Mitochondrial 'Birth-Death' coordinator: An intelligent hydrogen nanogenerator to enhance intervertebral disc regeneration.

Currently, mitochondrial dysfunction caused by oxidative stress is a growing concern in degenerative diseases, notably intervertebral disc degeneration (IVDD). Dysregulation of the balance of mitochondrial quality control (MQC) has been considered the key contributor, while it's still challenging to effectively harmonize different MQC components in a simple and biologically safe way. Hydrogen gas (H2) is a promising mitochondrial therapeutic molecule due to its bio-reductivity and diffusibility across cellular membranes, yet its relationship with MQC regulation remains unknown. Herein, we propose a mitochondrial 'Birth-Death' coordinator achieved by an intelligent hydrogen nanogenerator (Fe@HP-OD), which can sustainably release H2 in response to the unique microenvironment in degenerated IVDs. Both in vitro and in vivo results prove alleviation of cellular oxidative stress and restoration of nucleus pulposus cells function, thereby facilitating successful IVD regeneration. Significantly, this study for the first time proposes the mitochondrial 'Birth-Death' coordination mechanism: 1) attenuation of overactivated mitochondrial 'Death' process (UPRmt and unselective mitophagy); and 2) activation of Adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway for mitochondrial 'Birth-Death' balance (mitochondrial biogenesis and controlled mitophagy). These pioneering findings can fill in the gaps in molecular mechanisms for H2 regulation on MQC homeostasis, and pave the way for future strategies towards restoring equilibrium of MQC system against degenerative diseases.

A simple and rapid spectrophotometric method for the determination of trans-chalcone in raw-materialand topical formulation / Método espectrofotométrico simples e rápido paradeterminação de trans-chalcona em matéria-primae em formulação tópica

Trans-chalcone (TC) is a flavonoid precursor characterized by a wide spectrum of action, with anti-inflammatory and antioxidant effects. However, no validated methods are available in official compendia for the analysis of this substance. Thus, the aim of this work was to develop and validate a simple, fast, and reproducible spectrophotometric method for the analysis of TC in raw material, and in topical pharmaceutical formulation containing TC. The established conditions were: methanol as extracting solvent, and detection wavelength of 309 nm by UV spectrophotometer. All tests followed the rules of Resolution RDC 166, 2017. The proposed method was selective. Linearity was demonstrated in the concentration range of 1 to 8 µg/mL (r = 0.999). Repeatability and intermediate precision were confirmed by low relative standard deviation values of 1.53% and 2.70% for TC, and of 1.73% and 2.91% for formulation containing TC. Accuracy, evaluated through recovery test, was adequate, with minimum of 98.24% and maximum of 100.23% of recovery. It was observed that the small deliberate modifications done did not interfere with the results, demonstrating the method is robust. The results showed that the method was considered suitable for the intended purpose, inexpensive, easy to apply, selective, linear, precise, accurate, and robust for the determination TC, and pharmaceutical formulation containing TC. Thus, the method developed satisfies the need for an analytical method for the determination of TC, and topical formulation containing TC, being effective, innovative and able to aid in the development of the pharmaceutical field.

Trans-chalcona (TC) é um precursor de flavonoides caracterizado por um amplo espectro de ação, como efeitos anti-inflamatórios e antioxidantes. No entanto, não há método validado disponível em compêndio oficial para análise deste composto. Então, o objetivo deste trabalho foi desenvolver e validar um método espectrofotométrico, simples, rápido e reprodutível para análise de TC em matéria-prima, e em formulação farmacêutica tópica contendo TC. As condições estabelecidas foram: metanol como o solvente de extração, e detecção no comprimento de onda de 309 nm por espectrofotometria no UV. Todos os testes seguiram as normas da RDC 166, 2017. O método proposto foi seletivo. A linearidade foi demonstrada na faixa de concentração de 1 a 8 µg/mL (r = 0.999). A repetibilidade e a precisão intermediária foram confirmadas pelos valores baixos de desvio padrão relativo de 1,53% e 2,70% para a TC, e de 1,73% e 2,91% para a formulação contendo TC. A exatidão, avaliada por meio de testes de recuperação, foi adequada, com mínimo de 98,24% e máximo de 100,04% de recuperação. Observou-se que pequenas modificações no método não interferiram nos resultados, demonstrando que o método é robusto. Os resultados demonstraram que o método foi adequado para a finalidade pretendida, barato, de fácil aplicação, seletivo, linear, preciso, exato e robusto para determinação de TC, e de formulação contendo TC. Então o método desenvolvido satisfaz as necessidades de um método analítico para determinação de TC, e de formulação tópica contendo TC, e é eficaz, inovador e pode contribuir para o desenvolvimento da área farmacêutica.

The cluster analysis of traditional Chinese medicine authenticity identification technique assisted by chemometrics.

This study explore the authenticity identification technique of traditional Chinese medicine (TCM) using chemometrics in conjunction with cluster analysis. A clustering Gaussian mixture model was constructed and applied for the data clustering analysis of four types of TCM. Chemical measurements combined with discrete wavelet transform (DWT), Fourier transform infrared spectroscopy (FTIR), and Fourier self-deconvolution (FSD) were utilized for the detailed differentiation of Bupleurum scorzonerifolium, Bupleurum yinchowense, Bupleurum marginatum, and Bupleurum smithii Wolff var. parvifolium. Differences in the attenuated total reflection-FTIR (ATR-FTIR) spectra among the four TCMs were observed. Utilizing clustering algorithms, the one-dimensional DWT of the infrared spectra of samples was employed for the authentication of Chinese herbal medicines. The model demonstrates optimal performance throughout 2000 rounds of network training. The accuracy (88.6 %), sensitivity (86.5 %), and specificity (82.7 %) of the model constructed in this study significantly surpassed those of the CNN model: accuracy (67.7 %), sensitivity (70.4 %), and specificity (68.5 %) (P < 0.05). By setting the cluster size K = 5 and the number of Gaussian mixture model components to 5, the model effectively fits the actual number of categories within the dataset. Infrared spectroscopy analysis revealed distinct carbon-oxygen stretching vibration absorption peaks between 1025 and 1200 cm-1 for Bupleurum scorzonerifolium, Bupleurum yinchowense, Bupleurum marginatum, and Bupleurum smithii Wolff var. parvifolium, indicating strong absorption peaks of carbohydrates. A comprehensive structural information analysis revealed a similarity of above 0.982 among the four types of TCM. Combined with chemometrics and intelligent algorithm-based cluster analysis, successful and accurate authentication of TCM authenticity was achieved, providing an effective methodology for quality control in TCM.

Pipette-tip kapok fiber-based solid-phase extraction/in-situ derivatization for the rapid and green analysis of furfural compounds.

Furfural compounds, including 5-hydroxymethylfurfural, furfural, and 5-methylfurfural, are common in foods and pose health risks. This study presents a pipette-tip solid-phase extraction with in-situ derivatization (PT-KF-SPE/ISD) method for rapid analysis of furfural compounds in various food matrices. Utilizing natural kapok fiber as an efficient adsorbent, this method integrates extraction and derivatization into a single step via a simple pull-push operation. Derivatization with 2,4-dinitrophenylhydrazine increases the hydrophobicity and ultraviolet absorption of furfural compounds, enabling sensitive liquid chromatography-ultraviolet detection. The method shows good linearity, sensitivity, and reproducibility, with limits of detection in ranges of 3.9-6.0 ng/mL. Real sample analysis confirms its applicability in detecting furfural compounds in beverages and herbal products, offering a reliable and eco-friendly solution for food safety and quality control. Five greenness assessment metrics demonstrate the method's excellent environmental friendliness. This approach highlights the advantages of combining natural adsorbents with in-situ derivatization for efficient food analysis.

Lonicerae Japonicae Flos with the homology of medicine and food: a review of active ingredients, anticancer mechanisms, pharmacokinetics, quality control, toxicity and applications.

Lonicerae Japonicae Flos (LJF, called Jinyinhua in China), comes from the dried flower buds or flowers to be opened of Lonicera japonica Thunb. in the Lonicera family. It has a long history of medicinal use and has a wide range of application prospects. As modern research advances, an increasing number of scientific experiments have demonstrated the anticancer potential of LJF. However, there is a notable absence of systematic reports detailing the anti-tumor effects of LJF. This review integrates the principles of Traditional Chinese Medicine (TCM) with contemporary pharmacological techniques, drawing upon literature from authoritative databases such as PubMed, CNKI, and WanFang to conduct a comprehensive study of LJF. Notably, a total of 507 compounds have been isolated and characterized from the plant to date, which include volatile oils, organic acids, flavonoids, iridoids, triterpenes and triterpenoid saponins. Pharmacological studies have demonstrated that LJF extract, along with components such as chlorogenic acid, luteolin, rutin, luteoloside, hyperoside and isochlorogenic acid, exhibits potential anticancer activities. Consequently, we have conducted a comprehensive review and summary of the mechanisms of action and clinical applications of these components. Furthermore, we have detailed the pharmacokinetics, quality control, and toxicity of LJF, while also discussing its prospective applications in the fields of biomedicine and preventive healthcare. It is hoped that these studies will provide valuable reference for the clinical research, development, and application of LJF.

Simultaneous Determination of Ethanol and Methanol in Wines Using FTIR and PLS Regression.

Accurate quantification of ethanol and methanol is essential for regulatory compliance and product quality assurance. Fourier Transform Infrared Spectroscopy (FTIR) offers rapid, non-destructive analysis with minimal sample preparation, making it a promising tool for wine analysis. In this exploratory study, the use of FTIR and PLS regression for the simultaneous quantification of ethanol and methanol in wine samples of 11 different Portuguese mono-varietal wines and different vintages deriving from the same winery in Lisbon was investigated. A model was developed, demonstrating the feasibility of FTIR and PLS regression for the simultaneous quantification of ethanol and methanol in wine samples through dedicated models; it showed good prediction capacity for ethanol determination but poorer performance for methanol quantification. The model could be reliable enough for quality control in wine production, but to improve its performance should be enhanced in the future with more samples from different origins, wine types, and a wider concentration range in the case of methanol.

Establishment of a Reference Material in Quality Control for Use in Infectivity and Identity Assays of Recombinant COVID-19 Vaccine, in Accordance with International Standards Organization Guidance.

The COVID-19 pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), began in 2019. One of the strategies for pandemic control was mass vaccination. In Brazil, the recombinant COVID-19 vaccine (RCV) was produced on a large scale and offered at no charge to the population. The specifications for quality control analyses of RCV included identity and infectivity determination. To validate the results, a reference material (RM) must be analyzed in parallel with the sample vaccine. This research aimed to establish the RM for use in the identity and infectivity assay for RCV. The candidate RM was analyzed using homogeneity and stability studies. The RM was considered homogeneous for identity (cycle threshold (Ct) ≤ 25.19) and infectivity (average x- was 9.25 log10 infectious units/mL). The RM was considered adequately stable for identity during the total period in all studies, being stable at -70, 5, and 22.5 °C for 380, 313, and 14 days, respectively (Ct ≤ 21.81). For infectivity, the RM was stable at -70, 5, and 22.5 °C for 380, 97, and three days, respectively. Since the property identity and infectivity values of the RM were established, the new RM could be used in quality control analysis.

Application of handheld near infrared spectrometer in quality control of traditional Chinese medicine: Rapid screening and quantitative analysis of Lonicerae Japonicae Flos adulteration.

Traditional Chinese medicine (TCM) prescription, with its intricate formulations and nuanced compositions, is a cornerstone of holistic health practices. However, the expansion of the TCM market has led to a surge in herb adulteration, which significantly undermines the quality and safety of these medicinal products. A case in point is Lonicerae Japonicae Flos (LJF), a widely utilized herb for treating colds, which has been adulterated by the cheaper Lonicerae Flos (LF), thereby affecting its therapeutic effectiveness. Therefore, a method utilizing handheld NIR spectroscopy combined with chemometrics has been developed to provide a portable, real-time solution for the rapid and accurate detection and quantification of adulterants in TCM. By collecting NIR spectra from LJF, LF and adulterated samples (AS), we've established a spectral database enabling deep insights into the correlation between spectral features and sample compositions. Resultantly, a classification model with a 99.58 % cross-validation accuracy, reaching 100 % for test set, effectively identified adulterants. And further spectral similarity analysis and classification identification of samples with different adulteration ratios were carried out. The cross-validation accuracy under the optimal model reached 98.38 %, and the test set accuracy was 99.20 %. In addition, the study extends to quantifying different levels of adulteration, employing 20 standard adulterated samples across a 0-100 % adulteration gradient. Via data preprocessing, feature extraction, and regression techniques, the full concentration prediction models were developed, later refined by segmenting samples based on high and low adulteration ratios. Under the SGFD_CARS_PLS (Savitzky-Golay smoothing with the first derivative_competitive adaptive reweighted sampling_partial least squares) model, exceptional performance was achieved, with a R2p of 0.983, RMSEp of 3.402, and RPDp of 7.757 for the homemade adulterated prediction set. In conclusion, the application of this technology not only improves the efficiency and accuracy of screening, but also has the advantages of low cost, easy operation and rapid results compared with traditional chemical analysis methods. It effectively protects the safety of drugs for consumers, maintains the integrity of the TCM market, and provides a strong technical support for the on-site rapid detection of TCM.

Irisin Protects Musculoskeletal Homeostasis via a Mitochondrial Quality Control Mechanism.

Irisin, a myokine derived from fibronectin type III domain-containing 5 (FNDC5), is increasingly recognized for its protective role in musculoskeletal health through the modulation of mitochondrial quality control. This review synthesizes the current understanding of irisin's impact on mitochondrial biogenesis, dynamics, and autophagy in skeletal muscle, elucidating its capacity to bolster muscle strength, endurance, and resilience against oxidative-stress-induced muscle atrophy. The multifunctional nature of irisin extends to bone metabolism, where it promotes osteoblast proliferation and differentiation, offering a potential intervention for osteoporosis and other musculoskeletal disorders. Mitochondrial quality control is vital for cellular metabolism, particularly in energy-demanding tissues. Irisin's influence on this process is highlighted, suggesting its integral role in maintaining cellular homeostasis. The review also touches upon the regulatory mechanisms of irisin secretion, predominantly induced by exercise, and its systemic effects as an endocrine factor. While the therapeutic potential of irisin is promising, the need for standardized measurement techniques and further elucidation of its mechanisms in humans is acknowledged. The collective findings underscore the burgeoning interest in irisin as a keystone in musculoskeletal health and a candidate for future therapeutic strategies.

Botany, Traditional Use, Phytochemistry, Pharmacology and Quality Control of Taraxaci herba: Comprehensive Review.

Taraxaci herba, as a traditional Chinese medicine, is the name of the Taraxacum genus in the Asteraceae family. Documented in the Tang Herbal Medicine (Tang Dynasty, AD 657-659), its medicinal properties cover a wide range of applications such as acute mastitis, lung abscess, conjunctival congestion, sore throat, damp-heat jaundice, and vision improvement. In the Chinese Pharmacopoeia (Edition 2020), more than 40 kinds of China-patented drugs containing Taraxaci herba were recorded. This review explores the evolving scientific understanding of Taraxaci herba, covering facets of ethnopharmacology, botany, phytochemistry, pharmacology, artificial cultivation, and quality control. In particular, the chemical constituents and pharmacological research are reviewed. Taraxaci herba has been certified as a traditional medicine plant, and its flavonoids, phenolic acids, and terpenoids have been identified and separated, which include Chicoric acid, taraxasterol, Taraxasteryl acetate, Chlorogenic acid, isorhamnetin, and luteolin; they are responsible for anti-inflammatory, antioxidant, antibacterial, anti-tumor, and anti-cancer activities. These findings validate the traditional uses of Taraxaci herba and lay the groundwork for further scientific exploration. The sources used in this study include Web of Science, Pubmed, the CNKI site, classic monographs, the Chinese Pharmacopoeia, the Chinese Medicine Dictionary, and doctoral and master's theses.

Applications of Capillary Electrophoresis for the Detection of Adulterants in Dietary Supplements.

In recent years, the consumption of dietary supplements, particularly those incorporating plant-based ingredients, has increased greatly, driven by the perception of their natural origins and purported minimal health risks. However, one significant safety concern revolves around the adulteration of dietary supplements, wherein unscrupulous manufacturers may illegally incorporate pharmaceutical substances or their analogs into these products to achieve increased efficiency and bolster sales. This review assesses the role of capillary electrophoresis (CE) in ensuring the quality control of dietary supplement products over the past two decades. This study provides an overview of various applications of CE in analyzing dietary supplements, outlining the typical attributes of natural product analysis using CE. These analyses demonstrate the broad versatility of CE, exemplified by its diverse applications and detection modes. Moreover, the review highlights the growing prominence of CE as a separation technique in quality control, by comparison with more conventional methods like high-performance liquid chromatography (HPLC). Through this exploration, the review elucidates the pivotal role of CE in upholding the integrity and safety of dietary supplements, in connection with a landscape of evolving regulatory challenges and consumer demands.

Qualitative and Quantitative Analysis of Phytochemicals in Sayeok-Tang via UPLC-Q-Orbitrap-MS and UPLC-TQ-MS/MS.

Sayeok-tang (SYT) is a traditional herbal formula comprising three medicinal herbs: Glycyrrhiza uralensis, Zingiber officinale, and Aconitum carmichaeli. Several studies have employed liquid chromatography-mass spectrometry (LC-MS) to qualitatively analyze the components and metabolites of SYT in vitro and in vivo; however, studies on quantitative analysis of SYT, which is important for quality control, are absent or limited to only a few components. In this study, ultrahigh-performance liquid chromatography coupled with quadrupole (UPLC-Q)-Orbitrap-MS was used to screen the phytochemicals of SYT, revealing a total of 42 compounds. Among them, 24 compounds were simultaneously quantified within 20 min via UPLC-TQ-MS/MS in the multiple reaction monitoring mode. The developed analytical method was validated for its linearity (r2 ≥ 0.9992), precision (0.36-2.96%), accuracy (-6.52-4.64%), and recovery (94.39-119.07%) for all analytes, exhibiting acceptable results. The validated method was applied in the analysis of SYT extracts, and the 24 compounds were quantified in the range of 0.004-6.882 mg/g (CV ≤ 3.746%). Among them, liquiritin apioside (6.870-6.933 mg/g), glycyrrhizic acid (5.418-5.540 mg/g), and liquiritin (1.303-1.331 mg/g) from G. uralensis were identified as the relatively abundant compounds. The presented validated analytical method is highly promising for the comprehensive quality control of SYT, offering fast, highly sensitive, and reliable analysis.

Evaluation of [68Ga]Ga-DOTA-AeK as a Potential Imaging Tool for PET Imaging of Cell Wall Synthesis in Bacterial Infections.

The ability of bacteria to recycle exogenous amino acid-based peptides and amino sugars for peptidoglycan biosynthesis was extensively investigated using optical imaging. In particular, fluorescent AeK-NBD was effectively utilized to study the peptidoglycan recycling pathway in Gram-negative bacteria. Based on these promising results, we were inspired to develop the radioactive AeK conjugate [68Ga]Ga-DOTA-AeK for the in vivo localization of bacterial infection using PET/CT. An easy-to-implement radiolabeling procedure for DOTA-AeK with [68Ga]GaCI3 followed by solid-phase purification was successfully established to obtain [68Ga]Ga-DOTA-AeK with a radiochemical purity of ≥95%. [68Ga]Ga-DOTA-AeK showed good stability over time with less protein binding under physiological conditions. The bacterial incorporation of [68Ga]Ga-DOTA-AeK and its fluorescent Aek-NBD analog were investigated in live and heat-killed Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Unfortunately, no conclusive in vitro intracellular uptake of [68Ga]Ga-DOTA-AeK was observed for E. coli or S. aureus live and heat-killed bacterial strains (p > 0.05). In contrast, AeK-NBD showed significantly higher intracellular incorporation in live bacteria compared to the heat-killed control (p < 0.05). Preliminary biodistribution studies of [68Ga]Ga-DOTA-AeK in a dual-model of chronic infection and inflammation revealed limited localization at the infection site with non-specific accumulation in response to inflammatory markers. Finally, our study demonstrates proof that the intracellular incorporation of AeK is necessary for successful bacteria-specific imaging using PET/CT. Therefore, Ga-68 was not a suitable radioisotope for tracing the bacterial uptake of AeK tripeptide, as it required chelation with a bulky metal chelator such as DOTA, which may have limited its active membrane transportation. An alternative for optimization is to explore diverse chemical structures of AeK that would allow for radiolabeling with 18F or 11C.

Latent Diffusion Models to Enhance the Performance of Visual Defect Segmentation Networks in Steel Surface Inspection.

This paper explores the use of state-of-the-art latent diffusion models, specifically stable diffusion, to generate synthetic images for improving the robustness of visual defect segmentation in manufacturing components. Given the scarcity and imbalance of real-world defect data, synthetic data generation offers a promising solution for training deep learning models. We fine-tuned stable diffusion using the LoRA technique on the NEU-seg dataset and evaluated the impact of different ratios of synthetic to real images on the training set of DeepLabV3+ and FPN segmentation models. Our results demonstrated a significant improvement in mean Intersection over Union (mIoU) when the training dataset was augmented with synthetic images. This study highlights the potential of diffusion models for enhancing the quality and diversity of training data in industrial defect detection, leading to more accurate and reliable segmentation results. The proposed approach achieved improvements of 5.95% and 6.85% in mIoU of defect segmentation on each model over the original dataset.

Application of High-Resolution Infrared Thermography to Study the Effects of Technologically Processed Antibodies on the Near-Surface Layer of Aqueous Solutions.

A new class of biologics is obtained using the technologically processed of antibodies (TPA), which are used as the initial substance, and their dilution at each stage is accompanied by a controlled external vibrational (mechanical) treatment. This article focuses on the development and validation of a novel technique that can be applied for assessing the identity of TPA-based drugs. It has previously been found that after such treatment, the resulting solution either acquired new properties that were not present in the initial substance or a quantitative change in properties compared to the initial substance was observed. The use of mechanical treatment during the manufacture of the TPA-based drugs can cause the formation of new bonds between the solvent and antibody molecules. These changes manifest themselves in altered adsorption at the surface of the test solutions, which results in the formation of a near-surface film. One of the indicators of such events is the change in the surface temperature of the solution, which can be analyzed using high-resolution thermography. Unlike other methods, the high-resolution thermography allows the near-surface layer of a heterogeneous aqueous solution to be clearly visualized and quantified. A number of experiments were performed: seven replicates of sample preparations were tested; the influence of factors "day" or "operator" was investigated during 12 days of testing by two operators. The method also allowed us to distinguish between technologically processed antibodies and samples containing technologically processed buffer. The thermographic analysis has proven to be a simple, specific, and reproducible technique that can be used to analyze the identity of TPA-based drugs, regardless of the dosage form tested.

Lysosome quality control in health and neurodegenerative diseases.

Lysosomes are acidic organelles involved in crucial intracellular functions, including the degradation of organelles and protein, membrane repair, phagocytosis, endocytosis, and nutrient sensing. Given these key roles of lysosomes, maintaining their homeostasis is essential for cell viability. Thus, to preserve lysosome integrity and functionality, cells have developed a complex intracellular system, called lysosome quality control (LQC). Several stressors may affect the integrity of lysosomes, causing Lysosomal membrane permeabilization (LMP), in which membrane rupture results in the leakage of luminal hydrolase enzymes into the cytosol. After sensing the damage, LQC either activates lysosome repair, or induces the degradation of the ruptured lysosomes through autophagy. In addition, LQC stimulates the de novo biogenesis of functional lysosomes and lysosome exocytosis. Alterations in LQC give rise to deleterious consequences for cellular homeostasis. Specifically, the persistence of impaired lysosomes or the malfunctioning of lysosomal processes leads to cellular toxicity and death, thereby contributing to the pathogenesis of different disorders, including neurodegenerative diseases (NDs). Recently, several pieces of evidence have underlined the importance of the role of lysosomes in NDs. In this review, we describe the elements of the LQC system, how they cooperate to maintain lysosome homeostasis, and their implication in the pathogenesis of different NDs.

Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways.

A hallmark of neurodegenerative diseases is the progressive loss of proteostasis, leading to the accumulation of misfolded proteins or protein aggregates, with subsequent cytotoxicity. To combat this toxicity, cells have evolved degradation pathways (ubiquitin-proteasome system and autophagy) that detect and degrade misfolded proteins. However, studying the underlying cellular pathways and mechanisms has remained a challenge, as formation of many types of protein aggregates is asynchronous, with individual cells displaying distinct kinetics, thereby hindering rigorous time-course studies. Here, we merge a kinetically tractable and synchronous agDD-GFP system for aggregate formation with targeted gene knockdowns, to uncover degradation mechanisms used in response to acute aggregate formation. We find that agDD-GFP forms amorphous aggregates by cryo-electron tomography at both early and late stages of aggregate formation. Aggregate turnover occurs in a proteasome-dependent mechanism in a manner that is dictated by cellular aggregate burden, with no evidence of the involvement of autophagy. Lower levels of misfolded agDD-GFP, enriched in oligomers, utilizes UBE3C-dependent proteasomal degradation in a pathway that is independent of RPN13 ubiquitylation by UBE3C. Higher aggregate burden activates the NRF1 transcription factor to increase proteasome subunit transcription, and subsequent degradation capacity of cells. Loss or gain of NRF1 function alters the turnover of agDD-GFP under conditions of high aggregate burden. Together, these results define the role of UBE3C in degradation of this class of misfolded aggregation-prone proteins and reveals a role for NRF1 in proteostasis control in response to widespread protein aggregation.

Ageing, proteostasis, and the gut: Insights into neurological health and disease.

Recent research has illuminated the profound bidirectional communication between the gastrointestinal tract and the brain, furthering our understanding of neurological ailments facilitating possible therapeutic strategies. Technological advancements in high-throughput sequencing and multi-omics have unveiled significant alterations in gut microbiota and their metabolites in various neurological disorders. This review provides a thorough analysis of the role of microbiome-gut-brain axis in neurodegenerative disease pathology, linking it to reduced age-associated proteostasis. We discuss evidences that substantiate the existence of a gut-brain cross talk ranging from early clinical accounts of James Parkinson to Braak's hypothesis. In addition to understanding of microbes, the review particularly entails specific metabolites which are altered in neurodegenerative diseases. The regulatory effects of microbial metabolites on protein clearance mechanisms, proposing their potential therapeutic implications, are also discussed. By integrating this information, we advocate for a combinatory therapeutic strategy that targets early intervention, aiming to restore proteostasis and ameliorate disease progression. This approach not only provides a new perspective on the pathogenesis of neurodegenerative diseases but also highlights innovative strategies to combat the increasing burden of these age-related disorders.

[Legal and Practical Solutions for the Expanding the Roles of Medical Support Staff Nurses].

PURPOSE: Medical support staff nurses have traditionally performed various supportive tasks for physicians, often extending beyond standard nursing roles. Despite these long-standing practices, there is a notable lack of official recognition and legal protection for these expanded responsibilities, leading to increasing legal concerns. Therefore, there is a need for proposing a rational solution to address these issues. METHODS: The number of medical support staff nurses is rising, particularly as they fill gaps left by the 2024 resident physician strike. The study focuses on identifying potential challenges arising from this shift and developing strategic improvements to address these challenges effectively. RESULTS: This study proposed legally expanding the scope of nursing duties and creating a robust system for training and certifying nurses to handle these responsibilities effectively, by integrating these roles within the advanced practice nurse (APN) framework. CONCLUSION: Integrating these roles within the framework of APN can offer a sustainable and legally sound solution to the ongoing healthcare crisis, ensuring patient safety and safeguarding healthcare workers' legal rights.

A Set of FMRI Quality Control Tools in AFNI: Systematic, in-depth, and interactive QC with afni_proc.py and more.

Quality control (QC) assessment is a vital part of FMRI processing and analysis, and a typically underdiscussed aspect of reproducibility. This includes checking datasets at their very earliest stages (acquisition and conversion) through their processing steps (e.g., alignment and motion correction) to regression modeling (correct stimuli, no collinearity, valid fits, enough degrees of freedom, etc.) for each subject. There are a wide variety of features to verify throughout any single-subject processing pipeline, both quantitatively and qualitatively. We present several FMRI preprocessing QC features available in the AFNI toolbox, many of which are automatically generated by the pipeline-creation tool, afni_proc.py. These items include a modular HTML document that covers full single-subject processing from the raw data through statistical modeling, several review scripts in the results directory of processed data, and command line tools for identifying subjects with one or more quantitative properties across a group (such as triaging warnings, making exclusion criteria, or creating informational tables). The HTML itself contains several buttons that efficiently facilitate interactive investigations into the data, when deeper checks are needed beyond the systematic images. The pages are linkable, so that users can evaluate individual items across a group, for increased sensitivity to differences (e.g., in alignment or regression modeling images). Finally, the QC document contains rating buttons for each "QC block," as well as comment fields for each, to facilitate both saving and sharing the evaluations. This increases the specificity of QC, as well as its shareability, as these files can be shared with others and potentially uploaded into repositories, promoting transparency and open science. We describe the features and applications of these QC tools for FMRI.