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1.
Sci Bull (Beijing) ; 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33495714

RESUMO

The pandemic of SARS-CoV-2 has caused a high number of deaths in the world. To combat it, it is necessary to develop a better understanding of how the virus infects host cells. Infection normally starts with the attachment of the virus to cell-surface glycans like heparan sulfate (HS) and sialic acid-containing glycolipids/glycoproteins. In this study, we examined and compared the binding of the subunits and spike (S) proteins of SARS-CoV-2 and SARS-CoV, MERS-CoV to these glycans. Our results revealed that the S proteins and subunits can bind to HS in a sulfation-dependent manner and no binding with sialic acid residues was detected. Overall, this work suggests that HS binding may be a general mechanism for the attachment of these coronaviruses to host cells, and supports the potential importance of HS in infection and in the development of antiviral agents against these viruses.

2.
Ann Anat ; 235: 151672, 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33434657

RESUMO

Cellular FLICE-inhibitory protein (c-FLIP), an anti-apoptotic regulator, shows remarkable similarities to caspase-8, which plays a key role in the cleavage of gasdermin D (GSDMD). It has been reported that the oxygen-glucose deprivation/recovery (OGD/R) model and lipopolysaccharide (LPS)/adenosine triphosphate (ATP) treatment could induce inflammation and pyroptosis. However, the regulatory role of c-FLIP in the pyroptotic death of retinal neurons is unclear. In this study, we hypothesized that c-FLIP might regulate retinal neuronal pyroptosis by GSDMD cleavage. To investigate this hypothesis, we induced retinal neuronal damage in vitro (OGD/R and LPS/ATP) and in vivo (acute high intraocular pressure [aHIOP]). Our results demonstrated that the three injuries triggered the up-regulation of pyroptosis-related proteins, and c-FLIP could cleave GSDMD to generate a functional N-terminal (NT) domain of GSDMD, causing retinal neuronal pyroptosis. In addition, c-FLIP knockdown in vivo ameliorated the already established visual impairment mediated by acute IOP elevation. Taken together, these findings revealed that decreased c-FLIP expression protected against pyroptotic death of retinal neurons possibly by inhibiting GSDMD-NT generation. Therefore, c-FLIP might provide new insights into the pathogenesis of pyroptosis-related diseases and help to elucidate new therapeutic targets and potential treatment strategies.

3.
Histol Histopathol ; : 18297, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33398872

RESUMO

Mesenchymal stem cells play an important role in tissue damage and repair. This role is mainly due to a paracrine mechanism, and extracellular vesicles (EVs) are an important part of the paracrine function. EVs play a vital role in many aspects of cell homeostasis, physiology, and pathology, and EVs can be used as clinical biomarkers, vaccines, or drug delivery vehicles. A large number of studies have shown that EVs derived from mesenchymal stem cells (MSC-EVs) play an important role in the treatment of various diseases. However, the problems of low production, low retention rate, and poor targeting of MSC-EVs are obstacles to current clinical applications. The engineering transformation of MSC-EVs can make up for those shortcomings, thereby improving treatment efficiency. This review summarizes the latest research progress of MSC-EV direct and indirect engineering transformation from the aspects of improving MSC-EV retention rate, yield, targeting, and MSC-EV visualization research, and proposes some feasible MSC-EV engineering methods of transformation.

4.
Health Place ; 67: 102498, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33383367

RESUMO

We investigated relationships between independently observed, visual cues of residential environments and subsequent participant-reported stress within a population-based cohort of Black breast cancer survivors (n = 476). Greater visual cues of engagement - presence of team sports, yard decorations, outdoor seating - (compared to less engagement) was marginally associated with lower perceived stress in univariate models, but attenuated towards null with adjustment for socio-demographic, behavioral, and health-related covariates. Similarly, physical disorder and perceived stress were not associated in adjusted models. Relationships between observed built environment characteristics and perceived stress might be influenced by socioeconomic and health behavior factors, which longitudinal studies should investigate.

5.
Ophthalmic Surg Lasers Imaging Retina ; 51(11): 653-657, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33231700

RESUMO

The authors present the case of a 35-year-old male who was diagnosed with acute retinal necrosis syndrome that evolved into retinal detachment (RD), even after immediate treatment with systemic antiviral medications, as well as intravitreal injection and laser photocoagulation. Pars plana vitrectomy plus silicone oil tamponade was performed, but silicone oil emulsified 22 months later. Due to the widespread necrosis lesions and defects of the peripheral retina, RD was highly likely to reoccur after silicone oil removal; thus, foldable capsular vitreous body was implanted to support the retina. No recurrent RD was observed afterward. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:653-657.].

6.
Artigo em Inglês | MEDLINE | ID: mdl-33234556

RESUMO

BACKGROUND: The disproportionate burden of more aggressive breast cancer subtypes among African American/Black women may stem from multilevel determinants. However, data are limited regarding the impacts of neighborhood social environmental characteristics among Black women. METHODS: We evaluated the association between neighborhood-level socioeconomic status (nSES) and breast cancer subtypes in the Women's Circle of Health and Women's Circle of Health Follow-up Study, which included 1,220 Black women diagnosed from 2005 to 2017 with invasive breast cancer. nSES at diagnosis was measured using NCI's census tract-level SES index. We used multilevel multinomial logistic regression models to estimate the association of nSES with breast cancer subtypes [triple-negative breast cancer (TNBC), HER2-positive vs. luminal A], adjusting for individual-level SES, body mass index, and reproductive factors. We tested for interactions by neighborhood racial composition. RESULTS: Compared to census tracts characterized as high nSES, the relative risk ratios (RRR) for TNBC were 1.81 (95% CI: 1.20-2.71) and 1.95 (95% CI: 1.27-2.99) for women residing in areas with intermediate and low nSES, respectively (p-trend: .002). Neighborhood racial composition modified the association between nSES and TNBC; the highest relative risk of TNBC was among women residing in low nSES areas with low proportions of Black residents. CONCLUSIONS: Black women residing in socioeconomically disadvantaged neighborhoods may have an increased risk of TNBC, particularly among areas with lower proportions of Black residents. IMPACT: Places people live may influence breast tumor biology. A deeper understanding of multilevel pathways contributing to tumor biology is needed.

8.
Oxid Med Cell Longev ; 2020: 1295382, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123307

RESUMO

Excess iron has been reported to lead to osteoblastic cell damage, which is a crucial pathogenesis of iron overload-related osteoporosis. However, the cytotoxic mechanisms have not been fully documented. In the present study, we focused on whether necroptosis contributes to iron overload-induced osteoblastic cell death and related underlying mechanisms. Here, we showed that the cytotoxicity of iron overload in osteoblastic cells was mainly due to necrosis, as evidenced by the Hoechst 33258/PI staining, Annexin-V/PI staining, and transmission electronic microscopy. Furthermore, we revealed that iron overload-induced osteoblastic necrosis might be mediated via the RIPK1/RIPK3/MLKL necroptotic pathway. In addition, we also found that iron overload was able to trigger mitochondrial permeability transition pore (mPTP) opening, which is a critical downstream event in the execution of necroptosis. The key finding of our experiment was that iron overload-induced necroptotic cell death might depend on reactive oxygen species (ROS) generation, as N-acetylcysteine effectively rescued mPTP opening and necroptotic cell death. ROS induced by iron overload promote necroptosis via a positive feedback mechanism, as on the one hand N-acetylcysteine attenuates the upregulation of RIPK1 and RIPK3 and phosphorylation of RIPK1, RIPK3, and MLKL and on the other hand Nec-1, siRIPK1, or siRIPK3 reduced ROS generation. In summary, iron overload induced necroptosis of osteoblastic cells in vitro, which is mediated, at least in part, through the RIPK1/RIPK3/MLKL pathway. We also highlight the critical role of ROS in the regulation of iron overload-induced necroptosis in osteoblastic cells.

9.
Acta Pharm Sin B ; 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32895623

RESUMO

The pandemic of coronavirus disease 2019 (COVID-19) is changing the world like never before. This crisis is unlikely contained in the absence of effective therapeutics or vaccine. The papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays essential roles in virus replication and immune evasion, presenting a charming drug target. Given the PLpro proteases of SARS-CoV-2 and SARS-CoV share significant homology, inhibitor developed for SARS-CoV PLpro is a promising starting point of therapeutic development. In this study, we sought to provide structural frameworks for PLpro inhibitor design. We determined the unliganded structure of SARS-CoV-2 PLpro mutant C111S, which shares many structural features of SARS-CoV PLpro. This crystal form has unique packing, high solvent content and reasonable resolution 2.5 Å, hence provides a good possibility for fragment-based screening using crystallographic approach. We characterized the protease activity of PLpro in cleaving synthetic peptide harboring nsp2/nsp3 juncture. We demonstrate that a potent SARS-CoV PLpro inhibitor GRL0617 is highly effective in inhibiting protease activity of SARS-CoV-2 with the IC50 of 2.2±0.3 µmol/L. We then determined the structure of SARS-CoV-2 PLpro complex by GRL0617 to 2.6 Å, showing the inhibitor accommodates the S3-S4 pockets of the substrate binding cleft. The binding of GRL0617 induces closure of the BL2 loop and narrows the substrate binding cleft, whereas the binding of a tetrapeptide substrate enlarges the cleft. Hence, our results suggest a mechanism of GRL0617 inhibition, that GRL0617 not only occupies the substrate pockets, but also seals the entrance to the substrate binding cleft hence prevents the binding of the LXGG motif of the substrate.

10.
Support Care Cancer ; 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32995999

RESUMO

PURPOSE: Sleep disturbance may be an overlooked modifiable risk factor for health disparities among African-American breast cancer survivors (AABCS). This study aimed to identify the prevalence of and risk factors for sleep disturbance in a cohort of AABCS. METHODS: The study was conducted among participants in the Women's Circle of Health Follow-up Study, a longitudinal study of breast cancer in 10 counties in New Jersey. Cases were identified shortly after diagnosis by the New Jersey State Cancer Registry. Self-reported sleep disturbance (Pittsburgh Sleep Quality Index) and other factors (e.g., socioeconomic status, menopausal status) were assessed at pre-diagnosis (n = 637), 10 months post-diagnosis (n = 261), and 24 months post-diagnosis (n = 632). Clinical data were obtained via medical record abstraction, and height and weight were measured by study staff. RESULTS: Most AABCS (57%) reported clinically significant sleep disturbance before diagnosis, and this rate remained largely unchanged at 10 months (53%) and 24 months post-diagnosis (61%). Average sleep disturbance scores indicated clinically significant disturbance at all three assessments (M range = 6.67-7.57). Most reported sleeping fewer than the recommended 7 hours per night at each assessment (range 57-65%). Risk factors for sleep disturbance were identified at each assessment, including pre-diagnosis (less education), 10 months post-diagnosis (lack of insurance, treatment with chemotherapy), and 24 months post-diagnosis (younger age, less education, lower income, obesity, and lymphedema). Treatment with endocrine therapy was a protective factor at 10 months post-diagnosis. CONCLUSION: Most AABCS report clinically significant sleep disturbance from before diagnosis through 24 months post-diagnosis. These rates appear indicate AABCS experience significant sleep-related disparities.

11.
Eur J Epidemiol ; 35(11): 1025-1042, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32959149

RESUMO

While childbearing protects against risk of epithelial ovarian cancer (EOC), few studies have explored the impact on maternal EOC risk of sex of offspring, which may affect the maternal environment during pregnancy. We performed a pooled analysis among parous participants from 12 case-controls studies comprising 6872 EOC patients and 9101 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression for case-control associations and polytomous logistic regression for histotype-specific associations, all adjusted for potential confounders. In general, no associations were found between offspring sex and EOC risk. However, compared to bearing only female offspring, bearing one or more male offspring was associated with increased risk of mucinous EOC (OR = 1.45; 95% CI = 1.01-2.07), which appeared to be limited to women reporting menarche before age 13 compared to later menarche (OR = 1.71 vs 0.99; P-interaction = 0.02). Bearing increasing numbers of male offspring was associated with greater risks of mucinous tumors (OR = 1.31, 1.84, 2.31, for 1, 2 and 3 or more male offspring, respectively; trend-p = 0.005). Stratifying by hormonally-associated conditions suggested that compared to bearing all female offspring, bearing a male offspring was associated with lower risk of endometrioid cancer among women with a history of adult acne, hirsutism, or polycystic ovary syndrome (OR = 0.49, 95% CI = 0.28-0.83) but with higher risk among women without any of those conditions (OR = 1.64 95% CI = 1.14-2.34; P-interaction = 0.003). Offspring sex influences the childbearing-EOC risk relationship for specific histotypes and conditions. These findings support the differing etiologic origins of EOC histotypes and highlight the importance of EOC histotype-specific epidemiologic studies. These findings also suggest the need to better understand how pregnancy affects EOC risk.

12.
Breast Cancer Res Treat ; 184(3): 901-914, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32914357

RESUMO

PURPOSE: To determine the association of pre-diagnostic allostatic load (AL) with health-related quality of life (HRQOL) among Black women with breast cancer. METHODS: In a sample of 409 Black women with non-metastatic breast cancer enrolled in the Women's Circle of Health Follow-Up Study (WCHFS), two pre-diagnostic AL measures were estimated using medical records data from up to 12 months prior to breast cancer diagnosis: AL-lipid/metabolic profile-based measure and AL-inflammatory profile-based measure. HRQOL was assessed approximately 24 months post diagnosis, using the Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) instrument, including 5 subscale scores [presented by physical well-being (PWB), social & family well-being (SFWB), emotional well-being (EWB), functional well-being (FWB), and breast cancer-specific scale (BCS)] and 3 derived total scores [presented by trial outcome index (TOI), Functional Assessment of Cancer Therapy-General (FACT-G) and FACT-B]. We used multivariable logistic regression models, using dichotomized AL scores (lower AL: 0-3 points, higher AL: 4-8 points), to assess the associations between the two pre-diagnostic AL measures and HRQOL. RESULTS: Higher pre-diagnostic AL was associated with poorer FWB and lower FACT-G, but these associations were statistically significant for the AL-inflammatory profile-based measure (FWB: OR 1.63, 95% CI 1.04, 2.56; FACT-G: OR 1.62, 95% CI 1.04, 2.54), but not the AL-lipid/metabolic profile-based measure (FWB: OR 1.45, 95% CI 0.81, 2.59; FACT-G: OR 1.33, 95% CI 0.75, 2.37). CONCLUSION: These findings suggest that higher AL, particularly when measured using the inflammatory profile-based measure, was associated with poorer HRQOL, namely FWB and FACT-G, among Black breast cancer survivors.

13.
Cell Rep ; 32(6): 108041, 2020 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-32783928

RESUMO

Microglia are important immune cells in the central nervous system (CNS). Dysfunctions of gene-deficient microglia contribute to the development and progression of multiple CNS diseases. Microglia replacement by nonself cells has been proposed to treat microglia-associated disorders. However, some attempts have failed due to low replacement efficiency, such as with the traditional bone marrow transplantation approach. In this study, we develop three efficient strategies for microglia replacement: microglia replacement by bone marrow transplantation (mrBMT), microglia replacement by peripheral blood (mrPB), and microglia replacement by microglia transplantation (mrMT). mrBMT and mrPB allow microglia-like cells to efficiently replace resident microglia in the whole CNS. On the other hand, mrMT achieves microglia replacement in brain regions of interest. In summary, the present study offers effective tactics for microglia replacement with diverse application scenarios, which potentially opens up a window on treating microglia-associated CNS disorders.

14.
J Natl Cancer Inst ; 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32766851

RESUMO

BACKGROUND: Parity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated. METHODS: A pooled analysis of 10,470 invasive epithelial ovarian cancer cases and 16,942 controls was conducted. Odds ratios and 95% confidence intervals for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race/ethnicity, age, and education level, and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses. RESULTS: Ever having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (two-sided Ptrend <.001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer. CONCLUSIONS: Incomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.

15.
Ying Yong Sheng Tai Xue Bao ; 31(7): 2287-2292, 2020 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-32715693

RESUMO

Bacillus sp. SMrs28, metabolites from which had significant nematicidal activity, was isolated from the rhizosphere soil of Stellera chamaejasme. To determine the optimal fermentation conditions of the strain and the resin type of preliminary purified active ingredient, fermentation conditions were optimized by single factor experiment, while the macroporous resin types were screened in a static adsorption experiment. The results showed that the optimal fermentation conditions of SMrs28 strain were as follows: glucose and yeast powder were the best carbon source and nitrogen source, fermentation for 48 h, inoculum volume of 10%, temperature at 28 ℃,a rotation speed of 180 r·min-1, liquid volume of 30 mL in 150 mL triangular flask, and with an initial pH of 7.2. The static adsorption experiments showed that the adsorption and desorption of active ingre-dients in the fermentation broth by the macroporous adsorption resin D101 was significantly better than that of XAD-4, HP20 and AB-8, with the nematicidal activity of the desorption liquid being significantly improved. The nematicidal activity of fermentation broth was significantly improved by the optimization of fermentation conditions and the screening of optimal macroporous adsorption resins. These results laid a foundation for the further isolation and purification of active ingredients from SMrs28 strain, and provided theoretical basis for the development and utilization of microbial nematicides.


Assuntos
Bacillus , Nematoides , Adsorção , Animais , Fermentação , Rizosfera
16.
Cell Res ; 30(9): 823, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32636455

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

17.
Huan Jing Ke Xue ; 41(3): 1246-1255, 2020 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-32608626

RESUMO

Zooplankton, as an important part of the water food chain, plays an important role in lake ecosystems. It is an important monitoring indicator for water bodies. However, due to the lack of long-term monitoring data of zooplankton community structure, there is a lack of understanding about its long-term characteristics. Based on monthly monitoring data from 1997 to 2017 of Meiliang Bay in Lake Taihu, the long-term trends of zooplankton community structure and its relation to the environment were examined. The results showed that the abundance and biomass of zooplankton in Meiliang Bay significantly decreased from 1997 to 2017 (P<0.05). In particular, the abundance and biomass of rotifer and copepod slowly declined, and the abundance of cladocerans fluctuated but its biomass presented a significant decreasing trend (P<0.05). The cladocerous biomass contributed the most to the zooplankton biomass in Meiliang Bay. The dominance of smaller cladocerans and copepods increased with decreasing rotifer density, significantly decreasing the average body size of zooplankton (P<0.05). This study indicated that zooplankton were becoming smaller, potentially weakening the top-down control on phytoplankton. In addition, zooplankton abundance and biomass showed an upward trend in spring and decreased in autumn and winter, and reached maximum values of 1406.70 ind.·L-1 and 25.64 mg·L-1, respectively, in September. In the summer, their changes were the opposite. Pearson correlation analysis showed that zooplankton community structure was significantly related to water physical characteristics (alkalinity, electrical conductivity, water depth, suspended substance, and water temperature), chlorophyll a, and nitrogen (P<0.05). This indicated that the eutrophication of Meiliang Bay in Lake Taihu had a significant impact on the community structure of zooplankton.


Assuntos
Lagos , Zooplâncton , Animais , Baías , Biomassa , China , Clorofila A , Ecossistema , Monitoramento Ambiental , Fitoplâncton
18.
PLoS One ; 15(7): e0236176, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697792

RESUMO

BACKGROUND: Optimizing stimulation protocol is essential for clinical application of retinal prosthesis. Elongating stimulation pulse width (~25ms /phase) has been proposed as an effective method to improve spatial resolution of epi-retinal implants. However, it is unknown whether longer stimulus pulse width will increase the risk of damaging the retina. In addition, with the advent of next generation retinal prosthesis featuring high-density microelectrode array, it is tempting to optimizing a single set of parameters for all electrodes instead of optimizing parameters of each electrode, but this approach raised biosafety concern. We sought to study the effect of stimulus pulse width on the response of retinal ganglion cells to electrical stimulation, and evaluate if the single parameter set approach was valid based on biosafety measures. METHODS: We stimulated mouse retina using biphasic pulse waveform generated by chosen electrodes (single or a 3x3 assembly) from multiple microelectrode arrays, recorded their action potentials and performed spike sorting. We tested various stimulus intensity with two fixed pulse width: a short one for 1 millisecond per phase, and a long one for 25 milliseconds per phase. All these assays were performed on two mouse models: the wildtype C57BL/6J mice and the photoreceptor degenerated rd10 mice. The action-potential-frequency vs stimulus amplitude profiles were plotted, and three parameters were extracted: the threshold (the lowest stimulus amplitude activating RGC units), safety-limit (stimulus amplitude that attenuated the firing rate to half of the maximum response), and the stimulation amplitude range (the difference between threshold and safety limit parameters). RESULTS: In single-electrode stimulation experiment, we found that on average 85% of the recorded units showed attenuated response to extreme stimulation; among those units, an average of 51% stopped responding during stimulation ramping and failed to recover after one-hour post-stimulation, indicating extreme stimulation can damage RGC units. Twenty-five-millisecond pulse stimulation significantly reduced safety-limit and stimulation-amplitude-range parameters of recorded RGC units compared to 1ms pulse stimulation. During stimulus amplitude ramping, the maximum proportion of responsive healthy RGC units was 51% on average in 25ms pulse condition, and 76% on average in 1ms pulse condition, indicating long pulse may inflict more strain on RGCs, and a significant amount of inappropriately stimulated RGCs always exist. The contrast of these proportions could be explained by the tight correlation between the threshold and safety-limit parameter in 25ms pulse condition. These results were corroborated by those from 3x3 array stimulation experiments. CONCLUSION: Base on a biosafety measure (RGCs' evoked firing rate in response to electrical stimulation), we proposed that longer stimulation pulse width could lead to reduced retinal response and thus highlighted the importance of carefully setting the stimulation amplitude in this case. Our results also suggested that optimizing a single set of parameters for all electrodes without individual tweaking always generated a significant amount of inappropriately stimulated RGCs, especially in the long pulse stimulation condition.


Assuntos
Contenção de Riscos Biológicos/métodos , Estimulação Elétrica/métodos , Degeneração Retiniana/terapia , Células Ganglionares da Retina/fisiologia , Próteses Visuais/efeitos adversos , Potenciais de Ação/fisiologia , Animais , Estimulação Elétrica/instrumentação , Humanos , Camundongos , Microeletrodos , Fatores de Tempo
19.
Adv Mater ; 32(36): e2000096, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32705730

RESUMO

Covalent thermosets generally exhibit robust mechanical properties, while they are fragile and lack the ability to be reprocessed or recycled. Herein, a new strategy of incorporating noncovalent bonds into main-chains is developed to construct tough and multi-recyclable cross-linked supramolecular polyureas (CSPU), which are prepared via the copolymerization of diisocyanate monomers, noncovalently bonded diamine monomers linked by quadruple hydrogen bonds, and covalent diamine/triamine monomers. The CSPU exhibit remarkable solvent resistance and outstanding mechanical properties owing to the covalent cross-linking via triamine monomer. Through the incorporation of 9.7% and 14.6% quadruple hydrogen bonded diamine monomer, the transparent CSPU films are endowed with superior toughness of 74.17 and 124.17 MJ m-3 , respectively. Impressively, even after five generations of recycling processes, the mechanical properties of reprocessed CSPU can recover more than 95% of their original properties, displaying excellent multiple recyclablity. As a result, the superior toughness, remarkable solvent resistance, high transparency, and excellent multiple recyclability are well-combined in the CSPU. It is highly anticipated that this line of research will provide a facile and general method to construct various cross-linked polymer materials with superior recyclability and mechanical properties.

20.
Mol Cell ; 79(5): 824-835.e5, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32649882

RESUMO

DNA-protein crosslinks (DPCs) are highly toxic DNA lesions that threaten genomic integrity. Recent findings highlight that SPRTN, a specialized DNA-dependent metalloprotease, is a central player in proteolytic cleavage of DPCs. Previous studies suggest that SPRTN deubiquitination is important for its chromatin association and activation. However, the regulation and consequences of SPRTN deubiquitination remain unclear. Here we report that, in response to DPC induction, the deubiquitinase VCPIP1/VCIP135 is phosphorylated and activated by ATM/ATR. VCPIP1, in turn, deubiquitinates SPRTN and promotes its chromatin relocalization. Deubiquitination of SPRTN is required for its subsequent acetylation, which promotes SPRTN relocation to the site of chromatin damage. Furthermore, Vcpip1 knockout mice are prone to genomic instability and premature aging. We propose a model where two sequential post-translational modifications (PTMs) regulate SPRTN chromatin accessibility to repair DPCs and maintain genomic stability and a healthy lifespan.


Assuntos
Envelhecimento/genética , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Acetilação , Envelhecimento/metabolismo , Animais , Linhagem Celular , Dano ao DNA , Proteínas de Ligação a DNA/genética , Enzimas Desubiquitinantes/metabolismo , Endopeptidases/metabolismo , Feminino , Instabilidade Genômica , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Domínios Proteicos , Processamento de Proteína Pós-Traducional , Ubiquitinação
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