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The Integrator is a multi-subunit protein complex that catalyzes the maturation of snRNA transcripts via 3' cleavage, a step required for snRNA incorporation with snRNP for spliceosome biogenesis. Here we developed a GFP based in vivo snRNA misprocessing reporter as a readout of Integrator function and performed a genome-wide RNAi screen for Integrator regulators. We found that loss of the Argonaute encoding csr-1 gene resulted in widespread 3' misprocessing of snRNA transcripts that is accompanied by a significant increase in alternative splicing. Loss of the csr-1 gene down-regulates the germline expression of Integrator subunits 4 and 6 and is accompanied by a reduced protein translation efficiency of multiple Integrator catalytic and non-catalytic subunits. Through isoform and motif mutant analysis, we determined that CSR-1's effect on snRNA processing is dependent on its catalytic slicer activity but does not involve the CSR-1a isoform. Moreover, mRNA-sequencing revealed high similarity in the transcriptome profile between csr-1 and Integrator subunit knockdown via RNAi. Together, our findings reveal CSR-1 as a new regulator of the Integrator complex and implicate a novel role of this Argonaute protein in snRNA 3' processing.

Ethyl carbamate is a common contaminant prevalent in fermented food with probable carcinogenic effects in animals. To date, other toxicological properties of ethyl carbamate are not well characterized. Using the genetic model Caenorhabditis elegans, we found that chronic exposure to ethyl carbamate during larval development impedes growth while exposure during adulthood inhibits reproduction, shortens lifespan, and promotes degeneration to dopaminergic neurons. Through whole-transcriptome RNA-sequencing, we found that ethyl carbamate invokes a widespread transcriptomic response inducing the differential expression of > 4,000 genes by at least 2-fold. Functional analysis of RNA-sequencing data revealed that up-regulated genes enrich to various neuron regulatory processes and xenobiotic defense. Gene expression analysis confirms that various genes encoding antioxidant enzymes and those functioning within phase I and II detoxification responses along with ABC transporters are highly up-regulated after ethyl carbamate exposure, suggesting the onset of oxidative stress. Overall, these findings report new toxicological properties of chronic ethyl carbamate exposure and provide new insights on its effects on transcriptome regulation in the C. elegans model.

Abstract The myodural bridge (MDB) connects the suboccipital musculature to the spinal dura mater (SDM) as it passed through the posterior atlanto-occipital and the atlanto-axial interspaces. Although the actual function of the MDB is not understood at this time, it has recently been proposed that head movement may assist in powering the movement of cerebrospinal fluid (CSF) via muscular tension transmitted to the SDM via the MDB. But there is little information about it. The present study utilized dogs as the experimental model to explore the MDB’s effects on the CSF pressure (CSFP) during stimulated contractions of the suboccipital muscles as well as during manipulated movements of the atlanto-occiptal and atlanto-axial joints. The morphology of MDB was investigated by gross anatomic dissection and by histological observation utilizing both light microscopy and scanning electron microscopy. Additionally biomechanical tensile strength tests were conducted. Functionally, the CSFP was analyzed during passive head movements and electrical stimulation of the suboccipital muscles, respectively. The MDB was observed passing through both the dorsal atlanto-occipital and the atlanto-axial interspaces of the canine and consisted of collagenous fibers. The tensile strength of the collagenous fibers passing through the dorsal atlanto-occipital and atlanto-axial interspaces were 0.16 ± 0.04 MPa and 0.82 ± 0.57 MPa, respectively. Passive head movement, including lateral flexion, rotation, as well as flexion–extension, all significantly increased CSFP. Furthermore, the CSFP was significantly raised from 12.41 ± 4.58 to 13.45 ± 5.16 mmHg when the obliques capitis inferior (OCI) muscles of the examined specimens were electrically stimulated. This stimulatory effect was completely eliminated by severing the myodural bridge attachments to the OCI muscle. Head movements appeared to be an important factor affecting CSF pressure, with the MDB of the suboccipital muscles playing a key role this process. The present study provides direct evidence to support the hypothesis that the MDB may be a previously unappreciated significant power source (pump) for CSF circulation.

Aim: Magnetic hydrogels (MHGs) have been proposed to avoid the redistribution and loss of magnetic nanoparticles (MNPs) when administrated by intratumoral injection. However, the requirement of complex cooling systems and temperature monitoring systems still hinder the clinical application of MHGs. This study investigates the feasibility of developing an MHG to realize the self-regulation of hyperthermia temperature. Methods: The MHG was developed by dispersing the MNPs with self-regulating temperature property into the temperature-sensitive hydrogel through physical crosslinking. The MHG's gelation temperature was tested by measuring the storage modulus and loss modulus on a rotational rheometer. The biocompatibility of the MHG and MNPs was characterized by CCK-8 assay against HaCaT cells. The in vivo magnetic heating property was examined through monitoring the temperature in the MHG on mice back upon the application of the alternating magnetic field (400 ± 5 Oe, 100 ± 5 kHz) every week for successive six weeks. Results: The gelation temperature of the MHG falls in 28.4°C-37.4°C. At in vivo applied concentration of 80 mg/mL, the MHG exhibits over 80% cell viability after 72 h, significantly higher than 50% cell viability of the MNPs (p

Compared with liquid organic lithium-ion batteries, solid-state lithium-ion batteries have higher safety performance, so they are expected to become the next generation of energy storage devices and have attracted extensive research attention. The thermal management of the battery is a multi-coupling problem. Battery safety, cycle life, and even electrochemical reactions are all related to it. This Perspective presents the commonly used solid-state electrolytes and recent studies on their thermal stability and thermal transport properties. The thermal decomposition temperature and thermal conductivity are summarized, and we also present the summary and a brief outlook. This Perspective provides a reference for how to design and select high thermal conductive electrolyte materials, which is important for further advancement of solid-state lithium-ion batteries.

Abstract Background Adaptive responses to stress are essential for cell and organismal survival. In metazoans, little is known about the impact of environmental stress on RNA homeostasis. Results By studying the regulation of a cadmium-induced gene named numr-1 in Caenorhabditis elegans, we discovered that disruption of RNA processing acts as a signal for environmental stress. We find that NUMR-1 contains motifs common to RNA splicing factors and influences RNA splicing in vivo. A genome-wide screen reveals that numr-1 is strongly and specifically induced by silencing of genes that function in basal RNA metabolism including subunits of the metazoan integrator complex. Human integrator processes snRNAs for functioning with splicing factors, and we find that silencing of C. elegans integrator subunits disrupts snRNA processing, causes aberrant pre-mRNA splicing, and induces the heat shock response. Cadmium, which also strongly induces numr-1, has similar effects on RNA and the heat shock response. Lastly, we find that heat shock factor-1 is required for full numr-1 induction by cadmium. Conclusion Our results are consistent with a model in which disruption of integrator processing of RNA acts as a molecular damage signal initiating an adaptive stress response mediated by heat shock factor-1. When numr-1 is induced via this pathway in C. elegans, its function in RNA metabolism may allow it to mitigate further damage and thereby promote tolerance to cadmium.

The magnetic nanoparticles (MNPs) with decreasing heating efficiency (characterized by specific loss power, SLP) with temperature increase, especially around the Curie temperature (TC), are expected to realize the self-regulated temperature hyperthermia of the tumor. However, the actual decrease of the SLP is gradual, resulting in the deviation of self-regulated temperatures from the measured TC. So far, no method is available for evaluating the heating performances of those MNPs. Here, by simulating the temperature-dependent SLP, the heating performances of MNPs are evaluated from three clinically concerning aspects: the capacity for effective heating, the temperature uniformity in the tumor, and the temperature stability under environmental changes such as MNP loss or tumor progression. The developed methods were applied to ZnCoCrFeO, Fe3O4, and γ-Fe2O3 MNPs. It was found that the uniform temperature distribution relies on lowering the heating power in the inner regions of the tumor, and the stable control of temperature depends on the dynamic adaptation of the heating power to the tumor temperature change. The proposed method may be used to predict the heating ability of MNPs and help the selection of MNPs for hyperthermia.

Head injury has become a threat to human life in transportation accidents, construction. and sports. However, woodpeckers can avoid injuring their brain during high velocity and frequency pecking. To reveal the underlying secret, the pecking process of woodpeckers is simulated and compared with that of chickens and pigeons to study the stress wave propagation in their head. The pecking data of live chickens and pigeons are simultaneously obtained from the force sensor and the high-speed video system. The morphological information of the three birds’ heads is also investigated using Micro Computed Tomography (Micro-CT) scanning. The results show that the woodpecker has the highest skull volume fraction and beak length fraction, which could potentially increase its head structural strength and provide more space to dissipate impact stress. The finite element head models of the woodpecker, chicken, and pigeon are established based on the micro-CT images and performed pecking process simulations. The simulated results suggest that the stress wave propagates through both the upper-beak and lower-beak of the woodpecker to ensure the enough structural strength in order to overcome the fierce impact. On the other hand, the structural strength requirement of the chicken and pigeon is not as high as the woodpecker due to their lower pecking intensity. Setting the stouter lower-beak of the chicken and the pigeon as the primary wave propagation path not only ensures their head safety but also avoids direct impact to their brain. The biomechanical design of the bird’s heads, setting a special propagation path for the stress wave, may inspire new approaches to improve and design impact resistance equipment.

This article contains experimental data on the strain sweep, the calibration curve of drug (doxorubicin, DOX) and the characterizations of materials. Data included are related to the research article “Injectable and body temperature sensitive hydrogels based on chitosan and hyaluronic acid for pH sensitive drug release” (Zhang et al., 2017) [1]. The strain sweep experiments were performed on a rotational rheometer. The calibration curves were obtained by analyzing the absorbance of DOX solutions on a UV–vis-NIR spectrometer. Molecular weight (Mw) of the hyaluronic acid (HA) and chitosan (CS) were determined by gel permeation chromatography (GPC). The deacetylation degree of CS was measured by acid base titration.

The mechanistic target of rapamycin (mTOR) is a central regulator of cellular homeostasis that integrates environmental and nutrient signals to control cell growth and survival. Over the past two decades, extensive studies of mTOR have implicated the importance of this protein complex in regulating a broad range of metabolic functions, as well as its role in the progression of various human diseases. Recently, mTOR has emerged as a key signaling molecule in regulating animal entry into a hypometabolic state as a survival strategy in response to environmental stress. Here, we review current knowledge of the role that mTOR plays in contributing to natural hypometabolic states such as hibernation, estivation, hypoxia/anoxia tolerance, and dauer diapause. Studies across a diverse range of animal species reveal that mTOR exhibits unique regulatory patterns in an environmental stressor-dependent manner. We discuss how key signaling proteins within the mTOR signaling pathways are regulated in different animal models of stress, and describe how each of these regulations uniquely contribute to promoting animal survival in a hypometabolic state.

Posttranscriptional splicing of premessenger RNA (mRNA) is an evolutionarily conserved eukaryotic process for producing mature mRNA that is translated into proteins. Accurate splicing is necessary for normal growth and development, and aberrant splicing is increasingly evident in various human pathologies. To study environmental factors that influence RNA splicing, we employed a fluorescent Caenorhabditis elegans in vivo splicing reporter as a biomarker for splicing fidelity to screen against the US EPA ToxCast chemical library. We identified pararosaniline hydrochloride as a strong modifier of RNA splicing. Through gene expression analysis, we found that pararosaniline activates the oxidative stress response and alters the expression of key RNA splicing regulator genes. Physiological assays show that pararosaniline is deleterious to C. elegans development, reproduction, and aging. Through a targeted RNAi screen, we found that inhibiting protein translation can reverse pararosaniline's effect on the splicing reporter and provide significant protection against long-term pararosaniline toxicity. Together, this study reveals a new chemical modifier of RNA splicing and describes translation inhibition as a genetic mechanism to provide resistance. [ABSTRACT FROM AUTHOR]