Isobavachalcone Exhibits Potent Antifungal Efficacy by Inhibiting Enolase Activity and Glycolysis in Candida albicans.

Invasive fungal diseases (IFDs) are becoming increasingly acknowledged as a significant concern linked to heightened rates of morbidity and mortality. Regrettably, the available antifungal therapies for managing IFDs are constrained. Emerging evidence indicates that enolase holds promise as a potential target protein for combating IFDs; however, there is currently a deficiency in antifungal medications specifically targeting enolase. This study establishes that isobavachalcone (IBC) exhibits noteworthy antifungal efficacy both in vitro and in vivo. Moreover, our study has demonstrated that IBC effectively targets Eno1 in Candida albicans (CaEno1), resulting in the suppression of the glycolytic pathway. Additionally, our research has indicated that IBC exhibits a higher affinity for CaEno1 compared to human Eno1 (hEno1), with the presence of isoprenoid in the side chain of IBC playing a crucial role in its ability to inhibit enolase activity. These findings contribute to the comprehension of antifungal approaches that target Eno1, identifying IBC as a potential inhibitor of Eno1 in human pathogenic fungi.

What enlightenment has the development of lung cancer bone metastasis brought in the last 22 years.

BACKGROUND: Lung cancer bone metastasis (LCBM) is a disease with a poor prognosis, high risk and large patient population. Although considerable scientific output has accumulated on LCBM, problems have emerged, such as confusing research structures. AIM: To organize the research frontiers and body of knowledge of the studies on LCBM from the last 22 years according to their basic research and translation, clinical treatment, and clinical diagnosis to provide a reference for the development of new LCBM clinical and basic research. METHODS: We used tools, including R, VOSviewer and CiteSpace software, to measure and visualize the keywords and other metrics of 1903 articles from the Web of Science Core Collection. We also performed enrichment and protein-protein interaction analyses of gene expression datasets from LCBM cases worldwide. RESULTS: Research on LCBM has received extensive attention from scholars worldwide over the last 20 years. Targeted therapies and immunotherapies have evolved into the mainstream basic and clinical research directions. The basic aspects of drug resistance mechanisms and parathyroid hormone-related protein may provide new ideas for mechanistic study and improvements in LCBM prognosis. The produced molecular map showed that ribosomes and focal adhesion are possible pathways that promote LCBM occurrence. CONCLUSION: Novel therapies for LCBM face animal testing and drug resistance issues. Future focus should centre on advancing clinical therapies and researching drug resistance mechanisms and ribosome-related pathways.

Work-Related Musculoskeletal Disorders in Endoscopic Sinus and Skull Base Surgery: A Systematic Review With Meta-analysis.

OBJECTIVE: Endoscopic sinus and skull base surgery has led to significant improvements in patient outcomes, yet may have come at a cost to surgeons' musculoskeletal (MSK) health. We aimed to determine the prevalence and characteristics of work-related MSK disorders (WRMDs) in endoscopic sinus and skull base surgeons; to investigate contributing factors for WRMD in this population; and to evaluate the effectiveness of ergonomic interventions on the severity or prevalence of WRMD in this population. DATA SOURCES: Medline, Embase, CINAHL, Web of Science, and Scopus from inception to April 2, 2024. A bibliographic examination was performed for further papers. REVIEW METHODS: Inclusion criteria included original peer-reviewed papers with work-related MSK outcomes (prevalence, contributing factors, and interventions) relating to endoscopic sinus and/or skull base surgeons in any language. RESULTS: Of 25,772 unique citations, 37 studies met the inclusion criteria. The pooled lifetime, point, and 12-month prevalences of WRMD were 75.9% (95% confidence interval; I2, 67.2%-83.6%, I2 95.6%), 80.8% (77.0%-84.3%, I2 98.0%), and 82.0% (71.8%-90.3%, I2 60.96%) respectively. The neck, lumbar spine, and thoracic spine were the most commonly involved areas. One of 9 studies on contributing factors investigated discomfort as an outcome. The remainder focussed on surrogate outcomes (eg, posture, hand dysfunction). Two of the 13 intervention studies investigated pain or fatigue as an outcome. The remainder targeted posture, muscle activity, or workload. CONCLUSION: WRMDs are highly prevalent in endoscopic sinus and skull base surgeons. Further studies focusing on the direct outcomes of WRMD such as pain are needed.

Otilonium Bromide Exhibits Potent Antifungal Effects by Blocking Ergosterol Plasma Membrane Localization and Triggering Cytotoxic Autophagy in Candida Albicans.

Candidiasis, which presents a substantial risk to human well-being, is frequently treated with azoles. However, drug-drug interactions caused by azoles inhibiting the human CYP3A4 enzyme, together with increasing resistance of Candida species to azoles, represent serious issues with this class of drug, making it imperative to develop innovative antifungal drugs to tackle this growing clinical challenge. A drug repurposing approach is used to examine a library of Food and Drug Administration (FDA)-approved drugs, ultimately identifying otilonium bromide (OTB) as an exceptionally encouraging antifungal agent. Mechanistically, OTB impairs vesicle-mediated trafficking by targeting Sec31, thereby impeding the plasma membrane (PM) localization of the ergosterol transporters, such as Sip3. Consequently, OTB obstructs the movement of ergosterol across membranes and triggers cytotoxic autophagy. It is noteworthy that C. albicans encounters challenges in developing resistance to OTB because it is not a substrate for drug transporters. This study opens a new door for antifungal therapy, wherein OTB disrupts ergosterol subcellular distribution and induces cytotoxic autophagy. Additionally, it circumvents the hepatotoxicity associated with azole-mediated liver enzyme inhibition and avoids export-mediated drug resistance in C. albicans.

A Minimally Invasive, Visualized Method for Nasojejunal Tube Placement.

Malnutrition is a common issue in critically ill patients, often stemming from illness, injury, or surgery. Prolonged fasting leads to intestinal issues, emphasizing the importance of early enteral nutrition, specifically through jejunal nutrition. While enteral nutrition is crucial, complications with current techniques exist. Nasojejunal (NJ) tubes are commonly used, with placement methods categorized as surgical or non-surgical. Non-surgical methods, including endoscopic guidance, have varying success rates, with endoscopic-assisted placement being the most successful but requiring specialized expertise and logistics. This study introduces a bedside, visualized method for NJ tube placement to enhance success rates and reduce patient discomfort in the intensive care unit (ICU). In this study involving 19 ICU patients, the method achieved an initial success rate of 94.74% with an average insertion time of 11.2 ± 6.4 min. This visualized method demonstrates efficiency and reduces the need for additional imaging, and the introduction of a miniaturized endoscope shows promise, enabling successful intubation at the bedside and minimizing patient discomfort. Adjustments to the guidewire lens and catheter are necessary but pose opportunities for future refinements.

Mechanisms and recent advances in the diagnosis and treatment of nitrous oxide-induced peripheral neuropathy: a narrative review.

Under standard conditions, nitrous oxide (N2O) manifests as a colorless, odorless gas with a mildly sweet taste. The compound finds applications in various fields, including its use as an aerosol propellants, an accelerant in motor racing, and an anesthetic in surgical procedures and dentistry. Unfortunately, the recreational misuse of N2O has become prevalent among young individuals due to its euphoric and hallucinogenic effects. Compounding this issue is the fact that nitrous oxide can be easily obtained from over-the-counter household items, facilitating its non-medical use. The global community has witnessed a surge in the recreational utilization of nitrous oxide gas in recent years. Despite the widespread non-medical abuse of N2O, there remains inadequate understanding of the potential adverse effects resulting from exposure to it. This paper provides an overview of management findings, laboratory and electrodiagnostic characteristics, as well as clinical presentations associated with neurological disorders induced by nitrous oxide usage.

Pitavastatin Calcium Confers Fungicidal Properties to Fluconazole by Inhibiting Ubiquinone Biosynthesis and Generating Reactive Oxygen Species.

Fluconazole (FLC) is extensively employed for the prophylaxis and treatment of invasive fungal infections (IFIs). However, the fungistatic nature of FLC renders pathogenic fungi capable of developing tolerance towards it. Consequently, converting FLC into a fungicidal agent using adjuvants assumes significance to circumvent FLC resistance and the perpetuation of fungal infections. This drug repurposing study has successfully identified pitavastatin calcium (PIT) as a promising adjuvant for enhancing the fungicidal activity of FLC from a comprehensive library of 2372 FDA-approved drugs. PIT could render FLC fungicidal even at concentrations as low as 1 µM. The median lethal dose (LD50) of PIT was determined to be 103.6 mg/kg. We have discovered that PIT achieves its synergistic effect by inhibiting the activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, thereby impeding ubiquinone biosynthesis, inducing reactive oxygen species (ROS) generation, triggering apoptosis, and disrupting Golgi function. We employed a Candida albicans strain that demonstrated a notable tolerance to FLC to infect mice and found that PIT effectively augmented the antifungal efficacy of FLC against IFIs. This study is an illustrative example of how FDA-approved drugs can effectively eliminate fungal tolerance to FLC.

Identification and Genomic Characterization of Two Novel Hepatoviruses in Shrews from Yunnan Province, China.

Hepatitis A virus (HAV), a member of the genus Hepatovirus (Picornaviridae HepV), remains a significant viral pathogen, frequently causing enterically transmitted hepatitis worldwide. In this study, we conducted an epidemiological survey of HepVs carried by small terrestrial mammals in the wild in Yunnan Province, China. Utilizing HepV-specific broad-spectrum RT-PCR, next-generation sequencing (NGS), and QNome nanopore sequencing (QNS) techniques, we identified and characterized two novel HepVs provisionally named EpMa-HAV and EpLe-HAV, discovered in the long-tailed mountain shrew (Episoriculus macrurus) and long-tailed brown-toothed shrew (Episoriculus leucops), respectively. Our sequence and phylogenetic analyses of EpMa-HAV and EpLe-HAV indicated that they belong to the species Hepatovirus I (HepV-I) clade II, also known as the Chinese shrew HepV clade. Notably, the codon usage bias pattern of novel shrew HepVs is consistent with that of previously identified Chinese shrew HepV. Furthermore, our structural analysis demonstrated that shrew HepVs differ from other mammalian HepVs in RNA secondary structure and exhibit variances in key protein sites. Overall, the discovery of two novel HepVs in shrews expands the host range of HepV and underscores the existence of genetically diverse animal homologs of human HAV within the genus HepV.

Efficient and stabilized molecular doping of hole-transporting materials driven by a cyclic-anion strategy for perovskite solar cells.

Bis(trifluoromethane)sulfonimide lithium salt (Li-TFSI) is commonly used as an effective dopant to improve the performance of the hole-transporting material (HTM) in n-i-p perovskite solar cells (PSCs). However, the ultra-hygroscopic and migratory nature of Li-TFSI leads to inferior stability of PSCs. Here, we report on a strategy to regulate the anion unit in Li-TFSI from linear to cyclic, constructing a new dopant, lithium 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonimide (Li-CYCLIC), for the state-of-the-art poly[bis(4-phenyl)(2,4,6-trimethylphenyl)amine] (PTAA). Mechanistic and experimental results reveal that the cyclic anion CYCLIC- exhibits stronger interaction with Li+ and PTAA˙+ compared with the linear anion TFSI-, thus significantly restraining the moisture absorption and migration of Li+ and improving the thermodynamic stability of PTAA˙+CYCLIC-. With this molecular engineering, the resulting PSCs based on Li-CYCLIC obtained an improved efficiency, along with remarkably enhanced stability, retaining 96% of the initial efficiency after over 1150 hours under continuous 1 sun illumination in an N2 atmosphere, yielding an extrapolated T 80 of over 12 000 hours. In a broader context, the proposed strategy of linear-to-cyclic doping provides substantial guidance for the subsequent advancement in the development of effective dopants for photoelectric devices.

Prevalence and genetic diversity of Anaplasma and Ehrlichia in ticks and domesticated animals in Suizhou County, Hubei Province, China.

Anaplasma and Ehrlichia are tick-borne bacterial pathogens that cause anaplasmoses and ehrlichioses in humans and animals. In this study, we examined the prevalence of Anaplasma and Ehrlichia species in ticks and domesticated animals in Suizhou County, Hubei Province in the central China. We used PCR amplification and DNA sequencing of the 16S rRNA, groEL, and gltA genes to analyze. We collected 1900 ticks, including 1981 Haemaphysalis longicornis and 9 Rhipicephalus microplus, 159 blood samples of goats (n = 152), cattle (n = 4), and dogs (n = 3) from May to August of 2023. PCR products demonstrated that Anaplasma bovis, Anaplasma capra, and an Ehrlichia species were detected in the H. longicornis with the minimum infection rates (MIR) of 1.11%, 1.32%, and 0.05%, respectively; A. bovis, A. capra, and unnamed Anaplasma sp. were detected in goats with an infection rate of 26.31%, 1.31% and 1.97%, respectively. Anaplasma and Ehrlichia species were not detected from cattle, dogs and R. microplus ticks. The genetic differences in the groEL gene sequences of the Anaplasma in the current study were large, whereas the 16S rRNA and gltA gene sequences were less disparate. This study shows that ticks and goats in Suizhou County, Hubei Province carry multiple Anaplasma species and an Ehrlichia species, with relatively higher infection rate of A. bovis in goats. Our study indicates that multiple Anaplasma and Ehrlichia species exist in ticks and goats in the central China with potential to cause human infection.

Superficial thrombophlebitis in the forearm leading to entrapment of the radial nerve branch: a first case report and literature review.

This article reports a case of a female patient admitted with swelling and subcutaneous mass in the right forearm, initially suspected to be multiple nerve fibroma. However, through preoperative imaging and surgery, the final diagnosis confirmed superficial thrombophlebitis. This condition resulted in entrapment of the radial nerve branch, leading to noticeable nerve entrapment and radiating pain. The surgery involved the excision of inflammatory tissue and thrombus, ligation of the cephalic vein, and complete release of the radial nerve branch. Postoperative pathology confirmed the presence of Superficial Thrombophlebitis. Through this case, we emphasize the importance of comprehensive utilization of clinical, imaging, and surgical interventions for more accurate diagnosis and treatment. This is the first clinical report of radial nerve branch entrapment due to superficial thrombophlebitis.

Optimizing vancomycin dosing in pediatrics: a machine learning approach to predict trough concentrations in children under four years of age.

BACKGROUND: Vancomycin trough concentration is closely associated with clinical efficacy and toxicity. Predicting vancomycin trough concentrations in pediatric patients is challenging due to significant inter-individual variability and rapid physiological changes during maturation. AIM: This study aimed to develop a machine learning model to predict vancomycin trough concentrations and determine optimal dosing regimens for pediatric patients < 4 years of age using ML algorithms. METHOD: A single-center retrospective observational study was conducted from January 2017 to March 2020. Pediatric patients who received intravenous vancomycin and underwent therapeutic drug monitoring were enrolled. Seven ML models [linear regression, gradient boosted decision trees, support vector machine, decision tree, random forest, Bagging, and extreme gradient boosting (XGBoost)] were developed using 31 variables. Performance metrics including R-squared (R2), mean square error (MSE), root mean square error (RMSE), and mean absolute error (MAE) were compared, and important features were ranked. RESULTS: The study included 120 eligible trough concentration measurements from 112 patients. Of these, 84 measurements were used for training and 36 for testing. Among the seven algorithms tested, XGBoost showed the best performance, with a low prediction error and high goodness of fit (MAE = 2.55, RMSE = 4.13, MSE = 17.12, and R2 = 0.59). Blood urea nitrogen, serum creatinine, and creatinine clearance rate were identified as the most important predictors of vancomycin trough concentration. CONCLUSION: An XGBoost ML model was developed to predict vancomycin trough concentrations and aid in drug treatment predictions as a decision-support technology.

Identification of potential biomarkers and pathways for asthenozoospermia by bioinformatics analysis and experiments.

Background: Asthenozoospermia, a type of male infertility, is primarily caused by dysfunctional sperm mitochondria. Despite previous bioinformatics analysis identifying potential key lncRNAs, miRNAs, hub genes, and pathways associated with asthenospermia, there is still a need to explore additional molecular mechanisms and potential biomarkers for this condition. Methods: We integrated data from Gene Expression Omnibus (GEO) (GSE22331, GSE34514, and GSE160749) and performed bioinformatics analysis to identify differentially expressed genes (DEGs) between normozoospermia and asthenozoospermia. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to gain insights into biological processes and signaling pathways. Weighted Gene Co-expression Network Analysis (WGCNA) identified gene modules associated with asthenozoospermia. Expression levels of key genes were assessed using datasets and experimental data. Gene Set Enrichment Analysis (GSEA) and correlation analysis identified pathways associated with the hub gene and explore the relationship between the ZNF764 and COQ9 and mitochondrial autophagy-related genes. Competitive endogenous RNA (ceRNA) networks were constructed, and in vitro experiments using exosome samples were conducted to validate this finding. Results: COQ9 was identified as a marker gene in asthenozoospermia, involved in autophagy, ATP-dependent chromatin remodeling, endocytosis, and cell cycle, etc. The ceRNA regulatory network (LINC00893/miR-125a-5p/COQ9) was constructed, and PCR demonstrated that LINC00893 and COQ9 were downregulated in asthenozoospermia, while miR-125a-5p and m6A methylation level of LINC00893 were upregulated in asthenozoospermia compared to normozoospermic individuals. Conclusion: The ceRNA regulatory network (LINC00893/miR-125a-5p/COQ9) likely plays a crucial role in the mechanism of asthenozoospermia. However, further functional experiments are needed to fully understand its significance.

Integrating digital design with 3D printing technology achieves customized and precise approaches for flap transplantation to facilitate fingertip defect surgery.

OBJECTIVE: This study investigates the clinical efficacy of integrating digital design with three-dimension (3D) printing technology in the transplantation of flaps for fingertip defects. METHODS: A retrospective analysis was conducted from October 2019 to June 2021 on 90 cases of patients with fingertip defects. These included 45 cases in which digital design, coupled with 3D printing, assisted the operation (3D printing group), and another 45 cases where patients underwent traditional pedicle flap transplantation and skin grafting (traditional operation group). A six-month postoperative follow-up assessed various measurements between the two groups, comparing the skin flap survival rate, aesthetic outcome, cold intolerance, sensory recovery, and overall skin flap performance. RESULTS: ① Statistical analysis utilizing the independent samples t-test revealed a significant reduction in both operation time and flap anastomosis rate for the 3D printing group compared to the traditional operation group (P < 0.05). ② Conversely, the survival rate, aesthetic outcome, and cold intolerance showed no significant disparities between the groups (P > 0.05). ③ Further, the Mann-Whitney U test indicated no significant difference in sensory recovery and overall efficacy assessment between the two cohorts (P > 0.05). CONCLUSION: Integrating digital design with 3D printing technology facilitated the surgical management of fingertip defects, achieving customized and precise approaches in flap transplantation. This precision in personalized skin flap design contributed to reduced operative time and enhanced surgical efficiency in such procedures.

Study on the Mass Spectrometry Cleavage Pattern of Quinolone Antibiotics.

RATIONALE: Quinolone antibiotics are extensively used clinically for human treatment and in agriculture. However, improper and excessive use can lead to the persistence of quinolone residues in animal tissues, potentially accumulating in the human body and posing health risks. Investigating the correlation between mass spectrometry cleavage patterns and molecular structural features enhances the analytical framework for detecting trace or unknown impurities in quinolones. METHODS: To collect data, we employed triple quadrupole linear ion trap mass spectrometry in electrospray positive ion mode. Primary mass spectrometry scanning was utilized to confirm parent ions, while secondary mass spectrometry scanning enabled the observation of fragment ions. The cleavage characteristics and pathways of the compounds were inferred from accurate mass-to-charge ratios obtained from both primary and secondary mass spectrometry. RESULTS: Under soft ionization conditions, the compounds generally exhibited characteristic fragment ions of [M+H-H2O]+, [M+H-CO]+, and [M+H-H2O-CO]+. Additionally, subtle variations were observed in each compound due to differences in modifying groups. For instance, upon deacidification, the piperazine ring structure underwent breakage and rearrangement, yielding fragment ion peaks devoid of neutral molecules such as C2H5N, C3H7N, or C4H8N. Notably, compounds featuring a cyclopropyl substituent group at the N-1 position typically exhibited characteristic fragments resulting from the loss of the cyclopropyl radical (⋅C3H5). Moreover, substituents at the N-1 and C-8 positions, when linked to form a six-membered carbocyclic ring, were prone to cleavage, releasing the neutral C3H6 molecule. CONCLUSION: Quinolone antibiotics share structural similarities in their parent nuclei, leading to partially similar cleavage pathways. Nevertheless, distinct cleavage patterns emerge due to variations in functional groups. According to the difference of mass spectrometry cleavage patterns, it can provide an identification basis for the measured detection of antibiotics.

Different emotional states engage distinct descending pathways from the prefrontal cortex.

Emotion regulation, essential for adaptive behavior, depends on the brain's capacity to process a range of emotions. Current research has largely focused on individual emotional circuits without fully exploring how their interaction influences physiological responses or understanding the neural mechanisms that differentiate emotional valence. Using in vivo calcium imaging, electrophysiology, and optogenetics, we examined neural circuit dynamics in the medial prefrontal cortex (mPFC), targeting two key areas: the basal lateral amygdala (BLA) and nucleus accumbens (NAc). Our results demonstrate distinct activation patterns in the mPFC→BLA and mPFC→NAc pathways in response to social stimuli, indicating a mechanism for discriminating emotions: increased mPFC→BLA activity signals anxiety, while heightened mPFC→NAc responses are linked to exploration. Additionally, chronic emotional states amplify activity in these pathways-positivity enhances mPFC→NAc, while negativity boosts mPFC→BLA. This study sheds light on the nuanced neural circuitry involved in emotion regulation, revealing the pivotal roles of mPFC projections in emotional processing. Identifying these specific circuits engaged by varied emotional states advances our understanding of emotional regulation's biological underpinnings and highlights potential targets for addressing emotional dysregulation in psychiatric conditions. Significance statement: While existing circuitry studies have underscored the significance of emotional circuits, the majority of research has concentrated on individual circuits. The assessment of whether and how the balance among multiple circuits influences overall physiological outcomes is often overlooked. This study delves into the neural underpinnings of emotion regulation, focusing on how positive and negative valences are discriminated and managed. By examining the specific pathways from the medial prefrontal cortex (mPFC) to key emotional centers-the basal lateral amygdala (BLA) for negative valence and the nucleus accumbens (NAc) for positive one-we uncovered a novel dual-balanced neural circuit mechanism that enables this essential aspect of human cognition.

Role of Yme1 in mitochondrial protein homeostasis: from regulation of protein import, OXPHOS function to lipid synthesis and mitochondrial dynamics.

Mitochondria are essential organelles of eukaryotic cells and thus mitochondrial proteome is under constant quality control and remodelling. Yme1 is a multi-functional protein and subunit of the homo-hexametric complex i-AAA proteinase. Yme1 plays vital roles in the regulation of mitochondrial protein homeostasis and mitochondrial plasticity, ranging from substrate degradation to the regulation of protein functions involved in mitochondrial protein biosynthesis, energy production, mitochondrial dynamics, and lipid biosynthesis and signalling. In this mini review, we focus on discussing the current understanding of the roles of Yme1 in mitochondrial protein import via TIM22 and TIM23 pathways, oxidative phosphorylation complex function, as well as mitochondrial lipid biosynthesis and signalling, as well as a brief discussion of the role of Yme1 in modulating mitochondrial dynamics.

Disentangling microbial niche balance and intermediates' trade-offs for anaerobic digestion stability and regulation.

Anaerobic digestion (AD) is a key technology for converting organic matters to methane-rich biogas. However, nutrient imbalance can destabilize the whole digestion. To realize stable operation of AD and improve its efficiency, this work considers a new strategy to control the intermediate concentrations of poor AD under nutrient stress. For this purpose, long-term digestion under different nutrient conditions was investigated. Results showed that the feedstock with a low C/N ratio (= 6) caused VFA accumulation (2072 ± 632 mg/L), leading to the inhibition of methane production. Employing a substrate with a higher C/N ratio (= 11) and/or adding NH4HCO3 (200 mg NH4+-N/Ladd) could alleviate the VFA inhibition, but excessive dosage of NH4HCO3 would induce ammonia inhibition. Through the established digestion balance between free ammonia nitrogen (FAN) between 0 and 25 mg/L, volatile fatty acid (VFA) 510-2100 mg/L, and alkalinity (ALK) 3300-7800 mg/L, an efficient methane yield of 150-250 mL/g VS was achieved and stable operation of AD under nutrient stress (low C/N ratio) was realized. Metabolic reconstruction between Euryarchaeota sp. MAG162, Methanosarcina mazei MAG53 and Mesotoga infera MAG119 highlighted that microbial niche balance was developed as a result of digestion balance, which is beneficial for stable operation of AD. These findings improved our understanding of the interaction mechanism between intermediates and microbial niches for stability control in AD.

On the evolutionary trail of MagRs.

Magnetic sense, or termed magnetoreception, has evolved in a broad range of taxa within the animal kingdom to facilitate orientation and navigation. MagRs, highly conserved A-type iron-sulfur proteins, are widely distributed across all phyla and play essential roles in both magnetoreception and iron-sulfur cluster biogenesis. However, the evolutionary origins and functional diversification of MagRs from their prokaryotic ancestor remain unclear. In this study, MagR sequences from 131 species, ranging from bacteria to humans, were selected for analysis, with 23 representative sequences covering species from prokaryotes to Mollusca, Arthropoda, Osteichthyes, Reptilia, Aves, and mammals chosen for protein expression and purification. Biochemical studies revealed a gradual increase in total iron content in MagRs during evolution. Three types of MagRs were identified, each with distinct iron and/or iron-sulfur cluster binding capacity and protein stability, indicating continuous expansion of the functional roles of MagRs during speciation and evolution. This evolutionary biochemical study provides valuable insights into how evolution shapes the physical and chemical properties of biological molecules such as MagRs and how these properties influence the evolutionary trajectories of MagRs.

Determining the extent and frequency of on-site monitoring: a bayesian risk-based approach.

BACKGROUND: On-site monitoring is a crucial component of quality control in clinical trials. However, many cast doubt on its cost-effectiveness due to various issues, such as a lack of monitoring focus that could assist in prioritizing limited resources during a site visit. Consequently, an increasing number of trial sponsors are implementing a hybrid monitoring strategy that combines on-site monitoring with centralised monitoring. One of the primary objectives of centralised monitoring, as stated in the clinical trial guidelines, is to guide and adjust the extent and frequency of on-site monitoring. Quality tolerance limits (QTLs) introduced in ICH E6(R2) and thresholds proposed by TransCelerate Biopharma are two existing approaches for achieving this objective at the trial- and site-levels, respectively. The funnel plot, as another threshold-based site-level method, overcomes the limitation of TransCelerate's method by adjusting thresholds flexibly based on site sizes. Nonetheless, both methods do not transparently explain the reason for choosing the thresholds that they used or whether their choices are optimal in any certain sense. Additionally, related Bayesian monitoring methods are also lacking. METHODS: We propose a simple, transparent, and user-friendly Bayesian-based risk boundary for determining the extent and frequency of on-site monitoring both at the trial- and site-levels. We developed a four-step approach, including: 1) establishing risk levels for key risk indicators (KRIs) along with their corresponding monitoring actions and estimates; 2) calculating the optimal risk boundaries; 3) comparing the outcomes of KRIs against the optimal risk boundaries; and 4) providing recommendations based on the comparison results. Our method can be used to identify the optimal risk boundaries within an established risk level range and is applicable to continuous, discrete, and time-to-event endpoints. RESULTS: We evaluate the performance of the proposed risk boundaries via simulations that mimic various realistic clinical trial scenarios. The performance of the proposed risk boundaries is compared against the funnel plot using real clinical trial data. The results demonstrate the applicability and flexibility of the proposed method for clinical trial monitoring. Moreover, we identify key factors that affect the optimality and performance of the proposed risk boundaries, respectively. CONCLUSION: Given the aforementioned advantages of the proposed risk boundaries, we expect that they will benefit the clinical trial community at large, in particular in the realm of risk-based monitoring.