Structure and function of a near fully-activated intermediate GPCR-Gαβγ complex.

Unraveling the signaling roles of intermediate complexes is pivotal for G protein-coupled receptor (GPCR) drug development. Despite hundreds of GPCR-Gαβγ structures, these snapshots primarily capture the fully activated complex. Consequently, the functions of intermediate GPCR-G protein complexes remain elusive. Guided by a conformational landscape visualized via 19F quantitative NMR and molecular dynamics (MD) simulations, we determined the structure of an intermediate GPCR-mini-Gαsβγ complex at 2.6 Å using cryo-EM, by blocking its transition to the fully activated complex. Furthermore, we present direct evidence that the complex at this intermediate state initiates a rate-limited nucleotide exchange before transitioning to the fully activated complex. In this state, BODIPY-GDP/GTP based nucleotide exchange assays further indicated the α-helical domain of the Gα is partially open, allowing it to grasp a nucleotide at a non-canonical binding site, distinct from the canonical nucleotide-binding site. These advances bridge a significant gap in our understanding of the complexity of GPCR signaling

Balancing conflicting mitigation and adaptation behaviours of urban residents under climate change and the urban heat island effect

Under a warming climate and urban heat island effects, cooling behaviours are increasingly important for city dwellers. Cooling actions, especially air conditioning, receive increasing scrutiny in social science, as does engagement and communication on behaviours spanning adaptation and mitigation. In response, this paper evaluates the relation between residents’ adaptation and mitigation behaviours around cooling in Fukuoka, Japan, and draws lessons for communication on encouraging adaptation and mitigation actions. A survey distributed to residents in six areas of Fukuoka, Japan, assessed perceptions of global warming and urban heat island effects, frequency of mitigation and adaptation behaviours, use of air conditioning, electricity bills and evaluation of green spaces. We observe a difference between respondents using air conditioning with an energy-saving (i.e. mitigation) focus, versus those using air conditioning with an adaptation (i.e. cooling) focus. We also note residents emphasising mitigation behaviours may use shade in parks or cooling centres as alternative cooling strategies, but that awareness of effective air conditioning use may be lacking. Our findings build on existing literature by reinforcing – in a subtropical context – the need to reconsider practices around air conditioner use; and illustrate the value of a breadth of messages to promote joint mitigation and adaptation actions

Halogencarbene-free Ciamician-Dennstedt single-atom skeletal editing

Single-atom skeletal editing is an increasingly powerful tool for scaffold hopping-based drug discovery. However, the insertion of a functionalized carbon atom into heteroarenes remains rare, especially when performed in complex chemical settings. Despite more than a century of research, Ciamician-Dennstedt (C-D) rearrangement remains limited to halocarbene precursors. Herein, we report a general methodology for the Ciamician-Dennstedt reaction using α-halogen-free carbenes generated in situ from N-triftosylhydrazones. This one-pot, two-step protocol enables the insertion of various carbenes, including those previously unexplored in C-D skeletal editing chemistry, into indoles/pyrroles scaffolds to access 3-functionalized quinolines/pyridines. Mechanistic studies reveal a pathway involving the intermediacy of a 1,4-dihydroquinoline intermediate, which could undergo oxidative aromatization or defluorinative aromatization to form different carbon-atom insertion products

LLMs for User Interest Exploration in Large-scale Recommendation Systems

Traditional recommendation systems are subject to a strong feedback loop by learning from and reinforcing past user-item interactions, which in turn limits the discovery of novel user interests. To address this, we introduce a hybrid hierarchical framework combining Large Language Models (LLMs) and classic recommendation models for user interest exploration. The framework controls the interfacing between the LLMs and the classic recommendation models through "interest clusters", the granularity of which can be explicitly determined by algorithm designers. It recommends the next novel interests by first representing "interest clusters" using language, and employs a fine-tuned LLM to generate novel interest descriptions that are strictly within these predefined clusters. At the low level, it grounds these generated interests to an item-level policy by restricting classic recommendation models, in this case a transformer-based sequence recommender to return items that fall within the novel clusters generated at the high level. We showcase the efficacy of this approach on an industrial-scale commercial platform serving billions of users. Live experiments show a significant increase in both exploration of novel interests and overall user enjoyment of the platform

Propensity Score-Matched Analysis of Lesion Patterns in Stroke Patients With Patent Foramen Ovale and Patients With Spontaneous Intracranial Artery Dissection

Aims: To investigate the relationship between clinical and imaging features of stroke patients with patent foramen ovale (PFO) and those with spontaneous intracranial artery dissection (SIAD).Materials and methods: We retrospectively examined both clinical and imaging results of 40 stroke patients with PFO and 29 with SIAD. To reduce selection bias, we conducted a propensity score-matching analysis. The patients' propensity scores were estimated using a logistic regression model based on the following variables: age, sex, hypertension, diabetes mellitus, hypercholesterolemia, cigarette smoking, stroke histories, and their NIHSS scores. We compared the pattern of cerebral DWI lesions between patients with PFO and those with SIAD.Results: After propensity score matching, 21 pairs of patients were selected. Clinical characteristics of the 2 groups were well matched. The distribution of DWI lesion patterns differed between the 2 groups. Single lesions (cortical or subcortical) were more frequently observed in the PFO group than in the SIAD group (P = 0.026). Multiple lesions in one vascular territory occurred more frequently in the SIAD group than in the PFO group (P = 0.035).Conclusion: The present study suggests that lesion patterns observed from DWI of patients with PFO and SIAD might provide clues to the etiology of infarcts. Single lesions (cortical or subcortical) might be a typical feature of PFO associated strokes, while multiple lesions in one vascular territory might be a specific feature of SIAD associated strokes

Present and future of functionalized Cu current collectors for stabilizing lithium metal anodes

Li metal has been recognized as the most promising anode materials for next-generation high-energy-density batteries, however, the inherent issues of dendrite growth and huge volume fluctuations upon Li plating/stripping normally result in fast capacity fading and safety concerns. Functionalized Cu current collectors have so far exhibited significant regulatory effects on stabilizing Li metal anodes (LMAs), and hold a great practical potential owing to their easy fabrication, low-cost and good compatibility with the existing battery technology. In this review, a comprehensive overview of Cu-based current collectors, including planar modified Cu foil, 3D architectured Cu foil and nanostructured 3D Cu substrates, for Li metal batteries is provided. Particularly, the design principles and strategies of functionalized Cu current collectors associated with their functionalities in optimizing Li plating/stripping behaviors are discussed. Finally, the critical issues where there is incomplete understanding and the future research directions of Cu current collectors in practical LMAs are also prospected. This review may shed light on the critical understanding of current collector engineering for high-energy-density Li metal batteries

Quality attributes of paddy rice during storage as affected by accumulated temperature

In actual storage processes of rice, environment temperatures fluctuate rather than remain constant. Accumulated temperature is the sum of temperature during the storage period. In this research, six different temperature-varied conditions with two accumulated temperatures (low intensity: 7200°C⸱d; high intensity: 9000°C⸱d) were designed to store rice for 12 months and the stored rice samples were compared in quality. Three low-accumulated temperature conditions were set as follows: No. 4–15°C for 6 months followed by 25°C; No. 5–25°C for 6 months followed by 15°C; No. 8-alternating between 15°C and 25°C every 2 months. Similarly, three high-intensity conditions, No. 6, No. 7, and No. 9, were set with a temperature change from 25°C to 35°C. Three constant temperature conditions, No. 1, No. 2, and No. 3, with storage temperature of 15, 25, and 35°C, respectively, were used as controls. Under temperature-varied conditions, rice demonstrated a decline in germination rate (GR), catalase (CAT) and peroxidase (POD) activities, and an increase in fatty acid value (FAV) as storage time increased. After storage, rice exhibited higher water absorption rate (WAR) and volume expansion rate (VER), but reduced stickiness and sensory scores for appearance, taste and overall quality. Generally, three batches at high-accumulated temperature conditions had lower GR and sensory scores, and higher FAV, WAR, and VER compared to those under low-intensity conditions. Furthermore, variations in the sequence of temperature also affected quality parameters, even at the same accumulated temperature. These findings indicate that under temperature-varied conditions, increased accumulated temperature exacerbates rice deterioration, and different temperature sequences can influence quality at a given accumulated temperature

HIMO: A New Benchmark for Full-Body Human Interacting with Multiple Objects

Generating human-object interactions (HOIs) is critical with the tremendous advances of digital avatars. Existing datasets are typically limited to humans interacting with a single object while neglecting the ubiquitous manipulation of multiple objects. Thus, we propose HIMO, a large-scale MoCap dataset of full-body human interacting with multiple objects, containing 3.3K 4D HOI sequences and 4.08M 3D HOI frames. We also annotate HIMO with detailed textual descriptions and temporal segments, benchmarking two novel tasks of HOI synthesis conditioned on either the whole text prompt or the segmented text prompts as fine-grained timeline control. To address these novel tasks, we propose a dual-branch conditional diffusion model with a mutual interaction module for HOI synthesis. Besides, an auto-regressive generation pipeline is also designed to obtain smooth transitions between HOI segments. Experimental results demonstrate the generalization ability to unseen object geometries and temporal compositions.Project page: https://lvxintao.github.io/himo, accepted by ECCV 202