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Light adaptation enables the vertebrate visual system to operate over a wide range of ambient illumination. Regulation of phototransduction in photoreceptors is considered a major mechanism underlying light adaptation. However, various types of neurons and glial cells exist in the retina, and whether and how all retinal cells interact to adapt to light/dark conditions at the cellular and molecular levels requires systematic investigation. Therefore, we utilized single-cell RNA sequencing to dissect retinal cell-type-specific transcriptomes during light/dark adaptation in mice. The results demonstrated that, in addition to photoreceptors, other retinal cell types also showed dynamic molecular changes and specifically enriched signaling pathways under light/dark adaptation. Importantly, Müller glial cells (MGs) were identified as hub cells for intercellular interactions, displaying complex cell‒cell communication with other retinal cells. Furthermore, light increased the transcription of the deiodinase Dio2 in MGs, which converted thyroxine (T4) to active triiodothyronine (T3). Subsequently, light increased T3 levels and regulated mitochondrial respiration in retinal cells in response to light conditions. As cones specifically express the thyroid hormone receptor Thrb, they responded to the increase in T3 by adjusting light responsiveness. Loss of the expression of Dio2 specifically in MGs decreased the light responsive ability of cones. These results suggest that retinal cells display global transcriptional changes under light/dark adaptation and that MGs coordinate intercellular communication during light/dark adaptation via thyroid hormone signaling.

Retinitis pigmentosa (RP) is a form of inherited retinal degenerative diseases that ultimately involves the macula, which is present in primates but not in the rodents. Therefore, creating nonhuman primate (NHP) models of RP is of critical importance to study its mechanism of pathogenesis and to evaluate potential therapeutic options in the future. Here we applied adeno-associated virus (AAV)-delivered CRISPR/SaCas9 technology to knockout the RHO gene in the retinae of the adult rhesus macaque (Macaca mulatta) to investigate the hypothesis whether non-germline mutation of the RHO gene is sufficient to recapitulate RP. Through a series of studies, we were able to demonstrate successful somatic editing of the RHO gene and reduced RHO protein expression. More importantly, the mutant macaque retinae displayed clinical RP phenotypes, including photoreceptor degeneration, retinal thinning, abnormal rod subcellular structures, and reduced photoresponse. Therefore, we suggest somatic editing of the RHO gene is able to phenocopy RP, and the reduced time span in generating NHP mutant accelerates RP research and expands the utility of NHP model for human disease study.

Breast cancer is a common type of cancer in females. Our previous studies indicated that leucine aminopeptidase 3 (LAP3) promotes migration and invasion of breast cancer cells. Vimentin is a mesenchymal marker, and its upregulation represents the promotion of epithelial–mesenchymal transition. In this study, we found that LAP3 and vimentin were highly expressed in breast cancer tissues, and the overexpression of LAP3 in breast cancer cells promoted the expression of vimentin. Western blot analysis indicated that the overexpression of LAP3 upregulated the phosphorylation of Erk1/2. MEK inhibitor PD98059 downregulated the expression of vimentin, matrix metalloproteinase-2/9 (MMP-2/9), and fascin through the inhibition of Erk1/2 activity. We hypothesized that LAP3 promoted tumor migration and invasion by upregulating vimentin. The knockdown of vimentin resulted in the inhibited migration and invasion of MDA-MB-231 and MDA-MB-468 cells. The expression of MMP-2/9 and fascin could also be downregulated. In conclusion, vimentin might play an important role in the promotion of breast cancer metastasis by LAP3.

The chemoresistance of hepatocellular carcinoma (HCC) is a serious problem that directly hinders the effect of chemotherapeutic agents. We previously reported that Aminopeptidase N (CD13) inhibition can enhance the cytotoxic efficacy of chemotherapy agents. In the present study, we use liver cancer cells to explore the molecular mechanism accounting for the relationship between CD13 and chemoresistance. We demonstrate that CD13 overexpression activates the P38/heat shock protein 27/cAMP response element-binding protein (CREB) signaling pathway to limit the efficacy of cytotoxic agents. Moreover, blockade of P38 or CREB sensitizes HCC cells to 5-fluorouracil. Then we reveal that CREB binds to the autophagy related 7 (ATG7) promoter to induce autophagy and promote HCC cell chemoresistance. CD13 inhibition also downregulates the expression of ATG7, autophagy, and tumor cell growth in vivo. Overall, the combination a CD13 inhibitor and chemotherapeutic agents may be a potential strategy for overcoming drug resistance in HCC. SIGNIFICANCE STATEMENT: Our study demonstrates that Aminopeptidase N (CD13) promotes hepatocellular carcinoma (HCC) cell chemoresistance via the P38/heat shock protein 27/cAMP response element-binding protein (CREB) pathway. CREB regulates autophagy related 7 transcription and expression to induce autophagy. Our results collectively suggest that CD13 may serve as a potential target for overcoming HCC resistance.

Besides generating vision, light modulates various physiological functions, including mood. While light therapy applied in the daytime is known to have anti-depressive properties, excessive light exposure at night has been reportedly associated with depressive symptoms. The neural mechanisms underlying this day-night difference in the effects of light are unknown. Using a light-at-night (LAN) paradigm in mice, we showed that LAN induced depressive-like behaviors without disturbing the circadian rhythm. This effect was mediated by a neural pathway from retinal melanopsin-expressing ganglion cells to the dorsal perihabenular nucleus (dpHb) to the nucleus accumbens (NAc). Importantly, the dpHb was gated by the circadian rhythm, being more excitable at night than during the day. This indicates that the ipRGC→dpHb→NAc pathway preferentially conducts light signals at night, thereby mediating LAN-induced depressive-like behaviors. These findings may be relevant when considering the mental health effects of the prevalent nighttime illumination in the industrial world.

Real-time and high-efficient communication becomes a vital property for IoT-enabled equipment, since the application range of the Internet of Things has extended widely. At the same time, the centralized characterization of the cloud computing is gradually unable to meet the demand for both low latency and high computing efficiency. To resolve these issues, new computing paradigms have been introduced, such as edge, dew, and fog computing. Recently, Saurabh et al. introduced a mutual authentication protocol, which was claimed to resist various attacks without the requirement of a trusted server, for dew-assisted IoT devices. However, this paper will show that Saurabh et al.’s scheme lacks forward security and user anonymity. Then, a new authenticated key agreement (AKA) protocol, named e-SMDAS, will be put forward and formally proven secure under the eCK security model. Further, the analysis results of BAN logic and Scyther tool will also confirm the security of e-SMDAS. Finally, the comparative analysis of security features and computation efficiency between e-SMDAS and several recent schemes will be demonstrated at the end of this paper.

During development, melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) become light sensitive much earlier than rods and cones. IpRGCs project to many subcortical areas, whereas physiological functions of these projections are yet to be fully elucidated. Here, we found that ipRGC-mediated light sensation promotes synaptogenesis of pyramidal neurons in various cortices and the hippocampus. This phenomenon depends on activation of ipRGCs and is mediated by the release of oxytocin from the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) into cerebral-spinal fluid. We further characterized a direct connection between ipRGCs and oxytocin neurons in the SON and mutual projections between oxytocin neurons in the SON and PVN. Moreover, we showed that the lack of ipRGC-mediated, light-promoted early cortical synaptogenesis compromised learning ability in adult mice. Our results highlight the importance of light sensation early in life on the development of learning ability and therefore call attention to suitable light environment for infant care.

The human retina is a complex neural tissue that detects light and sends visual information to the brain. However, the molecular and cellular processes that underlie aging primate retina remain unclear. Here, we provide a comprehensive transcriptomic atlas based on 119,520 single cells of the foveal and peripheral retina of humans and macaques covering different ages. The molecular features of retinal cells differed between the two species, suggesting the distinct regional and species specializations of the human and macaque retinae. In addition, human retinal aging occurred in a region- and cell-type- specific manner. Aging of human retina exhibited a foveal to peripheral gradient. MYO9A− rods and a horizontal cell subtype were greatly reduced in aging retina, indicating their vulnerability to aging. Moreover, we generated a dataset showing the cell-type- and region- specific gene expression associated with 55 types of human retinal disease, which provides a foundation to understand the molecular and cellular mechanisms underlying human retinal diseases. Together, these datasets are valuable for understanding the molecular characteristics of primate retina, as well as the molecular regulation of aging progression and related diseases.

Retinitis pigmentosa (RP) is a form of inherited retinal degenerative disease that ultimately involves the macula, which is present in primates but not in the rodents. Therefore, creating nonhuman primate (NHP) models of RP is of critical importance to study its mechanism of pathogenesis and to evaluate potential therapeutic options in the future. Here we applied adeno-associated virus (AAV)-delivered CRISPR/SaCas9 technology to knockout the RHO gene in the retinae of the adult rhesus macaque (Macaca mulatta) to investigate the hypothesis whether non-germline mutation of the RHO gene is sufficient to recapitulate RP. Through a series of studies, we were able to demonstrate successful somatic editing of the RHO gene and reduced RHO protein expression. More importantly, the mutant macaque retinae displayed clinical RP phenotypes, including photoreceptor degeneration, retinal thinning, abnormal rod subcellular structures, and reduced photoresponse. Therefore, we suggest somatic editing of the RHO gene is able to phenocopy RP, and the reduced time span in generating NHP mutant accelerates RP research and expands the utility of NHP model for human disease study.

The human retina is a complex neural tissue that detects light and sends visual information to the brain. However, the molecular and cellular processes that underlie aging primate retina remain unclear. Here, we provide a comprehensive transcriptomic atlas based on 119,520 single cells of the foveal and peripheral retina of humans and macaques covering different ages. The molecular features of retinal cells differed between the two species, suggesting the distinct regional and species specializations of the human and macaque retinae. In addition, human retinal aging occurred in a region- and cell-type- specific manner. Aging of human retina exhibited a foveal to peripheral gradient. MYO9A− rods and a horizontal cell subtype were greatly reduced in aging retina, indicating their vulnerability to aging. Moreover, we generated a dataset showing the cell-type- and region- specific gene expression associated with 55 types of human retinal disease, which provides a foundation to understand the molecular and cellular mechanisms underlying human retinal diseases. Together, these datasets are valuable for understanding the molecular characteristics of primate retina, as well as the molecular regulation of aging progression and related diseases.

Heterogeneous phase interface with particular microstructure generally plays a key role in the mechanical behavior of nanostructured metals and alloys. Here, we reported a novel high-entropy phase interface with extraordinary property that is strongly dependent on the lattice mismatch and length scale in dual-phase high entropy alloys (DP-HEAs) multilayers. A disorder intermediate layer, fcc-to-amorphous and bcc-to amorphous transition sequentially take place in incoherent fcc/bcc DP-HEAs with decreasing layer thickness (h) owing to the mixture of multiple elements with different atomic radius at interface, producing the evolution from fcc/bcc interface to bcc/amorphous and then amorphous/amorphous interface. Therefrom, yield strength of fcc/bcc DP-HEAs reaches the maximum of 5.6 GPa at h = 10 nm, which is the highest reported strength of the metallic multilayers. However, the superior combination with high strength and uniform plastic strain is achieved through at h > 20 nm. The dominant deformation mechanism crossover from homogeneous co-deformation via interaction of dislocation with interface to catastrophic shear and multiple shear process, leading to the highest strength and good plasticity. This result implies that interfacial character could be accurately manipulated through mediating the interface atomic radius misfit, mixing enthalpy and intrinsic length scale, achieving strong and plastic DP-HEAs.

MnOx/Fe2O3/polypyrrole nanotubes have been fabricated by a facile method, which involves a hydrothermal method, chemical solution route, annealing process and a subsequent chemical polymerization method. Electrochemical measurement shows that MnOx/Fe2O3/polypyrrole nanotubes display excellent electrochemical properties. A reversible specific capacity of 1060 mA h g−1 is achieved after 100 cycles at the current density of 200 mA g−1. Even at higher current density of 5000 mA g−1, the specific capacity of the electrode can be kept at 630 mA h g−1. The excellent electrochemical performances are ascribed to the synergetic effect of different components and the conductive polypyrrole layer.

Perception of light not only results in image vision, but also modulates a number of biological functions that do not involve image formation, such as pupil light reflex and photoentrainment of circadian rhythm. Such non-image-forming vision is primarily mediated by a subset of retinal ganglion cells, termed as intrinsically photosensitive retinal ganglion cells (ipRGCs), which express the photopigment melanopsin thereby exhibiting intrinsic photosensitivity. Since the groundbreaking discovery of ipRGCs approximately two decades ago, ample evidence suggests that ipRGCs project to various subcortical nuclei, and probably participate in a wider range of physiological processes than initially known. This article reviews important laboratory and clinical evidence and recent progress regarding phototransduction of ipRGCs and brain circuitry in non-image vision.

In this study, we report that the NiFe 2 O 4 /C hollow spheres composed of mesoporous nanospheres have been fabricated through hydrothermal method, calcination treatment and subsequently carbon-coated process. The obtained composite possesses a high surface area (236.44 m 2 g −1 ) and mesopores (2.3 nm), which can efficiently increase the contact area for electrode/electrolyte and buffer the volume change during electrochemical cycling. Combining with the synergistic effect of NiO, Fe 2 O 3 and carbon, the NiFe 2 O 4 /C electrode displays superior electrochemical properties in terms of high reversible capacity, good cycle stability, and excellent rate performance. A specific capacity as high as 1266 mAh g −1 can be obtained after 100 cycles at the current density of 0.2 A g −1 . Even at high current rate of 10 A g −1 , the reversible capacity still remains at 633.3 mAh g −1 after 250 cycles. Therefore, the mesoporous NiFe 2 O 4 /C electrode material may be a promising anode in lithium-ion battery applications.

The mesoporous MnCo2O4/polypyrrole (PPy) composites have been successfully fabricated through three facile steps, solvothermal synthesis, calcination treatment and subsequent in-situ chemical polymerization. The mesoporous MnCo2O4/PPy displays good electrochemical performance in terms of high reversible capacity, good rate performance, and excellent stability. The high discharge capacity of 910 mAh g−1 is achieved after 100 cycles at the current density of 200 mA g−1. The reversible capacity still remains as high as 598 mAh g−1 at the higher current density of 2000 mA g−1. The improved electrochemical performance is mainly attributed to the mesoporous structure and the coating layer of PPy, which effectively mitigate the volume change and enable good conductivity and thus enhance fast charge transfer.

An HDR-based Cas9/RecA system was developed to precisely correct the Pde6b mutation in rods of rd1 mice to restore their vision., Although Cas9-mediated genome editing has been widely used to engineer alleles in animal models of human inherited diseases, very few homology-directed repair (HDR)–based genetic editing systems have been established in postnatal mouse models for effective and lasting phenotypic rescue. Here, we developed an HDR-based Cas9/RecA system to precisely correct Pde6b mutation with increased HDR efficiency in postnatal rodless (rd1) mice, a retinitis pigmentosa (RP) mutant model characterized by photoreceptor degeneration and loss of vision. The Cas9/RecA system incorporated Cas9 endonuclease enzyme to generate double-strand breaks (DSBs) and bacterial recombinase A (RecA) to increase homologous recombination. Our data revealed that Cas9/RecA treatment significantly promoted the survival of both rod and cone photoreceptors, restored the expression of PDE6B in rod photoreceptors, and enhanced the visual functions of rd1 mice. Thus, this study provides a precise therapeutic strategy for RP and other genetic diseases.

Summary Mammals cannot see light over 700 nm in wavelength. This limitation is due to the physical thermodynamic properties of the photon-detecting opsins. However, the detection of naturally invisible near-infrared (NIR) light is a desirable ability. To break this limitation, we developed ocular injectable photoreceptor-binding upconversion nanoparticles (pbUCNPs). These nanoparticles anchored on retinal photoreceptors as miniature NIR light transducers to create NIR light image vision with negligible side effects. Based on single-photoreceptor recordings, electroretinograms, cortical recordings, and visual behavioral tests, we demonstrated that mice with these nanoantennae could not only perceive NIR light, but also see NIR light patterns. Excitingly, the injected mice were also able to differentiate sophisticated NIR shape patterns. Moreover, the NIR light pattern vision was ambient-daylight compatible and existed in parallel with native daylight vision. This new method will provide unmatched opportunities for a wide variety of emerging bio-integrated nanodevice designs and applications. Video Abstract

Some supersymmetric models predict long lived charged sleptons. If they are exist, the τ ˜ , the supersymmetry partner of τ lepton, could be produced inside the earth by collisions of high energy neutrinos with nucleons. The possible signals of upgoing τ ˜ have been studied in various ways. Taking the atmospheric neutrino flux into account, the muon flux as main background is also estimated. By using the Waxman-Bahcall limit on the extraterrestrial neutrino flux, the resultant spectra show that there are about 70 events per year passing a km-scale underground experiment, such as ICECUBE.

The paper shows good agreement between the atmospheric muon spectra measured by L3+C and the COMUGEN Monte-Carlo model. The atmospheric neutrino spectrum is inferred.

We calculate numerically the hydrodynamic evolution of a gamma-ray burst fireball. The results show that refluence will emerge during fireball expansion due to negative-pressure effect. The refluence will collide with outward fluid, then shock wave will form. Electrons moving between the inward and outward fluid shells can be accelerated to 10(4)- 10(5) MeV by one order Femi-type acceleration with high efficiency after several collisions. Radiation of electrons with such high energy may be the observed gamma-ray bursts.

In this paper we discuss the problems contained in the solution to the equations of quasi 3-D accretion disk model, and point out that the angular momentum equation should not be integrated directly. Finally, we develop a criterion of the existence of a disconnected solution to this model.

[1] We analyzed observation data collected by the Instrument for the Detection of Particles (IDP) on board the DEMETER satellite during a period of 17 months in 2007 and 2008. In the meantime, the VLF transmitter located at North West Cape (NWC) ground station was shut down during 7 months and working for a total of 10 months. By an (on-off) method, our analysis for the first time revealed in detail the transient properties of the space electron precipitation belt which is induced by the man-made VLF wave emitted from NWC. We mapped the electron flux distribution and figured out the space regions that the NWC belt covered. The NWC electron spectrograms have been investigated in a wide range of the McIlwain parameter L (1.1–3.0). Furthermore, we obtained the averaged energy spectra of the NWC electrons within the drift loss cone and compared their characteristics during daytime and nighttime. Our results confirm the previous studies of the enhancement of NWC electrons, the wisp structure, and the day/night difference of the electron flux. In addition, more detailed information is provided. We provide not only evidence of a momentary flux enhancement up to 3 orders of magnitude but also a flux reduction at higher L shells with a maximum up to 60% of the original value. For the first time, the energy spectra of NWC electrons covering the entire IDP energy band are presented for both nighttime and daytime and are quantitatively compared. At the end, our results are discussed, and their agreement with the theory of wave-particle interactions is checked.

The complexity of Web services composition process is intuitively relevant to the effects such as readability, testability, reliability, and maintainability. Analyzing the complexity at all stages of process design and development helps avoid the drawbacks associated with high-complexity processes. In this paper, we present a control-flow complexity measure of the structured process of Web service composition. The measure is defined based on a data structure named Structure Tree. By the complexity computing algorithm based on Structure Tree, we can get complexity of a process and its substructures simultaneously. The characteristics of different structure types and the nesting level are taken into consideration in the complexity measure. Since Weyuker’s properties are a widely known formal analytical approach of complexity metric, we evaluate our measure in terms of these properties in order to guarantee its effectiveness.