motility. However, the functional role and structural basis of the interactions between the different intracellular domains of plexins remained unclear. Here we present the 2.4 Å crystal structure of the complete intracellular region of human plexin-B1. The structure is monomeric and reveals that the GAP domain is folded into one structure from two segments, separated by the Rho GTPase binding domain (RBD). The RBD is not dimerized, as observed previously. Instead, binding of a conserved loop region appears to compete with dimerization and anchors the RBD to the GAP domain. Cell-based assays on mutant proteins confirm the functional importance of this coupling loop. Molecular modeling based on structural homology to p120GAP-Ras suggests that Ras GTPases can bind to the plexin GAP region. Experimentally, we show that the monomeric intracellular plexin-B1 binds R-Ras but not H-Ras. These findings suggest that the monomeric form of the intracellular region is primed for GAP activity and extend a model for plexin activation. [ABSTRACT FROM AUTHOR]

Summary: The plexin family of transmembrane receptors are important for axon guidance, angiogenesis, but also in cancer. Recently, plexin-B1 somatic missense mutations were found in both primary tumors and metastases of breast and prostate cancers, with several mutations mapping to the Rho GTPase binding domain (RBD) in the cytoplasmic region of the receptor. Here we present the NMR solution structure of this domain, confirming that the protein has both a ubiquitin-like fold and surface features. Oncogenic mutations T1795A and T1802A are located in a loop region, perturb the average structure locally, and have no effect on Rho GTPase binding affinity. Mutations L1815F and L1815P are located at the Rho GTPase binding site and are associated with a complete loss of binding for Rac1 and Rnd1. Both are found to disturb the conformation of the β3-β4 sheet and the orientation of surrounding side chains. Our study suggests that the oncogenic behavior of the mutants can be rationalized with reference to the structure of the RBD of plexin-B1. [Copyright &y& Elsevier]

Abstract: The self-association reaction of a 79-residue fragment of staphylococcal nuclease (SNase79) was studied by far-UV CD, size-exclusion chromatography, and heteronuclear multidimensional NMR spectroscopy. A large population of SNase79 is in self-associated state while a small population of SNase79 is essentially in a monomeric state. The sequence region Thr13-Val39 is responsible for association interface of SNase79. The trans-conformation of X-prolyl bond Gln30-Pro31 may make residues Tyr27-Gln30, serve as a folding nucleation site, and lead the segment Thr13-Val39 of SNase79 to adopt a native-like β-sheet conformation, which results in the self-association of SNase79. The non-native conformation of the segment Thr13-Val39 of SNase79 associated with the cis-conformation of X-prolyl bond Gln30-Pro31 may preclude SNase79 from the soluble aggregates. [Copyright &y& Elsevier]

Summary: Oligomerization is important for the structure and function of many proteins, but frequently complicates their characterization. It is often desirable to obtain the protein in monomeric form. Here, we report a strategy that allows the generation of monomers from weakly associated oligomers but does not require knowledge of the three-dimensional structure of the protein. The dynamics of protein association are used in solution NMR spectroscopy to identify regions of the polypeptide chain that are likely to be responsible for the interaction. Protein sequence analysis further refines the selection, as conserved sites with moderate hydrophobicity are targeted for modification. Gel filtration and activity assays straightforwardly reveal the consequences of the change and are used to screen for the desired mutants. The strategy is demonstrated for the Rac1 binding domain of plexin-B1. A monomeric variant is generated which preserves the Rac1 binding activity and the wild-type protein structure. [Copyright &y& Elsevier]

Investigates the orientation of the peptide formation of N-phosphoryl amino acids in solution. Separation of the phosphoryl dipeptides in sephadex gel column; Analysis of the dipeptides by electrospray ionization tandem mass spectrometry; Detection of the dipeptides in all the reation systems.

Halide perovskites are among the most attractive research hotspots in optoelectronic applications due to their excellent luminescence properties. In this paper, Li+ was successfully incorporated into a one-dimensional perovskite CsCu2I3 host and constructed as a novel neutron/gamma detection scintillator via the Bridgman method. XRD and ICP-MS were carried out, and the results were discussed. The Li-doped CsCu2I3 crystal exhibits a main emission peak at 575 nm originating from strongly localized 1D exciton emission and a high photoluminescence quantum efficiency of 18.7%. The CsCu2I3:Li crystal has a light yield of 10 900 photons per MeV and an energy resolution of 11.5% under 137Cs irradiation. The figure-of-merit (FoM) of the CsCu2I3:Li crystal has been estimated (about 0.8) under 252Cf radiation source. The crystal has a potential application for dual gamma–neutron detection. [ABSTRACT FROM AUTHOR]

• The optimal non-stoichiometric ratio for growing Cs 2 LiYCl 6 :Ce crystals was obtained. • High quality Cs 2 LiYCl 6 :Ce single crystals codoped with Ca2+ and Sr2+ ions were grown by the Multi-ampoule Bridgman method. • The energy resolution of Cs 2 LiYCl 6 :Ce was improved from 4.6 % to 3.8 % by co-doping 0.05 % Sr2+. Cs 2 LiYCl 6 :Ce is a novel scintillation crystal with good energy resolution, high light yield, and outstanding neutron/gamma discrimination capability. However, its complex composition and incongruent melting behavior pose many challenges to the crystal growth. In this study, five different compositions of Cs 2 LiYCl 6 :Ce crystals were grown using the vertical Bridgman method. These compositions included LiCl at 57 mol%, 60 mol%, and 63 mol%, as well as CsCl and YCl 3 at ratios of 1.9:1 and 2.1:1. It was found that the highest CLYC phase volume fraction could be obtained in the recipe with a LiCl composition of 60 mol%, while changing the ratio of CsCl to YCl 3 did not show any significant positive effect on crystal growth. In addition, Ca2+/Sr2+ was applied to modify the scintillation performance of CLYC:Ce. A batch of Φ11mm crystals with different co-doping concentrations of Ca2+ and Sr2+ were successfully grown by using the Multi-ampoule Bridgman method, no cracks or inclusions were observed in the grown crystals. Co-doping showed little effect on the radiation luminescence and transmittance spectra of CLYC. The scintillation decay curves demonstrated that the decay times depend on the co-doping concentration. Most notably, the energy resolution of CLYC:Ce is improved from 4.6 % to 3.8 % by co-doping 0.05 % Sr2+ under 662 keV gamma-ray excitation. However, the light yield is reduced because of co-doping of Ca2+ and Sr2+, especially Ca2+ having a more pronounced effect. [ABSTRACT FROM AUTHOR]

NaI:Tl single crystals codoped with 6LiI have been considered as promising neutron-gamma scintillators due to low cost, scalability, and high efficiency in detecting and discriminating neutrons and gamma-rays. This study aims to study the effects of 6LiF and 6LiCl codoping on the NaI:Tl single crystals grown by the multi-ampoule Bridgman method. The impact of 6LiF and 6LiCl on the optical properties, gamma spectroscopy, and pulse shape discrimination (PSD) of neutron and gamma detection performance were analyzed. Both ⁶LiF and ⁶LiCl caused a decrease in gamma-ray light yield and a deterioratrion of energy resolution with increasing codoping concentrations, similar to the scenarios of ⁶LiI codoping. Nonetheless, for NaI:Tl,6LiF, the light yield and PSD Figure-of-Merit (FoM) are almost unchanged about 37,500 photons/MeV and 4.6 when the Li content reaches 2 at%, which is better than the scenario of 6LiI codoping. Combing with the advantages of non-hygroscopic nature of LiF and a higher utilization yield of Li element in LiF comparing with LiI, NaI:Tl,6LiF single crystals could be regarded as more cost-effective scintillators for neutron detection applications. • High-quality NaI:Tl crystals codoped with 6LiCl and 6LiF were grown by the Bridgman method. • 6LiF codoped NaI:Tl can achieve decent n-γ discrimination capability with a PSD FoM of 4.6. • Introducing 6LiCl will cause a decrease in scintillation yield, energy resolution, and PSD FoM. [ABSTRACT FROM AUTHOR]

NaI:Tl,6Li bulk crystals are regarded as promising neutron-gamma (n-γ) scintillators because of low production cost and superior n-γ pulse shape discrimination (PSD) performance. In this work, some rare earth elements (Gd, Y, Lu and Sc) co-doped NaI:Tl,6Li single crystals were grown by the multi-ampoule Bridgman method. It was found that the rare earth co-doping significantly improves the pulse height discrimination (PHD) capability of NaI:Tl,6Li with high alpha/beta (α/β) ratio, approaching to 100%. The optimal α/β ratios achieved for Gd, Y, Lu and Sc co-doped NaI:Tl,6Li are 0.85, 0.93, 0.95, and 0.83, respectively. Electron equivalent energy per neutron interaction is above 3.96 MeV and can be as high as 4.54 MeV, close to the Q value of 4.78 MeV for 6Li(n, α)3H interaction. Moreover, the rare earth co-doped NaI:Tl,6Li crystals still maintain the superior PSD capability with figure of merit (FoM) in the range of 2.1–3.3. These results highlight the great potential of rare-earth co-doped NaI:Tl,6Li crystals serving as high-performance n-γ scintillators. [ABSTRACT FROM AUTHOR]

Deubiquitinases (DUBs) have been the subject of intense scrutiny in recent years. Many of their diverse enzymatic mechanisms are well characterized in vitro; however, our understanding of these enzymes at the cellular level lags due to the lack of quality tool reagents. DUBs play a role in seemingly every biological process and are central to many human pathologies, thus rendering them very desirable and challenging therapeutic targets. This review aims to provide researchers entering the field of ubiquitination with knowledge of the pharmacological modulators and tool molecules available to study DUBs. A focus is placed on small molecule inhibitors, ubiquitin variants (UbVs), and activity-based probes (ABPs). Leveraging these tools to uncover DUB biology at the cellular level is of particular importance and may lead to significant breakthroughs. Despite significant drug discovery efforts, only approximately 15 chemical probe-quality small molecule inhibitors have been reported, hitting just 6 of about 100 DUB targets. UbV technology is a promising approach to rapidly expand the library of known DUB inhibitors and may be used as a combinatorial platform for structure-guided drug design. [ABSTRACT FROM AUTHOR]

Low‐dimensional copper‐based halide single crystals are considered excellent scintillators for indirect X‐ray detection, but their potential in direct X‐ray detection has not been investigated. Herein, high‐quality pure Cs3Cu2I5 and Li‐doped Cs3Cu2I5:Li single crystals are grown by the Bridgman method. The Li+ dopant enhances the photoelectric properties of the Cs3Cu2I5 single crystal by extending the carrier lifetime, improving the carrier mobility from 6.49 to 9.52 cm2 V−1 s−1, and increasing the mobility‐lifetime (µτ) product from 1.4 × 10−4 to 2.9 × 10−4 cm2 V−1. The sensitive direct X‐ray detector with a vertical device configuration of Au/Cs3Cu2I5:Li single crystal/PCBM/Au is fabricated and demonstrated to have a high sensitivity of 831.1 µC Gyair−1 cm−2 and low detection limit of 34.8 nGyair s−1. Furthermore, the detector shows negligible baseline current drift and excellent stability upon X‐ray radiation. [ABSTRACT FROM AUTHOR]

Ubiquitin-specific peptidase 16 (USP16) is a deubiquitinase that plays a role in the regulation of gene expression, cell cycle progression, and various other functions. It was originally identified as the major deubiquitinase for histone H2A and has since been found to deubiquitinate a range of other substrates, including proteins from both the cytoplasm and nucleus. USP16 is phosphorylated when cells enter mitosis and dephosphorylated during the metaphase/anaphase transition. While much of USP16 is localized in the cytoplasm, separating the enzyme from its substrates is considered an important regulatory mechanism. Some of the functions that USP16 has been linked to include DNA damage repair, immune disease, tumorigenesis, protein synthesis, coronary artery health, and male infertility. The strong connection to immune response and the fact that multiple oncogene products are substrates of USP16 suggests that USP16 may be a potential therapeutic target for the treatment of certain human diseases. [ABSTRACT FROM AUTHOR]

Abstract: 1–79 residues SNase fragment (SNase79) has chain length containing a sequence for helix α1, ω-loop, βI-sheet, and partial βII-sheet of native SNase. The incomplete “β-barrel” structural region of SNase79 makes this fragment to be interested in investigation of its conformation. For this study, we use CD, fluorescence, and NMR spectroscopy to probe the folding capacity and the residual structures in SNase79. The optical spectra obtained for SNase79 and its mutants reveal the presence of retained capacity for folding of the fragment. The NMR derived 13Cα secondary chemical shifts, 3 J NH–Hα coupling constants, amide-proton temperature coefficients, interresidue NOEs, and 15N relaxation data determine the intrinsic propensities for helix- and turn- or β-sheet-like conformations of SNase79, which is not the result of stabilizing inter-molecular interactions by oligomerization effects. The residual turn- and helix-like structures may serve as potential local nucleation sites, whereas the residual βI-sheet-like structure can be regarded as a potential non-local nucleation site in the folding of SNase79. The intrinsic local and non-local interactions in these potential initiation sites are insufficient to stabilize the folding of SNase79 due to the shortage of relevant long-range interactions from other part of the fragment. The conformational ensemble of SNase79 is a highly heterogeneous collection of interconverting conformations having transiently populated helix- and β-sheet- or turn-like structures. [Copyright &y& Elsevier]

[Display omitted] • The ARID domain of RBBP1 can bind to dsDNA without sequence specificity. • A disordered loop L12 on the ARID domain of RBBP1 inhibits the DNA-binding activity. • Loop L12 weakly interacts with the Tudor and chromobarrel domains as a DNA mimic. • Loop L12 strongly binds to the histone H2A-H2B heterodimer. • A model of chromatin recognition by RBBP1 with multiple roles of L12 is proposed. Retinoblastoma-binding protein 1 (RBBP1) is involved in gene regulation, epigenetic regulation, and disease processes. RBBP1 contains five domains with DNA-binding or histone-binding activities, but how RBBP1 specifically recognizes chromatin is still unknown. An AT-rich interaction domain (ARID) in RBBP1 was proposed to be the key region for DNA-binding and gene suppression. Here, we first determined the solution structure of a tandem PWWP-ARID domain mutant of RBBP1 after deletion of a long flexible acidic loop L12 in the ARID domain. NMR titration results indicated that the ARID domain interacts with DNA with no GC- or AT-rich preference. Surprisingly, we found that the loop L12 binds to the DNA-binding region of the ARID domain as a DNA mimic and inhibits DNA binding. The loop L12 can also bind weakly to the Tudor and chromobarrel domains of RBBP1, but binds more strongly to the DNA-binding region of the histone H2A-H2B heterodimer. Furthermore, both the loop L12 and DNA can enhance the binding of the chromobarrel domain to H3K4me3 and H4K20me3. Based on these results, we propose a model of chromatin recognition by RBBP1, which highlights the unexpected multiple key roles of the disordered acidic loop L12 in the specific binding of RBBP1 to chromatin. [ABSTRACT FROM AUTHOR]

Cs3Cu2I5 Single Crystal for Efficient Direct X‐Ray Detection In article number 2300247, Laishun Qin, Hongsheng Shi, Yanliang Liu, Xue‐Feng Yu, and colleagues demonstrate a high‐quality Li‐doped Cs3Cu2I5 single crystal grown by the Bridgman method that was initially applied as a semiconductor for direct X‐ray detection. The Cs3Cu2I5:Li X‐ray detector exhibits a high sensitivity of 831.1 µC Gyair−1 cm−2 and low detection limit of 34.8 nGyair s−1, and it reveals a clear outline of the key image in the scanning mode under X‐ray excitation. [ABSTRACT FROM AUTHOR]

Keywords: copper-based halides; Cs3Cu2I5:Li single crystal; direct X-ray detection; semiconductors EN copper-based halides Cs3Cu2I5:Li single crystal direct X-ray detection semiconductors 1 1 1 10/06/23 20231001 NES 231001 B Cs SB 3 sb Cu SB 2 sb I SB 5 sb Single Crystal for Efficient Direct X-Ray Detection b In article number 2300247, Laishun Qin, Hongsheng Shi, Yanliang Liu, Xue-Feng Yu, and colleagues demonstrate a high-quality Li-doped Cs SB 3 sb Cu SB 2 sb I SB 5 sb single crystal grown by the Bridgman method that was initially applied as a semiconductor for direct X-ray detection. Copper-based halides, Cs3Cu2I5:Li single crystal, direct X-ray detection, semiconductors The Cs SB 3 sb Cu SB 2 sb I SB 5 sb :Li X-ray detector exhibits a high sensitivity of 831.1 µC Gy SB air sb SP -1 sp cm SP -2 sp and low detection limit of 34.8 nGy SB air sb s SP -1 sp , and it reveals a clear outline of the key image in the scanning mode under X-ray excitation. [Extracted from the article]

The performance of two 6Li enriched elpasolite scintillators Cs 2 LiYCl 6 : Ce 3 + (CLYC) and Cs 2 LiLaBr 6 : Ce 3 + (CLLB) were investigated using mono-energetic fast neutrons generated by a 3 MV tandem accelerator. The Pulse Shape Discrimination (PSD) ability, response and energy resolution to fast neutrons and scattered slow neutrons were studied. The 6Li enriched CLYC had excellent discrimination ability between neutron and gamma rays with the Figure of Merit (FOM) value better than 2.4. An Artificial neural network (ANN) model could discriminate fast neutrons and scattered slow neutrons effectively with an accuracy of 97%, which render the Li-6 enriched CLYC capable to detect thermal neutrons with high efficiency and the energy spectrum of fast neutrons simultaneously. The quenching factors are calculated to be 0.92 and 0.48 for the 35Cl(n, p)35S and 35Cl (n, α)32P reaction, while the detection efficiency is about 0.1%–0.75% for fast neutrons within the energy range of 0.9–5.2 MeV. Unlike CLYC, CLLB was only sensitive to slow neutrons, and the discrimination ability between neutrons and gamma rays is worse than CLYC, while the ANN model exhibit better performance which has an accuracy of 97%. [ABSTRACT FROM AUTHOR]

Post-translational modification of the p53 signaling pathway plays an important role in cell cycle progression and stress-induced apoptosis. Indeed, a large body of work has shown that dysregulation of p53 and its E3 ligase MDM2 by the ubiquitin-proteasome system (UPS) promotes carcinogenesis and malignant transformation. Thus, drug discovery efforts have focused on the restoration of wild-type p53 activity or inactivation of oncogenic mutant p53 by targeted inhibition of UPS components, particularly key deubiquitinases (DUBs) of the ubiquitin-specific protease (USP) class. However, development of selective small-molecule USP inhibitors has been challenging, partly due to the highly conserved structural features of the catalytic sites across the class. To tackle this problem, we devised a protein engineering strategy for rational design of inhibitors for DUBs and other UPS proteins. We employed a phage-displayed ubiquitin variant (UbV) library to develop inhibitors targeting the DUBs USP7 and USP10, which are involved in regulating levels of p53 and MDM2. We were able to identify UbVs that bound USP7 or USP10 with high affinity and inhibited deubiquitination activity. We solved the crystal structure of UbV.7.2 and rationalized the molecular basis for enhanced affinity and specificity for USP7. Finally, cell death was increased significantly by UbV.7.2 expression in a colon cancer cell line that was treated with the chemotherapy drug cisplatin, demonstrating the therapeutic potential of inhibiting USP7 by this approach. [ABSTRACT FROM AUTHOR]

Background Seven in absentia homologs (SIAHs) comprise a family of highly conserved E3 ubiquitin ligases that play an important role in regulating signalling pathways in tumorigenesis, including the DNA damage repair and hypoxia response pathways. SIAH1 and SIAH2 have been found to function as a tumour repressor and a proto-oncogene, respectively, despite the high sequence identity of their substrate binding domains (SBDs). Ubiquitin-specific protease USP19 is a deubiquitinase that forms a complex with SIAHs and counteracts the ligase function. Much effort has been made to find selective inhibitors of the SIAHs E3 ligases. Menadione was reported to inhibit SIAH2 specifically. Methods We used X-ray crystallography, peptide array, bioinformatic analysis, and biophysical techniques to characterize the structure and interaction of SIAHs with deubiquitinases and literature reported compounds. Results We solved the crystal structures of SIAH1 in complex with a USP19 peptide and of the apo form SIAH2. Phylogenetic analysis revealed the SIAH/USP19 complex is conserved in evolution. We demonstrated that menadione destabilizes both SIAH1 and SIAH2 non-specifically through covalent modification. Conclusions The SBDs of SIAH E3 ligases are structurally similar with a subtle stability difference. USP19 is the only deubiquitinase that directly binds to SIAHs through the substrate binding pocket. Menadione is not a specific inhibitor for SIAH2. General significance The crystallographic models provide structural insights into the substrate binding of the SIAH family E3 ubiquitin ligases that are critically involved in regulating cancer-related pathways. Our results suggest caution should be taken when using menadione as a specific SIAH2 inhibitor. [ABSTRACT FROM AUTHOR]

Motivation Protein ubiquitination plays a central role in important cellular machineries such as protein degradation or chromatin-mediated signaling. With the recent discovery of the first potent ubiquitin-specific protease inhibitors, and the maturation of proteolysis targeting chimeras as promising chemical tools to exploit the ubiquitin-proteasome system, protein target classes associated with ubiquitination pathways are becoming the focus of intense drug-discovery efforts. Results We have developed UbiHub, an online resource that can be used to visualize a diverse array of biological, structural and chemical data on phylogenetic trees of human protein families involved in ubiquitination signaling, including E3 ligases and deubiquitinases. This interface can inform target prioritization and drug design, and serves as a navigation tool for medicinal chemists, structural and cell biologists exploring ubiquitination pathways. Availability and implementation https://ubihub.thesgc.org. [ABSTRACT FROM AUTHOR]

Summary Sox2 is a key factor for maintaining embryonic stem cell (ESS) pluripotency, but little is known about its posttranslational regulation. Here we present evidence that the precise level of Sox2 proteins in ESCs is regulated by a balanced methylation and phosphorylation switch. Set7 monomethylates Sox2 at K119, which inhibits Sox2 transcriptional activity and induces Sox2 ubiquitination and degradation. The E3 ligase WWP2 specifically interacts with K119-methylated Sox2 through its HECT domain to promote Sox2 ubiquitination. In contrast, AKT1 phosphorylates Sox2 at T118 and stabilizes Sox2 by antagonizing K119me by Set7 and vice versa. In mouse ESCs, AKT1 activity toward Sox2 is greater than that of Set7, leading to Sox2 stabilization and ESC maintenance. In early development, increased Set7 expression correlates with Sox2 downregulation and appropriate differentiation. Our study highlights the importance of a Sox2 methylation-phosphorylation switch in determining ESC fate. [ABSTRACT FROM AUTHOR]

Summary Transforming members of the MYC family (MYC , MYCL1 , and MYCN) encode transcription factors containing six highly conserved regions, termed MYC homology boxes (MBs). By conducting proteomic profiling of the MB interactomes, we demonstrate that half of the MYC interactors require one or more MBs for binding. Comprehensive phenotypic analyses reveal that two MBs, MB0 and MBII, are universally required for transformation. MBII mediates interactions with acetyltransferase-containing complexes, enabling histone acetylation, and is essential for MYC-dependent tumor initiation. By contrast, MB0 mediates interactions with transcription elongation factors via direct binding to the general transcription factor TFIIF. MB0 is dispensable for tumor initiation but is a major accelerator of tumor growth. Notably, the full transforming activity of MYC can be restored by co-expression of the non-transforming MB0 and MBII deletion proteins, indicating that these two regions confer separate molecular functions, both of which are required for oncogenic MYC activity. Graphical Abstract Highlights • Protein interaction screening identifies 336 MYC-interacting partner proteins • MB0 interacts with TFIIF to modulate transcription and accelerates tumor growth • MBII interacts with TRRAP-HAT complexes and is essential for tumor initiation • Co-expression of dysfunctional ΔMBII and ΔMB0 MYC proteins restores MYC activity Kalkat et al. identify the protein-protein interaction landscape of six conserved MYC regions and identify a universal requirement for two MYC-containing protein complexes in cellular transformation. These findings demonstrate that multiple non-redundant MYC complexes are simultaneously required for transformation and have broad implications for the therapeutic targeting of MYC. [ABSTRACT FROM AUTHOR]

Summary SH3 domains are protein modules that mediate protein-protein interactions in many eukaryotic signal transduction pathways. The majority of SH3 domains studied thus far act by binding to proline-rich sequences in partner proteins, but a growing number of studies have revealed alternative recognition mechanisms. We have comprehensively surveyed the specificity landscape of human SH3 domains in an unbiased manner using peptide-phage display and deep sequencing. Based on ∼70,000 unique binding peptides, we obtained 154 specificity profiles for 115 SH3 domains, which reveal that roughly half of the SH3 domains exhibit non-canonical specificities and collectively recognize a wide variety of peptide motifs, most of which were previously unknown. Crystal structures of SH3 domains with two distinct non-canonical specificities revealed novel peptide-binding modes through an extended surface outside of the canonical proline-binding site. Our results constitute a significant contribution toward a complete understanding of the mechanisms underlying SH3-mediated cellular responses. [ABSTRACT FROM AUTHOR]