Social experiences switch states of memory engrams through regulating hippocampal Rac1 activity.

In pathological or artificial conditions, memory can be formed as silenced engrams that are unavailable for retrieval by presenting conditioned stimuli but can be artificially switched into the latent state so that natural recall is allowed. However, it remains unclear whether such different states of engrams bear any physiological significance and can be switched through physiological mechanisms. Here, we show that an acute social reward experience switches the silent memory engram into the latent state. Conversely, an acute social stress causes transient forgetting via turning a latent memory engram into a silent state. Such emotion-driven bidirectional switching between latent and silent states of engrams is mediated through regulation of Rac1 activity­dependent reversible forgetting in the hippocampus, as stress-activated Rac1 suppresses retrieval, while reward recovers silenced memory under amnesia by inhibiting Rac1. Thus, data presented reveal hippocampal Rac1 activity as the basis for emotion-mediated switching between latent and silent engrams to achieve emotion-driven behavioral flexibility.

Light-Activated Hypoxia-Sensitive Covalent Organic Framework for Tandem-Responsive Drug Delivery.

Covalent organic frameworks (COFs) have received much attention in the biomedical area. However, little has been reported about stimuli-responsive COF for drug delivery. Herein, we synthesized a hypoxia-responsive azo bond-containing COF with nanoscale size and immobilized both photosensitizers chlorin e6 (Ce6) and hypoxia-activated drug tirapazamine (TPZ) into the COFs. When such a COF entered the hypoxic environment and tumor, the COF structure was ruptured and loaded drugs were released from the COF. Together, upon near-infrared (NIR) light irradiation, Ce6 consumed oxygen to produce cytotoxic reactive oxygen species, leading to elevated hypoxia. Such two-step hypoxia stimuli successively induced the deintegration of COF, drug release and activation of TPZ. This promoted the TPZ to generate massive biotoxic oxyradical. In vitro and in vivo evaluation indicated that this two-step hypoxia-activated COF drug delivery system could kill cancer cells and inhibit the growth of tumors effectively.

A light-activatable theranostic combination for ratiometric hypoxia imaging and oxygen-deprived drug activity enhancement.

While performing oxygen-related tumour treatments such as chemotherapy and photodynamic therapy, real-time monitoring hypoxia of tumour is of great value and significance. Here, we design a theranostic combination for light-activated ratiometric hypoxia imaging, hypoxia modulating and prodrug activation. This combination consisted of an oxygen-sensitive near-infrared-emitting ratiometric phosphorescence probe and a hypoxia-activated prodrug-loaded covalent organic framework. In this combination, the probe plays two roles, including quantitative monitoring of oxygen concentration by ratiometric imaging and consuming the oxygen of tumour under light excitation by photodynamic therapy. Meanwhile, the enhanced hypoxia microenvironment of tumour can raise the cytotoxicity of prodrug loaded in covalent organic framework, resulting in boosting antitumour therapeutic effects in vivo. This theranostic combination can precisely provide therapeutic regime and screen hypoxia-activated prodrugs based on real-time tumour hypoxia level, offering a strategy to develop hypoxia mediated tumour theranostics with hypoxia targeted prodrugs.

Identification of GABAergic subpopulations in the lateral hypothalamus for home-driven behaviors in mice.

Home information profoundly influences behavioral states in both humans and animals. However, how "home" is represented in the brain and its role in driving diverse related behaviors remain elusive. Here, we demonstrate that home bedding contains sufficient home information to modulate affective behaviors, including aversion responses, defensive aggression, and mating behaviors. These varied responses to home information are mediated by gama-aminobutyric acid (GABA)ergic neurons in the lateral hypothalamus (LHGABA). Inhibiting LHGABA abolishes, while activating mimics, the effects of home bedding on these behaviors across different contexts. Specifically, projections from LHGABA to the ventral tegmental area (VTA) mediate the relaxation of aversive emotion, while projections to the periaqueductal gray (PAG) initiate defensive concerns. Thus, our data suggest that home information in different contexts converges to activate distinct subgroups of the LHGABA, which, in turn, elicit appropriate affective behaviors in relieving aversion, fighting intruders, or enhancing mating through involving distinct downstream projections.

Using Twitter to Understand COVID-19 Vaccine-Related Ageism During the Pandemic.

BACKGROUND AND OBJECTIVES: During the rollout of coronavirus 2019 (COVID-19) vaccines, older adults in high-income countries were often prioritized for inoculation in efforts to reduce COVID-19-related mortality. However, this prioritization may have contributed to intergenerational tensions and ageism, particularly with the limited supply of COVID-19 vaccines. This study examines Twitter discourse to understand vaccine-related ageism during the COVID-19 pandemic to inform future vaccination policies and practices to reduce ageism. RESEARCH DESIGN AND METHODS: We collected 1,369 relevant tweets on Twitter using the Twint application in Python from December 8, 2020, to December 31, 2021. Tweets were analyzed using thematic analysis, and steps were taken to ensure rigor. RESULTS: Our research identified four main themes including (a) blame and hostility: "It's all their fault"; (b) incompetence and misinformation: "clueless boomer"; (c) ageist political slander; and (d) combatting ageism: advocacy and accessibility. DISCUSSION AND IMPLICATIONS: Our findings exposed issues of victim-blaming, hate speech, pejorative content, and ageist political slander that is deepening the divide of intergenerational conflict. Although a subset of tweets countered negative outcomes and demonstrated intergenerational solidarity, our findings suggest that ageism may have contributed to COVID-19 vaccine hesitancy among older adults. Consequently, urgent action is needed to counter vaccine misinformation, prohibit aggressive messaging, and promote intergenerational unity during the COVID-19 pandemic and beyond.

Phenylboronic acid-modified nanoscale multi-arm polymers for tumor-targeted therapy.

Unimolecular polymer nanomaterials (UPNs) have well-defined structures, desirable stability and designable functional groups, and hence exhibit great application potential in drug delivery. However, the syntheses of UPNs are generally time-consuming and tedious, which greatly limit their applications. In this paper, we present the preparation of a ß-cyclodextrin-cored star-shaped polymer with 21 poly(tert-butyl acrylate) arms. This polymer was facilely synthesized by one-step atom transfer radical polymerization (ATRP). After cleaving the tert-butyl ester protecting groups, the abundant carboxylic acid side groups were used to incorporate doxorubicin (DOX), phenylboronic acid (PBA) groups and poly(ethylene glycol) (PEG) to achieve drug loading and tumor drug delivery. Due to the tumor-targeting ability of the PBA groups, this UPN-based nanomedicine showed high tumor accumulation, penetration and therapeutic efficacy.

Hippocampal Activation of Rac1 Regulates the Forgetting of Object Recognition Memory.

Forgetting is a universal feature for most types of memories. The best-defined and extensively characterized behaviors that depict forgetting are natural memory decay and interference-based forgetting [1, 2]. Molecular mechanisms underlying the active forgetting remain to be determined for memories in vertebrates. Recent progress has begun to unravel such mechanisms underlying the active forgetting [3-11] that is induced through the behavior-dependent activation of intracellular signaling pathways. In Drosophila, training-induced activation of the small G protein Rac1 mediates natural memory decay and interference-based forgetting of aversive conditioning memory [3]. In mice, the activation of photoactivable-Rac1 in recently potentiated spines in a motor learning task erases the motor memory [12]. These lines of evidence prompted us to investigate a role for Rac1 in time-based natural memory decay and interference-based forgetting in mice. The inhibition of Rac1 activity in hippocampal neurons through targeted expression of a dominant-negative Rac1 form extended object recognition memory from less than 72 hr to over 72 hr, whereas Rac1 activation accelerated memory decay within 24 hr. Interference-induced forgetting of this memory was correlated with Rac1 activation and was completely blocked by inhibition of Rac1 activity. Electrophysiological recordings of long-term potentiation provided independent evidence that further supported a role for Rac1 activation in forgetting. Thus, Rac1-dependent forgetting is evolutionarily conserved from invertebrates to vertebrates.