Vitrimers make up a class of polymeric materials combining the advantages of thermosets and thermoplastics, because they can be reprocessed while being at the same time permanently cross-linked. ...However, a long heating duration or an elevated temperature is necessary for most vitrimers to relax the stress from deformation and exhibit malleability. Herein, a disulfide-containing carboxylic acid is applied as a curing agent to synthesize epoxy vitrimers with simultaneous disulfide metathesis and carboxylate transesterification. The insoluble networks exhibit rapid stress relaxation and have relaxation times ranging from 1.5 s (200 °C) to 5500 s (60 °C), while the temperature of malleability is as low as 65 °C. Moreover, this vitrimer can be efficiently reprocessed at 100 °C in 1 h with full recovery of mechanical strength for at least four cycles. Additionally, such a material is simply synthesized from commercially available chemicals and may have potential applications in the electronics industry where a high temperature is not allowed.
The early Aptian (~120 Ma) Oceanic Anoxic Event 1a (OAE 1a) was associated with marked changes in palaeoclimate linked to a perturbation of the global carbon cycle. While it is well-studied in the ...marine realm, OAE 1a is poorly known from continental records. Here, we fill that knowledge-gap by describing OAE 1a from lacustrine facies in the East Asia continental margin (Jiaolai Basin and Lingshan Island in eastern China). Specifically, we integrate data from bulk organic carbon-isotopes (δ13Corg), total organic carbon (TOC), and redox-and productivity-sensitive trace elements, as well as existing records on depositional environments, clay mineral compositions, elemental geochemistry and the latest detrital zircon UPb ages. We propose a conceptual model of the response of the lake system to OAE 1a through analysis of the palaeoenvironmental and palaeoclimatic context. During the initial stage, an extreme greenhouse climatic event resulted in an abrupt increase in palaeosalinity in the lake system. This led to anoxic conditions, resulting in a high preservation rate of TOC and the development of organic-rich black shale. Organic carbon isotopes documented in the organic-rich black shale show negative and then positive excursions, consistent with the carbon cycle disturbance found in marine OAE 1a records. In addition, the data show that this event may have been associated with a transition from an extreme greenhouse climate to a cooling phase. The framework presented here facilitates further research on the expression of OAE 1a in continental ecosystems and its fingerprint in lacustrine depositional systems.
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•Evidence of OAE1a was identified in lacustrine depositional systems.•Lacustrine black shale in East China preserves information on early Aptian C-cycle perturbation during OAE 1a.•Palaeosalinity and RSTE data indicate environmental instability of inland lakes in East China during OAE 1a.•Terrestrial records suggest an extreme greenhouse climate led to OAE 1a.•The OAE 1a itself may represent a period of transition from an extreme greenhouse climate to a cooling phase.
Neuropathic pain is a refractory disease characterized by maladaptive changes in gene transcription and translation in the sensory pathway. Long noncoding RNAs (lncRNAs) are emerging as new players ...in gene regulation, but how lncRNAs operate in the development of neuropathic pain is unclear. Here we identify a conserved lncRNA, named Kcna2 antisense RNA, for a voltage-dependent potassium channel mRNA, Kcna2, in first-order sensory neurons of rat dorsal root ganglion (DRG). Peripheral nerve injury increased Kcna2 antisense RNA expression in injured DRG through activation of myeloid zinc finger protein 1, a transcription factor that binds to the Kcna2 antisense RNA gene promoter. Mimicking this increase downregulated Kcna2, reduced total voltage-gated potassium current, increased excitability in DRG neurons and produced neuropathic pain symptoms. Blocking this increase reversed nerve injury-induced downregulation of DRG Kcna2 and attenuated development and maintenance of neuropathic pain. These findings suggest endogenous Kcna2 antisense RNA as a therapeutic target for the treatment of neuropathic pain.
PEGylation is one of the most successful technologies for reducing immunogenicity, improving the stability and circulation time of nanocarriers, and has been applied in the clinic for over three ...decades. However, linear PEG-modified nanocarriers have been found to induce anti-PEG IgM at the first injection, which triggers the accelerated blood clearance (ABC) phenomenon upon repeated injections. Furthermore, clinical and research evidence has revealed that anti-PEG antibodies also cause serious complement activation-related pseudoallergies (CARPA), which greatly reduce the safety of linear PEGylated nanocarriers. In this study, as an alternative to linear PEG, branched PEG was selected owing to its low antigenicity. We pioneer the use of branched PEG lipid derivatives DSPE-mPEG2,n (n = 2, 10, and 20 kDa) to modify nanoemulsions (PE2,n) and liposomes (PL2,n). Upon characterization, PE2,n and PL2,n showed similar physicochemical properties to linear DSPE-mPEG2000-modified nanocarriers in terms of size, polydispersity index (PDI), and zeta potential. However, our pharmacokinetics study surprisingly indicated that PE2,n and PL2,n did not induce the ABC phenomenon after repeated injection. This may be attributed to the fact that PE2,n and PL2,n induced noticeably lower levels of anti-PEG IgM than linear PEG-modified nanocarriers and did not activate the complement system. Furthermore, we are the first to investigate the anti-tumor efficacy of DSPE-mPEG2,n-modified liposomal doxorubicin (DOX). The pharmacodynamic experiments showed that DSPE-mPEG2,n-m-modified liposomal DOX had better in vivo anti-tumor effects than linear DSPE-mPEG2000-modified liposomes. Therefore, we speculate that DSPE-mPEG2,n-modified nanocarriers possess promising prospects in avoiding the ABC phenomenon, reducing CARPA, and improving the anti-tumor efficacy of encapsulated drugs.
Scheme 1. (A) In vivo pharmacokinetics of DSPE-mPEG2,n-modified nanoemulsions and liposomes after repeated injections (B) In vivo anti-tumor pharmacodynamics of DSPE-mPEG2,n-modified liposomal doxorubicin (DOX). Display omitted
The meniscus is a semilunar fibrocartilage between the tibia and femur that is essential for the structural and functional integrity of the keen joint. In addition to pain and knee joint dysfunction, ...meniscus injuries can also lead to degenerative changes of the knee joint such as osteoarthritis, which further affect patient productivity and quality of life. However, with intrinsic avascular property, the tearing meniscus tends to be nonunion and the augmentation of post-injury meniscus repair has long time been a challenge. Stem cell-based therapy with potent regenerative properties has recently attracted much attention in repairing meniscus injuries, among which mesenchymal stem cells were most explored for their easy availability, trilineage differentiation potential, and immunomodulatory properties. Here, we summarize the advances and achievements in stem cell-based therapy for meniscus repair in the last 5 years. We also highlight the obstacles before their successful clinical translation and propose some perspectives for stem cell-based therapy in meniscus repair.
Abstract
Background
Pulmonary arterial hypertension (PAH) is a rare complication of primary Sjögren’s syndrome (pSS). Several genes have proven to be associated with pSS and PAH. However, there is no ...study specifically addressing the genetic susceptibility in pSS combined with PAH.
Methods
Thirty-four unrelated patients with pSS-PAH were recruited from April 2019 to July 2021 at Peking Union Medical College Hospital. Demographic and clinical data were recorded in detail, and peripheral blood samples were collected for whole-exome sequencing (WES). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to predict the functional effect of mutant genes. Genetic variants identified by WES were confirmed by polymerase chain reaction (PCR)-Sanger sequencing.
Results
We totally identified 141 pathogenic variant loci of 129 genes in these 34 pSS-PAH patients, using WES analysis. Patients with a family history of rheumatic diseases are more likely to carry
FLG
mutations or carry gene variations related to the biosynthesis of the amino acids pathway (
p
< 0.05). According to Sanger sequencing confirmation and pathogenicity validation, we totally identified five candidate pathogenic variants including
FLG
c.12064A > T,
BCR
c.3275_3278dupCCGG,
GIGYF2
c.3463C > A,
ITK
c.1741C > T, and
SLC26A4
c.919-2A > G.
Conclusion
Our findings provide preliminary data of exome sequencing to identify susceptibility loci for pSS-PAH and enriched our understanding of the genetic etiology for pSS-PAH. The candidate pathogenic genes may be the potential genetic markers for early warning of this disease.
Development of a methodology to achieve the rapid degradation of thermosets under mild conditions is an important challenge. In this paper, we present a new method for rapid disassembly of ...thermosetting polyurethanes (PUs), using synergism of multiple stimuli. The PUs were prepared using multi-sensitivity dynamic disulfide bonds as the cross-linker. When soaked in DMF, the fabricated PUs only swell but undissolve. While reducing agent was added, the polymer completely dissolved after 12 h immersion at 25 °C, owing to the thiol-disulfide exchange mechanism. Moreover, as the temperature increases from 25 °C to 60 °C, the time required for complete dissolution of the PUs decreases from 12 h to 50 min, indicating that the synergistic effect of reducing agent and temperature can accelerate the degradation. In addition, other combined multi-stimuli, including reducing agent and ultrasound, can also be used to adjust the dissolution rate of the disulfide bonds cross-linked thermosets. When used as adhesives, the rapidly detachable PUs have potential applications in recycling the valuable adhesive components conveniently.
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•Polyurethanes cross-linked by multi-responsive dynamic disulfide bonds are prepared.•Obtained polyurethanes can degrade rapidly under mild conditions.•Degradation is controlled by DTT concentration, temperature, and ultrasound.•External stimuli synergistic effect can efficiently accelerate the degradation.•Detachable polyurethanes have applications in recycling the valuable components.
The therapeutic efficacy of chemotherapy is dramatically hindered by multidrug resistance (MDR), which is induced by the overexpression of P-glycoprotein (P-gp). The codelivery of an antitumor drug ...and siRNA is an effective strategy recently applied in overcoming P-gp-related MDR. In this study, a multifunctional drug delivery system with both pH-sensitive feature and active targetability was designed, in which MDR1-siRNA and DOX were successfully loaded. The resulting carrier EphA10 antibody-conjugated pH-sensitive doxorubicin (DOX), MDR1-siRNA coloading lipoplexes (shortened as DOX + siRNA/ePL) with high serum stability had favorable physicochemical properties. DOX + siRNA/ePL exhibited an incremental cellular uptake, enhanced P-gp downregulation efficacy, as well as a better cell cytotoxicity in human breast cancer cell line/adriamycin drug-resistant (MCF-7/ADR) cells. The results of the intracellular colocalization study indicated that DOX + siRNA/ePL possessed the ability for pH-responsive rapid endosomal escape in a time-dependent characteristic. Meanwhile, the in vivo antitumor activities suggested that DOX + siRNA/ePL could prolong the circulation time as well as specifically accumulate in the tumor cells via receptor-mediated endocytosis after intravenous administration into the blood system. The histological study further demonstrated that DOX + siRNA/ePL could inhibit the proliferation, induce apoptosis effect, and downregulate the P-gp expression in vivo. Altogether, DOX + siRNA/ePL was expected to be a suitable codelivery system for overcoming the MDR effect.
Internet addiction (IA) is a growing social problem with negative mental and social outcomes; the present study examined whether rejection sensitivity mediates the relationship between interparental ...conflict and adolescent IA and the moderating role of school connectedness. One thousand and seven adolescents (51.84% females;
Mean
age
= 13.17;
SD
= 0.69) anonymously completed questionnaires to assess interparental conflict, school connectedness, rejection sensitivity, IA, and demographic information. The model results showed that: (1) the positive association between interparental conflict and adolescent IA was partially mediated by rejection sensitivity; (2) this indirect link was moderated by the school connectedness and was stronger for adolescents with high school connectedness. The results provide support for the attachment theory that high interparental conflict could increase adolescents’ rejection sensitivity, and high school connectedness plays a double-edged role that adolescents show more rejection sensitivity while reporting high interparental conflict and high school connectedness.
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