Altered assembly paths mitigate interference among paralogous complexes.

Protein complexes are fundamental to all cellular processes, so understanding their evolutionary history and assembly processes is important. Gene duplication followed by divergence is considered a primary mechanism for diversifying protein complexes. Nonetheless, to what extent assembly of present-day paralogous complexes has been constrained by their long evolutionary pathways and how cross-complex interference is avoided remain unanswered questions. Subunits of protein complexes are often stabilized upon complex formation, whereas unincorporated subunits are degraded. How such cooperative stability influences protein complex assembly also remains unclear. Here, we demonstrate that subcomplexes determined by cooperative stabilization interactions serve as building blocks for protein complex assembly. We further develop a protein stability-guided method to compare the assembly processes of paralogous complexes in cellulo. Our findings support that oligomeric state and the structural organization of paralogous complexes can be maintained even if their assembly processes are rearranged. Our results indicate that divergent assembly processes by paralogous complexes not only enable the complexes to evolve new functions, but also reinforce their segregation by establishing incompatibility against deleterious hybrid assemblies.

Identification of diagnostic biomarkers of rheumatoid arthritis based on machine learning-assisted comprehensive bioinformatics and its correlation with immune cells.

Background: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by inflammatory cell infiltration, which can lead to chronic disability, joint destruction and loss of function. At present, the pathogenesis of RA is still unclear. The purpose of this study is to explore the potential biomarkers and immune molecular mechanisms of rheumatoid arthritis through machine learning-assisted bioinformatics analysis, in order to provide reference for the early diagnosis and treatment of RA disease. Methods: RA gene chips were screened from the public gene GEO database, and batch correction of different groups of RA gene chips was performed using Strawberry Perl. DEGs were obtained using the limma package of R software, and functional enrichment analysis such as gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), disease ontology (DO), and gene set (GSEA) were performed. Three machine learning methods, least absolute shrinkage and selection operator regression (LASSO), support vector machine recursive feature elimination (SVM-RFE) and random forest tree (Random Forest), were used to identify potential biomarkers of RA. The validation group data set was used to verify and further confirm its expression and diagnostic value. In addition, CIBERSORT algorithm was used to evaluate the infiltration of immune cells in RA and control samples, and the correlation between confirmed RA diagnostic biomarkers and immune cells was analyzed. Results: Through feature screening, 79 key DEGs were obtained, mainly involving virus response, Parkinson's pathway, dermatitis and cell junction components. A total of 29 hub genes were screened by LASSO regression, 34 hub genes were screened by SVM-RFE, and 39 hub genes were screened by Random Forest. Combined with the three algorithms, a total of 12 hub genes were obtained. Through the expression and diagnostic value verification in the validation group data set, 7 genes that can be used as diagnostic biomarkers for RA were preliminarily confirmed. At the same time, the correlation analysis of immune cells found that γδT cells, CD4+ memory activated T cells, activated dendritic cells and other immune cells were positively correlated with multiple RA diagnostic biomarkers, CD4+ naive T cells, regulatory T cells and other immune cells were negatively correlated with multiple RA diagnostic biomarkers. Conclusions: The results of novel characteristic gene analysis of RA showed that KYNU, EVI2A, CD52, C1QB, BATF, AIM2 and NDC80 had good diagnostic and clinical value for the diagnosis of RA, and were closely related to immune cells. Therefore, these seven DEGs may become new diagnostic markers and immunotherapy markers for RA.

Helically twisted nonlinear photonic crystals.

Nonlinear photonic crystals with a helical structure in the second-order nonlinear coefficient (χ(2)) are fabricated using infrared femtosecond laser poling in ferroelectric Sr0.61Ba0.39Nb2O6 crystals. The quasi-orbital angular momentum of the helical χ(2) structure can be imprinted on the interacting photons during nonlinear optical processes, allowing the topological charge of the generated photons at new frequencies to be controlled. Here we study the case of a double-helix nonlinear photonic structure for the generation of a second-harmonic vortex beam from a Gaussian pump beam without phase singularity. The conservation law for orbital angular momentum in the second-harmonic process is also verified, with the topological charge of the pump photons being fully compensated by the double-helix structure. The flexible control of light carrying orbital angular momentum (OAM) at new frequencies will find important applications in both classical and quantum photonics, such as nonlinear wavefront shaping and multidimensional entanglement of photons.

Red-light-dependent chlorophyll synthesis kindles photosynthetic recovery of chlorotic dormant cyanobacteria using a dark-operative enzyme.

Chlorosis dormancy resulting from nitrogen starvation and its resuscitation upon available nitrogen contributes greatly to the fitness of cyanobacterial population under nitrogen-fluctuating environments. The reinstallation of the photosynthetic machinery is a key process for resuscitation from a chlorotic dormant state; however, the underlying regulatory mechanism is still elusive. Here, we reported that red light is essential for re-greening chlorotic Synechocystis sp. PCC 6803 (a non-diazotrophic cyanobacterium) after nitrogen supplement under weak light conditions. The expression of dark-operative protochlorophyllide reductase (DPOR) governed by the transcriptional factor RpaB was strikingly induced by red light in chlorotic cells, and its deficient mutant lost the capability of resuscitation from a dormant state, indicating DPOR catalyzing chlorophyll synthesis is a key step in the photosynthetic recovery of dormant cyanobacteria. Although light-dependent protochlorophyllide reductase is widely considered as a master switch in photomorphogenesis, this study unravels the primitive DPOR as a spark to activate the photosynthetic recovery of chlorotic dormant cyanobacteria. These findings provide new insight into the biological significance of DPOR in cyanobacteria and even some plants thriving in extreme environments.

Enhancing Healthcare Efficiency: Integrating ChatGPT in Nursing Documentation.

Our study at Chi Mei Medical Center introduced "A+ Nurse," a ChatGPT-based LLM tool, into the nursing documentation process to enhance efficiency and accuracy. The tool offers optimized recording and critical reminders, reducing documentation time from 15 to 5 minutes per patient while maintaining record quality. Nurses appreciated the tool's intuitive design and its effectiveness in improving documentation. This successful integration of AI-generated content in healthcare illustrates the potential of AI to streamline processes and improve patient care, setting a precedent for future AI-driven healthcare innovations.

RNA-seq revealed the protective effect of Huangqi Guizhi Wuwu Decoction against cisplatin induced PC12 cell injury.

BACKGROUND: Chemotherapy-induced peripheral neuropathy not only affects the tolerability of chemotherapy, but also causes intolerable and prolonged neuropathic pain in cancer patients. Currently, duloxetine is the only drug used to treat chemotherapy-induced peripheral neuropathy. However, the clinical use of this drug still faces several challenges. Therefore, we focused on traditional Chinese medicine to find an effective and safe alternative medicine. Huangqi Guizhi Wuwu Decoction is a traditional Chinese medicine that has been clinically used for treating nerve pain for thousands of years. This study aimed to investigate the neuroprotective effect of Huangqi Guizhi Wuwu Decoction on cisplatin-induced nerve injury in PC12 cells and to elucidate its potential mechanism of action. METHODS: Huangqi Guizhi Wuwu Decoction-containing serum and blank serum were prepared from a rat model. The protective effects of Huangqi Guizhi Wuwu Decoction on cisplatin (10 µmol/L)-induced PC12 cell injury were assessed by a Cell Counting Kit-8 assay. RNA expression in Huangqi Guizhi Wuwu Decoction-protected PC12 cells was analyzed using RNA-seq, and subsequently, differentially expressed genes were further analyzed using Gene Ontology and Gene Set Enrichment Analysis. RESULTS: The Cell Counting Kit-8 results showed that pretreatment of PC12 cells with Huangqi Guizhi Wuwu Decoction-containing serum (5%, 10%, 15%) significantly increased cells' viability to 10 µmol/L cisplatin-induced cell death. RNA-seq analysis revealed 843 differentially expressed genes in the chemotherapy-induced peripheral neuropathy group and 249 in the Huangqi Guizhi Wuwu Decoction group. The gene set enrichment analysis results in this study suggest that Huangqi Guizhi Wuwu Decoction may treat chemotherapy-induced peripheral neuropathy by enhancing axon guidance. CONCLUSIONS: This study provides valuable evidence for using Huangqi Guizhi Wuwu Decoction in treating chemotherapy-induced peripheral neuropathy, partially achieved by improving axon guidance pathways.

A 40-nm 169mW Ultrasound Imaging Processor Supporting Advanced Modes for Hand-Held Devices.

Hand-held ultrasound devices have been widely used in the field of healthcare and power-efficient, real-time imaging is essential. This work presents the world's first ultrasound imaging processor supporting advanced modes, including vector flow imaging and elastography imaging. Plane-wave beamforming is utilized to ensure that the pulse repetition frequency (PRF) is sufficiently high for the advanced mode. The storage size and power consumption are minimized through algorithm-architecture co-optimization. The proposed plane-wave beamforming reduces the storage size of the required delay values by 43.7%. By exchanging the processing order, the storage size is reduced by 78.1% for elastography imaging. Parallel beamforming and interleaved firing are employed to achieve real-time imaging for all the supported modes. Fabricated in 40-nm CMOS technology, the proposed processor integrates 4.7M logic gates in core area of 3.24mm2. This work achieves a 20.3× higher beamforming rate with 5.3-to-29.1× lower power consumption than the state-of- the-art design. It also has 60% lower hardware complexity (in terms of gate count), in addition to the capability for supporting the advanced mode.

Polaritonic Chemistry Enabled by Non-Local Metasurfaces.

Vibrational strong coupling can modify chemical reaction pathways in unconventional ways. Thus far, Fabry-Perot cavities formed by pairs of facing mirrors have been mostly utilized to achieve vibrational strong coupling. In this study, we demonstrate the application of non-local metasurfaces that can sustain surface lattice resonances, enabling chemical reactions under vibrational strong coupling. We show that the solvolysis kinetics of para-nitrophenyl acetate can be accelerated by a factor of 2.7 by strong coupling to the carbonyl bond of the solvent and the solute with a surface lattice resonance. Our work introduces a new platform to investigate polaritonic chemical reactions. In contrast to Fabry-Perot cavities, metasurfaces define open optical cavities with single surfaces, which removes alignment hurdles, facilitating polaritonic chemistry across large areas.

Lower extremity function and cardiovascular disease risk in hemodialysis patients: A multicenter cross-sectional study.

Physical performance in hemodialysis patients declines and serves as a cardiovascular disease (CVD) incidence and mortality predictor. However, lower extremity function's role remains unclear. This study aimed to quantify the association between lower extremity function and CVD risk in hemodialysis patients. This was a multicenter cross-sectional study enrolling 868 participants (532 males, 336 females) from seven hemodialysis centers in Shanghai, China. Patients were divided into three groups per lower extremity function, evaluated by short physical performance battery (SPPB) scores: 0-6, 7-9, and 10-12. Upper extremity function was quantified through grip strength assessment. CVD risk was assessed using the Framingham Risk Score. Approximately 35% of hemodialysis patients had impaired lower extremity function (SPPB score < 10). Participants with high SPPB scores had stronger handgrip and lower Framingham CVD risk scores than those with low and moderate SPPB scores (p < 0.05). After adjusting clinical confounders, SPPB was independently associated with CVD risk, as a categorized variable (odds ratio: 0.577, 95% confidence interval [CI]: 0.388-0.857, p = 0.006) and as a continuous variable (odds ratio: 0.858, 95% CI: 0.772-0.953, p = 0.004). An SPPB score < 10 predicted an increased CVD risk (area under curve: 0.649, 95% CI: 0.599-0.699, p < 0.001). Causality between physical performance and CVD risk was not considered. Some upper limb results may not be generalizable to peritoneal dialysis and kidney transplant patients. Lower extremity function was significantly associated with CVD risk in hemodialysis patients. Further studies are needed to explore the long-term relationship between lower extremity function and CVD risk.

Engineering Bacteria and Their Derivatives for Cancer Immunotherapy.

Leveraging bacteria for cancer immunotherapy has gradually attracted wide attention since the discovery of "Cloey's toxin." However, one of the persistent challenges for bacteria-based therapy is striking a balance between safety and immunogenicity. Genetically engineered bacteria with virulence factors removed could further enhance antitumor ability by integrating genetic elements. In addition, bacterial derivatives, including outer membrane vesicles (OMVs) produced by bacterial secretion and nanovesicles synthesized by modification of OMVs, could enhance antitumor immunity while improving safety. This perspective discusses the unique advantages of engineered bacteria and their derivatives for immunotherapy, as well as the challenges that need to be overcome to achieve clinical translation.

L-Cysteine: A promising nutritional supplement for alleviating anxiety disorders.

Anxiety disorders are prevalent chronic psychological disease with complex pathogenic mechanisms. Current anxiolytics have limited efficacy and numerous side effects in many anxiety patients, highlighting the urgent need for new therapies. Recent research has been focusing on nutritional supplements, particularly amino acids, as potential therapies for anxiety disorders. Among these, L-Cysteine plays a crucial role in various biological processes. L-Cysteine exhibits antioxidant properties that can enhance the antioxidant functions of the central nervous system (CNS). Furthermore, metabolites of L-cysteine, such as glutathione and hydrogen sulfide have been shown to alleviate anxiety through distinct molecular mechanisms. Long-term administration of L-Cysteine has anxiolytic, antidepressant, and memory-improving effects. L-Cysteine depletion can lead to increased oxidative stress in the brain. This review delves into the potential mechanisms of L-Cysteine and its main products, glutathione (GSH) and hydrogen sulfide (H2S) in the management of anxiety and related diseases.

Reconstruction of single-cell lineage trajectories and identification of diversity in fates during the epithelial-to-mesenchymal transition.

Exploring the complexity of the epithelial-to-mesenchymal transition (EMT) unveils a diversity of potential cell fates; however, the exact timing and mechanisms by which early cell states diverge into distinct EMT trajectories remain unclear. Studying these EMT trajectories through single-cell RNA sequencing is challenging due to the necessity of sacrificing cells for each measurement. In this study, we employed optimal-transport analysis to reconstruct the past trajectories of different cell fates during TGF-beta-induced EMT in the MCF10A cell line. Our analysis revealed three distinct trajectories leading to low EMT, partial EMT, and high EMT states. Cells along the partial EMT trajectory showed substantial variations in the EMT signature and exhibited pronounced stemness. Throughout this EMT trajectory, we observed a consistent downregulation of the EED and EZH2 genes. This finding was validated by recent inhibitor screens of EMT regulators and CRISPR screen studies. Moreover, we applied our analysis of early-phase differential gene expression to gene sets associated with stemness and proliferation, pinpointing ITGB4, LAMA3, and LAMB3 as genes differentially expressed in the initial stages of the partial versus high EMT trajectories. We also found that CENPF, CKS1B, and MKI67 showed significant upregulation in the high EMT trajectory. While the first group of genes aligns with findings from previous studies, our work uniquely pinpoints the precise timing of these upregulations. Finally, the identification of the latter group of genes sheds light on potential cell cycle targets for modulating EMT trajectories.

The Influencing Factors of Implementation in Emergency Medical Service Systems - A Scoping Review.

OBJECTIVES: Emergency medical services (EMS) provide health care in situations with limited time and resources. Challenges arise when introducing novel medications, treatments, or technologies or modifying existing practices in these settings. Effective implementation strategies are pivotal for their success. This study aims to identify and categorize potential facilitators and barriers in the implementation of prehospital EMS through a review of relevant research articles. METHODS: We searched PubMed and EMbase to identify studies published before December 2023, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for our search strategy and scoping review. We included original articles written in English that report on the factors that influence the implementation in prehospital settings. We extracted and categorized the factors into different themes. RESULTS: Out of the 371 retrieved papers, we selected 19 (5%) for inclusion in this review. We extracted 46 influencing factors from the selected articles and categorized them into ten themes: (1) Outer system, (2) Inner system, (3) Practitioner characteristics, (4) Resources, (5) Communication and collaboration, (6) Patient factors, (7) Intervention characteristics, (8) De-implementation of prior practices, (9) Logistical issues, and (10) Quality improvement. CONCLUSIONS: This study examined the literature on EMS implementation factors and proposed a 10-theme EMS model framework. Key factors include training/education, equipment/tools, communication with hospitals, and practitioners' attitudes.

A Validated Estimate of Visceral Adipose Tissue Volume in Relation to Cancer Risk.

BACKGROUND: Despite the recognized role of visceral adipose tissue (VAT) in carcinogenesis, its independent association with cancer risk beyond traditional obesity measures remains unknown due to limited availability of imaging data. METHODS: We developed an estimation equation for VAT volume (L) using Elastic Net Regression based on demographic and anthropometric data in a subcohort of participants in the UK Biobank (UKB; N = 23,148) with abdominal MRI scans. This equation was externally validated in 2,713 participants from the 2017-2018 National Health and Nutrition Examination Survey (NHANES) according to sex, age, and race groups. We then applied the equation to the overall UKB cohort of 461,665 participants to evaluate the prospective association between estimated VAT (eVAT) and cancer risk using Cox proportional hazards models. We also calculated the population attributable risk (PAR) of cancer associated with eVAT and BMI. RESULTS: eVAT showed a high correlation with measured VAT in internal and external validations (r = 0.81-0.86). During a median 12-year follow-up in the UKB, we documented 37,397 incident cancer cases; eVAT was significantly associated with elevated risk of obesity-related and individual cancers, independent of BMI and waist circumference. PAR for total cancer associated with high (quartiles 2-4 vs 1) eVAT (9.0-11.6%) was higher than high BMI (Q2-4 vs 1; 5.0-8.2%). CONCLUSIONS: eVAT showed robust performance in both UKB and NHANES and was associated with cancer risk independent of BMI and waist circumference. This study provides a potential clinical tool for VAT estimation and underscores that VAT can be an important target for cancer prevention.

Elucidating the Transition of 3D Morphological Evolution of Binary Alloys in Molten Salts with Metal Ion Additives.

Molten salts serve as effective high-temperature heat transfer fluids and thermal storage media used in a wide range of energy generation and storage facilities, including concentrated solar power plants, molten salt reactors and high-temperature batteries. However, at the salt-metal interfaces, a complex interplay of charge-transfer reactions involving various metal ions, generated either as fission products or through corrosion of structural materials, takes place. Simultaneously, there is a mass transport of ions or atoms within the molten salt and the parent alloys. The precise physical and chemical mechanisms leading to the diverse morphological changes in these materials remain unclear. To address this knowledge gap, this work employed a combination of synchrotron X-ray nanotomography and electron microscopy to study the morphological and chemical evolution of Ni-20Cr in molten KCl-MgCl2, while considering the influence of metal ions (Ni2+, Ce3+, and Eu3+) and variations in salt composition. Our research suggests that the interplay between interfacial diffusivity and reactivity determines the morphological evolution. The summary of the associated mass transport and reaction processes presented in this work is a step forward toward achieving a fundamental comprehension of the interactions between molten salts and alloys. Overall, the findings offer valuable insights for predicting the diverse chemical and structural alterations experienced by alloys in molten salt environments, thus aiding in the development of protective strategies for future applications involving molten salts.

Mitochondrial copper overload promotes renal fibrosis via inhibiting pyruvate dehydrogenase activity.

Copper is a trace element essential for numerous biological activities, whereas the mitochondria serve as both major sites of intracellular copper utilization and copper reservoir. Here, we investigated the impact of mitochondrial copper overload on the tricarboxylic acid cycle, renal senescence and fibrosis. We found that copper ion levels are significantly elevated in the mitochondria in fibrotic kidney tissues, which are accompanied by reduced pyruvate dehydrogenase (PDH) activity, mitochondrial dysfunction, cellular senescence and renal fibrosis. Conversely, lowering mitochondrial copper levels effectively restore PDH enzyme activity, improve mitochondrial function, mitigate cellular senescence and renal fibrosis. Mechanically, we found that mitochondrial copper could bind directly to lipoylated dihydrolipoamide acetyltransferase (DLAT), the E2 component of the PDH complex, thereby changing the interaction between the subunits of lipoylated DLAT, inducing lipoylated DLAT protein dimerization, and ultimately inhibiting PDH enzyme activity. Collectively, our study indicates that mitochondrial copper overload could inhibit PDH activity, subsequently leading to mitochondrial dysfunction, cellular senescence and renal fibrosis. Reducing mitochondrial copper overload might therefore serve as a strategy to rescue renal fibrosis.

GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the Hedgehog cascade.

During Hedgehog (Hh) signal transduction in development and disease, the atypical G protein-coupled receptor (GPCR) SMOOTHENED (SMO) communicates with GLI transcription factors by binding the protein kinase A catalytic subunit (PKA-C) and physically blocking its enzymatic activity. Here, we show that GPCR kinase 2 (GRK2) orchestrates this process during endogenous mouse and zebrafish Hh pathway activation in the primary cilium. Upon SMO activation, GRK2 rapidly relocalizes from the ciliary base to the shaft, triggering SMO phosphorylation and PKA-C interaction. Reconstitution studies reveal that GRK2 phosphorylation enables active SMO to bind PKA-C directly. Lastly, the SMO-GRK2-PKA pathway underlies Hh signal transduction in a range of cellular and in vivo models. Thus, GRK2 phosphorylation of ciliary SMO and the ensuing PKA-C binding and inactivation are critical initiating events for the intracellular steps in Hh signaling. More broadly, our study suggests an expanded role for GRKs in enabling direct GPCR interactions with diverse intracellular effectors.

Source-independent quantum secret sharing with entangled photon pair networks.

The large-scale deployment of quantum secret sharing (QSS) in quantum networks is currently challenging due to the requirements for the generation and distribution of multipartite entanglement states. Here we present an efficient source-independent QSS protocol utilizing entangled photon pairs in quantum networks. Through the post-matching method, which means the measurement events in the same basis are matched, the key rate is almost independent of the number of participants. In addition, the unconditional security of our QSS against internal and external eavesdroppers can be proved by introducing an equivalent virtual protocol. Our protocol has great performance and technical advantages in future quantum networks.