Glucosamine-loaded injectable hydrogel promotes autophagy and inhibits apoptosis after cartilage injury.

The ability of cartilage to regenerate and repair is limited. N-acetyl- d-glucosamine (GlcNAc) is a nutritional supplement commonly used to activate chondrocytes. To prolong the duration of action of GlcNAc and improve its curative effect after cartilage injury, a GlcNAc thermosensitive hydrogel is prepared based on Pluronic F127 (PF127). The physicochemical properties results indicate that this hydrogel is injectable and retards the release of GlcNAc. Further, the therapeutic benefits of GlcNAc hydrogel are detected through intra-articular injection in rat specimens with cartilage injury. Behavioral experiments results indicate that the rats treated with GlcNAc hydrogel had longer step lengths, smaller foot angles and slower fall times. Compared with the sham group, the expression of Sox9 was 1.5 times and the level of collagen II was 2.4 times in the hydrogel treated group. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining result confirmed that the GlcNAc hydrogel reduce apoptosis by about 50%. Our results of immunohistochemical staining, Western blotting assays and enzyme activity detection all suggested that GlcNAc hydrogel reduce the expression of cleaved-caspase3 and caspase8 (Compared to the sham group, the protein contents were reduced by about 50% in the GlcNAc hydrogel group). We also found that GlcNAc hydrogel activates autophagy through ERK signal pathway. The results of Western blotting indicated that GlcNAc hydrogel increase the levels of LC3B and Becline1 (hydrogel group & sham group, LC3B: 1.56 ± 0.07 & 1.00 ± 0.14; Becline1: 1.98 ± 0.07 & 1.00 ± 0.13). Whereas, the content of P62 reduced after GlcNAc hydrogel treatment, the relative level in sham group and hydrogel group are 1.00 ± 0.02 and 0.73 ± 0.06. Our results revealed that the number of P-ERK positive cells in the hydrogel group (57.36 ± 3.56%) was higher when compared with the sham (24.82 ± 2.72%). And, the ratio of P-ERK and ERK was higher than that in the sham group (1.48 ± 0.07 & 1.00 ± 0.08). The GlcNAc thermosensitive hydrogel is a promising and sustainable drug delivery system for intra-articular injection in the treatment of cartilage injury.

10×10 Gbs directly modulated DFB laser array based on the REC technique.

We proposed and experimentally demonstrated a directly modulated distributed feedback (DFB) laser array with a transmission rate of 100 Gbps (10c h a n n e l s×10G b p s). The grating design is based on the reconstruction equivalent chirp (REC) technique, which enables precise control of the channel wavelength spacing to 100 GHz, as specified in the ITU-DWDM standard. DFB laser arrays incorporating the REC technique demonstrate excellent consistency performance, with a side-mode suppression ratio exceeding 48 dB, threshold current of approximately 20 mA, and modulation bandwidth of greater than 13 GHz at a bias current of 100 mA. We evaluated the laser's performance by loading a 10 Gbps nonreturn-to-zero signal onto the laser using direct modulation and transmitting it over a 10 km single-mode fiber. Based on our experimental results, the proposed DFB laser array is promising to be utilized in the next generation of low-cost, 100 Gbps DWDM communication systems.

RNF167-mediated ubiquitination of Tollip inhibits TNF-α-triggered NF-κB and MAPK activation.

Toll-interacting protein (Tollip) is a multifunctional regulator in cellular activities. However, whether its functions are subjected to post-translational modifications remains elusive. Here, we identified ubiquitination as a post-translational modification on Tollip. We found that Tollip interacted with ring finger protein 167 (RNF167) through its C-terminal coupling of ubiquitin to ER degradation (CUE) domain, and RNF167 functioned as the potential E3 ligase to attach K33-linked poly-ubiquitin chains to the Lys235 (K235) site of Tollip. Furthermore, we discovered Tollip could inhibit TNF-α-induced nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) activation, and substitution of Lys235 on Tollip to arginine failed to suppress TNF-α-NF-κB/MAPK (JNK) cascades, revealing the role of Tollip and its ubiquitination in NF-κB/MAPK pathways. Thus, our study reveals the novel biological function of Tollip and RNF167-dependent ubiquitination of Tollip in TNF-α signaling.

Dual delivery of an NF-κB inhibitor and IL-10 through supramolecular hydrogels polarizes macrophages and promotes cardiac repair after myocardial infarction.

The use of anti-inflammatory strategies has the potential to be a definitive treatment for ventricular remodeling post myocardial infarction (MI). The regulation of macrophage phenotypes by anti-inflammatory agents contributes to the alleviation of myocardial fibrosis. However, their poor retention rates severely affect treatment efficacy. Here, we propose a supramolecular compound, NapFFY, to co-assemble with IL-10 and SN50 as a novel anti-inflammatory SN50/IL-10/NapFFY hydrogel with cardioprotective properties. Results from the in vitro and in vivo experiments in murine cell line and rats, respectively, demonstrated that the SN50/IL-10/NapFFY hydrogel exhibits an ideal and sustained release of IL-10 and SN50. Intramyocardial injection of the SN50/IL-10/NapFFY hydrogel in a rat model of MI significantly inhibited the expression of proinflammatory cytokines. It promoted the polarization of M2 macrophages, which reduced cardiomyocyte apoptosis and improved vascularization at the border zones. Specifically, the SN50/IL-10/NapFFY hydrogel significantly improved heart function and ameliorated ventricular remodeling 28 days post MI. We envision that the SN50/IL-10/NapFFY hydrogel could serve as a new anti-inflammatory agent for the clinical treatment of MI in future studies. STATEMENT OF SIGNIFICANCE: Anti-inflammation is an ideal strategy for the treatment of ventricular remodeling post myocardial infarction (MI). SN50 and IL-10 have been shown to have diverse roles in antiinflammatory process, respectively. However, direct intravenous administration or intramyocardial injection of SN50 or IL-10 is not a viable option given its poor half-life in vivo. This study aimed to evaluate the synergistic cardioprotective effects of a supramolecular hydrogel loaded with an NF-κB inhibitor (SN50) and IL-10. Animal experiments showed that the SN50/IL-10/NapFFY hydrogels ameliorated the inflammatory microenvironment, and improved cardiac function to the infarct area in a rat model of MI. We anticipate that SN50/IL10NapFFY hydrogel could be used clinically to treat MI in the near future.

MMP 9-instructed assembly of bFGF nanofibers in ischemic myocardium to promote heart repair.

Background: The only effective treatment for myocardial infarction (MI) is the timely restoration of coronary blood flow in the infarcted area, but further reperfusion exacerbates myocardial injury and leads to distal coronary no-reflow, which affects patient prognosis. Angiogenesis could be an important therapeutic strategy for re-establishing the blood supply to save the ischemic myocardium after MI. Basic fibroblast growth factor (bFGF) has been shown to promote angiogenesis. However, direct intravenous administration of bFGF is not a viable option given its poor half-life in vivo. Methods: Herein, we developed a peptide Lys-Lys-Pro-Leu-Gly-Leu-Ala-Gly-Phe-Phe (K2) to encapsulate bFGF to form bFGF@K2 micelle and proposed an enzyme-instructed self-assembly (EISA) strategy to deliver and slowly release bFGF in the ischemic myocardium. Results: The bFGF@K2 micelle exerted a stronger cardioprotective effect than free bFGF in a rat model of myocardial ischemia-reperfusion (MI/R). In vitro results revealed that the bFGF@K2 micelle could be cleaved by matrix metallopeptidase 9 (MMP-9) to yield bFGF@Nanofiber through amphipathic changes. In vivo experiments indicated that intravenous administration of bFGF@K2 micelle could lead to their restructuring into bFGF@Nanofiber and long term retention of bFGF in the ischemic myocardium of rat due to high expression of MMP-9 and assembly-induced retention (AIR) effect, respectively. Twenty-eight days after MI/R model establishment, bFGF@K2 micelle treatment significantly reduced fibrosis and improved cardiac function of the rats. Conclusion: We predict that our strategy could be applied in clinic for MI treatment in the future.

V1-Cal hydrogelation enhances its effects on ventricular remodeling reduction and cardiac function improvement post myocardial infarction.

Myocardial infarction (MI) is a major cause of disability and mortality worldwide. A cell permeable peptide V1-Cal has shown remarkable therapeutic effects on ML However, using V1-Cal to improve long-term cardiac function after MI is presently limited by its short half-life. Herein, we co-assembled V1-Cal with a well-known hydrogelator Nap-Phe-Phe-Tyr (NapFFY) to obtain a new supramolecular hydrogel V1-Cal/NapFFY. We found that the hydrogel could significantly enhance the therapeutic effects of V1-Cal on ventricular remodeling reduction and cardiac function improvement in a myocardial infarction rat model. In vitro experiments indicated that co-assembly of V1-Cal with NapFFY significantly increased mechanic strength of the hydrogel, enabling a sustained release of V1-Cal for more than two weeks. In vivo experiments supported that sustained release of V1-Cal from V1-Cal/NapFFY hydrogel could effectively decrease the expression and activation of TRPV1, reduce apoptosis and the release of inflammatory factors in a MI rat model. In particular, V1-Cal/NapFFY hydrogel significantly decreased infarct size and fibrosis, while improved cardiac function 28 days post MI. We anticipate that V1-Cal/NapFFY hydrogel could be used clinically to treat MI in the near future.

Multimodal Imaging and Synergetic Chemodynamic/Photodynamic Therapy Achieved Using an NaGdF4 ,Yb,Er@ NaGdF4 ,Yb,Tm@NaYF4 @Fe-MOFs Nanocomposite.

Here, NaGdF4 ,Yb,Er@NaGdF4 ,Yb,Tm@NaYF4 core@shell@shell three-layer structure of upconversion nanoparticles (UCNPs) coated with Fe-Tetrakis (4-carboxyphenyl) porphine (TCPP) metal-organic frameworks (Fe-MOFs) nanocomposite (UCNPs@MOFs) was designed and constructed for multimodal imaging and synergetic chemodynamic therapy (CDT)/photodynamic therapy (PDT) of tumors. The UCNPs@MOFs were successfully applied for tumor cells imaging in vitro and in vivo in near-infrared (NIR) region. The doped Gd was used as contrast agent for the magnetic resonance imaging (MRI) of mouse tumors. The luminescence in the UV-vis region was absorbed by the Fe-MOFs to produce singlet oxygen (1 O2 ) for PDT. The Fe3+ doped in the MOFs can catalyze H2 O2 to produce oxygen and hydroxyl radical (⋅OH). Hydroxyl radical is used in CDT and cooperates with the 1 O2 of PDT. Based on the CDT/PDT synergistic effects, the UCNPs@MOFs nanocomposite had obviously enhanced tumor inhibitory efficiency in vivo. These results described that the asprared UCNPs@MOFs nanocomposite have great potential in the effective multimodal imaging and treatment of tumors.

Applications of Red Mud as a Masonry Material: A Review.

Red mud (RM) is a highly alkaline by-product produced by the aluminium industry. The total stockpile of RM in the world is evaluated to be close 4 billion tons, which caused serious soil and water pollution. The use of RM in masonry materials has proven to be a prospective strategy to alleviate the environmental problems caused by RM. During the past decades, various economical treatment methods have been developed for utilization of RM as a masonry material. There are two general categories of products using RM in masonry materials: sintered products and non-sintered products. In this review, the physicochemical properties of RM are introduced, and the different application scenarios for RM in masonry materials are summarized, which is valuable for solving the environmental problems caused by the accumulation of bauxite residue. Moreover, the potential environmental risks of utilizing RM are described. Finally, suggestions for solving the RM problem are proposed.

Improved water splitting efficiency of Au-NP-loaded Ga2O3 thin films in the visible region under strong coupling conditions.

We fabricate a novel photoanode consisting of TiO2/Au nanoparticles (Au-NPs)/Ga2O3/TiN/Au-film (TAGA), efficiently increasing light absorption and electron transfer from Au-NPs to Ga2O3 under modal strong coupling. A TiN thin layer deposited on an Au film enables stable high-temperature deposition of Ga2O3 onto the reflective Au film mirror. Modal strong coupling is observed when the resonance wavelength of the Ga2O3/TiN/Au-film Fabry-Pérot cavity overlaps with the plasmon resonance wavelength of Au-NPs partially inlaid in a thin TiO2 layer. Under strong coupling conditions, the light absorption and photoelectrochemical conversion efficiency in the visible region increased more than in the samples without coupling. In this structure, the TiO2 layer partially inlaying Au-NPs plays a vital role in effectively enhancing the coupling strength. We accomplish water splitting at zero bias potential by taking advantage of the intrinsically negative conduction band potential of Ga2O3.

Nanosecond tunable laser for the all-optical switching network.

The optically switched network can offset the increasing gap between datacenter traffic growth and electrical switch capacity due to the slowdown of Moore's law. Ultra-high-speed wavelength tunable lasers are especially vital for the high integration and performance improvement of the all-optical switching system. In this paper, a fast tunable laser based on a laser array is realized. The 2×8 matrix structure of the laser array is fabricated by the reconstruction-equivalent-chirp (REC) technique. Aiming at the 2×8 array, a drive control system is designed to provide stable and fast switching, to achieve high-speed switching of the laser wavelength, and to keep the wavelength stable after switching. The simulation and experimental results show that the switching time between any two wavelength channels of the laser is less than 10 ns. The switching time of any two channels of the laser can be reduced by 2-3 ns after the pre-emphasis processing of the electrical signal.

Room Temperature Phosphorescent (RTP) Thermoplastic Elastomers with Dual and Variable RTP Emission, Photo-Patterning Memory Effect, and Dynamic Deformation RTP Response.

Room temperature phosphorescent (RTP) polymers have advantages of strength, toughness, and processing and application flexibility over organic small molecular crystals, but the current RTP polymers are all from rigid plastics and involve chemical linkage and hydrogen and ionic bonds, and thermoplastic RTP elastomer has not been attempted and realized. Moreover, solution-processed films by simply mixing polymers and organic RTP materials can only show weak and single blue RTP. Here it is presented that such elastomer films, once thermomechanically plasticized, can emit bright and long-lived dual RTP. Moreover, they exhibit photo-activation memory effect, variable RTP colors and dynamic deformation RTP response. These results reveal that thermoplasticizing has altered the dispersion states and micro-environment of RTP molecules in matrix, and the cohesion of elastic polymer itself can also greatly restrict non-radiative relaxations to boost both blue mono-molecular and yellow micro-crystalline RTP. This work provides an effective and versatile processing strategy for tuning and enhancing the RTP properties of doped RTP polymers.

Experimental demonstration of a photonic convolutional accelerator based on a monolithically integrated multi-wavelength distributed feedback laser.

We propose and experimentally demonstrate a simple and energy-efficient photonic convolutional accelerator based on a monolithically integrated multi-wavelength distributed feedback semiconductor laser using the superimposed sampled Bragg grating structure. The photonic convolutional accelerator operates at 44.48 GOPS for one 2 × 2 kernel with a convolutional window vertical sliding stride of 2 and generates 100 images of real-time recognition. Furthermore, a real-time recognition task on the MNIST database of handwritten digits with a prediction accuracy of 84% is achieved. This work provides a compact and low-cost way to realize photonic convolutional neural networks.

Effect of Electrolytic Manganese Residue in Fly Ash-Based Cementitious Material: Hydration Behavior and Microstructure.

Electrolytic manganese residue (EMR) is a solid waste with a main mineralogical composition of gypsum. It is generated in the production of metal manganese by the electrolysis process. In this research, EMR, fly ash, and clinker were blended to make fly ash-based cementitious material (FAC) to investigate the effect of EMR on strength properties, hydration behavior, microstructure, and environmental performance of FAC. XRD, TG, and SEM studied the hydration behavior of FAC. The pore structure and [SiO4] polymerization degree were characterized by MIP and 29Si NMR, respectively. The experimental results indicate that FAC shows excellent mechanical properties when the EMR dosage is 10%. Moderate content of sulfate provided by EMR can promote hydration reaction of FAC, and it shows a denser pore structure and higher [SiO4] polymerization degree in this case. Heavy metal ions derived from EMR can be adsorbed in the hydration products of FAC to obtain better environmental properties. This paper presents an AFt covering model for the case of excessive EMR in FAC, and it importantly provides theoretical support for the recycling of EMR in cementitious materials.

Gaining New Insights into Trace Guest Doping Role in Manipulating Organic Crystal Phosphorescence.

Trace guest doping systems often show better room temperature phosphorescence (RTP), but trace guest doping role and mechanism are not recognized well. Here we cocrystallize commercial (CCZ) and self-made (LCZ) carbazole derivatives and verify that 0.2‰ isomer doping can afford the deserved crystal RTP, but further increasing the isomer amount hardly improves RTP. Isomer doping does not affect crystal stacking modes and intermolecular interactions and is inefficient in monomolecular and amorphous states. LCZ derivatives are intrinsically phosphorescent, but crystallization itself cannot effectively inhibit thermal deactivation, and isomer doping restricts nonradiative relaxation and reduces the energy level of the triplet emissive state via space action at a distance rather than currently described adjacent intermolecular interactions. This work has updated some existing views and represented an important conceptual advance in a fresh understanding of trace guest doping RTP systems.

Circulating Fluidized Bed Fly Ash Mixed Functional Cementitious Materials: Shrinkage Compensation of f-CaO, Autoclaved Hydration Characteristics and Environmental Performance.

Circulating fluidized bed (CFB) fly ash is a by-product from CFB power generation, which is hard to utilize in cement because it contains f-CaO and SO3. This work aims to explore the mechanism of the shrinkage compensation of free-CaO (f-CaO) and the autoclaved hydration characteristics and environmental performance of CFB fly ash mixed cementitious materials (CMM). In this work, long-term volume stability of CMM is improved with the addition of CFBFA. These findings suggest that the compressive strength of sample CMM0.5 is the highest under both standard condition (67.21 MPa) and autoclaved condition (89.56 MPa). Meanwhile, the expansion rate (0.0207%) of sample CMM0.5 is the lowest, which proves the shrinkage compensation effect of f-CaO in CFBFA. The main hydration products of CMM0.5 are Ca2SiO4•H2O (C-S-H) gel, CaAl2Si2O7(OH)2•H2O (C-A-S-H) gel and Ca(OH)2. In addition, the high polymerization degree of [Si(Al)O4] and the densified microstructure are presented at the sample CMM0.5. The leaching results indicates that the heavy metals in CMM0.5 satisfies the WHO standards for drinking water due to physical encapsulation and charge balance. Therefore, this investigation provides a novel method of using CFB fly ash in cement.

Rapid Evaluation of the Pozzolanic Activity of Bayer Red Mud by a Polymerization Degree Method: Correlations with Alkali Dissolution of (Si+Al) and Strength.

A large amount of Bayer process red mud is discharged in the process of alumina production, which has caused significant pollution in the environment. The pozzolanic activity of Bayer red mud as a supplementary cementitious material is a research hotspot. In this work, a new method for Fourier-transform infrared spectrometry is used to determine the polymerization degree of Bayer red mud in order to evaluate its pozzolanic activity. Based on the results of the dissolution concentration of (Si+Al), strength index and polymerization degree of Bayer red mud, the relationships between different evaluation methods were analyzed, and the relevant calculation formulas of pozzolanic activity were obtained. The results showed that different evaluation methods can reflect the variation law of pozzolanic activity in Bayer red mud. The polymerization degree of Bayer red mud had a good linear relationship with the pozzolanic activity index obtained by the strength index and dissolution concentration of (Si+Al), respectively. The polymerization degree was negatively correlated with pozzolanic activity index and dissolution concentration of (Si+Al), and the correlation coefficients were greater than 0.85. Therefore, this method was found to be effective and hence can be used as a rapid and simple test for pozzolanic activity evaluation of Bayer red mud.

Pharmacological postconditioning with sappanone A ameliorates myocardial ischemia reperfusion injury and mitochondrial dysfunction via AMPK-mediated mitochondrial quality control.

Pharmacological postconditioning (PPC), drug intervention before or during the early minutes of reperfusion, could stimulate cardioprotection as ischemic postconditioning. In this study, we examined whether PPC with sappanone A (SA), a homoisoflavanone with potent antioxidant and anti-inflammatory activity, has a protective effect on myocardial ischemia reperfusion injury (MIRI), and explored the underlying mechanism. A MIRI model was established using the Langendorff method. After 30 min of ischemia, isolated rat hearts were treated with SA at the onset of reperfusion to stimulate PPC. The changes in myocardial infarct size, mitochondrial function, mitochondrial biogenesis, mitophagy, and mitochondrial fission and fusion were detected. The results showed that SA postconditioning decreased the myocardial infarct size, inhibited the release of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), and cardiac troponin (cTnI), as well as improved cardiac function, enhanced myocardial ATP content and mitochondrial complex activity, and prevented the loss of mitochondrial membrane potential and opening of mitochondrial permeability transition pore (mPTP). Mechanistically, we found that SA was an AMP-activated protein kinase (AMPK) activator, and SA postconditioning could facilitate mitochondrial biogenesis by increasing mitochondrial DNA (mtDNA) copy number and the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α). In addition, it balanced mitochondrial dynamics by decreasing fission and increasing fusion, and enhanced mitophagy in an AMPK-dependent manner. Moreover, AMPK silencing abolished the cardioprotection of SA postconditioning. Collectively, our study demonstrated that SA postconditioning ameliorated MIRI and mitochondrial dysfunction by regulation of mitochondrial quality control via activating AMPK. This finding provides a new insight into pharmacological action and clinical use of SA.

Tailings after Iron Extraction in Bayer Red Mud by Biomass Reduction: Pozzolanic Activity and Hydration Characteristics.

Bayer red mud (BRM) is a kind of solid waste with high hematite content, and its effective utilization is difficult due to the special physicochemical properties. In this work, Fe2O3 in BRM was reduced to Fe3O4 by biomass, and iron concentrate and high activity tailings were obtained after magnetic separation. The pozzolanic activity and hydration characteristics of the tailings were systematically studied. The results showed that the relatively stable polymerization structures of Si-O and Al-O in BRM are destroyed under the effect of biomass reduction at 650 °C, and some fracture bonds and activation points are formed in the structures. The aluminosilicate phases in the BRM were easy to transform into the active substances of Si and Al. The pozzolanic activity of tailings is greatly improved, and its pozzolanic activity index is 91%. High polymerization degree of gel and ettringite are formed since more active substances and alkali in the tailings promote the hydration reaction of cement-based cementitious materials, which made cementitious materials have dense matrix, good mechanical properties, and environmental performance. This work has realized the full quantitative utilization of BRM and provided a feasible way for the resource utilization of BRM.

CLEC5A knockdown protects against cardiac dysfunction after myocardial infarction by suppressing macrophage polarization, NLRP3 inflammasome activation, and pyroptosis.

Increasing evidence has shown that the NOD-like receptor protein 3 (NLRP3) inflammasome and pyroptotic cell death play vital roles in the pathophysiology of myocardial infarction (MI), a common cardiovascular disease characterized by cardiac dysfunction. C-type lectin member 5A (CLEC5A) has been reported to be strongly associated with activation of the NLRP3 inflammasome and pyroptosis. In this study, an in vivo MI model was established by ligation of the left anterior descending coronary artery in male C57BL/6 mice, and CLEC5A knockdown was further achieved by intra-myocardial injection of adenovirus delivering shRNA-CLEC5A. CLEC5A was found to be highly expressed in the left ventricle of MI mice, while CLEC5A knockdown alleviated cardiac dysfunction in MI mice. In addition, MI-induced classical activation of macrophages was significantly inhibited after CLEC5A silencing. Additionally, CLEC5A knockdown dramatically inhibited MI-triggered activation of NLRP3 inflammasome, pyroptosis, and NF-κB signaling in the left ventricle of mice. In vitro experiments further validated that CLEC5A knockdown suppressed M1 polarization in LPS/IFNγ-stimulated RAW264.7 cells and inhibited the polarized RAW264.7-induced activation of NLRP3 inflammasome/pyroptosis signaling in co-cultured cardiomyocytes. In conclusion, CLEC5A knockdown protects against MI-induced cardiac dysfunction by regulating macrophage polarization, NLRP3 inflammasome, and cell pyroptosis.

Cancer-associated 53BP1 mutations induce DNA damage repair defects.

TP53 binding protein 1 (53BP1) plays an important role in DNA damage repair and maintaining genomic stability. However, the mutations of 53BP1 in human cancers have not been systematically examined. Here, we have analyzed 541 somatic mutations of 53BP1 across 34 types of human cancer from databases of The Cancer Genome Atlas, International Cancer Genome Consortium and Catalogue of Somatic Mutations in Cancer. Among these cancer-associated 53BP1 mutations, truncation mutations disrupt the nuclear localization of 53BP1 thus abolish its biological functions in DNA damage repair. Moreover, with biochemical analyses and structural modeling, we have examined the detailed molecular mechanism by which missense mutations in the key domains causes the DNA damage repair defects. Taken together, our results reveal the functional defects of a set of cancer-associated 53BP1 mutations.