β₂-microglobulin (β₂m) is the light chain of the type I major histocompatibility complex. It deposits as amyloid fibrils within joints during long-term hemodialysis treatment. Despite the devastating effects of dialysis-related amyloidosis, full understanding of how fibrils form from soluble β₂m remains elusive. Here we show that β₂m can oligomerize and fibrillize via three-dimensional domain swapping. Isolating a covalently bound, domain-swapped dimer from β₂m oligomers on the pathway to fibrils, we were able to determine its crystal structure. The hinge loop that connects the swapped domain to the core domain includes the fibrillizing segment LSFSKD, whose atomic structure we also determined. The LSFSKD structure reveals a class 5 steric zipper, akin to other amyloid spines. The structures of the dimer and the zipper spine fit well into an atomic model for this fibrillar form of β₂m, which assembles slowly under physiological conditions.

Ionizing radiation (IR) is a well-known carcinogen, however the mechanism of radiation induced thymic lymphoma is not well known. Moreover, an easy and effective method to protect mice from radiation induced thymic lymphoma is still unknown. Hydrogen, or H(2), is seldom regarded as an important agent in medical usage, especially as a therapeutic gas. Here in this study, we found that H(2) protects mice from radiation induced thymic lymphoma in BALB/c mice.

Abnormally increased levels of iron in the brain trigger cascade amplification in Alzheimer's disease patients, resulting in neuronal death. This study investigated whether components extracted from the Chinese herbs epimedium herb, milkvetch root and kudzuvine root could relieve the abnormal expression of iron metabolism-related protein in Alzheimer's disease patients. An APPswe /PS1ΔE9 double transgenic mouse model of Alzheimer's disease was used. The intragastric administration of compounds from epimedium herb, milkvetch root and kudzuvine root improved pathological alterations such as neuronal edema, increased the number of neurons, downregulated divalent metal transporter 1 expression, upregulated ferroportin 1 expression, and inhibited iron overload in the cerebral cortex of mice with Alzheimer's disease. These compounds reduced iron overload-induced impairment of the central nervous system, indicating a new strategy for developing novel drugs for the treatment of Alzheimer's disease.

Ceria nanoparticles (CNPs) have recently been shown to protect cells and animals from radiation-induced damage. However, most of the CNPs used in previous studies were either naked or weakly protected by surfactants, which inevitably encounter many obstacles in biological applications. Here, alendronate was used as an ideal anchor to graft polyethylene glycol (PEG) onto CNPs, leading to enhanced stability, reduced cytotoxicity, and improved biological properties. Further investigation assessed the protective ability of the nanoparticles against radiation-induced effects for human normal liver cells (L-02), indicating that the PEGylated CNPs (CNPs-AL-PEG) were more efficient than naked CNPs. We determined that enhanced Ce(3+)/Ce(4+) ratios improved intracellular dispersion and that the ameliorated intracellular distribution of CNPs-AL-PEG contributes to the elevated expression of SOD2, which leads to increased protection of normal cells against ROS and reduces the oxidatively generated DNA damage. These studies hold tremendous promise for radioprotection and biological applications.

Dendritic cells (DCs) play important roles in the initiation and maintenance of the immune response. The dysfunction of DCs contributes to tumor evasion and growth. Here we report our findings on the dysfunction of DCs in radiation-induced thymic lymphomas, and the up-regulation of the expression of the lipoprotein lipase (LPL) and the fatty acid binding protein (FABP4), and the level of triacylglycerol (TAG) in serum after total body irradiation, which contribute to DCs lipid accumulation. DCs with high lipid content showed low expression of co-stimulatory molecules and DCs-related cytokines, and were not able to effectively stimulate allogeneic T cells. Normalization of lipid abundance in DCs with an inhibitor of acetyl-CoA carboxylase restored the function of DCs. A high-fat diet promoted radiation-induced thymic lymphoma growth. In all, our study shows that dysfunction of DCs in radiation-induced thymic lymphomas was due to lipid accumulation and may represent a new mechanism in radiation-induced carcinogenesis.

It has been reported dysregulation of certain microRNAs (miRNAs / miRs) is involved in tumorigenesis. However, the miRNAs associated with radiocarcinogenesis remain undefined. In this study, we validated the upregulation of miR-467a in radiation-induced mouse thymic lymphoma tissues. Then, we investigated whether miR-467a functions as an oncogenic miRNA in thymic lymphoma cells. For this purpose, we assessed the biological effect of miR-467a on thymic lymphoma cells. Using miRNA microarray, we found four miRNAs (miR-467a, miR-762, miR-455 and miR-714) were among the most upregulated (>4-fold) miRNAs in tumor tissues. Bioinformatics prediction suggests miR-467a may potentially regulate apoptosis pathway via targeting Fas and Bax. Consistently, in miR-467a-transfected cells, both proliferation and colony formation ability were significantly increased with decrease of apoptosis rate, while, in miR-467a-knockdown cells, proliferation was suppressed with increase of apoptosis rate, indicating that miR-467a may be involved in the regulation of apoptosis. Furthermore, miR-467a-knockdown resulted in smaller tumors and better prognosis in an in vivo tumor-transplanted model. To explain the mechanism of apoptosis suppression by miR-467a, we explore the expression of candidate target genes (Fas and Bax) in miR-467a-transfected relative to negative control transfected cells using flow cytometry and immunoblotting. Fas and Bax were commonly downregulated in miR-467a-transfected EL4 and NIH3T3 cells, and all of the genes harbored miR-467a target sequences in the 3'UTR of their mRNA. Fas and Bax were actually downregulated in radiation-induced thymic lymphoma tissues, and therefore both were identified as possible targets of miR-467a in thymic lymphoma. To ascertain whether downregulation of Fas and / or Bax is involved in apoptosis suppression by miR-467a, we transfected vectors expressing Fas and Bax into miR-467a-upregulated EL4 cells. Then we found that both Fas- and Bax-overexpression decreased cell viability with increase of apoptosis rate, indicating that downregulation of Fas and Bax may be at least partly responsible for apoptosis suppression by miR-467a. These data suggest that miR-467a may have oncogenic functions in radiation-induced thymic lymphoma cells and that its increased expression may confer a growth advantage on tumor cells via aberrant expression of Fas and Bax.

Chamber tests are usually used to determine the source characteristics of semi-volatile organic compounds (SVOCs) which are critical to quantify indoor exposure to SVOCs. In contrast to volatile organic compounds (VOCs), the sorption effect of SVOCs to chamber surfaces usually needs to be considered due to the much higher surface/air partition coefficients, resulting in a long time to reach steady state, frequently on the order of months, and complicating the mathematical analysis of the resulting data. A chamber test is also complicated if the material-phase concentration is not constant. This study shows how to design a chamber to overcome these limitations. A dimensionless mass transfer analysis is used to specify conditions for (1) neglecting the SVOC sorption effect to chamber surfaces, (2) neglecting the convective mass transfer resistance at sorption surfaces if the sorption effect cannot be neglected, and (3) regarding the material-phase concentration in the source as constant. Several practical and quantifiable ways to improve chamber design are proposed. The approach is illustrated by analyzing available data from three different chambers in terms of the accuracy with which the model parameters can be determined and the time needed to conduct the chamber test. The results should greatly facilitate the design of chambers to characterize SVOC emissions and the resulting exposure.

Differentiated cells retain the genetic information of the donor but the extent to which phenotypic differences between donors or batches of differentiated cells are explained by variation introduced during the differentiation process is not fully understood. In this study, we evaluated four separate batches of commercially available neurons originating from the same iPSCs to investigate whether the differentiation process used in manufacturing iPSCs to neurons affected genome-wide gene expression and modified cytosines, or neuronal sensitivity to drugs. No significant changes in gene expression, as measured by RNA-Seq, or cytosine modification levels, as measured by the Illumina 450K arrays, were observed between batches relative to changes over time. As expected, neurotoxic chemotherapeutics affected neuronal outgrowth, but no inter-batch differences were observed in sensitivity to paclitaxel, vincristine and cisplatin. As a testament to the utility of the model for studies of neuropathy, we observed that genes involved in neuropathy had relatively higher expression levels in these samples across different time points. Our results suggest that the process used to differentiate iPSCs into neurons is consistent, resulting in minimal intra-individual variability across batches. Therefore, this model is reasonable for studies of human neuropathy, druggable targets to prevent neuropathy, and other neurological diseases.

Acute lung injury (ALI) is characterized by suppressed fibrinolytic activity in bronchoalveolar lavage fluid (BALF) attributed to elevated plasminogen activator inhibitor-1 (PAI-1). Restoring pulmonary fibrinolysis by delivering tissue-type plasminogen activator (tPA), urokinase plasminogen activator (uPA), and plasmin could be a promising approach.

Ionizing radiation often causes severe injuries to radiosensitive tissues, especially haematopoietic system. Novel radioprotective drugs with low toxicity and high effectiveness are required. Prolyl hydroxylases domain (PHD) inhibitors have been reported to protect against radiation-induced gastrointestinal toxicity. In this study, we demonstrated the protective effects of a PHD inhibitor, roxadustat (FG-4592), against radiation-induced haematopoietic injuries in vitro and in vivo.

CRL4, a well-defined E3 ligase, has been reported to be upregulated and is proposed to be a potential drug target in ovarian cancers. However, the biological functions of CRL4 and the underlying mechanism regulating cancer chemoresistance are still largely elusive. Here, we show that CRL4 is considerably increased in cisplatin-resistant ovarian cancer cells, and CRL4 knockdown with shRNAs is able to reverse cisplatin-resistance of ovarian cancer cells. Moreover, CRL4 knockdown markedly inhibits the expression of BIRC3, one of the inhibitors of apoptosis proteins (IAPs). Besides, lower expression level of BIRC3 is associated with better prognosis of ovarian cancer patients, and BIRC3 knockdown in ovarian cancer cells can recover their sensitivity to cisplatin. More importantly, we demonstrate that CRL4 regulates BIRC3 expression by mediating the STAT3, but not the PI3K pathway. Therefore, our results identified CRL4 as an important factor in ovarian cancer chemoresistance, suggesting that CRL4 and BIRC3 may serve as novel therapeutic targets for relapsed patients after treatment with cisplatin and its derivative to overcome the bottle neck of ovarian cancer chemoresistance.

Transmembrane protein with epidermal growth factor-like and two follistatin-like domains 1 (TMEFF1) has an anticarcinogenic effect in brain tumors. However, little is known about the role of TMEFF1 in epithelial ovarian cancer (EOC).

It proved that Zymosan-A protected the haematopoietic system from radiation-induced damage via Toll-Like Receptor2 in our previous study. In this study, we investigated the potential mechanism for the radioprotective effects of Zymosan-A. The mice were treated with Zymosan-A (50 mg/kg, dissolved in NS) via peritoneal injection 24 and 2 hours before ionizing radiation. Apoptosis of bone marrow cells and the levels of IL-6, IL-12, G-CSF and GM-CSF were evaluated by flow cytometry assay. DNA damage was determined by γ-H2AX foci assay. In addition, RNA sequencing was performed to identify differentially expressed genes (DEGs). Zymosan-A protected bone marrow cells from radiation-induced apoptosis, up-regulated IL-6, IL-12, G-CSF and GM-CSF in bone marrow cells. Zymosan-A also protected cells from radiation-induced DNA damage. Moreover, RNA sequencing analysis revealed that Zymosan-A induced 131 DEGs involved in the regulation of immune system process and inflammatory response. The DEGs were mainly clustered in 18 KEGG pathways which were also associated with immune system processes. Zymosan-A protected bone marrow cells from radiation-induced apoptosis and up-regulated IL-6, IL-12, G-CSF and GM-CSF. Moreover, Zymosan-A might also exhibit radioprotective effects through regulating immune system process and inflammatory response. These results provided new knowledge regarding the radioprotective effect of Zymosan-A.

MicroRNAs (miRNAs) are a key factor in epigenetic regulation of gene expression, but miRNA responses to fine particulate matter (PM2.5) air pollution and their potential contribution to cardiovascular effects of PM2.5 are unknown.

Radiation-induced lung injury (RILI) is one of the most common and fatal complications of thoracic radiotherapy. It is characterized with two main features including early radiation pneumonitis and fibrosis in later phase. This study was to investigate the potential radioprotective effects of polydatin (PD), which was shown to exert anti-inflammation and anti-oxidative capacities in other diseases. In this study, we demonstrated that PD-mitigated acute inflammation and late fibrosis caused by irradiation. PD treatment inhibited TGF-β1-Smad3 signalling pathway and epithelial-mesenchymal transition. Moreover, radiation-induced imbalance of Th1/Th2 was also alleviated by PD treatment. Besides its free radical scavenging capacity, PD induced a huge increase of Sirt3 in culture cells and lung tissues. The level of Nrf2 and PGC1α in lung tissues was also elevated. In conclusion, our data showed that PD attenuated radiation-induced lung injury through inhibiting epithelial-mesenchymal transition and increased the expression of Sirt3, suggesting PD as a novel potential radioprotector for RILI.

Ovarian cancer is one of the most deadly gynecological malignancies and inclined to recurrence and drug resistance. Previous studies showed that the tumorigenesis of ovarian cancers and their major histotypes are associated with genomic instability caused by defined sets of pathogenic mutations. In contrast, the mechanism that influences the development of drug resistance and disease recurrence is not well elucidated. Solid tumors are prone to chromosomal instability (CIN) and micronuclei formation (MN). Although MN is traditionally regarded as the outcome of genomic instability, recent investigation on its origin and final consequences reveal that the abnormal DNA metabolism in MN is a driver force for some types of catastrophic genomic rearrangements, accelerating dramatic genetic variation of cancer cells.

Information overload remains a challenge for patients seeking clinical trials. We present a novel system (DQueST) that reduces information overload for trial seekers using dynamic questionnaires.

A droplet impacting on inclined surfaces yields more complex outcomes than on normal impact and the effect of the inclining angle on the impact dynamics is still in controversy. Here, we show that a drop impacting on inclined superhydrophobic surfaces exhibits an asymmetric rebound with a distinctive spreading and retraction along the lateral and tangential directions. Meanwhile, there is an obvious contact time reduction with the increase of the inclining angle and impact velocity. We demonstrate that the contact time reduction is attributed to the asymmetric drop spreading and retraction, which endows a fast drop detachment. Simple analyses are presented to interpret this phenomenon, which is in a good agreement with the experimental results.

Many biological materials form via liquid-liquid phase separation (LLPS), followed by maturation into a solid-like state. Here, using a biologically inspired assembly mechanism designed to recapitulate these sequential assemblies, we develop ultrastrong underwater adhesives made from engineered proteins containing mammalian low-complexity (LC) domains. We show that LC domain-mediated LLPS and maturation substantially promotes the wetting, adsorption, priming, and formation of dense, uniform amyloid nanofiber coatings on diverse surfaces (e.g., Teflon), and even penetrating difficult-to-access locations such as the interiors of microfluidic devices. Notably, these coatings can be deposited on substrates over a broad range of pH values (3 to 11) and salt concentrations (up to 1 M NaCl) and exhibit strong underwater adhesion performance. Beyond demonstrating the utility of mammalian LC domains for driving LLPS in soft materials applications, our study illustrates a powerful example of how combining LLPS with subsequent maturation steps can be harnessed for engineering protein-based materials.

New technologies for imaging and analysis of morphological characters offer opportunities to enhance revisionary taxonomy and better integrate it with the rest of biology. In this study, we revise the Afrotropical fauna of the ant genus Zasphinctus Wheeler, and use high-resolution X-ray microtomography (micro-CT) to analyse a number of morphological characters of taxonomic and biological interest. We recognise and describe three new species: Z. obamaisp. n., Z. sarowiwaisp. n., and Z. wilsonisp. n. The species delimitations are based on the morphological examination of all physical specimens in combination with 3D scans and volume reconstructions. Based on this approach, we present a new taxonomic discrimination system for the regional fauna that consists of a combination of easily observable morphological characters visible at magnifications of around 80-100 ×, less observable characters that require higher magnifications, as well as characters made visible through virtual dissections that would otherwise require destructive treatment. Zasphinctus are rarely collected ants and the material available to us is comparatively scarce. Consequently, we explore the use of micro-CT as a non-invasive tool for the virtual examination, manipulation, and dissection of such rare material. Furthermore, we delineate the treated species by providing a diagnostic character matrix illustrated by numerous images and supplement that with additional evidence in the form of stacked montage images, 3D PDFs and 3D rotation videos of scans of major body parts and full body (in total we provide 16 stacked montage photographs, 116 images of 3D reconstructions, 15 3D rotation videos, and 13 3D PDFs). In addition to the comparative morphology analyses used for species delimitations, we also apply micro-CT data to examine certain traits, such as mouthparts, cuticle thickness, and thoracic and abdominal muscles in order to assess their taxonomic usefulness or gain insights into the natural history of the genus. The complete datasets comprising the raw micro-CT data, 3D PDFs, 3D rotation videos, still images of 3D models, and coloured montage photos have been made available online as cybertypes (Dryad, http://dx.doi.org/10.5061/dryad.4s3v1).