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Oncolytic virotherapy can lead to systemic antitumor immunity, but the therapeutic potential of oncolytic viruses in humans is limited due to their insufficient ability to overcome the immunosuppressive tumor microenvironment (TME). Here, we showed that locoregional oncolytic virotherapy upregulated the expression of PD-L1 in the TME, which was mediated by virus-induced type I and type II IFNs. To explore PD-1/PD-L1 signaling as a direct target in tumor tissue, we developed a novel immunotherapeutic herpes simplex virus (HSV), OVH-aMPD-1, that expressed a single-chain variable fragment (scFv) against PD-1 (aMPD-1 scFv). The virus was designed to locally deliver aMPD-1 scFv in the TME to achieve enhanced antitumor effects. This virus effectively modified the TME by releasing damage-associated molecular patterns, promoting antigen cross-presentation by dendritic cells, and enhancing the infiltration of activated T cells; these alterations resulted in antitumor T-cell activity that led to reduced tumor burdens in a liver cancer model. Compared with OVH, OVH-aMPD-1 promoted the infiltration of myeloid-derived suppressor cells (MDSC), resulting in significantly higher percentages of CD155+ granulocytic-MDSCs (G-MDSC) and monocytic-MDSCs (M-MDSC) in tumors. In combination with TIGIT blockade, this virus enhanced tumor-specific immune responses in mice with implanted subcutaneous tumors or invasive tumors. These findings highlighted that intratumoral immunomodulation with an OV expressing aMPD-1 scFv could be an effective stand-alone strategy to treat cancers or drive maximal efficacy of a combination therapy with other immune checkpoint inhibitors.

Resource scarcity challenges individuals’ willingness to share limited resources with other people. Still, lots of field studies and laboratory experiments have shown that sharing behaviors do not disappear under scarcity. Rather, some individuals are willing to share their scarce resources with others in a similar way as when the resource is abundant, which is crucial for the maintenance and development of human society. Here, we designed a novel paradigm in which subjects decided whether (and how much) to share an amount of “relieving resources” for counteracting unpleasant noises, which mimics real-life situations that people cost their own resources to help others escape from adversity. Overall, the robustness of resource sharing under scarcity was positively correlated with individual level of the cognitive component of empathy across two independent experiments. Resource insufficiency modulated the activations of several brain regions (including the TPJ, mPFC, and PCC) as well as the functional connection (from the rTPJ to the mPFC) within the mentalizing brain network, but the modulatory effect decreased as a function of cognitive empathy. We also applied the administration of oxytocin and found significant effects on sharing behavior among individuals with a higher level of cognitive empathy, but not their low-level counterparts. These findings highlight the importance of empathy to resource sharing under scarcity and explain the underlying neurobiological mechanisms.

People as third-party observers, without direct self-interest, may punish norm violators to maintain social norms. However, third-party judgment and the follow-up punishment might be susceptible to the way we frame (i.e., verbally describe) a norm violation. We conducted a behavioral and a neuroimaging experiment to investigate the above phenomenon, which we call the “third-party framing effect”. In these experiments, participants observed an anonymous perpetrator deciding whether to keep her/his economic benefit while exposing a victim to a risk of physical pain (described as “harming others” in one condition and “not helping others” in the other condition), then they had a chance to punish that perpetrator at their own cost. Our results showed that the participants were more willing to execute third-party punishment under the harm frame compared to the help frame, manifesting a framing effect. Self-reported anger toward perpetrators mediated the relationship between empathy toward victims and the framing effect. Meanwhile, activation of the insula mediated the relationship between mid-cingulate cortex activation and the framing effect; the functional connectivity between these regions significantly predicted the size of the framing effect. These findings shed light on the psychological and neural mechanisms of the third-party framing effect.

Saline-sodic soil is one of the major threats to crop growth, production, and quality. Biochar amendment could alleviate the adverse impacts of saline-sodic stress in crops. However, the effect of biochar on root morphological, root physiological functions, and rice yield in saline-sodic paddy soil has not been studied. Here, the underlying mechanisms of positive effects in morphological characteristics and physiological functions of rice roots under heavily saline-sodic paddy soil amended with biochar were evaluated. The soil was amended with biochar at zero-biochar (CK), 15g kg-1 soil (T1), 30 g kg-1 soil (T2), or 45 g kg-1 soil (T3). Biochar addition significantly increased root length, root volume, root dry weight, and root-shoot ratio at all growth stages. The root absorption vigor and root oxidization capacity were enhanced and increased significantly by decreasing Na+/K+ ratio, MDA content, and increasing K+ concentration in rice root after biochar amendment. The root bleeding rate of biochar treatments at different growth stage were 11.01% to 67.73% greater than these of CK. The yield of rice was increased significantly under saline-sodic paddy soil after biochar amendment. It was concluded that biochar had positive effect on the morphological characteristics and physiological functions in rice roots in saline-sodic paddy soil.

Forecasting multiple-step value-at-risk (VaR) consistently across asset classes is hindered by the limited sample size of low-frequency returns and the potential model misspecification when assuming identical return distributions over different holding periods. This paper hence investigates the predictive power for multi-step VaR of a framework that models separately the volatility component and the error term of the return distribution. The proposed model is illustrated with ten asset returns series including global stock markets, commodity futures, and currency exchange products. The estimation results confirm that the volatility-filter residuals demonstrate distinguished tail dynamics to that of the return series. The estimation results suggest that volatility-filtered residuals may have either negative or positive tail dependence, unlike the unanimous negative tail dependence in the return series. By comparing the proposed model to several alternative approaches, the results from both the formal and informal tests show that the specification under concern performs equivalently well if not better than its top competitors at the 2.5% and 5% risk level in terms of accuracy and validity. The proposed model also generates more consistent VaR forecasts under both the 5-step and 10-step setup than the MIDAS-Q model. AcknowledgmentThe authors are grateful to the editor and an anonymous referee. This research is sponsored by the National Natural Science Foundation of China (Award Number: 71501117). All remaining errors are our own.

Oncolytic virotherapy can lead to systemic antitumor immunity, but the therapeutic potential of oncolytic viruses in humans is limited due to their insufficient ability to overcome the immunosuppressive tumor microenvironment (TME). Here, we showed that locoregional oncolytic virotherapy upregulated the expression of PD-L1 in the TME, which was mediated by virus-induced type I and type II IFNs. To explore PD-1/PD-L1 signaling as a direct target in tumor tissue, we developed a novel immunotherapeutic herpes simplex virus (HSV), OVH-aMPD-1, that expressed a single-chain variable fragment (scFv) against PD-1 (aMPD-1 scFv). The virus was designed to locally deliver aMPD-1 scFv in the TME to achieve enhanced antitumor effects. This virus effectively modified the TME by releasing damage-associated molecular patterns, promoting antigen cross-presentation by dendritic cells, and enhancing the infiltration of activated T cells; these alterations resulted in antitumor T-cell activity that led to reduced tumor burdens in a liver cancer model. Compared with OVH, OVH-aMPD-1 promoted the infiltration of myeloid-derived suppressor cells (MDSC), resulting in significantly higher percentages of CD155+ granulocytic-MDSCs (G-MDSC) and monocytic-MDSCs (M-MDSC) in tumors. In combination with TIGIT blockade, this virus enhanced tumor-specific immune responses in mice with implanted subcutaneous tumors or invasive tumors. These findings highlighted that intratumoral immunomodulation with an OV expressing aMPD-1 scFv could be an effective stand-alone strategy to treat cancers or drive maximal efficacy of a combination therapy with other immune checkpoint inhibitors.

Infections caused by herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) remain a serious global health issue, and the medical countermeasures available thus far are limited. Virus-neutralizing monoclonal antibodies (NAbs) are crucial tools for studying host-virus interactions and designing effective vaccines, and the discovery and development of these NAbs could be one approach to treat or prevent HSV infection. Here, we report the isolation of five HSV NAbs from mice immunized with both HSV-1 and HSV-2. Among these were two antibodies that potently cross-neutralized both HSV-1 and HSV-2 with the 50% virus-inhibitory concentrations (IC

Previous behavioral studies have shown that sharing painful experiences can strengthen social bonds and promote mutual prosociality, yet the neural mechanisms underlying this phenomenon remain unclear. We hypothesized that sharing a painful experience induces brain-to-brain synchronization and mutual empathy for each other's pain between pain-takers and pain-observers, which then leads to enhanced social bonding. To test this hypothesis, we adopted an electroencephalographic (EEG) hyper-scanning technique to assess neuronal and behavioral activity during a Pain-Sharing task in which high- or low-intensity pain stimulation was randomly delivered to one participant of a dyad on different experimental trials. Single-brain analysis showed that sensorimotor α-oscillation power was suppressed more when expecting high-intensity pain than when expecting low-intensity pain similarly for self-directed or partner-directed pain. Dual-brain analysis revealed that expecting high-intensity pain induced greater brain-to-brain synchronization of sensorimotor α-oscillation phases between pain-takers and pain-observers than did expecting low-intensity pain. Mediation analysis further revealed that brain-to-brain synchronization of sensorimotor α-oscillations mediated the effects of pain-stimulation intensity on mutual affective sharing for partner-directed pain. This mutual affective empathy during the task predicted the social bonding, as indexed by prosocial inclinations measured after the task. These results support the hypothesis that sharing a painful experience triggers emotional resonance between pairs of individuals through brain-to-brain synchronization of neuronal α-oscillations recorded over the sensorimotor cortex, and this emotional resonance further strengthens social bonds and motivates prosocial behavior within pairs of individuals.

Here we report a simple and low-cost colorimetric assay for ultrasensitive detection of copper (II) ions (Cu2+) based on pH-dependent formation of plasmonic MoO3-x nanosheets. The reaction between ascorbic acid (AA) and Cu2+ gives birth to hydrogen ions, which remarkably promotes the reduction of MoO3 nanosheets by AA to form oxygen vacancies-rich MoO3-x nanosheets that increase the free carrier concentration, generating a strong local surface plasmon resonance (LSPR) absorption. The Cu2+-triggered LSPR is utilized for development of the colorimetric assay. Under the optimal experimental conditions, this colorimetric assay can be used for selective detection of Cu2+, and the limit of detection is 0.8 nM, which is lower than that of most of the reported methods. Additionally, the present colorimetric assay has also been successfully employed for Cu2+ determination in real serum and human hair samples with satisfactory recoveries ranging from 96% to 108%.

Predictability has been suggested to modulate both the anticipation and perception of self-pain. Considering the overlapping neural circuits between self-pain and other-pain perceptions, the present study investigated how the predictability of forthcoming pain modulates the anticipation and perception of self-pain and other-pain. We used a balanced, within-participant experimental design in which a visual cue indicating the recipient, intensity and predictability of an upcoming painful electrical stimulation was presented before its delivery. Subjective ratings and electroencephalography activities to the anticipation and perception of self-pain and other-pain were recorded and compared between certain and uncertain conditions. Results showed that predictability affected the perception of self-pain and other-pain in a similar manner such that the differences in behavioral ratings and event-related potentials to high-intensity and low-intensity pain were significantly reduced when the intensity was uncertain. The strengths of predictability-induced modulation of self-pain and other-pain perceptions were positively correlated with each other. Furthermore, predictability also modulated the anticipation of both self-pain and other-pain such that pre-stimulus high-frequency α-oscillation power at sensorimotor electrodes contralateral to the stimulation side was maximally suppressed when anticipating certain high-intensity pain. These findings demonstrate that predictability-induced modulation on pain anticipation and perception was similarly applied to both self-pain and other-pain.

BackgroundOncolytic viruses (OVs) are capable to inflame the tumor microenvironment (TME) and elicit infiltrating tumor-specific T cell responses. However, OV treatment negatively alters the cancer-immune set point in tumors to attenuate the antitumor immune response, which suggests the necessity of dissecting the immune landscape of the virus-treated tumors and developing novel strategies to maximize the potential of OVs. The aim of this study is to investigate the effect of the single-chain variable fragment (scFv)-armed OVs targeting PD-1 on the TME, and ultimately overcome localized immunosuppression to sensitize tumors to immunotherapies.MethodsA tumor-selective oncolytic herpes simplex virus vector was engineered to encode a humanized scFv against human PD-1 (hPD-1scFv) (YST-OVH). The antitumor efficacy of YST-OVH was explored in multiple therapeutic mouse models. The neurotoxicity and safety of YST-OVH were evaluated in nonhuman primates. The precise dynamics in the TME involved in YST-OVH treatment were dissected using cytometry by time-of-flight (CyTOF).ResultsThe identified hPD-1scFv showed superior T-cell activating activity. Localized delivery of hPD-1scFv by YST-OVH promotes systemic antitumor immunity in humanized PD-1 mouse models of established cancer. Immune profiling of tumors using CyTOF revealed the enhanced antitumor effect of YST-OVH, which largely relied on CD8+T cell activity by augmenting the tumor infiltration of effector CD8+T cells and establishment of memory CD8+T cells and reducing associated CD8+T cell exhaustion. Furthermore, YST-OVH treatment modified the cancer-immune set point of tumors coupled to coexpression of CTLA-4 and TIM-3 on exhausted CD8+T cells and high levels of CTLA-4+Treg cells. A combination approach incorporating anti-CTLA-4 or anti-TIM-3 further improved efficacy by increasing tumor immunogenicity and activating antitumor adaptive immune responses. Moreover, this therapeutic strategy showed no neurotoxicity and was well tolerated in nonhuman primates. The benefit of intratumoral hPD-1scFv expression was also observed in humanized mice bearing human cancer cells.ConclusionLocalized delivery of PD-1 inhibitors by engineered YST-OVH was a highly effective and safe strategy for cancer immunotherapy. YST-OVH also synergized with CTLA-4 or TIM-3 blockade to enhance the immune response to cancer. These data provide a strong rationale for further clinical evaluation of this novel therapeutic approach.

Land resources can accommodate extra floodwaters, thus playing an important role in integrated flood risk management (FRM). However, potential conflicts emerge as the lands that are used as temporal room for floodwaters are also home to human beings, which is common in the flood detention zones (FDZs) in China. To date, little is known about how Chinese policies address the conflicts and how local stakeholders perceive the policies. This paper aims to address this research gap using a case study of the FDZs in the middle Huaihe River, China. A mixed method is applied including an official document survey, a multi-layer interview (15 respondents), and questionnaires (123 respondents). We find that three major strategies are employed to enhance the flood detention function and reduce flood risk inside the FDZs: 1) returning parts of the FDZs to rivers; 2) flood-adaptive farming; and 3) reducing population density via a massive relocation. However, the local residents have a low engagement willingness, which are associated with a poor perception of the policies and a lack of short-term economic attractiveness. Policy delivery gaps thus exist. Information sharing should be enhanced to encourage public participation. A public-private partnership involving more social and financial resources, particularly including the downstream beneficiaries, could help to increase the policy’s economic feasibility. The findings can enrich a policy shift toward a more land-based FRM, particularly in developing countries.

People as third-party observers, without direct self-interest, may punish norm violators to maintain social norms. However, third-party judgment and the follow-up punishment might be susceptible to the way we frame (i.e., verbally describe) a norm violation. We conducted a behavioral and a neuroimaging experiment to investigate the above phenomenon, which we call “third-party framing effect.” In these experiments, participants observed an anonymous player A decided whether to retain her/his economic benefit while exposing player B to a risk of physical pain (described as “harming others” in one condition and “not helping others” in the other condition), then they had a chance to punish player A at their own cost. Participants were more willing to execute third-party punishment under the harm frame compared to the help frame, manifesting as a framing effect. Self-reported moral outrage toward player A mediated the relationship between empathy toward player B and the framing effect size. Correspondingly, the insula (possibly related to empathy) and cerebellum (possibly related to anger) were activated more strongly under the harm frame than the help frame. Functional connectivity between these regions showed strongest weight when predicting the framing effect size. These findings shed light on the psychological and neural mechanisms of the third-party framing effect.Graphic abstract

The present study combined a novel hypothetical investment game with functional magnetic resonance imaging systemtically examined how morality modulates economic decision making in decision phase and outcome phase. We manipulated the morality of the investments by choosing each investment project based on subjective ratings on their moral valence and social benefits. There were three categories of investment morality: Green (moral), Red (immoral), and Neutral. The behavioral and neural responses during the investment decision and outcome phases were recorded and compared. Results showed that: behaviorally, people are willing to invest a larger amount of money into a moral project that may benefit society than they are into an immoral project that they think will harm society. They also rate gains in moral investments as more pleasant and losses as the most unpleasant. In the brain, we found that the reward system, especially the bilateral striatum, was involved in modulating functional connectivity during both phases, but in different ways. During decision making, the functional connectivity between fusiform gyrus and striatum might underlie the observed investing bias (Green over Red projects), while the covariation of BOLD signals in bilateral striatum with the behavioral tendency might explain the effect observed during the outcome evaluations. Our study provides evidence that morality modulates both the decision making and the outcome evaluation in economic situations.

In this paper, we discuss side-channel attacks on the CRT-RSA scheme (RSA scheme with Chinese Remainder Theorem) implemented by the left-to-right sliding window method. This method calculates exponentiations by repeating squaring and multiplication. In CHES 2017, Bernstein et al. proposed side-channel attacks on the CRT-RSA signature scheme implemented by the left-to-right sliding window method. We can obtain square-and-multiply sequences by their side-channel attacks, but cannot calculate CRT-RSA secret keys because there are multiple candidates of multiplications. Then, Bernstein et al. calculated CRT-RSA secret keys by using two methods. First, they recovered CRT-RSA secret keys partially and calculated all secret key bits by using the Heninger–Shacham method. Second, they applied the Heninger–Shacham method to square-and-multiply sequences directly. They showed that we can calculate CRT-RSA secret keys more efficiently when we use square-and-multiply sequences directly. They also showed that we can recover CRT-RSA secret keys in polynomial time when \(w \le 4\). Moreover, they experimentally showed that we can recover secret keys of 2048-bit CRT-RSA scheme when \(w=5\). However, their latter method is simple and has room for improvement. Here, we study bit recovery more profoundly to improve their method. First, we calculate the exact rate of all knowable bits. Next, we propose a new method for calculating the proportion of each bit 0 or 1 in each nonrecovery bit. Finally, we propose a new method for calculating CRT-RSA secret key using this bit information. In our proposed algorithm, we extend Bernstein et al.’s method in combination with Kunihiro et al.’s method. We calculate more secret keys when \(w=5\) by our proposed method compared to Bernstein et al.’s method.

Oncolytic viruses represent a promising therapeutic modality, but they have yet to live up to their therapeutic potential. Safety and efficacy concerns impel us to identify least toxic oncolytic agents that would generate durable and multifaceted anti-tumor immune responses to disrupt the tumors. Here we describe a rational engineered oncolytic herpes virus (OVH) that is a selective killer for targeting tumors, has strong safety records, induces complete regression of tumors in multiple tumor models, and elicits potent antitumor immunity. By far, the potential of OVs in promoting the tumor antigen-specific humoral immune responses remains obscure. In this study, we found that effective treatment by OVH induced immunogenic cell death, which facilitates to elicit humoral immune responses. Depletion experiments revealed that B cells were required for maximal antitumor efficacy of oncolytic immunotherapy. Both serum transfer and antibody treatment experiments revealed that endogenous oncolysis-induced antigen-targeting therapeutic antibodies can lead to systemic tumor regression. Our data demonstrate that tumor-targeting immune modulatory properties confer oncolytic OVH virotherapy as potent immunotherapeutic cancer vaccines that can generate specific and efficacious antitumor humoral responses by eliciting endogenous tumor antigen-targeting therapeutic antibodies in situ, resulting in an efficacious and tumor-specific therapeutic effect.

“Snow lotus” is a famous Chinese Materia Medica derived from species of the genus Saussurea (Compositae). To differentiate three representative easily-confused snow lotus herbs, namely, Saussurea involucrata (Kar. et Kir.) Sch.-Bip, Saussurea laniceps Hand.-Mazz., and Saussurea medusa Maxim., macroscopic features of the three herbs were systemically observed, and microscopic features were compared by using ordinary light microscopy, polarized light microscopy and scanning electron microscopy (SEM). The results indicate that, as for macroscopic identification, capitula situation and arrangement, and as for microscopic identification, pollen grains, nonglandular hairs, glandular hairs, and cells of inner surface of the microdiodange can be used to authenticate the three snow lotus herbs. Comprehensive table comparing the characteristics were presented in this study. SEM has been found to provide a number of unique characteristics of pollen grains. Based on the observation of pollen grains, evolution sequence of the three species was speculated. The present method was proven to be efficient, convenient, simple, and reliable, which was successfully applied to the authentication of three snow lotus herbs. Microsc. Res. Tech.1 77:631–641, 2014. © 2014 Wiley Periodicals, Inc.

"Snow lotus" is a famous Chinese Materia Medica derived from species of the genus Saussurea (Compositae). To differentiate three representative easily-confused snow lotus herbs, namely, Saussurea involucrata (Kar. et Kir.) Sch.-Bip, Saussurea laniceps Hand.-Mazz., and Saussurea medusa Maxim., macroscopic features of the three herbs were systemically observed, and microscopic features were compared by using ordinary light microscopy, polarized light microscopy and scanning electron microscopy (SEM). The results indicate that, as for macroscopic identification, capitula situation and arrangement, and as for microscopic identification, pollen grains, nonglandular hairs, glandular hairs, and cells of inner surface of the microdiodange can be used to authenticate the three snow lotus herbs. Comprehensive table comparing the characteristics were presented in this study. SEM has been found to provide a number of unique characteristics of pollen grains. Based on the observation of pollen grains, evolution sequence of the three species was speculated. The present method was proven to be efficient, convenient, simple, and reliable, which was successfully applied to the authentication of three snow lotus herbs.