ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells.

Brain endothelial LDL receptor-related protein 1 (LRP1) is involved in the clearance of Aß peptides across the blood-brain barrier (BBB). Here we show that endothelial deficiency of ankyrin repeat and SAM domain containing 1 A (ANKS1A) reduces both the cell surface levels of LRP1 and the Aß clearance across the BBB. Association of ANKS1A with the NPXY motifs of LRP1 facilitates the transport of LRP1 from the endoplasmic reticulum toward the cell surface. ANKS1A deficiency in an Alzheimer's disease mouse model results in exacerbated Aß pathology followed by cognitive impairments. These deficits are reversible by gene therapy with brain endothelial-specific ANKS1A. In addition, human induced pluripotent stem cell-derived BBBs (iBBBs) were generated from endothelial cells lacking ANKS1A or carrying the rs6930932 variant. Those iBBBs exhibit both reduced cell surface LRP1 and impaired Aß clearance. Thus, our findings demonstrate that ANKS1A regulates LRP1-mediated Aß clearance across the BBB.

The Potential of Chatbots for Emotional Support and Promoting Mental Well-Being in Different Cultures: Mixed Methods Study.

BACKGROUND: Artificial intelligence chatbot research has focused on technical advances in natural language processing and validating the effectiveness of human-machine conversations in specific settings. However, real-world chat data remain proprietary and unexplored despite their growing popularity, and new analyses of chatbot uses and their effects on mitigating negative moods are urgently needed. OBJECTIVE: In this study, we investigated whether and how artificial intelligence chatbots facilitate the expression of user emotions, specifically sadness and depression. We also examined cultural differences in the expression of depressive moods among users in Western and Eastern countries. METHODS: This study used SimSimi, a global open-domain social chatbot, to analyze 152,783 conversation utterances containing the terms "depress" and "sad" in 3 Western countries (Canada, the United Kingdom, and the United States) and 5 Eastern countries (Indonesia, India, Malaysia, the Philippines, and Thailand). Study 1 reports new findings on the cultural differences in how people talk about depression and sadness to chatbots based on Linguistic Inquiry and Word Count and n-gram analyses. In study 2, we classified chat conversations into predefined topics using semisupervised classification techniques to better understand the types of depressive moods prevalent in chats. We then identified the distinguishing features of chat-based depressive discourse data and the disparity between Eastern and Western users. RESULTS: Our data revealed intriguing cultural differences. Chatbot users in Eastern countries indicated stronger emotions about depression than users in Western countries (positive: P<.001; negative: P=.01); for example, Eastern users used more words associated with sadness (P=.01). However, Western users were more likely to share vulnerable topics such as mental health (P<.001), and this group also had a greater tendency to discuss sensitive topics such as swear words (P<.001) and death (P<.001). In addition, when talking to chatbots, people expressed their depressive moods differently than on other platforms. Users were more open to expressing emotional vulnerability related to depressive or sad moods to chatbots (74,045/148,590, 49.83%) than on social media (149/1978, 7.53%). Chatbot conversations tended not to broach topics that require social support from others, such as seeking advice on daily life difficulties, unlike on social media. However, chatbot users acted in anticipation of conversational agents that exhibit active listening skills and foster a safe space where they can openly share emotional states such as sadness or depression. CONCLUSIONS: The findings highlight the potential of chatbot-assisted mental health support, emphasizing the importance of continued technical and policy-wise efforts to improve chatbot interactions for those in need of emotional assistance. Our data indicate the possibility of chatbots providing helpful information about depressive moods, especially for users who have difficulty communicating emotions to other humans.

Olfactory modulation of stress-response neural circuits.

Stress responses, which are crucial for survival, are evolutionally conserved throughout the animal kingdom. The most common endocrine axis among stress responses is that triggered by corticotropin-releasing hormone neurons (CRHNs) in the hypothalamus. Signals of various stressors are detected by different sensory systems and relayed through individual neural circuits that converge on hypothalamic CRHNs to initiate common stress hormone responses. To investigate the neurocircuitry mechanisms underlying stress hormone responses induced by a variety of stressors, researchers have recently developed new approaches employing retrograde transsynaptic viral tracers, providing a wealth of information about various types of neural circuits that control the activity of CRHNs in response to stress stimuli. Here, we review earlier and more recent findings on the stress neurocircuits that converge on CRHNs, focusing particularly on olfactory systems that excite or suppress the activities of CRHNs and lead to the initiation of stress responses. Because smells are arguably the most important signals that enable animals to properly cope with environmental changes and survive, unveiling the regulatory mechanisms by which smells control stress responses would provide broad insight into how stress-related environmental cues are perceived in the animal brain.

Lateral hypothalamic leptin receptor neurons drive hunger-gated food-seeking and consummatory behaviours in male mice.

For survival, it is crucial for eating behaviours to be sequenced through two distinct seeking and consummatory phases. Heterogeneous lateral hypothalamus (LH) neurons are known to regulate motivated behaviours, yet which subpopulation drives food seeking and consummatory behaviours have not been fully addressed. Here, in male mice, fibre photometry recordings demonstrated that LH leptin receptor (LepR) neurons are correlated explicitly in both voluntary seeking and consummatory behaviours. Further, micro-endoscope recording of the LHLepR neurons demonstrated that one subpopulation is time-locked to seeking behaviours and the other subpopulation time-locked to consummatory behaviours. Seeking or consummatory phase specific paradigm revealed that activation of LHLepR neurons promotes seeking or consummatory behaviours and inhibition of LHLepR neurons reduces consummatory behaviours. The activity of LHLepR neurons was increased via Neuropeptide Y (NPY) which acted as a tonic permissive gate signal. Our results identify neural populations that mediate seeking and consummatory behaviours and may lead to therapeutic targets for maladaptive food seeking and consummatory behaviours.

User-Chatbot Conversations During the COVID-19 Pandemic: Study Based on Topic Modeling and Sentiment Analysis.

BACKGROUND: Chatbots have become a promising tool to support public health initiatives. Despite their potential, little research has examined how individuals interacted with chatbots during the COVID-19 pandemic. Understanding user-chatbot interactions is crucial for developing services that can respond to people's needs during a global health emergency. OBJECTIVE: This study examined the COVID-19 pandemic-related topics online users discussed with a commercially available social chatbot and compared the sentiment expressed by users from 5 culturally different countries. METHODS: We analyzed 19,782 conversation utterances related to COVID-19 covering 5 countries (the United States, the United Kingdom, Canada, Malaysia, and the Philippines) between 2020 and 2021, from SimSimi, one of the world's largest open-domain social chatbots. We identified chat topics using natural language processing methods and analyzed their emotional sentiments. Additionally, we compared the topic and sentiment variations in the COVID-19-related chats across countries. RESULTS: Our analysis identified 18 emerging topics, which could be categorized into the following 5 overarching themes: "Questions on COVID-19 asked to the chatbot" (30.6%), "Preventive behaviors" (25.3%), "Outbreak of COVID-19" (16.4%), "Physical and psychological impact of COVID-19" (16.0%), and "People and life in the pandemic" (11.7%). Our data indicated that people considered chatbots as a source of information about the pandemic, for example, by asking health-related questions. Users turned to SimSimi for conversation and emotional messages when offline social interactions became limited during the lockdown period. Users were more likely to express negative sentiments when conversing about topics related to masks, lockdowns, case counts, and their worries about the pandemic. In contrast, small talk with the chatbot was largely accompanied by positive sentiment. We also found cultural differences, with negative words being used more often by users in the United States than by those in Asia when talking about COVID-19. CONCLUSIONS: Based on the analysis of user-chatbot interactions on a live platform, this work provides insights into people's informational and emotional needs during a global health crisis. Users sought health-related information and shared emotional messages with the chatbot, indicating the potential use of chatbots to provide accurate health information and emotional support. Future research can look into different support strategies that align with the direction of public health policy.

A new AMPK isoform mediates glucose-restriction induced longevity non-cell autonomously by promoting membrane fluidity.

Dietary restriction (DR) delays aging and the onset of age-associated diseases. However, it is yet to be determined whether and how restriction of specific nutrients promote longevity. Previous genome-wide screens isolated several Escherichia coli mutants that extended lifespan of Caenorhabditis elegans. Here, using 1H-NMR metabolite analyses and inter-species genetics, we demonstrate that E. coli mutants depleted of intracellular glucose extend C. elegans lifespans, serving as bona fide glucose-restricted (GR) diets. Unlike general DR, GR diets don't reduce the fecundity of animals, while still improving stress resistance and ameliorating neuro-degenerative pathologies of Aß42. Interestingly, AAK-2a, a new AMPK isoform, is necessary and sufficient for GR-induced longevity. AAK-2a functions exclusively in neurons to modulate GR-mediated longevity via neuropeptide signaling. Last, we find that GR/AAK-2a prolongs longevity through PAQR-2/NHR-49/Δ9 desaturases by promoting membrane fluidity in peripheral tissues. Together, our studies identify the molecular mechanisms underlying prolonged longevity by glucose specific restriction in the context of whole animals.

Bacteria-derived metabolite, methylglyoxal, modulates the longevity of C. elegans through TORC2/SGK-1/DAF-16 signaling.

Gut microbes play diverse roles in modulating host fitness, including longevity; however, the molecular mechanisms underlying their mediation of longevity remain poorly understood. We performed genome-wide screens using 3,792 Escherichia coli mutants and identified 44 E. coli mutants that modulated Caenorhabditis elegans longevity. Three of these mutants modulated C. elegans longevity via the bacterial metabolite methylglyoxal (MG). Importantly, we found that low MG-producing E. coli mutants, Δhns E. coli, extended the lifespan of C. elegans through activation of the DAF-16/FOXO family transcription factor and the mitochondrial unfolded protein response (UPRmt). Interestingly, the lifespan modulation by Δhns did not require insulin/insulin-like growth factor 1 signaling (IIS) but did require TORC2/SGK-1 signaling. Transcriptome analysis revealed that Δhns E. coli activated novel class 3 DAF-16 target genes that were distinct from those regulated by IIS. Taken together, our data suggest that bacteria-derived MG modulates host longevity through regulation of the host signaling pathways rather than through nonspecific damage on biomolecules known as advanced glycation end products. Finally, we demonstrate that MG enhances the phosphorylation of hSGK1 and accelerates cellular senescence in human dermal fibroblasts, suggesting the conserved role of MG in controlling longevity across species. Together, our studies demonstrate that bacteria-derived MG is a novel therapeutic target for aging and aging-associated pathophysiology.