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N 6 -methyladenosine (m 6 A) is the most abundant epigenetic modification of RNA, and its dysregulation drives aberrant transcription and translation programs that promote cancer occurrence and progression. Although defective gene regulation resulting from m 6 A often affects oncogenic and tumor-suppressing networks, m 6 A can also modulate tumor immunogenicity and immune cells involved in anti-tumor responses. Understanding this counterintuitive concept can aid the design of new drugs that target m 6 A to potentially improve the outcomes of cancer immunotherapies. Here, we provide an up-to-date and comprehensive overview of how m 6 A modifications intrinsically affect immune cells and how alterations in tumor cell m 6 A modifications extrinsically affect immune cell responses in the tumor microenvironment (TME). We also review strategies for modulating endogenous anti-tumor immunity and discuss the challenge of reshaping the TME. Strategies include: combining specific and efficient inhibitors against m 6 A regulators with immune checkpoint blockers; generating an effective programmable m 6 A gene-editing system that enables efficient manipulation of individual m 6 A sites; establishing an effective m 6 A modification system to enhance anti-tumor immune responses in T cells or natural killer cells; and using nanoparticles that specifically target tumor-associated macrophages (TAMs) to deliver messenger RNA or small interfering RNA of m 6 A-related molecules that repolarize TAMs, enabling them to remodel the TME. The goal of this review is to help the field understand how m 6 A modifications intrinsically and extrinsically shape immune responses in the TME so that better cancer immunotherapy can be designed and developed.

Dysregulation of the Notch signaling pathway, which is highly conserved across species, can drive aberrant epigenetic modification, transcription, and translation. Defective gene regulation caused by dysregulated Notch signaling often affects networks controlling oncogenesis and tumor progression. Meanwhile, Notch signaling can modulate immune cells involved in anti- or pro-tumor responses and tumor immunogenicity. A comprehensive understanding of these processes can help with designing new drugs that target Notch signaling, thereby enhancing the effects of cancer immunotherapy. Here, we provide an up-to-date and comprehensive overview of how Notch signaling intrinsically regulates immune cells and how alterations in Notch signaling in tumor cells or stromal cells extrinsically regulate immune responses in the tumor microenvironment (TME). We also discuss the potential role of Notch signaling in tumor immunity mediated by gut microbiota. Finally, we propose strategies for targeting Notch signaling in cancer immunotherapy. These include oncolytic virotherapy combined with inhibition of Notch signaling, nanoparticles (NPs) loaded with Notch signaling regulators to specifically target tumor-associated macrophages (TAMs) to repolarize their functions and remodel the TME, combining specific and efficient inhibitors or activators of Notch signaling with immune checkpoint blockers (ICBs) for synergistic anti-tumor therapy, and implementing a customized and effective synNotch circuit system to enhance safety of chimeric antigen receptor (CAR) immune cells. Collectively, this review aims to summarize how Notch signaling intrinsically and extrinsically shapes immune responses to improve immunotherapy.

Purpose To explore the worldwide, regional, and country-specific burden of early-onset colorectal cancer (EO-CRC) and identify its associated risk factors between 1990 and 2021, and to project its incidence and mortality rates for 2036. Methods We acquired data on EO-CRC categorized by gender, socio-demographic index (SDI), and risk factors based on the Global Burden of Disease (GBD) Study 2021. Joinpoint regression analysis was utilized to explore the variation in disease burden. The autoregressive integrated moving average (ARIMA) model was performed to forecast the disease burden up to 2036. Results Globally, the incidence rate, prevalence rate, mortality rate, and disability-adjusted life years (DALYs) rate of EO-CRC were estimated at 5.37 (95%UI: 4.91 to 5.86)/100,000, 34 (95%UI: 30.96 to 37.35)/100,000, 2.01 (95%UI: 1.84 to 2.19)/100,000, and 101.37 (95%: 92.85 to 110.18)/100,000 in 2021. The prevalence and incidence rates of EO-CRC showed an ascending trajectory, whilst the DALYs and mortality rates demonstrated a downward trajectory between 1990 to 2021. The high-middle SDI regions and East Asia exhibited the highest EO-CRC burden among the five SDI regions and 21 GBD regions respectively. A low-whole-grains diet was the chief risk factor contributing to EO-CRC. It was predicted that the age-standardized rate (ASR) of EO-CRC incidence would increase by 5.56%, while the ASR of mortality would decrease by 13.9% globally until 2036. Conclusion The current and future global burden of EO-CRC is heavy and varies significantly across different regions and countries.

Online product reviews may be subject to self-selection biases that impact consumer purchase behavior, online ratings' time series, and consumer surplus. This occurs if early buyers hold different preferences than do later consumers about the quality of a given product. Readers of early product reviews may not successfully correct for these preference differences when interpreting ratings and making purchases. In this study, we develop a model that examines how idiosyncratic preferences of early buyers can affect long-term consumer purchase behavior as well as the social welfare created by review systems. Our model provides an explanation for the structure of product ratings over time, which we empirically test using online book reviews posted on Amazon.com. Our analysis suggests that firms could benefit from altering their marketing strategies such as pricing, advertising, or product design to encourage consumers likely to yield positive reports to self-select into the market early and generate positive word-of-mouth for new products. On the other hand, self-selection bias, if not corrected, decreases consumer surplus.

Research summary: Innovation requires inventors to have both new knowledge and the ability to combine and configure knowledge (i.e., combinatory knowledge), and such knowledge may flow through networks. We argue that both combinatory knowledge and new knowledge are accessed through collaboration networks, but that inventors' abilities to access such knowledge depends on its location in the network. Combinatory knowledge transfers from direct contacts, but not easily from indirect contacts. In contrast, new knowledge transfers from both direct and indirect contacts, but is far more likely to be new and useful when it comes from indirect contacts. Exploring knowledge flows in 69,476 patents and 89,930 unique inventors reveals evidence that combinatory knowledge from direct contacts and new knowledge from indirect contacts significantly affects innovative performance. Managerial summary: Inventors often combine ideas to create innovations. To do this, they need ideas to combine and they need the ability to combine those ideas. Inventors can get ideas to combine as well as the ability to combine ideas through prior co-workers. Prior co-workers can share ideas that may be relevant for the inventor's project and can tell the inventor about other things that other people are working on, especially people the inventor may not know. This can help inventors easily learn about ideas from friends-of-friends. The ability to combine ideas, however, is much harder to pass on. Prior co-workers must carefully work with the inventor to teach him or her the complex processes of combining ideas. This means that it is very hard to learn how to combine knowledge from a friend-of-a-friend, but it may be possible to learn from prior co-workers. We explore this phenomenon in the social relationships of software inventors.

Neuroprotection in cerebral ischemia (CI) has received increasing attention. However, efficient delivery of therapeutic agents to the brain remains a major challenge due to the complex environment of the brain. Nose-to-brain-based delivery is a promising approach. Here, we optimized a nanocarrier formulation of neuroprotective agents that can be used for nose-to-brain delivery by obtaining RVG29 peptide-modified polyethylene glycol-polylactic acid-co-glycolic acid nanoparticles (PEG-PLGA RNPs) that have physicochemical properties that lead to stable and sustained drug release and thereby improve the bioavailability of neuroprotective agents. The brain-targeting ability of PEG-PLGA RNPs administered through nasal inhalation was verified in a rat model of CI. It was found that delivery to the whole brain can be achieved with little delivery to the peripheral circulation. Baicalin (BA) was selected as the neuroprotective agent for delivery. After intranasal administration of BA-PEG-PLGA RNPs, the neurological dysfunction of rats with ischemic brain injury was significantly alleviated, the cerebral infarction area was reduced, and nerve trauma and swelling were relieved. Furthermore, it was demonstrated that the neuroprotective effects of BA in a rat model of CI may be mediated by inhibition of inflammation and alleviation of oxidative stress. The immunohistochemical results obtained after treatment with nanoparticles loaded with BA showed that Nrf2/HO-1 was activated in the area in which ischemic brain damage had occurred and that its expression was significantly higher in the group treated with BA-PEG-PLGA RNPs than in the other groups. The ELISA results showed that the levels of IL-1β, IL-6, and TNF-α were abnormally increased in the serum of rats with cerebral ischemia. After treatment with BA-loaded nanoparticles, IL-1β, IL-6, and TNF-α levels decreased significantly. Oxidative stress was alleviated; the levels of glutathione and superoxide dismutase increased; and the levels of reactive oxygen species and malondialdehyde decreased, in animals to which BA-PEG-PLGA RNPs were delivered by intranasal inhalation. In conclusion, BA-PEG-PLGA RNPs can effectively deliver BA to rats and thereby exert neuroprotective effects against CI.

Symbiotic nitrogen fixation (SNF) provides sufficient nitrogen (N) to meet most legume nutrition demands. In return, host plants feed symbionts carbohydrates produced in shoots. However, the molecular dialogue between shoots and symbionts remains largely mysterious. Here, we report the map-based cloning and characterization of a natural variation in GmNN1 , the ortholog of Arabidopsis thaliana FLOWERING LOCUS T ( FT2a ) that simultaneously triggers nodulation in soybean and modulates leaf N nutrition. A 43-bp insertion in the promoter region of GmNN1/FT2a significantly decreased its transcription level and yielded N deficiency phenotypes. Manipulating GmNN1 / GmFT2a significantly enhanced soybean nodulation, plant growth, and N nutrition. The near-isogenic lines (NILs) carrying low mRNA abundance alleles of GmNN1 / FT2a , along with stable transgenic soybeans with CRISPR/Cas9 knockouts of GmNN1 / FT2a , had yellower leaves, lower N concentrations, and fewer nodules than wild-type control plants. Grafting together with split-root experiments demonstrated that only shoot GmNN1/FT2a was responsible for regulating nodulation and thereby N nutrition through shoot-to-root translocation, and this process depends on rhizobial infection. After translocating into roots, shoot-derived GmNN1/FT2a was found to interact with GmNFYA-C (nuclear factor-Y subunit A-C) to activate symbiotic signaling through the previously reported GmNFYA-C-ENOD40 module. In short, the description of the critical soybean nodulation regulatory pathway outlined herein sheds novel insights into the shoot-to-root signaling required for communications between host plants and root nodulating symbionts.

Influenza A virus (IAV), a highly infectious respiratory pathogen, has continued to be a significant threat to global public health. To complete their life cycle, influenza viruses have evolved multiple strategies to interact with a host. A large number of studies have revealed that the evolution of influenza A virus is mainly mediated through the mutation of the virus itself and the re-assortment of viral genomes derived from various strains. The evolution of influenza A virus through these mechanisms causes worldwide annual epidemics and occasional pandemics. Importantly, influenza A virus can evolve from an animal infected pathogen to a human infected pathogen. The highly pathogenic influenza virus has resulted in stupendous economic losses due to its morbidity and mortality both in human and animals. Influenza viruses fall into a category of viruses that can cause zoonotic infection with stable adaptation to human, leading to sustained horizontal transmission. The rapid mutations of influenza A virus result in the loss of vaccine optimal efficacy, and challenge the complete eradication of the virus. In this review, we highlight the current understanding of influenza A virus evolution caused by the mutation and re-assortment of viral genomes. In addition, we discuss the specific mechanisms by which the virus evolves.

Growth mindset, consistency of interest, and perseverance of effort have been demonstrated to positively influence students’ mathematical abilities. This study investigates how these characteristics interact and affect non-cognitive skills, enabling mathematics teachers to develop tailored interventions that enhance learning and persistence among rural students. We examined the profiles of growth mindset and Grit among 1495 rural Chinese students from three secondary schools in China, analyzing their relationships with math anxiety, motivation, and self-efficacy in mathematics lessons. Our analysis identified four distinct profiles: Fixed-Oriented Mindset, Lower Tendency Toward Growth, Tendency Toward Growth, and Growth-Oriented Mindset. Interestingly, there was no significant difference in students’ mathematics motivation between the Lower Tendency Toward Growth, Tendency Toward Growth, and Growth Mindset profiles. However, increases in mindset are associated with increased math anxiety among rural students. This research offers new insights into the effects of cultivating a growth mindset and Grit on mathematics anxiety among rural students.

Dissipative Kerr-soliton combs are laser pulses regularly sustained by a localized solitary wave on top of a continuous-wave background inside a nonlinear resonator. Usually, the intrinsic interactions between the background light and solitons are weak and localized. Here, we demonstrate a strong interaction between the generated soliton comb and the background light in a Brillouin-Kerr microcomb system. This strong interaction enables the generation of a monostable single-soliton microcomb on a silicon chip. Also, new phenomena related to soliton physics including solitons hopping between different states as well as controlling the formations of the soliton states by the pump power, are observed owing to such strong interaction. Utilizing this monostable single-soliton microcomb, we achieve the 100% deterministic turnkey operation successfully without any feedback controls. Importantly, it allows to output turnkey ultra-low-noise microwave signals using a free-running pump. Here the authors demonstrate a strong interaction between the generated solitons and background light in a Brillouin-Kerr microcomb system. Based on this unique physical mechanism, they achieve a monostable single soliton microcomb and a turnkey single-soliton microcomb without employing any optical/electrical control or feedback.