High Degree Research Articles

Abstract 618: Preclinical assessment of APL-030, a selective and orally bioavailable inhibitor of the integrated stress response regulator GCN2 with activity against acute myeloid leukemia

Abstract GCN2 (EIF2AK4) is an evolutionarily conserved kinase and a pivotal regulator of the Integrated Stress Response (ISR), an adaptive cellular program triggered primarily by amino acid scarcity. Active GCN2 phosphorylates the translation initiation factor eIF2α, resulting in the attenuation of global protein synthesis and a largely ATF4-driven program of resource enhancement. GCN2 promotes cancer cell survival under conditions of microenvironmental or drug-induced intracellular nutrient scarcity. Here, we describe the preclinical development of APL-030, a novel and selective ATP-competitive inhibitor of GCN2. APL-030 was confirmed as a potent inhibitor of GCN2 in an on-target biochemical kinase assay with a Ki of 4.4nM. In a cell-based assay APL-030 decreased eIF2α phosphorylation in a dose-dependent manner via direct GCN2 inhibition with an IC50 of 50.8nM. In acute myeloid leukemia (AML) cell lines GCN2 inhibition resulted in a decrease in gene expression of effector genes CHAC1 and DDIT3. Moreover, treatment with APL-030 dose-dependently decreased cell viability in multiple AML cell lines, which was accompanied by an increase in caspase 3/7 activity. Bulk mRNA sequencing of MOLM-13 AML cells showed that APL-030 inhibited the extensive transcriptome changes triggered by glutamine depletion, in line with a high degree of selectivity of APL-030 for GCN2-mediated ISR signaling. In cells grown in rich medium, APL-030 triggered a largely ISR-independent transcriptome response that was dominated by the enrichment of pathways related to cell cycle as well as RNA and protein metabolism. In vivo, APL-030 treatment of an AML xenograft animal model completely inhibited tumor growth and prolonged survival time. Inhibition of AML tumor growth was shown to be a consequence of decreased cell viability and induction of caspase-dependent apoptosis. APL-030 was also tested on primary diagnostic AML cells, which were assessed for cell death by flow cytometry following staining for Annexin-V, 7-AAD, CD45, CD34, and CD38. Treatment with APL-030 caused a statistically significant increase in AML cell death in all six samples studied. Three samples exhibited a measurable CD34+/CD38- compartment, enabling evaluation of this leukemic stem cell-enriched population. APL-030 caused a statistically significant increase in cell death in the leukemic stem cell-enriched population in all three samples studied. APL-030 is a novel GCN2 inhibitor that that has shown encouraging efficacy in preclinical studies using both AML cell lines and patient-derived AML samples. Based on these preclinical results, a phase 1/2 study is planned in hematological tumors. Citation Format: Monica Roman-Trufero, Gavin Whitlock, Matthew Fuchter, Maxmila Jeyakumar, Panagiota Chaida, Sereina Annik Herzog, Armin Zebisch, Richard Butt, Holger W. Auner, Nadine Clemo. Preclinical assessment of APL-030, a selective and orally bioavailable inhibitor of the integrated stress response regulator GCN2 with activity against acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 618.

FACTORS ASSOCIATED TO BURN-OUT AMONG IBN SINA HOSPITAL PUBLIC HEALTH PROFESSIONALS

Burn-out or exhaustion syndrome is caused by a prolonged exposure to a chronic professional stress. Public Health Professionals are the most exposed to this kind of risk. The ulti- mate goal here is to determine the prevalence of the burn-out and search for factors associated with this pathology among those who work in the field of health.Our sample, which is from the Ibn Sina Hospital in Rabat, consists of 150 nurses, 80 doctors, and 40 administrators. A self-questionnaire was employed, the Maslach Burnout In- ventory (MBI) as well as a clinical interview.The results of this study show a high degree of burnout. Moreover, 56.66% of participants show a high level of emotio - nal exhaustion, 45.18% suffer from a high level of depression. Meanwhile, the loss of a sense of personal accom plish ment is high among 48.51% of those surveyed. The emotional exhaustion observed among people who have worked for a long time ago is associated with the means of transportation used and to the unsuitable hours of work. Depersonalization exists among elderly people and the oldest at work.This study confirms the existence of a high level of burnout among health professionals. Many socio-demographic and socio-professional factors contribute to the increase in the level that people are affected. These factors encourage the promotion of better working life conditions.

Predicting nuclear G-quadruplex RNA-binding proteins with roles in transcription and phase separation

RNA-binding proteins are central for many biological processes and their characterization has demonstrated a broad range of functions as well as a wide spectrum of target structures. RNA G-quadruplexes are important regulatory elements occurring in both coding and non-coding transcripts, yet our knowledge of their structure-based interactions is at present limited. Here, using theoretical predictions and experimental approaches, we show that many chromatin-binding proteins bind to RNA G-quadruplexes, and we classify them based on their RNA G-quadruplex-binding potential. Combining experimental identification of nuclear RNA G-quadruplex-binding proteins with computational approaches, we build a prediction tool that assigns probability score for a nuclear protein to bind RNA G-quadruplexes. We show that predicted G-quadruplex RNA-binding proteins exhibit a high degree of protein disorder and hydrophilicity and suggest involvement in both transcription and phase-separation into membrane-less organelles. Finally, we present the G4-Folded/UNfolded Nuclear Interaction Explorer System (G4-FUNNIES) for estimating RNA G4-binding propensities at http://service.tartaglialab.com/new_submission/G4FUNNIES.

Emotion recognition and social functioning in individuals with autism spectrum condition and intellectual disability.

Most previous studies have examined emotion recognition in autism spectrum condition (ASC) without intellectual disability (ID). However, ASC and ID co-occur to a high degree. The main aims of the study were to examine emotion recognition in individuals with ASC and co-occurring intellectual disability (ASC-ID) as compared to individuals with ID alone, and to investigate the relationship between emotion recognition and social functioning. The sample consisted of 30 adult participants with ASC-ID and a comparison group of 29 participants with ID. Emotion recognition was assessed by the facial emotions test, while. social functioning was assessed by the social responsiveness scale-second edition (SRS-2). The accuracy of emotion recognition was significantly lower in individuals with ASC-ID compared to the control group with ID, especially when it came to identifying angry and fearful emotions. Participants with ASC-ID exhibited more pronounced difficulties in social functioning compared to those with ID, and there was a significant negative correlation between emotion recognition and social functioning. However, emotion recognition accounted for only 8% of the variability observed in social functioning. Our data indicate severe difficulties in the social-perceptual domain and in everyday social functioning in individuals with ASC-ID.

Uncertainty assessment of aquifer hydraulic parameters from pumping test data

Data from pumping tests is a noisy process, and therefore, performing the pumping test numerous times will not get the same drawdown values. As a consequence, various pumping experiments lead to different values for aquifer parameter estimates. The data of pumping tests are usually analyzed using traditional methods (aquifer tests and AQtesolv software), which depend on trial and error technique. During these methods, non-unique values of hydraulic parameters are selected, which usually have a high level of uncertainty. Uncertainty must be taken into account in determining aquifer parameters, especially when using groundwater models for decision makers. The main goal of this study is to build a comprehensive tool for quantifying uncertainty associated with hydraulic parameter estimation from different pumping test conditions for fully penetrating wells in confined and semi-confined aquifers. To achieve the previous objective, a FORTRAN code was developed to apply the Markov Chain Monte Carlo (MCMC) algorithm using different likelihood functions (exponential, inverse, and log). This developed tool can be used to detect the most probable range of aquifer parameters that are consistent with pumping test data with a high degree of confidence. The tool was successfully used to several hypothetical cases to demonstrate the uncertainty in the quantification of aquifer parameters and compare the findings to the standard method's results. Also, the concept was verified numerically (using Modflow program) with satisfactory results using a hypothetical case with well-known aquifer parameters. Finally, the tool was applied for actual pumping test data with good results.

Firefighters and police search dog handlers’ experiences working closely with paramedics in urban search and rescue incidents: a qualitative focus group study from Oslo

BackgroundRescue operations are in Norway defined as situations where patients are difficult to access or that more resources are needed than the health services alone possess and can put in operation (Bull A, Redningshåndboken er endelig her! [Internet]. Hovedredningssentralen. 2018 [cited 2023 May 15]. Available from: https://www.hovedredningssentralen.no/redningshandboken-er-endelig-her/). Rescue operations after large incidents may include civil protection, military forces, non-governmental organizations and other resources, but the initial rescue effort must be performed by the emergency services as time often is of essence. The central area of an accident where special training and personal protection equipment is necessary or mandatory is called the Hot Zone. This study examines Urban Search And Rescue (USAR) firefighters and police officers reported experiences from ambulance personnel’s contribution in the Hot Zone.MethodsWe conducted five focus group interviews with USAR-trained firefighters and police officers. The interviewees were those on duty on the agreed dates. The interviews were taped, transcribed, and analysed using thematic analysis as described by Braun & Clarke.ResultsThree themes were identified; Feeling safe during missions, Building USAR capacity, and Trust-building within USAR-teams. The firefighters and police officers reported their and the patients’ safety are best managed by EMS-personnel, whose presence strongly contributes to their own feeling of safety in a dangerous area. When EMS handles victims and injured emergency workers, firefighters and police officers can focus on their own primary tasks. Indeed, interviewees reported that building a USAR capacity depends on having USAR-trained EMS-personnel in the Hot Zone. The interviewees have clear and consistent opinions on how to establish an interagency USAR capacity effectively. Trust is paramount to the interviewees, and they express a high degree of trust within USAR Oslo.ConclusionsFirefighters and police officers regard USAR-trained EMS-personnel as a natural and integrated part in urban search and rescue teams. EMS-personnel in the dangerous area deliver safety and medical professional assistance to both rescue workers and patients. Informants in this study had clear opinions on how to establish and maintain such a service.

Many Patients Will Experience Stool and Bowel Movement-Related Symptoms After Treatment for Colorectal and Anal Cancer-A Descriptive Study

Purpose: Stool-related late complications have a major impact on patients’ quality of life. The objective of this study was to investigate stool and bowel movements as late complications to colorectal and anal cancer treatment. Methods: We performed a prospective cohort study from a single center using patient reported outcome measurements. We included patients who had surgery for colorectal and anal cancer from October 2019 to January 2022. This was supplemented by a subgroup of patients with late complications after chemo-radiation therapy for anal cancer. The study population comprised 293 patients. The main outcome included descriptive data on stool and bowel movement related complications. We used the Low Anterior Resection Symptom score (LARS), St Mark´s incontinence score, Bristol stool form scale, Patient Assessment of Constipation Symptoms Score (PAC-SYM), colostomy impact factor and self-rated health on a visual analog scale as measurement tools. Results: The low anterior resection symptom score was median 36 (range 24-41) in patients with rectum cancer, for patients with anal cancer it was 39 (4-41), for patients with a right or left sided hemicolectomy it was 26 (4-41) and 25 (0-41), respectively. Conclusion: Patients who had surgery for rectum cancer had in 90% of the cases major Low Anterior Resection Syndrome (LARS). Patients who underwent surgery for colon cancer would in about one third of the cases experience stool or bowel movement impairments. Patients with anal cancer who had chemo-radiation therapy experienced a very high degree of stool and bowel movement impairment.

A topographical atlas of α-synuclein dosage and cell type-specific expression in adult mouse brain and peripheral organs

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide and presents pathologically with Lewy pathology and dopaminergic neurodegeneration. Lewy pathology contains aggregated α-synuclein (αSyn), a protein encoded by the SNCA gene which is also mutated or duplicated in a subset of familial PD cases. Due to its predominant presynaptic localization, immunostaining for the protein results in a diffuse reactivity pattern, providing little insight into the types of cells expressing αSyn. As a result, insight into αSyn expression-driven cellular vulnerability has been difficult to ascertain. Using a combination of knock-in mice that target αSyn to the nucleus (SncaNLS) and in situ hybridization of Snca in wild-type mice, we systematically mapped the topography and cell types expressing αSyn in the mouse brain, spinal cord, retina, and gut. We find a high degree of correlation between αSyn protein and RNA levels and further identify cell types with low and high αSyn content. We also find high αSyn expression in neurons, particularly those involved in PD, and to a lower extent in non-neuronal cell types, notably those of oligodendrocyte lineage, which are relevant to multiple system atrophy pathogenesis. Surprisingly, we also found that αSyn is relatively absent from select neuron types, e.g., ChAT-positive motor neurons, whereas enteric neurons universally express some degree of αSyn. Together, this integrated atlas provides insight into the cellular topography of αSyn, and provides a quantitative map to test hypotheses about the role of αSyn in network vulnerability, and thus serves investigations into PD pathogenesis and other α-synucleinopathies.

Identification of key genes for atherosclerosis in different arterial beds

Atherosclerosis (AS) is the pathologic basis of various cardiovascular and cerebrovascular events, with a high degree of heterogeneity among different arterial beds. However, mechanistic differences between arterial beds remain unexplored. The aim of this study was to explore key genes and potential mechanistic differences between AS in different arterial beds through bioinformatics analysis. Carotid atherosclerosis (CAS), femoral atherosclerosis (FAS), infrapopliteal atherosclerosis (IPAS), abdominal aortic atherosclerosis (AAS), and AS-specific differentially expressed genes (DEGs) were screened from the GSE100927 and GSE57691 datasets. Immune infiltration analysis was used to identify AS immune cell infiltration differences. Unsupervised cluster analysis of AS samples from different regions based on macrophage polarization gene expression profiles. Weighted gene co-expression network analysis (WGCNA) was performed to identify the most relevant module genes with AS. Hub genes were then screened by LASSO regression, SVM-REF, and single-gene differential analysis, and a nomogram was constructed to predict the risk of AS development. The results showed that differential expression analysis identified 5, 4, 121, and 62 CAS, FAS, IPAS, AAS-specific DEGs, and 42 AS-common DEGs, respectively. Immune infiltration analysis demonstrated that the degree of macrophage and mast cell enrichment differed significantly in different regions of AS. The CAS, FAS, IPAS, and AAS could be distinguished into two different biologically functional and stable molecular clusters based on macrophage polarization gene expression profiles, especially for cardiomyopathy and glycolipid metabolic processes. Hub genes for 6 AS (ADAP2, CSF3R, FABP5, ITGAX, MYOC, and SPP1), 4 IPAS (CLECL1, DIO2, F2RL2, and GUCY1A2), and 3 AAS (RPL21, RPL26, and RPL10A) were obtained based on module gene, gender stratification, machine learning algorithms, and single-gene difference analysis, respectively, and these genes were effective in differentiating between different regions of AS. This study demonstrates that there are similarities and heterogeneities in the pathogenesis of AS between different arterial beds.

How consumers assess retailer brand substitution strategy: Impact of perceived similarity and consumer attachment

The objective of this study is to examine how consumers assess brand substitution strategies implemented by retailers, focusing specifically on the transition from Promogro to MG (Magasin Général) retailer brand. A quantitative study involving 351 Tunisian customers who regularly patronize supermarkets (Promogro and MG) was conducted to test hypotheses and analyze the impact of various factors in April 2022. The research model was evaluated through structural equation modeling (SEM) using the AMOS 22 software. The results indicate a negative correlation between consumers’ attachment to the old retail brand and their attitude toward the brand substitution process (β = –0.09*, p < 0.01). Furthermore, perceptions of the retailer brand emerged as a significant mediating factor influencing the relationship between attitudes and consumers’ intention to revisit the new retailer brand (β = 0.29**, confidence interval [0.17; 0.51]). Additionally, the study found that the association between consumer attachment and perceptions of the new retailer brand is positively moderated by perceived similarity (β = 0.226, p = 0.00). Specifically, when there is a high degree of resemblance between the two retailer brands, customers with a stronger attachment to the former brand tend to have a more favorable perception of the new retailer brand. This study provides valuable insights for managers, helping them identify critical success criteria that facilitate customer acceptance of brand changes and offering guidance on effectively substituting retailer brand names.

Deep learning-based solar power forecasting model to analyze a multi-energy microgrid energy system

Multi-energy microgrids (MEM) are a new class of power grids focusing on the distributed form of generation and integrating different energy sectors. The primary idea of MEM is to increase renewable energy share in the final energy demand while maintaining the energy balance at all times. However, integrating renewable technology into the grid has some technical limitations that must be analyzed before being deployed in the real world. This study examines the impact of increasing renewable penetration and portfolio design on a multi-energy microgrid energy system from a technical standpoint. As the accuracy of the system analysis is primarily a factor of modeling accuracy, an artificial neural network-based model is trained and deployed to develop forecasts for solar power generation. The forecasting model is integrated with the EnergyPLAN simulation tool to analyze the multi-energy microgrid system regarding renewable share in primary energy consumption and import/export of energy from the primary grid. The Norwegian energy system is considered a case study, as the energy generation and consumption patterns are interesting from both renewable energy and demand contexts for a cold country. One interesting conclusion is that the portfolio and capacities of coupling components such as combined heat and power plants negatively impact renewable integration, while heat pumps positively impact renewable integration by increasing renewable energy utilization. Additionally, the photovoltaic system size has a high degree of correlation to imports and exports compared to wind generation systems.

Overlap of International League of Associations for Rheumatology and Preliminary Pediatric Rheumatology International Trials Organization Classification Criteria for Nonsystemic Juvenile Idiopathic Arthritis in an Established UK Multicentre Inception Cohort.

The goal was to assess the degree of overlap between existing International League of Associations for Rheumatology (ILAR) and preliminary Paediatric Rheumatology International Trials Organisation (PRINTO) classification criteria for juvenile idiopathic arthritis (JIA). Participants from the Childhood Arthritis Prospective Study, a multicenter UK JIA inception cohort, were classified using the PRINTO and ILAR classification criteria into distinct categories. Systemic JIA was excluded because several classification items were not collected in this cohort. Adaptations to PRINTO criteria were required to apply to a UK health care setting, including limiting the number of blood biomarker tests required. The overlap between categories under the two systems was determined, and any differences in characteristics between groups were described. A total of 1,223 children and young people with a physician's diagnosis of JIA were included. Using PRINTO criteria, the majority of the patients had "other JIA" (69.5%). There was a high degree of overlap (91%) between the PRINTO enthesitis/spondylitis- and ILAR enthesitis-related JIA categories. The PRINTO rheumatoid factor (RF)-positive category was composed of 48% ILAR RF-positive polyarthritis and 52% undifferentiated JIA. The early-onset antinuclear antibodies-positive PRINTO category was largely composed of ILAR oligoarthritis (50%), RF-negative polyarthritis (24%), and undifferentiated JIA (23%). A few patients were unclassified under PRINTO (n=3) and would previously have been classified as enthesitis-related JIA (n=1) and undifferentiated JIA (n=2) under ILAR. Under the preliminary PRINTO classification criteria for childhood arthritis, most children are not yet classified into a named category. These data can help support further delineation of the PRINTO criteria to ensure homogenous groups of children can be identified.

Continuous auction mechanism model for safety electric energy market transaction

With the rapid development of microgrid in the electric power industry, the microgrid electric energy transaction has begun to be marketized, and the research on the microgrid electric energy trusted transaction has important theoretical research value and social value. The existing blockchain-based microgrid electric energy trusted transaction models mostly focus on energy management and scheduling control between microgrids when conducting electric energy transactions, and do not fully consider the bidding problems in the market-based transaction of microgrid electric energy, resulting in trading strategies are difficult to adapt to new market changes. In response to this problem, this paper proposes a reliable transaction approach for microgrid electric energy based on a continuous two-way auction mechanism. The proposed strategy accounts for the volatility of electricity prices in the microgrid trading market and employs the continuous two-way auction mechanism to evaluate the microgrid electricity trading tactics. In the microgrid electric energy transaction, the self-adaptive learning theory is applied to adjust the quotations of both parties, so that both parties can make reasonable quotations according to the market environment. By simulating experimental data, the findings indicate that the continuous two-way auction mechanism transaction strategy enables both parties to modify their quotations based on market transaction information, thereby displaying a high degree of flexibility in microgrid electricity’s market-oriented trading.

JUN mRNA translation regulation is mediated by multiple 5' UTR and start codon features.

Regulation of mRNA translation by eukaryotic initiation factors (eIFs) is crucial for cell survival. In humans, eIF3 stimulates translation of the JUN mRNA which encodes the transcription factor JUN, an oncogenic transcription factor involved in cell cycle progression, apoptosis, and cell proliferation. Previous studies revealed that eIF3 activates translation of the JUN mRNA by interacting with a stem loop in the 5' untranslated region (5' UTR) and with the 5' -7-methylguanosine cap structure. In addition to its interaction site with eIF3, the JUN 5' UTR is nearly one kilobase in length, and has a high degree of secondary structure, high GC content, and an upstream start codon (uAUG). This motivated us to explore the complexity of JUN mRNA translation regulation in human cells. Here we find that JUN translation is regulated in a sequence and structure-dependent manner in regions adjacent to the eIF3-interacting site in the JUN 5' UTR. Furthermore, we identify contributions of an additional initiation factor, eIF4A, in JUN regulation. We show that enhancing the interaction of eIF4A with JUN by using the compound Rocaglamide A (RocA) represses JUN translation. We also find that both the upstream AUG (uAUG) and the main AUG (mAUG) contribute to JUN translation and that they are conserved throughout vertebrates. Our results reveal additional layers of regulation for JUN translation and show the potential of JUN as a model transcript for understanding multiple interacting modes of translation regulation.

Academic Output of Fellows of the American Association for Respiratory Care.

Research is critical for the advancement of respiratory care. Fellows of the American Association for Respiratory Care (FAARCs) are nominated based on their significant contributions to the respiratory care profession. Research output is potentially an important component of qualification for FAARC. The purpose of this study is to report the academic output of respiratory therapist (RT) FAARCs. We identified FAARCs from the AARC web site. Research output was assessed by searching the Scopus and PubMed databases. We collected total research documents, citations, h-index, co-authors, and document type. We compared those with only the FAARC designation with RTs who are fellows in both the Society of Critical Care Medicine (FCCMs) and FAARC. We identified a total of 371 RT FAARCs, 4 RT FCCMs, and 10 with both designations. FAARCs were 70% male, 22% had a doctorate, 37% had a master's, 13% had a bachelor's, and 29% did not have a degree reported. There were no differences in sex or highest degree between FAARCs and FCCMs. FAARCs had a total of 3,724 publications and 110,207 citations while those with both designations had 1,304 publications and 43,181 citations. In Scopus, 46% of FAARCs had no publications, and 27% had ≥ 10 publications; of those with both credentials, 10% had no publications, and 70% had ≥ 10 publications. FAARCs inducted in 1998 and 1999 had significantly (P < .001) more publications than other eras. Compared to those with both credentials, FAARCs had fewer median publications (1 vs 50), lower h-index (1 vs 18), and fewer citations (1 vs 1,486), P < .001 for all. Total publications in PubMed were lower, and differences in publications were similar. RT FAARCs had a large number of publications and citations, although nearly half did not have any publications. Those with both FAARC and FCCM had significantly more academic output per fellow, although there are only 10 individuals with both credentials.

Continuous monitoring of endotracheal tube position with near infrared light.

Endotracheal intubation is a common approach for airway management in critically ill patients. However, the position of the endotracheal tube (ETT) may be altered during the procedure due to head movements. Accidental displacement or dislodge of the ETT may reduce the airflow, leading to moderate to severe complications, and in some cases even fatality. Therefore, timely detection of changes in ETT position in the trachea is critical to ensure immediate and intermediate interventions to maintain the ETT in the proper position. Currently, there are no widely utilized tools for real-time monitoring of ETT positions. The goal of this study is to develop a cost-effective and easy-to-use near-infrared (NIR) device, named Opt-ETT, capable of continuously monitoring the ETT position in the trachea of a patient. A side-firing fiber is attached to the side of the ETT to illuminate the trachea tissue with NIR light, and a detector board containing five phototransistors is affixed to the chest skin to measure the intensity of diffusely transmitted light. Displacement of the ETT is estimated using second-order polynomial fitting to the ratios of the phototransistor readings. Monte Carlo simulations, ex vivo experiment on porcine tissue, and in vivo experiments using a swine model have been conducted to assess the feasibility of the device. The design of the Opt-ETT device has been verified by the Monte Carlo simulations and ex vivo experiment. The estimation of displacement from in vivo experiments using the Opt-ETT exhibited a high degree of agreement with that measured by a reference sensor, with a discrepancy between to within a displacement range from to . The Opt-ETT device provides a potentially cost-effective solution for real-time and continuous monitoring of ETT position in patient during an intubation procedure.

Item response theory analysis of daytime sleepiness as a symptom of obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a sleep disorder which is linked to many health risks. The gold standard to evaluate OSA in clinical trials is the Apnea-Hypopnea Index (AHI). However, it is time-consuming, costly, and disregards aspects such as quality of life. Therefore, it is of interest to use patient-reported outcomes like the Epworth Sleepiness Scale (ESS), which measures daytime sleepiness, as surrogate end points. We investigate the link between AHI and ESS, via item response theory (IRT) modeling. Through the developed IRT model it was identified that AHI and ESS are not correlated to any high degree and probably not measuring the same sleepiness construct. No covariate relationships of clinical relevance were found. This suggests that ESS is a poor choice as an end point for clinical development if treatment is targeted at improving AHI, and especially so in a mild OSA patient group.

Photoisomerization and Light-Controlled Antibacterial Activity of Fluoroquinolone-Azoisoxazole Hybrids.

Photopharmacology holds a huge untapped potential to locally treat diseases involving photoswitchable drugs via the elimination of drugs' off-target effects. The growth of this field has created a pressing demand to develop such light-active drugs. We explored the potential for creating photoswitchable antibiotic hybrids by attaching pharmacophores norfloxacin/ciprofloxacin and azoisoxazole (photoswitch). All compounds exhibited a moderate to a high degree of bidirectional photoisomerization, long thermal cis half-lives, and impressive photoresistance. Gram-negative pathogens were found to be insensitive to these hybrids, while against Gram-positive pathogens, all hybrids in their trans states exhibited antibacterial activity that is comparable to that of the parent drugs. Notably, the toxicity of the irradiated hybrid 6 was found to be 2-fold lower than the nonirradiated trans isomer, indicating that the pre-inactivated cis-enriched drug can be employed for the site-specific treatment of bacterial infection using light, which could potentially eliminate the unwanted exposure of toxic antibiotics to both beneficial and untargeted harmful microbes in our body. Molecular docking revealed different binding affinity of the cis and trans isomers with the topoisomerase IV enzyme, due to their different shapes.

Diversity and distribution of biosynthetic gene clusters in agricultural soil microbiomes.

Bacterial secondary metabolites serve as an important source of molecules for drug discovery. They also play an important function in mediating the interactions of microbial producers with their living environment and surrounding organisms. However, little is known about the genetic novelty, distribution, and community-level impacts of soil bacterial biosynthetic potential on a large geographic scale. Here, we constructed the first catalog of 11,149 biosynthetic gene clusters (BGCs) from agricultural soils across China and unearthed hidden biosynthetic potential for new natural product discovery from the not-yet-cultivated soil bacteria. Notably, we revealed soil pH as the strongest environmental driver of BGC biogeography and predicted that soil acidification and global climate change could damage the biosynthetic potential of the soil microbiome. The co-occurrence network of bacterial genomes revealed two BGC-rich species, i.e., Nocardia niigatensis from Actinobacteriota and PSRF01 from Acidobacteriota, as the module hub and connector, respectively, indicating their keystone positions in the soil microbial communities. We also uncovered a dominant role of BGC-inferred biotic interactions over environmental drivers in structuring the soil microbiome. Overall, this study achieved novel insights into the BGC landscape in agricultural soils of China, substantially expanding our understanding of the diversity and novelty of bacterial secondary metabolism and the potential role of secondary metabolites in microbiota assembly.IMPORTANCEBacterial secondary metabolites not only serve as the foundation for numerous therapeutics (e.g., antibiotics and anticancer drugs), but they also play critical ecological roles in mediating microbial interactions (e.g., competition and communication). However, our knowledge of bacterial secondary metabolism is limited to only a small fraction of cultured strains, thus restricting our comprehensive understanding of their diversity, novelty, and potential ecological roles in soil ecosystems. Here, we used culture-independent metagenomics to explore biosynthetic potentials in agricultural soils of China. Our analyses revealed a high degree of genetic diversity and novelty within biosynthetic gene clusters in agricultural soil environments, offering valuable insights for biochemists seeking to synthesize novel bioactive products. Furthermore, we uncovered the pivotal role of BGC-rich species in microbial communities and the significant relationship between BGC richness and microbial phylogenetic turnover. This information emphasizes the importance of biosynthetic potential in the assembly of microbial communities.

Ensemble Detection of DNA Engineering Signatures.

Synthetic biology is creating genetically engineered organisms at an increasing rate for many potentially valuable applications, but this potential comes with the risk of misuse or accidental release. To begin to address this issue, we have developed a system called GUARDIAN that can automatically detect signatures of engineering in DNA sequencing data, and we have conducted a blinded test of this system using a curated Test and Evaluation (T&E) data set. GUARDIAN uses an ensemble approach based on the guiding principle that no single approach is likely to be able to detect engineering with perfect accuracy. Critically, ensembling enables GUARDIAN to detect sequence inserts in 13 target organisms with a high degree of specificity that requires no subject matter expert (SME) review.