Nanoscale control of non-reciprocal ripple writing.

Femtosecond laser-induced deep-subwavelength structures have attracted much attention as a nanoscale surface texturization technique. A better understanding of the formation conditions and period control is required. Herein, we report a method of non-reciprocal writing via a tailored optical far-field exposure, where the period of ripples varies along different scanning directions, and achieve a continuous manipulation of the period from 47 to 112 nm (±4 nm) for a 100-nm-thick indium tin oxide (ITO) on glass. A full electromagnetic model was developed to demonstrate the redistributed localized near-field at different stages of ablation with nanoscale precision. It explains the formation of ripples and the asymmetry of the focal spot determines the non-reciprocity of ripple writing. Combined with beam shaping techniques, we achieved non-reciprocal writing (regarding scanning direction) using an aperture-shaped beam. The non-reciprocal writing is expected to open new paths for precise and controllable nanoscale surface texturing.

Optical near fields for ablation of periodic structures.

The formation mechanism of laser-induced periodic surface structures (LIPSS) has been a key to high-resolution sub-diffraction lithography or high-efficiency large-area nanotexturing. We show the evolution of LIPSS formation from a nanohole seed structure to high-spatial-frequency LIPSS by using a tightly focused and rectangular-shaped laser beam with different shape-polarization orientations. Formation of LIPSS based on light intensity distribution without invoking any long-range electromagnetic modes achieved quantitative match between modeling and experiment. Our results clearly show the entire step-like and deterministic process of LIPSS evolution based on experimental data and numerical simulations, revealing the dominant structural near-field enhancement on the ripple formation. A rectangular-shaped beam with an aspect ratio of 7:3 was used to break the symmetry of a circularly shaped focus. By azimuthally rotating the orientation of the focal spot and the polarization, it is possible to visualize the far-field effect for the initial seed structure formation and the competition between the far and near fields in the subsequent structure evolution.

Cerebral cortical networking for mental workload assessment under various demands during dual-task walking.

While several studies have examined attentional reserve (via event-related potentials) and mental effort (via EEG spectral content) from various cortical regions during dual-task walking, none have assessed changes in the magnitude of interregional (cortico-cortical) communication as a measure of mental workload. Therefore, by deploying a traditional montage of electrode sites centered over the motor planning region as well as a more comprehensive graph theory-based approach encompassing the entire scalp, this study aimed to systematically examine changes in the magnitude of functional connectivity underlying cortico-cortical communication to assess changes in mental workload under various levels of challenge. Specifically, the Weighted Phase Lag Index (WPLI) was computed to assess the changes in magnitude of functional connectivity as participants performed a cognitive task under two demands (low and high) and two conditions (seated and walking). The results revealed enhanced fronto-centro-temporo-parietal theta connectivity during dual-task walking relative to being seated as well as a reduced inhibition of fronto-centro-temporo-parieto-occipital alpha networking as the demand on the secondary cognitive task increased. Collectively, these findings may reflect greater recruitment of task relevant processes to respond to increased cognitive-motor demands and thus an elevation of mental workload in an effort to maintain performance under varying levels of challenge. This work has the potential to inform future mental workload assessment applications in patient populations, including those who employ prostheses during cognitive-motor performance under various task demands.

Drug resistance mechanism and reversal strategy in lung cancer immunotherapy.

Among all malignant tumors, lung cancer has the highest mortality and morbidity rates. The non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are the most common histological subtypes. Although there are a number of internationally recognized lung cancer therapy regimens, their therapeutic effects remain inadequate. The outlook for individuals with lung carcinoma has ameliorated partly thanks to the intensive study of the tumor microenvironment and immune checkpoint inhibitors. Numerous cancers have been effectively treated with immunotherapy, which has had positive therapeutic results. Global clinical trials have validated that PD-1/PD-L1 inhibitors are effective and safe for treating lung cancer either independently or in combination, and they are gradually being recommended as systemic treatment medications by numerous guidelines. However, the immunotherapy resistance restricts the immunotherapy efficacy due to the formation of tumor immunosuppressive microenvironment and tumor mutations, and immunotherapy is only effective for a small percentage of lung cancer patients. To summarize, while tumor immunotherapy is benefiting an increasing number of lung cancer patients, most of them still develop natural or acquired resistance during immunotherapy. Consequently, a crucial and urgent topic is understanding and tackling drug resistance triggered by immunotherapy in lung cancer treatment. This review will outline the presently recognized mechanisms of immunotherapy resistance and reversal strategies in lung cancer.

Multiscale Visual-Attribute Co-Attention for Zero-Shot Image Recognition.

Zero-shot image recognition aims to classify data from unseen classes, by exploring the association between visual features and the semantic representations of each class. Most existing approaches focus on learning a shared single-scale embedding space (often at the output layer of the network) for both visual and semantic features, ignoring a fact that different-scale visual features exhibit different semantics. In this article, we propose a multi-scale visual-attribute co-attention (mVACA) model, considering both visual-semantic alignment and visual discrimination at multiple scales. At each scale, a hybrid visual attention is realized by attribute-related attention and visual self-attention. The attribute-related attention is guided by a pseudo attribute vector inferred via a mutual information regularization (MIR). The visual self-attentive features further influence the attribute attention to emphasize visual-associated attributes. Leveraging multiscale visual discrimination, mVACA unifies standard zero-shot learning (ZSL) and generalized ZSL tasks in one framework, achieving state-of-the-art or competitive performance on several commonly used benchmarks of both setups. To better understand the interaction between images and attributes in mVACA, we also provide visualized analysis.

Nanoscale Printing of Indium-Tin-Oxide by Femtosecond Laser Pulses.

For constructing optical and electrical micro-devices, the deposition/printing of materials with sub-1 µm precision and size (cross-section) is required. Crystalline c-ITO (indium tin oxide) nanostructures were patterned on glass with sufficient precision to form 20-50 nm gaps between individual disks or lines of ∼250 nm diameter or width. The absorbed energy density [J/cm3] followed a second-order dependence on pulse energy. This facilitated high-resolution and precise nanoscale laser-writing at a laser wavelength of 515 nm. Patterns for optical elements such as circular gratings and micro-disks were laser-printed using ITO as a resist. Unexposed amorphous a-ITO was chemically removed in aqueous 1% vol. HF solution. This use of a-ITO as a solid resist holds promise for metamaterial and micro-optical applications.

Highly Deformable High-Performance Paper-Based Perovskite Photodetector with Improved Stability.

Paper-based photodetectors have attracted extensive research interest owing to their environmentally friendly and highly deformable properties. Although perovskite crystals with outstanding optoelectronic properties have proved to be one of the most promising candidates for photodetectors, the development of paper-based photodetectors is hindered by the moisture absorptivity of paper and the instability of perovskite crystals in a humid atmosphere. In this study, we demonstrate a highly deformable and high-performance paper-based perovskite photodetector. The photodetector maintains its excellent performance even after exposure to a relative humidity of 60% for 120 h.

Perovskite Single-Crystal Microwire-Array Photodetectors with Performance Stability beyond 1 Year.

Compared with thin-film morphology, 1D perovskite structures such as micro/nanowires with fewer grain boundaries and lower defect density are very suitable for high-performance photodetectors with higher stability. Although the stability of perovskite microwire-based photodetectors has been substantially enhanced in comparison with that of photodetectors based on thin-film morphology, practical applications require further improvements to the stability before implementation. In this study, a template-assisted method is developed to prepare methylammonium lead bromide (MAPbBr3 ) micro/nanowire structures, which are encapsulated in situ by a protective hydrophobic molecular layer. The combination of the protective layer, high crystalline quality, and highly ordered microstructures significantly improve the stability of the MAPbBr3 single-crystal microwire arrays. Consequently, these MAPbBr3 single-crystal microwire-array-based photodetectors exhibit significant long-term stability, maintaining 96% of the initial photocurrent after 1 year without further encapsulation. The lifetime of such photodetectors is hence approximately four times longer than that of the most stable previously reported perovskite micro/nanowire-based photodetector; this is thought to be the most stable perovskite photodetector reported thus far. Furthermore, this work should contribute further toward the realization of perovskite 1D structures with long-term stability.

Template-confined growth of Ruddlesden-Popper perovskite micro-wire arrays for stable polarized photodetectors.

The detection of the polarization states of light is of great significance for the analysis of biological tissue morphologies, image display systems and sensors. Although organic-inorganic hybrid perovskite crystals have excellent photoelectric properties, which make them very suitable for the preparation of photodetectors, their applications in polarized light detection are hindered by their isotropy and instability. Here, we solved this problem by fabricating a stable 2D layered Ruddlesden-Popper perovskite into anisotropic micro-wire arrays with a template-confined method. Based on this anisotropic structure, a high-performance photodetector with a dark current as low as 10-12 A, high responsivity of 3.5 A W-1, detectivity exceeding 1 × 1015 Jones and a fast response with a rise time of 4.1 ms and a decay time of 3.3 ms was achieved and successfully applied for high-performance polarization detection. More importantly, the device maintained a superior performance even after being exposed to an environment of 60% relative humidity without encapsulation.

Mechanism of Stiff Substrates up-Regulate Cultured Neuronal Network Activity.

Our previous work provided compelling evidence showing that substrate stiffness is crucial for regulating synaptic connectivity and excitatory synaptic transmission among neurons in the neuronal network. However, the underlying mechanisms remain elusive. In our study, polydimethylsiloxane (PDMS) substrates with different stiffness have been fabricated to investigate the mechanisms by which the substrate stiffness upregulates the formation and activity of the cultured neuronal network. Here we report that stiff substrate increased both the number of synapses and the efficacy of excitatory synaptic transmission. More colocalization of synaptotagmin and PSD-95 was observed in the neuronal network on stiff substrate, which indicated the synapse number has increased. We also found that the increased synapse number was mediated by Hevin and SPARC that are secreted from astrocyte. The increased efficacy of excitatory synaptic transmission induced by stiff substrate was explored in three aspects. First, stiff substrate enhanced the presynaptic activity through increasing the vesicular release probability (Pr) of neurotransmitters as well as the calcium influx. Second, stiff substrate reduced voltage-dependent Mg2+ blockade to N-methyl-d-aspartate receptor (NMDAR) channels, which led to higher postsynaptic activity. Third, our work suggested that the increased excitatory synaptic transmission in the neural network on stiff substrate involved the upregulated synaptic glutamate concentration. Taken together, these findings may provide a molecular mechanism underlying substrate stiffness regulation of excitatory synaptic transmission in the cultured neural network.

Gold nanoparticle densely packed micro/nanowire-based pressure sensors for human motion monitoring and physiological signal detection.

Flexible pressure sensors have gained ever-increasing attention because of their widespread applications in wearable devices. The sensor fabrication technologies reported so far are generally complicated, limiting their industrial applications. It is therefore of great importance to develop a simple method to fabricate high-performance flexible pressure sensors. Herein, we report an approach of assembling gold nanoparticles into strictly aligned and densely stacked micro/nanowires by imprinting for flexible pressure sensors with high performance. By our method, the whole assembly process takes only 1 min. The pressure sensor exhibits a best detection limit as low as 25 Pa. The sensors could be attached to any part of the human body and are so sensitive that even pulses in different regions of the body and the differences between a pregnant woman and a nonpregnant woman could be distinguished.

The Saffold Virus-Penang 2B and 3C Proteins, but not the L Protein, Induce Apoptosis in HEp-2 and Vero Cells.

Our previous work has shown that Saffold virus (SAFV) induced several rodent and primate cell lines to undergo apoptosis (Xu et al. in Emerg Microb Infect 3:1-8, 2014), but the essential viral proteins of SAFV involved in apoptotic activity lack study. In this study, we individually transfected the viral proteins of SAFV into HEp-2 and Vero cells to assess their ability to induce apoptosis, and found that the 2B and 3C proteins are proapoptotic. Further investigation indicated the transmembrane domain of the 2B protein is essential for the apoptotic activity and tetramer formation of the 2B protein. Our research provides clues for the possible mechanisms of apoptosis induced by SAFV in different cell lines. It also opens up new directions to study viral proteins (the 2B, 3C protein), and sets the stage for future exploration of any possible link between SAFV, inclusive of its related uncultivable genotypes, and multiple sclerosis.

The Pathogenesis of Saffold Virus in AG129 Mice and the Effects of Its Truncated L Protein in the Central Nervous System.

Saffold Virus (SAFV) is a human cardiovirus that has been suggested to cause severe infection of the central nervous system (CNS). Compared to a similar virus, Theiler's murine encephalomyelitis virus (TMEV), SAFV has a truncated Leader (L) protein, a protein essential in the establishment of persistent CNS infections. In this study, we generated a chimeric SAFV by replacing the L protein of SAFV with that of TMEV. We then compared the replication in cell cultures and pathogenesis in a mouse model. We showed that both SAFV and chimeric SAFV are able to infect Vero and Neuro2a cells well, but only chimeric SAFV was able to infect RAW264.7. We then showed that mice lacking IFN-α/ß and IFN-γ receptors provide a good animal model for SAFV infection, and further identified the locality of the infection to the ventral horn of the spine and several locations in the brain. Lastly, we showed that neither SAFV nor chimeric SAFV causes persistence in this model. Overall, our results provide a strong basis on which the mechanisms underlying Saffold virus induced neuropathogenesis can be further studied and, hence, facilitating new information about its pathogenesis.

Cooperative effect of the VP1 amino acids 98E, 145A and 169F in the productive infection of mouse cell lines by enterovirus 71 (BS strain).

Enterovirus 71 (EV71) is a neurotrophic virus that causes hand, foot and mouth disease (HFMD) and occasional neurological infection among children. It infects primate cells but not rodent cells, primarily due to the incompatibility between the virus and the expressed form of its receptor, scavenger receptor class B member 2 (SCARB2) protein, on rodent cells (mSCARB2). We previously generated adapted strains (EV71:TLLm and EV71:TLLmv) that were shown to productively infect primate and rodent cell lines and whose genomes exhibited a multitude of non-synonymous mutations compared with the EV71:BS parental virus. In this study, we aimed to identify mutations that are necessary for productive infection of murine cells by EV71:BS. Using reverse genetics and site-directed mutagenesis, we constructed EV71 infectious clones with specific mutations that generated amino acid substitutions in the capsid VP1 and VP2 proteins. We subsequently assessed the infection induced by clone-derived viruses (CDVs) in mouse embryonic fibroblast NIH/3T3 and murine neuroblastoma Neuro-2a cell lines. We found that the CDV:BS-VP1(K98E,E145A,L169F) with three substitutions in the VP1 protein-K98E, E145A and L169F-productively infected both mouse cell lines for at least three passages of the virus in murine cells. Moreover, the virus gained the ability to utilize the mSCARB2 protein to infect murine cell lines. These results demonstrate that the three VP1 residues cooperate to effectively interact with the mSCARB2 protein on murine cells and permit the virus to infect murine cells. Gain-of-function studies similar to the present work provide valuable insight into the mutational trajectory required for EV71 to infect new host cells previously non-susceptible to infection.

Intracellular localization of Saffold virus Leader (L) protein differs in Vero and HEp-2 cells.

The Saffold virus (SAFV) genome is translated as a single long polyprotein precursor and co-translationally cleaved to yield 12 separate viral proteins. Little is known about the activities of SAFV proteins although their homologs in other picornaviruses have already been described. To further support research on functions and activities of respective viral proteins, we investigated the spatio-temporal distribution of SAFV proteins in Vero and HEp-2 cells that had been either transfected with plasmids that express individual viral proteins or infected with live SAFV. Our results revealed that, with the exception of the Leader (L) protein, all viral proteins were localized in the cytoplasm at all the time points assayed. The L protein was found in the cytoplasm at an early time point but was subsequently translocated to the nucleus of HEp-2, but not Vero, cells. This was observed in both transfected and infected cells. Further mutational analysis of L protein revealed that Threonine 58 of the Ser/Thr-rich domain of L protein is crucial for protein trafficking between the cytoplasm and nucleus in HEp-2 cells. These findings contribute to a deeper understanding and stimulate investigation of the differetial cellular responses of HEp-2 cells in comparison to other mammalian cell lines during SAFV infection.

A clinically authentic mouse model of enterovirus 71 (EV-A71)-induced neurogenic pulmonary oedema.

Enterovirus 71 (EV-A71) is a neurotropic virus that sporadically causes fatal neurologic illness among infected children. Animal models of EV-A71 infection exist, but they do not recapitulate in animals the spectrum of disease and pathology observed in fatal human cases. Specifically, neurogenic pulmonary oedema (NPE)-the main cause of EV-A71 infection-related mortality-is not observed in any of these models. This limits their utility in understanding viral pathogenesis of neurologic infections. We report the development of a mouse model of EV-A71 infection displaying NPE in severely affected animals. We inoculated one-week-old BALB/c mice with an adapted EV-A71 strain and identified clinical signs consistent with observations in human cases and other animal models. We also observed respiratory distress in some mice. At necropsy, we found their lungs to be heavier and incompletely collapsed compared to other mice. Serum levels of catecholamines and histopathology of lung and brain tissues of these mice strongly indicated onset of NPE. The localization of virally-induced brain lesions also suggested a potential pathogenic mechanism for EV-A71-induced NPE. This novel mouse model of virally-induced NPE represents a valuable resource for studying viral mechanisms of neuro-pathogenesis and pre-clinical testing of potential therapeutics and prophylactics against EV-A71-related neurologic complications.

Saffold virus is able to productively infect primate and rodent cell lines and induces apoptosis in these cells.

Saffold virus (SAFV), a newly discovered human cardiovirus of the Picornaviridae family, causes widespread infection among children, as shown by previous seroprevalence studies. To determine the host cell range of SAFV and its cytopathogenicity, eight mammalian cell lines that were available in the laboratory were screened for productive SAFV infection by a laboratory-adapted SAFV of genotype 3. Five of the cell lines (Neuro2A, CHO-K1, NIH/3T3, Vero and HEp-2) were found to be permissible. The time required for SAFV to induce complete lysis as a cytopathic effect (CPE) in these permissibly infected cells and the resultant end point virus titer differed for each cell type. HEp-2 exhibited the shortest time frame to reach full CPE compared to the others. All infected cell lines produced a high virus titer at 72 h post-infection. In addition to causing lytic cell death, SAFV also induced apoptotic cell death in host cells through both extrinsic and intrinsic pathways, although the apoptotic events in HEp-2 cells appeared to have been blocked between the early and late stages. In conclusion, laboratory-adapted SAFV is able to productively infect a number of mammalian cell lines and induce apoptosis in the infected host cells. However, apoptosis in HEp-2 cells is blocked before the end stage.

Phenotypic and genotypic characteristics of novel mouse cell line (NIH/3T3)-adapted human enterovirus 71 strains (EV71:TLLm and EV71:TLLmv).

Since its identification in 1969, Enterovirus 71 (EV71) has been causing periodic outbreaks of infection in children worldwide and most prominently in the Asia-Pacific Region. Understanding the pathogenesis of Enterovirus 71 (EV71) is hampered by the virus's inability to infect small animals and replicate in their derived in vitro cultured cells. This manuscript describes the phenotypic and genotypic characteristics of two selected EV71 strains (EV71:TLLm and EV71:TLLmv), which have been adapted to replicate in mouse-derived NIH/3T3 cells, in contrast to the original parental virus which is only able to replicate in primate cell lines. The EV71:TLLm strain exhibited productive infection in all primate and rodent cell lines tested, while EV71:TLLmv exhibited greater preference for mouse cell lines. EV71:TLLmv displayed higher degree of adaptation and temperature adaptability in NIH/3T3 cells than in Vero cells, suggesting much higher fitness in NIH/3T3 cells. In comparison with the parental EV71:BS strain, the adapted strains accumulated multiple adaptive mutations in the genome resulting in amino acid substitutions, most notably in the capsid-encoding region (P1) and viral RNA-dependent RNA polymerase (3D). Two mutations, E167D and L169F, were mapped to the VP1 canyon that binds the SCARB2 receptor on host cells. Another two mutations, S135T and K140I, were located in the VP2 neutralization epitope spanning amino acids 136-150. This is the first report of human EV71 with the ability to productively infect rodent cell lines in vitro.

[Analysis of 61 cases undergoing sphincter-preserving procedure with intersphincteric resection by telescopic anastomosis for ultra-low rectal cancer].

OBJECTIVE: To investigate the efficacy and safety of sphincter-preserving procedure with transabdominal intersphincteric resection for ultra-low rectal cancer. METHODS: Clinical data of 61 cases with ultra-low rectal cancer (distance from anal verge ranged from 4-5 cm) were analyzed retrospectively. The patients underwent sphincter-preserving procedure with intersphincteric resection and telescopic anastomosis. RESULTS: There were 34 males and 27 females. The mean age was 56.7 years. The inferior border of the tumor was 4 cm above the anal verge in 21 cases, and 5 cm in 40 cases. There 55 patients with rectal adenocarcinoma in this cohort. The tumor was well-differentiated in 24 cases, moderately-differentiated in 29 cases, and poorly-differentiated in 2 cases. There were 6 cases with malignant adenoma. The TNM staging was T1N0M0 in 36 cases, T2N0M0 in 23, and T3N1M0 in 2. The ability to control defecation significantly improved in 1-3 months postoperatively, and returned to normal in 6-12 months. Two patients developed anastomotic leak (3.3%), and 3 anastomotic stenosis (4.9%) postoperatively. Fifty-four patients(88.5%) had follow-up. The median follow-up time was 6.2 years. The local recurrence rate was 5.6%, and the 5-year-survival rate was 73.5%. CONCLUSION: Sphincter-preserving procedure with intersphincteric resection and telescopic anastomosis is a safe and effective procedure for ultra-low rectal cancer.