T-bet deficiency and Hic1 induction override TGF-ß-dependency in the formation of CD103+ intestine-resident memory CD8+ T cells.

Transforming growth factor ß (TGF-ß) represents a well-established signal required for tissue-resident memory T cell (TRM) formation at intestinal surfaces, regulating the expression of a large collection of genes coordinately promoting intestinal TRM differentiation. The functional contribution from each TGF-ß-controlled transcription factor is not entirely known. Here, we find that TGF-ß-induced T-bet downregulation and Hic1 induction represent two critical events during intestinal TRM differentiation. Importantly, T-bet deficiency significantly rescues intestinal TRM formation in the absence of the TGF-ß receptor. Hic1 induction further strengthens TRM maturation in the absence of TGF-ß and T-bet. Our results reveal that provision of certain TGF-ß-induced molecular events can partially replace TGF-ß signaling to promote the establishment of intestinal TRMs, which allows the functional dissection of TGF-ß-induced transcriptional targets and molecular mechanisms for TRM differentiation.

Hydrazone-Linked Covalent Organic Frameworks.

Hydrazone-linked covalent organic frameworks (COFs) with structural flexibility, heteroatomic sites, post-modification ability and high hydrolytic stability have attracted great attention from scientific community. Hydrazone-linked COFs, as a subclass of Schiff-base COFs, was firstly reported in 2011 by Yaghi's group and later witnessed prosperous development in various aspects. Their adjustable structures, precise pore channels and plentiful heteroatomic sites of hydrazone-linked structures possess much potential in diverse applications, for example, adsorption/separation, chemical sensing, catalysis and energy storage, etc. Up to date, the systematic reviews about the reported hydrazone-linked COFs are still rare. Therefore, in this review, we will summarize their preparation methods, characteristics and related applications, and discuss the opportunity or challenge of hydrazone-linked COFs. We hope this review could provide new insights about hydrazone-linked COFs for exploring more appealing functions or applications.

Revealing intact neuronal circuitry in centimeter-sized formalin-fixed paraffin-embedded brain.

Tissue-clearing and labeling techniques have revolutionized brain-wide imaging and analysis, yet their application to clinical formalin-fixed paraffin-embedded (FFPE) blocks remains challenging. We introduce HIF-Clear, a novel method for efficiently clearing and labeling centimeter-thick FFPE specimens using elevated temperature and concentrated detergents. HIF-Clear with multi-round immunolabeling reveals neuron circuitry regulating multiple neurotransmitter systems in a whole FFPE mouse brain and is able to be used as the evaluation of disease treatment efficiency. HIF-Clear also supports expansion microscopy and can be performed on a non-sectioned 15-year-old FFPE specimen, as well as a 3-month formalin-fixed mouse brain. Thus, HIF-Clear represents a feasible approach for researching archived FFPE specimens for future neuroscientific and 3D neuropathological analyses.

Molecular mechanisms of secretory autophagy and its potential role in diseases.

Autophagy is a cellular degradation system that recycles or degrades damaged organelles, viral particles, and aggregated proteins through the lysosomal pathway. Autophagy plays an indispensable role in cellular homeostasis and communication processes. An interesting aspect is that autophagy also mediates the secretion of cellular contents, a process known as secretory autophagy. Secretory autophagy differs from macroautophagy, which sequesters recruited proteins, organelles, or viral particles into autophagosomes and degrades these sequesters in lysosomes, while the secretory autophagy pathway participates in the extracellular export of cellular contents sequestered by autophagosomes through autophagy and endosomal modulators. Recent evidence reveals that secretory autophagy is pivotal in the occurrence and progression of diseases. In this review, we summarize the molecular mechanisms of secretory autophagy. Furthermore, we review the impact of secretory autophagy on diseases, including cancer, viral infectious diseases, neurodegenerative diseases, and cardiovascular diseases. Considering the pleiotropic actions of secretory autophagy on diseases, studying the mechanism of secretory autophagy may help to understand the relevant pathophysiological processes.

Empowering personalized pharmacogenomics with generative AI solutions.

OBJECTIVE: This study evaluates an AI assistant developed using OpenAI's GPT-4 for interpreting pharmacogenomic (PGx) testing results, aiming to improve decision-making and knowledge sharing in clinical genetics and to enhance patient care with equitable access. MATERIALS AND METHODS: The AI assistant employs retrieval-augmented generation (RAG), which combines retrieval and generative techniques, by harnessing a knowledge base (KB) that comprises data from the Clinical Pharmacogenetics Implementation Consortium (CPIC). It uses context-aware GPT-4 to generate tailored responses to user queries from this KB, further refined through prompt engineering and guardrails. RESULTS: Evaluated against a specialized PGx question catalog, the AI assistant showed high efficacy in addressing user queries. Compared with OpenAI's ChatGPT 3.5, it demonstrated better performance, especially in provider-specific queries requiring specialized data and citations. Key areas for improvement include enhancing accuracy, relevancy, and representative language in responses. DISCUSSION: The integration of context-aware GPT-4 with RAG significantly enhanced the AI assistant's utility. RAG's ability to incorporate domain-specific CPIC data, including recent literature, proved beneficial. Challenges persist, such as the need for specialized genetic/PGx models to improve accuracy and relevancy and addressing ethical, regulatory, and safety concerns. CONCLUSION: This study underscores generative AI's potential for transforming healthcare provider support and patient accessibility to complex pharmacogenomic information. While careful implementation of large language models like GPT-4 is necessary, it is clear that they can substantially improve understanding of pharmacogenomic data. With further development, these tools could augment healthcare expertise, provider productivity, and the delivery of equitable, patient-centered healthcare services.

Epidemiology and risk factors of bloodstream infections among adolescents and young adults with acute lymphoblastic leukaemia: An 11-year retrospective cohort study.

Adolescent and young adults (AYAs) belong to a unique category of patients diagnosed with acute lymphoblastic leukaemia (ALL). Bloodstream infection (BSI) is a leading cause of treatment-related mortality in ALL patients. However, the epidemiology and risk factors for mortality from BSIs in AYA patients remain unclear. In this study, we analysed these aspects in AYAs patients and compared similarities and differences with children (<15 years old) and older adults (>39 years old). We analysed the pathogenic epidemiology, antibiotic resistance and BSI risk factors of 73 children, 180 AYAs, and 110 older adults with ALL in three comprehensive hospitals from January 2010 to August 2021. The data on BSIs in AYAs were compared to that of the other two groups. In this study, the epidemiology of BSIs in AYAs was similar to that of older adult patients. Concerning clinical characteristics, most AYAs and older adults with BSIs were in a relapsed or uncontrolled state (34.5% vs. 35.4%, p = 0.861). In terms of pathogen distribution, Gram-negative bacteria (GNB) were the most common causative pathogens in AYAs and older adult groups. Extended-spectrum beta-lactamase (ESBL)-producing bacteria were more commonly found in AYAs than in children (32.8% vs. 16.4%, p = 0.09). Regarding risk factors, the length of hospitalization (>14 days) and renal inadequacy (creatinine ≥ 177 µmol/L) were influencing factors for 30-day mortality in AYAs patients with BSIs. In our study, AYA patients with BSIs showed clinical characteristics and pathogen distributions similar to those of older adult patients but quite different from those of children.

Development and application of emotion recognition technology - a systematic literature review.

BACKGROUND: There is a mutual influence between emotions and diseases. Thus, the subject of emotions has gained increasing attention. OBJECTIVE: The primary objective of this study was to conduct a comprehensive review of the developments in emotion recognition technology over the past decade. This review aimed to gain insights into the trends and real-world effects of emotion recognition technology by examining its practical applications in different settings, including hospitals and home environments. METHODS: This study followed the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines and included a search of 4 electronic databases, namely, PubMed, Web of Science, Google Scholar and IEEE Xplore, to identify eligible studies published between 2013 and 2023. The quality of the studies was assessed using the Critical Appraisal Skills Programme (CASP) criteria. The key information from the studies, including the study populations, application scenarios, and technological methods employed, was summarized and analyzed. RESULTS: In a systematic literature review of the 44 studies that we analyzed the development and impact of emotion recognition technology in the field of medicine from three distinct perspectives: "application scenarios," "techniques of multiple modalities," and "clinical applications." The following three impacts were identified: (i) The advancement of emotion recognition technology has facilitated remote emotion recognition and treatment in hospital and home environments by healthcare professionals. (ii) There has been a shift from traditional subjective emotion assessment methods to multimodal emotion recognition methods that are grounded in objective physiological signals. This technological progress is expected to enhance the accuracy of medical diagnosis. (iii) The evolving relationship between emotions and disease throughout diagnosis, intervention, and treatment processes holds clinical significance for real-time emotion monitoring. CONCLUSION: These findings indicate that the integration of emotion recognition technology with intelligent devices has led to the development of application systems and models, which provide technological support for the recognition of and interventions for emotions. However, the continuous recognition of emotional changes in dynamic or complex environments will be a focal point of future research.

Cost-utility analysis of treating mild stage normal tension glaucoma by surgery in China: a decision-analytic Markov model.

BACKGROUND: Many individuals suffer from normal tension glaucoma (NTG) in China. This study utilized Markov models to evaluate the cost-utility of applying many medications and surgery for mild-stage NTG when disease progression occurred at a mild stage. METHODS: A 10-year decision-analytic Markov model was developed for the cost-utility analysis of treating mild-stage NTG with surgery and increased application of medication. We hypothesized that all 100,000 samples with a mean age of 64 were in mild stages of NTG. Transitional probabilities from the mild to moderate to severe stages and the basic parameters acquired from the CNTGS were calculated. Incremental cost-utility ratios (ICUR) were calculated for treating all patients with NTG by probabilistic sensitivity analysis (PSA) and Monte Carlo simulation. One-way sensitivity analysis were conducted by adjusting the progression rate, cost of medications or trabeculectomy, cost of follow-up, and surgical acceptance rate. RESULTS: The ICUR of treating mild stage NTG with medication over 10 years was $12743.93 per quality-adjusted life years (QALYs). The ICUR for treating mild stage NTG patients with a 25% and 50% surgery rate with medication were $8798.93 and $4851.93 per QALYs, respectively. In this model, the cost-utility of treating NTG was sensitive to disease progression rate, surgical treatment rate, and medication costs. CONCLUSIONS: According to the results of the cost-utility analysis, it was a reasonable and advantageous strategy to administer a lot of medication and surgery for NTG in the mild stages of the disease. In the model, the greater the probability of patients undergoing surgery, the strategy becomes more valuable.

An HDBB-based fluorescent probe for the sensitive detection of human serum albumin.

The detection of human serum albumin (HSA) in bodily fluids is of great significance in the biomedical area because HSA in bodily fluids is commonly used as a biomarker for the early diagnosis of diseases. To detect HSA, we employed HDBB, 4,4'-(hydrazine-1,2-diylidene bis(methanylylidene)) bis(3-hydroxybenzoic acid), as a fluorescent probe with a large Stokes shift. HDBB had obvious excited state intramolecular proton transfer (ESIPT) and aggregation-induced emission (AIE) features. We elucidated the ESIPT characteristics of HDBB through the DFT approach. We also performed a molecular docking simulation between HDBB and HSA, showing that HDBB primarily bonded to HSA via hydrophobic force and hydrogen bonds. The FL intensities of HDBB with HSA concentrations had a linear range of 0.01-0.2 mg mL-1 (R2 = 0.9995), and the LOD was 1.104 µg mL-1. We also used the probe to detect HSA in urine, with spiked recoveries of 98.10-105.33%. Given its high selectivity and feasible synthesis, HDBB has potential applications in detecting HSA in real biological systems.

BHLHE40 Inhibits Ferroptosis in Pancreatic Cancer Cells via Upregulating SREBF1.

Pancreatic cancer (PCa) is one of the most fatal human malignancies. The enhanced infiltration of stromal tissue into the PCa tumor microenvironment limits the identification of key tumor-specific transcription factors and epigenomic abnormalities in malignant epithelial cells. Integrated transcriptome and epigenetic multiomics analyses of the paired PCa organoids indicate that the basic helix-loop-helix transcription factor 40 (BHLHE40) is significantly upregulated in tumor samples. Increased chromatin accessibility at the promoter region and enhanced mTOR pathway activity contribute to the elevated expression of BHLHE40. Integrated analysis of chromatin immunoprecipitation-seq, RNA-seq, and high-throughput chromosome conformation capture data, together with chromosome conformation capture assays, indicate that BHLHE40 not only regulates sterol regulatory element-binding factor 1 (SREBF1) transcription as a classic transcription factor but also links the enhancer and promoter regions of SREBF1. It is found that the BHLHE40-SREBF1-stearoyl-CoA desaturase axis protects PCa cells from ferroptosis, resulting in the reduced accumulation of lipid peroxidation. Moreover, fatostatin, an SREBF1 inhibitor, significantly suppresses the growth of PCa tumors with high expressions of BHLHE40. This study highlights the important roles of BHLHE40-mediated lipid peroxidation in inducing ferroptosis in PCa cells and provides a novel mechanism underlying SREBF1 overexpression in PCa.

Decreased YB-1 expression denervates brown adipose tissue and contributes to age-related metabolic dysfunction.

Thermogenesis in brown adipose tissue (BAT) declines with aging, however, the underlying mechanism remains unclear. Here, we show that the expression of Y-box binding protein 1 (YB-1), a critical DNA/RNA binding protein, decreased in the BAT of aged mice due to the reduction of microbial metabolite butyrate. Genetic ablation of YB-1 in the BAT accelerated diet-induced obesity and BAT thermogenic dysfunction. In contrast, overexpression of YB-1 in the BAT of aged mice was sufficient to promote BAT thermogenesis, thus alleviating diet-induced obesity and insulin resistance. Interestingly, YB-1 had no direct effect on adipose UCP1 expression. Instead, YB-1 promoted axon guidance of BAT via regulating the expression of Slit2, thus potentiating sympathetic innervation and thermogenesis. Moreover, we have identified that a natural compound Sciadopitysin, which promotes YB-1 protein stability and nuclear translocation, alleviated BAT aging and metabolic disorders. Together, we reveal a novel fat-sympathetic nerve unit in regulating BAT senescence and provide a promising strategy against age-related metabolic disorders.

The effects of art therapy on quality of life and psychosomatic symptoms in adults with cancer: a systematic review and meta-analysis.

BACKGROUND: Cancer-related psychological and physical disorders can mean stressful and painful experiences for patients. Art therapy, a form of complementary and alternative medicine, is an increasingly popular way to decrease emotional stress, alleviate somatic symptoms, and improve quality of life in patients with cancer. However, current systematic reviews have not explored the beneficial effects of art therapy. Moreover, there have been inconsistent findings on the effect of this therapy, and there is insufficient evidence to confirm the effects in adults with cancer. The objective of this study was to determine the efficacy of art therapy in improving quality of life and psychosomatic symptoms in adults with cancer. METHODS: This systematic review and meta-analysis included adults with all kinds of cancer. Six English-language and three large Chinese-language databases were comprehensively searched for relevant studies. Gray literature and references were also checked. The quality of the included studies was evaluated using the Cochrane risk-of-bias assessment tool. RESULTS: Eight eligible randomized controlled trials conducted in four countries were included. Art therapy improved overall quality of life, but had no significant effect on psychological health or physical health sub-dimensions in women with cancer. Moreover, art therapy alleviated anxiety and depression, but had only a tendency toward an effect on somatic symptoms. CONCLUSIONS: Moderate-quality evidence shows that art therapy is beneficial for women with cancer in terms of improving the overall quality of life and alleviating emotional symptoms (anxiety and depression). However, more high-quality randomized controlled trials are needed to determine the efficacy of this therapy on somatic symptoms.

Towards practical single-shot phase retrieval with physics-driven deep neural network.

Phase retrieval (PR), a long-established challenge for recovering a complex-valued signal from its Fourier intensity-only measurements, has attracted considerable attention due to its widespread applications in optical imaging. Recently, deep learning-based approaches were developed and allowed single-shot PR. However, due to the substantial disparity between the input and output domains of the PR problems, the performance of these approaches using vanilla deep neural networks (DNN) still has much room to improve. To increase the reconstruction accuracy, physics-informed approaches were suggested to incorporate the Fourier intensity measurements into an iterative estimation procedure. Since the approach is iterative, they require a lengthy computation process, and the accuracy is still not satisfactory for images with complex structures. Besides, many of these approaches work on simulation data that ignore some common problems such as saturation and quantization errors in practical optical PR systems. In this paper, a novel physics-driven multi-scale DNN structure dubbed PPRNet is proposed. Similar to other deep learning-based PR methods, PPRNet requires only a single Fourier intensity measurement. It is physics-driven that the network is guided to follow the Fourier intensity measurement at different scales to enhance the reconstruction accuracy. PPRNet has a feedforward structure and can be end-to-end trained. Thus, it is much faster and more accurate than the traditional physics-driven PR approaches. Extensive simulations and experiments on an optical platform were conducted. The results demonstrate the superiority and practicality of the proposed PPRNet over the traditional learning-based PR methods.

Bone Marrow-Derived GCA+ Immune Cells Drive Alzheimer's Disease Progression.

Alzheimer's disease (AD) is an age-related degenerative disease of the central nervous system (CNS), whereas the role of bone marrow immune cells in the pathogenesis of AD remains unclear. Here, the study reveals that compared to matched healthy individuals, AD patients have higher circulating grancalcin (GCA) levels, which negatively correlate with cognitive function. Bone marrow-derived GCA+ immune cells, which secret abundant GCA and increase during aging, preferentially invaded the hippocampus and cortex of AD mouse model in a C-C Motif Chemokine Receptor 10 (CCR10)-dependent manner. Transplanting GCA+ immune cells or direct stereotaxic injection of recombinant GCA protein intensified amyloid plaque load and aggravated cognitive and memory impairments. In contrast, genetic ablation of GCA in the hematopoietic compartment improves cognitive and memory function. Mechanistically, GCA competitively binds to the low-density lipoprotein receptor-related protein 1 (LRP1) in microglia, thus inhibiting phagocytosis and clearance of Aß and potentiating neuropathological changes. Importantly, GCA-neutralizing antibody treatment rejuvenated cognitive and memory function and constrained AD progression. Together, the study demonstrates a pathological role of GCA+ immune cells instigating cognitive and memory decline, suggesting that GCA+ immune cells can be a potential target for innovative therapeutic strategies in AD.

Surgical treatment of severe anterior capsular organized hard core cataract: A case report.

BACKGROUND: Complicated cataract surgery is challenging, especially in cases of hard nuclear cataract with severe anterior capsule organization. It is important to avoid the risk of surgery and improve the surgical skills of surgeons. CASE SUMMARY: A 60-year-old man presented with severe cataract and visual impairment. The anterior capsule of the lens was irregularly organized and pulled to the surrounding capsule, and white porcelain organized cord and brown-black lens nucleus were clearly visible. In phacoemulsification, maintaining the anterior capsule round and intact plays a key role in a successful surgery. In this case, if the conventional capsule treatment method was used, the anterior capsule would be torn. Therefore, we adopted a segmented anterior capsule treatment method, and a blasting method to release energy when dealing with the lens nucleus, and achieved good surgical results. CONCLUSION: Complicated cataract surgery is challenging and requires precise skills. Operation plans should be made reasonably to predict the risk of surgery, and improve the visual quality of the patients.

Effects of Post-Annealing on the Properties of ZnO:Ga Films with High Transparency (94%) and Low Sheet Resistance (29 Ω/square).

This study presents gallium-doped zinc oxide (ZnO:Ga, GZO) thin films. GZO thin films with both high transparency and low sheet resistance were prepared by RF sputtering and then post-annealed under nitrogen and hydrogen forming gas. With post-annealing at 450 °C, the proposed films with a film thickness of 100 nm showed high transparency (94%), while the sheet resistance of the films was reduced to 29 Ω/square, which was comparable with the performances of commercial indium tin oxide (ITO) samples. Post-annealing under nitrogen and hydrogen forming gas enhanced the films' conductivity while altering the thin-film composition and crystallinity. Nitrogen gas played a role in improving the crystallinity while maintaining the oxygen vacancy of the proposed films, whereas hydrogen did not dope into the thin film, thus maintaining its transparency. Furthermore, hydrogen lowered the resistance of GZO thin films during the annealing process. Then, the detailed mechanisms were discussed. Hydrogen post-annealing helped in the removal of oxygen, therefore increasing the Ga3+ content, which provided extra electrons to lower the resistivity of the films. After the preferable nitrogen/hydrogen forming gas treatment, our proposed films maintained high transparency and low sheet resistance, thus being highly useful for further opto-electronic applications.