bluuebunny/crossref_metadata_2025 huggingface dataset:
0990 Examining the Relationship Between Sleep Duration and Depression
Authors: Alla Rupini , Thakur Bhaskar , Strenth Chance , Gonzalez Leo , Martinez Alejandro , Khan Safia
Published: April 2024

Introduction

The full psychological effects of sleep on depression and anxiety are still being investigated. It has been hypothesized that genetic contributions to depressive symptoms increase at both short and long sleep durations. This study aims to see if there is a correlation between duration of sleep and depression and if sociodemographic factors affect this correlation.

Methods

A secondary dataset from National Health and Nutrition Examination Surveys conducted during 2015 – 2018 with 11,689 individuals was obtained. Questions were asked in the home by trained interviewers regarding sleep duration with the following questions “what time do you usually go to sleep on weekdays or workdays,” “what time do you usually wake up on weekdays or workdays,” and “how much sleep do you usually get at night on weekdays or workdays?” Depression was assessed with the standard PHQ-9 with 0-4 defined as minimal depression, 5-14 as moderate, and 15-27 as severe depression.

Results

The unadjusted data analysis showed that those with short sleep duration had 1.72 times higher likelihood for mild to moderate depression (p< 0.001) and 2.05 times higher likelihood for moderate to severe depression (p< 0.001). Those with long sleep duration had 1.54 times higher likelihood of mild to moderate depression (p< 0.001) and 2.01 times higher chance of moderate to severe depression (p< 0.001). When adjusted for the following variables: ethnicity, marital status, education, income, alcohol consumption, obesity, and smoking, those with short sleep duration had 1.63 times higher chance of mild to moderate depression (p< 0.001) and 1.84 times higher chance of moderate to severe depression (p< 0.001) and those with long sleep duration had 1.32 times higher likelihood of mild to moderate depression (p< 0.001) and 1.65 times higher chance of moderate to severe depression (p= 0.002).

Conclusion

These results confirm that any change to sleep duration, whether short or long, is correlated with increased rates of either moderate or severe depression. This study reflects correlation not causation therefore it is possible that sleep duration affects depression or vice versa. While there are many sociodemographic factors that can affect this correlation, the correlation persists when adjusting for these factors.

Support (if any)
0993 Impaired Executive Functioning Is Linked to Suicidality in Youth with Insomnia Disorder
Authors: Sit Hao Fong , Wong Yee Lok , Chan Ngan Yin , Chan Joey , Wing Yun Kwok , Li Shirley Xin
Published: April 2024

Introduction

Suicide, a critical global mental health issue, has been linked to sleep difficulties. Previous studies have also found that psychological distress and negative thinking styles could contribute to a higher risk of suicide. While cognitive deficit is one of the most common complaints among individuals with insomnia, its impact on suicidality in the context of insomnia has seldom been investigated. The current study aimed to investigate the relationship between executive functioning and suicidality among youth with insomnia.

Methods

Adolescents with DSM-5 insomnia disorder were recruited from local schools, universities, and the community in Hong Kong. Eligible participants completed self-reported measures, including Depressive Symptom Index - Suicidality Subscale (DSISS), Hospital Anxiety and Depression Scale (HADS), Insomnia Severity Index (ISI), Ruminative Response Scale (RRS), and were administered Wisconsin Card Sorting Test (WCST). The total scores of HADS were used to indicate psychological distress. Failure to maintain set (FMS) from WCST was used to indicate distractibility, an aspect of executive function, with higher scores suggesting greater distractibility.

Results

A total of 115 adolescents with insomnia disorder (Age: 18.34 ± 1.56, 14-20, female: 65.22%) were recruited. Multivariate regressions revealed that higher HADS (b=0.06, p=.045), RRS (b=0.05, p<.001), and FMS (b=0.30, p=.035) scores were all significantly associated with DSISS. The results remained significant after controlling for insomnia severity, gender, and age.

Conclusion

Our findings showed a link between impaired executive functioning, specifically distractibility, and suicidality. Distractibility may be attributed to the reduced suppression of the default mode network, which is associated with depression and rumination, thereby increasing the risk for suicidality. Future neuroimaging research is needed to further explore the underlying mechanism of such associations.

Support (if any)

This work was funded by General Research Fund (Ref. 17613820), Research Grants Council, University Grants Committee, Hong Kong SAR, China.
0994 Legal Considerations for Sleep and Mental Health: A Review of Foster Care Bedroom Guidelines Among 50 U.S. States
Authors: Rusin Karolina , Neblett Grace , Wolfson Amy , Ripple Carol , McGlinchey Eleanor , Alfano Candice
Published: April 2024

Introduction

Each year, the foster care system provides out-of-home placement for over 400,000 children, who are temporarily or permanently separated from their families. The prevalence of sleep and mental health problems in this population is well-documented. Persistent sleep problems associated with past and ongoing trauma independently elevate long-term risk for a host of physical and psychiatric disorders. While federal laws provide universal requirements for safe foster placements, the extent to which individual state laws and guidelines address child sleep health and environments varies. The aim of this policy review of administrative codes and guidelines regarding sleep/bedroom arrangements for children in foster care in all 50 U.S. states was to document that variability and examine whether state regulations incorporate sleep research findings.

Methods

Applicable bedroom and bed sharing guidelines were retrieved from each state’s government websites, followed by coding, categorization, and a systematic review. Categories included 7 broad themes: Bed Sharing, Room Sharing, Space Requirements, Bed Requirements, Caregiver-Child Requirements, Health, and Miscellaneous.

Results

While 39 states (78%) required an individual bed for each child in care, specific guidelines regarding bed and bedroom sharing with other children varied greatly by state. There was an even distribution across states that allowed bed or bedroom sharing for siblings (50%) and those that did not address this topic (50%), but only 6 states stated the importance of keeping sibling groups together when determining appropriate sleeping arrangements. In addition, a few states mentioned history of neglect, abuse, and trauma as factors to consider for sleep/bedroom guidelines. Only 10 states (20%) allowed bedroom sharing with a caregiver during emergencies, such as illness or periods of emotional distress.

Conclusion

Despite the universal importance of healthy sleep for all aspects of child development, we found striking differences between states regarding rules and guidelines for sleep and bedroom sharing. Most requirements lack consideration of children’s potential history of abuse and trauma, which contribute to sleep problems in this population. Also concerning is the lack of clear regulations regarding caregiver intervention in case of emergencies. We urge policymakers to reconsider current guidelines in accordance with sleep research and evidence-based practices.

Support (if any)
0995 Mental Health and Substance Use Outcomes Associated with Use of Cannabis as a Sleep Aid: A Co-twin Control Study
Authors: Panchal Zoë , Sakai Joseph , Goldstein-Piekarski Andrea , Ellingson Jarrod , Hopfer Christian , Corley Robin , Vrieze Scott , McGue Matt , Hewitt John , Iacono William , Ross J
Published: April 2024

Introduction

Using cannabis as a sleep aid is common. However, little is known about how this practice relates to mental health and substance use. To address this, we examined associations between using cannabis as a sleep aid with mental health and substance use outcomes using a co-twin control design.

Methods

Participants were 3,165 adults (Mage=36.7 (SD=5.3)) from two population-based twin cohorts. Outcomes of interest included mental health constructs (e.g. depression, impulsivity), substance use measures (frequency and problems from use of specific substances), and use of other substances for sleep. First, we conducted regression models to test phenotypic associations between endorsing past month use of cannabis to aid sleep (yes/no) and the above outcomes. Next, we used multilevel models to examine whether significant phenotypic associations were due to between-family effects (genetic and environmental factors shared by co-twins) or within-twin pair effects (genetic and environmental factors which differ between co-twins). All analyses controlled for sleep quality and cannabis frequency.

Results

The sample was 56.7% monozygotic twins, 39.6% male, and 92.7% Caucasian. Phenotypic associations were significant between endorsement of using cannabis for sleep and most outcomes. All significant associations were in the direction of worse mental health, greater use of other substances for sleep, and greater frequency of, and problems from, substance use. All significant phenotypic effects remained significant at the between-family level, but not all remained significant at the within-family level. At the within-family level, the twin who endorsed using cannabis as a sleep aid (vs. their co-twin who did not) reported more frequent use of alcohol (B=0.44, p<.001) and medication (B=0.26, p=.022) for sleep, greater frequency of alcohol use (B=13.0, p=.018), and more problems from cannabis use (B=0.85, p=.007).

Conclusion

Associations between using cannabis for sleep with worse mental health, after controlling for sleep quality and cannabis frequency, are likely due to shared genetic and/or environmental factors. Associations with substance use measures that were not accounted for by shared genetic and/or environmental factors include greater alcohol use frequency, more problems from cannabis use, and more frequent use of other substances for sleep.

Support (if any)

DA042755, DA057894, DA053693, DA056408, DA032555, DA054212, MH125758 (NIH), 1101101 (ICR)
0996 Parental Sleep Disturbance and Its Impact on Childhood Medication Adherence
Authors: Rios Christina , Meadows Amy
Published: April 2024

Introduction

Childhood medication adherence is paramount in treating both acute and chronic medical conditions. Sleep disturbances in children and adults have been linked to cognitive performance, cardiovascular function, immune regulation and behavioral disturbances. Despite documented interactions between concomitant parental substance use, depressive symptoms, and financial strain with sleep, there is limited data on how parental sleep disturbances impact childhood medication adherence.

Methods

Data was extracted from a mTURK dataset with 740 participants who were 18 years and older with at least one child who had been prescribed a medication within the prior three months. Parental sleep was measured using the PHQ-9 with a scale of 0 for “no trouble”, 1 for “several days”, 2 for “more than half of the days”, or 3 for “nearly all the days”. The Adverse Childhood Experiences (ACE) scale was used to determine a total ACE score (0-10). Children medication adherence was measured based on the following questions, “How often has your child followed his/her medical treatment instructions in the past three months?” and “How often has your child taken medication as prescribed in the past three months?” Responses were coded as “Adherent” if parents responded “Always” to both questions, but were otherwise coded as non-adherent. Statistical analysis was performed using RStudio software. Logistic regression analysis and Pearson’s correlation coefficient were used to test association between variables.

Results

We found a statistically significant relationship between the parental response to the sleep question on the PHQ-9 and the parent’s report of child’s adherence to medication. For every point increase in PHQ-3, the odds of having high adherence to a child’s medication decreased by 17%, when controlling for parental gender, chronic disease status, and parental ACE status (p< 0.05). There was also a weak positive correlation (0.19) with higher parental ACE score and sleep difficulties as measured by the PHQ-9.

Conclusion

There is a positive correlation between parental sleep disturbances and childhood medication adherence; this is a potential area for therapeutic intervention.

Support (if any)
0999 Stress, Sleep Disturbances and Coping Strategies Among Taiwanese Primary Family Caregivers in Intensive Care Units
Authors: Chang Pei-Yu , Shen Huan-Ting , Tzeng I-Shiang , Tang Chia-Chun , Tsai Shao-Yu
Published: April 2024

Introduction

The primary family caregivers in the intensive care unit (ICU) often experience stress and sleep disturbances. Exploring coping strategies for these caregivers is crucial for preventing burnout and alleviating adverse psychological and health outcomes. This study aimed to examine stress, sleep disturbances, and coping strategies among primary family caregivers in the ICU.

Methods

Data were extracted from the baseline assessment of an ongoing pilot experimental study conducted in four adult ICUs in a teaching hospital in central Taiwan. Eligible participants were (1) unpaid primary family caregivers acknowledged by either patients or their family members and (2) individuals with a family member who underwent mechanical ventilation for more than 48 hours while in the ICU. Participants completed a set of study questionnaires, including the Impact of Events Scale-Revised (IES-R), General Sleep Disturbance Scale (GSDS), Brief COPE, and Multidimensional Scale of Perceived Social Support (MSPSS).

Results

Eight primary family caregivers were recruited from 12 November 2023 to 8 December 2023. The mean age of these caregivers was 55.5±10.17 years, and 3 (37.5%) of them were female. The primary family caregivers experienced high stress levels (mean IES-R score > 32), sleep disturbance (mean GSDS score > 3), and poor sleep quality (mean subscale score of GSDS > 3). The primary family caregivers most often used acceptance, active coping, and positive reframing strategies to manage stress, and they received more social support from their families than from friends. Those caregivers who perceived higher stress levels reported more sleep disturbances (rs = .74, p < .05) and poorer sleep quantity (rs = .95, p < .05). They also relied more on self-distraction (rs = .79, p < .05), emotional support (rs = .76, p < .05) and planning coping to manage stress (rs = .77, p < .05).

Conclusion

The results of this ongoing study showed that primary family caregivers in the ICU experienced heightened stress perception and sleep disturbance. Future studies should focus on exploring effective coping strategies to help primary family caregivers in the ICU to manage stress.

Support (if any)

This work was supported by Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taiwan, TTCRD112-30.
A tendency toward evening chronotype associates with less healthy diet among preschoolers: cross-sectional findings from the DAGIS study
Authors: Abdollahi Anna M , Li Xinyue , Merikanto Ilona , Vepsäläinen Henna , Lehto Reetta , Rahkola Jenna , Nissinen Kaija , Kanerva Noora , Roos Eva , Erkkola Maijaliisa
Published: April 2024

Study Objectives

Evidence suggests that adolescents and adults with a later chronotype have poorer sleep habits and are more susceptible to unhealthy behaviors, but little is known about these associations in younger children. The objective of the study was to (1) identify and compare individual chronotype tendencies among preschool-aged children and (2) investigate associations of sleep dimensions and chronotype with diet.

Methods

Participants were 636 3–6 years old (mean ± SD age: 4.74 ± 0.89 years, 49% girls) preschoolers from the cross-sectional Increased Health and Well-Being in Preschoolers (DAGIS) study in Finland. Sleep duration, sleep variability (in duration and midpoint), social jetlag, and midsleep on weekends adjusted for sleep debt (MSWEadj) were measured with 7-day actigraphy. Morning, intermediate, and evening chronotype tendencies were defined based on the lowest and highest 10th percentile cutoffs of MSWEadj. Food, energy, and macronutrient intake were assessed from 3-day records. Associations between sleep dimensions and diet were assessed with regression models.

Results

MSWEadj was 1:13 ± 14 minutes for morning (n = 64), 2:25 ± 28 minutes for intermediate (n = 560), and 3:38 ± 15 minutes for evening (n = 64) chronotype tendency. Children with an evening chronotype tendency had greater social jetlag and sleep variability. Having an evening chronotype tendency was associated with higher added sugar, higher sugary food consumption, and lower vegetable consumption compared to intermediate tendency types. A later chronotype (MSWEadj) was associated with higher sugary food consumption, as well as lower vegetable and fiber intake. Sleep duration, social jetlag, and sleep variability were not associated with diet.

Conclusions

Several less healthy sleep and diet behaviors were observed among children with later chronotypes. Future public health interventions aimed towards children would benefit from taking into account chronotype.
CISG in the digital world digital economy: data, products, and assets
Authors: Perales Viscasillas Pilar
Published: April 2024

This article focuses on the question of whether the United Nations Convention on Contracts for the International sale of Goods (CISG) applies to the new digital world: a world where exchange or a combination of computer programs, licenses, software, and data as well as services are part of the new digital economy. These are new phenomena that are not regulated at all, or under-regulated, in domestic legal systems where courts and scholars struggle to accommodate these new digital realities in the already existent rules and traditional contract categories and to find appropriate solutions for mixed contracts for goods and services by an expanded interpretation of the traditional rules. By contrast, a recent tendency is observed at an international level either to review the already existent uniform law instruments in order to see whether they can cover the digital economy, or to create new soft law instruments. The CISG is not immune to the ‘danger’ that soft law instruments recently drafted to cover some transactions of the digital economy might create the wrong impression that the CISG, a hard law instrument, cannot cover them.
Propranolol Alleviates Cardiac Injury After Acute Catecholamine Infusion Through p38-MAPK Pathways
Authors: Liu Tzu-Hao , Hsieh Rebecca Jen-Ling , Chen Hsin-Hung , Kuo Tzu-Jiun , Lee Jui-Chen , Lu Wen-Hsien
Published: April 2024

Hypercatecholaminergic conditions are known to cause heart failure and cardiac fibrosis when severe. Although previous investigations have studied the effects of beta-blockade in experimental models of catecholaminergic states, the detailed benefits of beta-blockade in more realistic models of hyper-adrenergic states were less clear. In this study, we examined acute cardiac changes in rats with hyperacute catecholamine-induced heart failure with and without propranolol treatment. Male Sprague–Dawley rats (n = 12) underwent a 6-hour infusion of epinephrine and norepinephrine alone, with an additional propranolol bolus (1 mg/kg) at hour 1 (n = 6). Cardiac tissues were examined after 6 hours. Cardiac immunohistochemistry revealed significantly decreased expression of phosphorylated p-38 (left ventricle, P = 0.021; right ventricle, P = 0.021), with upregulation of reactive oxidative species and other profibrosis proteins, after catecholamine infusion alone. After 1 propranolol 1 mg/kg bolus, the levels of phosphorylated-p38 returned to levels comparable with sham (left ventricle, P = 0.021; right ventricle, P = 0.043), with additional findings including downregulation of the apoptotic pathway and profibrotic proteins. We conclude that catecholamine-induced heart failure exerts damage through the p-38 mitogen-activated protein kinase pathway and demonstrates profibrotic changes mediated by matrix metalloproteinase 9, alpha-smooth muscle actin, and fibroblast growth factor 23. Changes in these pathways attenuated acute catecholamine-induced heart failure after propranolol bolus 1 mg/kg. We conclude that propranolol bolus at 1 mg/kg is able to mediate the effects of catecholamine excess through the p-38 mitogen-activated protein kinase pathway, profibrosis, and extrinsic apoptosis pathway.
Aggregation of an FG nucleoporin under crowded conditions
Authors: Maguire Laura , Reskin Sophie , Wall Kathryn , Arroyo Elena , Marchando Paul , Whited A. M. , Erbse Annette , Whitten Steven T. , Hough Loren E.
Published: April 2024

Macromolecular crowding can affect the aggregation behavior of intrinsically disordered proteins in unexpected ways. We studied the aggregation of a peptide derived from the disordered FG nucleoporins which line the nuclear pore complex. We measured its aggregation kinetics in the presence of both inert and non-specifically interacting crowding agents. Using fluorescence emission and NMR spectroscopy, we probed differences in the local chemical microenvironment of the peptide’s residues. Our results indicate differences in aggregation kinetics and residue microenvironment depending on the identity of the crowder, including differences between crowding with PEG and PVP, two polymers which are often used interchangeably as inert crowding agents.
Inference of Causal Interaction Networks of Gut Microbiota Using Transfer Entropy
Authors: Park Chanho , Kim Junil , Lee Julian
Published: April 2024

Understanding the complex dynamics of gut microbiota interactions is essential for unraveling their influence on human health. In this study, we employed transfer entropy analysis to construct a causal interaction network among gut microbiota genera from the time-series data of bacterial abundances. Based on the longitudinal microbiome data from two subjects, we found that the constructed gut microbiota regulatory networks exhibited power-law degree distribution, intermediate modularity, and enrichment of feedback loops. Interestingly, the networks of the two subjects displayed differential enrichment of feedback loops, which may be associated with the differential recovery dynamics of the two subjects. In summary, the transfer entropy-based network construction provides us with valuable insights into the ecosystem of gut microbiota and allows us to identify key microbial hubs that play pivotal roles in shaping the microbial balances.
Modeling of HIV-1 prophylactic efficacy and toxicity with islatravir shows non-superiority for oral dosing, but promise as a subdermal implant
Authors: Kim Hee-yeong , Zhang Lanxin , Hendrix Craig W , Haberer Jessica E , von Kleist Max
Published: April 2024

HIV prevention with pre-exposure prophylaxis (PrEP) constitutes a major pillar in fighting the ongoing epidemic. While daily oral PrEP adherence may be challenging, long-acting (LA-)PrEP in oral or implant formulations could overcome frequent dosing with convenient administration. The novel drug islatravir (ISL) may be suitable for LA-PrEP, but high doses have been associated with lymphopenia. We developed a mathematical model to predict ISL pro-drug levels in plasma and active intracellular ISL-triphosphate concentrations after oral vs. subdermal implant dosing. Using phase-II trial data, we simulated antiviral effects and estimated HIV risk reduction for multiple dosages and dosing frequencies. We then established non-toxic exposure thresholds and evaluated low-dose regimens. Our findings suggest that implants with 56-62 mg ISL offer safe, effective HIV risk reduction without being toxic. Oral 0.1 mg daily, 3-5 mg weekly, and 10 mg bi-weekly ISL provide comparable efficacy, but weekly and bi-weekly doses resulted in residual toxicity, while adherence requirements for daily dosing were similar to established oral PrEP regimen. Oral 0.5-1 mg on-demand provided > 90% protection, while not being suitable for post-exposure prophylaxis.
A New Large-Scale Extracellular Vesicle Production Strategy for Biomedical Drug Development
Authors: Yang Shiyi , Zhang Lei , Zhou Xin , Peng Xincheng , Zhang Xin , Wang Wenli , Zhao Jinxiu , He Xinjun , Xu Ke
Published: April 2024

1.

Extracellular Vesicles (EVs) are nanoscale to microscale membranous vesicles released by cells. They are vital for intercellular communications in physiological and pathological conditions, offering immense potential in diagnostics and therapeutical applications due to their ability to transfer diverse biological cargos between cells. While research of EVs is continuously gaining popularity in academia, large-scale manufacturing aiming for clinical applications remains challenging. Herein, we introduce a novel large-scale EV production strategy, including an upstream process with fed-batch suspension HEK293 cell culture, and a downstream process with chromatographic purification for ultra-pure EVs. Such promising EV production strategy enables the potential capability of large scale GMP manufacture of EVs for clinical applications.
Elucidating Electronic Structure Variations in Nucleic Acid-Protein Complexes Involved in Transcription Regulation Using a Tight-Binding Approach
Authors: Du Likai , Liu Chengbu
Published: April 2024

Transcription factor (TF) are proteins that regulates the transcription of genetic information from DNA to messenger RNA by binding to a specific DNA sequence. Nucleic acid-protein interactions are crucial in regulating transcription in biological systems. This work presents a quick and convenient method for constructing tight-binding models and offers physical insights into the electronic structure properties of transcription factor complexes and DNA motifs. The tight binding Hamiltonian parameters are generated using the random forest regression algorithm, which reproduces the givenab-initiolevel calculations with reasonable accuracy. We present a library of residue-level parameters derived from extensive electronic structure calculations over various possible combinations of nucleobases and amino acid side chains from high-quality DNA-protein complex structures. As an example, our approach can reasonably generate the subtle electronic structure details for the orthologous transcription factors human AP-1 and Epstein-Barr virus Zta within a few seconds on a laptop. This method potentially enhances our understanding of the electronic structure variations of gene-protein interaction complexes, even those involving dozens of proteins and genes. We hope this study offers a powerful tool for analyzing transcription regulation mechanisms at an electronic structural level.

Topic of Content

Transcription factors that bind to DNA modulate gene expression, with the stability and reactivity of their interactions elucidated by eigenvalues derived from the tight-binding model. Visualization of these interactions reveals the Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO), the gap between which determines the reactivity and stability of the molecular complex. This approach advances our understanding of gene regulation by revealing the dynamics of charge transfer and electronic states within transcription factor-DNA complexes.
High-efficiency PET Degradation with a Duo-enzyme System Immobilized on Magnetic Nanoparticles
Authors: Kotnis Siddhi , Gulati Siddhant , Sun Qing
Published: April 2024

The widespread consumption of PET worldwide has necessitated the search for environment-friendly methods for PET degradation and recycling. Among these methods, biodegradation stands out as a promising approach for recycling PET. The discovery of duo enzyme system PETase and MHETase in 2016, along with their engineered variants, has demonstrated significant potential in breaking down PET. Previous studies have also demonstrated that the activity of the enzyme PETase increases when it is immobilized on nanoparticles. To achieve highly efficient and complete PET depolymerization, we immobilized both FAST PETase and MHETase at a specific ratio on magnetic nanoparticles. This immobilization resulted in a 2.5-fold increase in product release compared with free enzymes. Additionally, we achieved reusability and enhanced stability of the enzyme bioconjugates.
Quantifying the evolutionary paths to endomembranes
Authors: Schavemaker Paul E. , Lynch Michael
Published: April 2024

Eukaryotes exhibit a complex and dynamic internal meshwork of membranes—theendomembrane system—used to insert membrane proteins, ingest food, and digest cells and macromolecules. Verbal models explaining the origin of endomembranes abound, but explicit quantitative considerations of fitness are lacking. A wealth of quantitative data on vesicle sizes, local protein abundances, protein residence times at functional loci, nutrient transporter rates, membrane protein insertion rates, etc., have been made available in the past couple of decades. Drawing on these data allows for the derivation of two biologically-grounded analytical models of endomembrane evolution that quantify organismal fitness: 1) vesicle-based uptake of nutrient molecules—pinocytosis, and 2) vesicle-based insertion of membrane proteins—proto-endoplasmic reticulum. Surprisingly, pinocytosis doesn’t provide a net fitness gain under biologically sensible parameter ranges. Explaining why it is primarily used for protein, and not small molecule, uptake in contemporary organisms. The proto-endoplasmic reticulum does provide net fitness gains, making it the more likely candidate for initiating the origin of the endomembrane system. With modifications, the approach developed here can be used to understand the present-day endomembrane system and to further flesh out the cell-level fitness landscape of endomembranes and illuminate the origin of the eukaryotic cell.
Tumoroid-on-a-Plate (ToP): Physiologically Relevant Cancer Model Generation and Therapeutic Screening
Authors: Seyfoori Amir , Liu Kaiwen , Caruncho Hector , Walter Patrick , Akbari Mohsen
Published: April 2024

Employing three-dimensional (3D)in vitromodels, including tumor organoids and spheroids, stands pivotal in enhancing cancer therapy. These models bridge the gap between 2D cell cultures and complex in vivo environments, effectively mimicking the intricate cellular interplay and microenvironmental factors found in solid tumors. Consequently, they offer versatile tools for comprehensive studies into cancer progression, drug responses, and tailored therapies. In this study, we present a novel open-surface microfluidic-integrated platform called the Tumoroid-on-a-Plate (ToP) device, designed for generating intricate predictive 3D solid tumor models. By incorporating a tumor mass, stromal cells, and extracellular matrix components, we successfully replicate the complexity of glioblastoma (GBM) and pancreatic adenocarcinoma (PDAC) within our system. Using our advanced ToP model, we were able to successfully screen the effect of various GBM extracellular matrix compositions, such as Collagen and Reelin, on the invasiveness of the GBM cells with the ToP model. The ToP in vitro model also allowed for the screening of chemotherapeutic drugs such as temozolomide and iron-chelators in a single and binary treatment setting on the complex ECM-embedded tumoroids. This helped to investigate the toxic effect of different therapeutics on the viability and apoptosis of our in vitro GBM and PDAC cancer models. Additionally, by co-culturing human-derived fibroblast cells with PDAC tumoroids, the pro-invasive impact of the stromal component of the tumor microenvironment on growth behaviour and drug response of the tumoroids was revealed. This study underscores the transformative role of predictive 3D models in deciphering cancer intricacies and highlights the promise of ToP in advancing therapeutic understanding.
Receptor activity modifying protein modulation of parathyroid hormone-1 receptor function and signalling
Authors: Avgoustou Paris , Jailani Ameera B. A. , Desai Aditya J. , Roberts Dave J. , Lilley Ewan R. , Stothard Grant W. , Skerry Timothy M. , Richards Gareth O.
Published: April 2024

Receptor activity-modifying proteins (RAMPs) are known to modulate the pharmacology and function of several G protein-coupled receptors (GPCRs), including the parathyroid hormone 1 receptor (PTH1R). However, the precise effects of different RAMPs on PTH1R signalling and trafficking remain poorly understood. Here we investigated the impact of RAMP2 and RAMP3 on PTH1R function using a range of PTHand PTH-related protein (PTHrP)-derived ligands.

FRET imaging revealed that PTH1R preferentially interacts with RAMP2 and, to a lesser extent, RAMP3, but not RAMP1. Interestingly, RAMP3 co-expression resulted in reduced cell surface expression of PTH1R, suggesting a potential role in receptor trafficking or internalization. The presence of RAMP2 significantly enhanced PTH1R-mediated cAMP accumulation, β-arrestin recruitment, and calcium signalling in response to PTH (1–34), PTHrP (1-34), PTH (1-84), and the PTH (1-17) analogue ZP2307. In contrast, RAMP3 co-expression attenuated or completely abolished those responses.

We found that full-length PTHrP analogues, PTHrP (1-108) and PTHrP (1-141), exhibited lower potency and efficacy than PTHrP (1-34) in activating PTH1R. RAMP2 significantly increased potency and/or efficacy when compared to PTH1R alone cells, while RAMP3 significantly reduced these responses. Antibody-capture scintillation proximity assays demonstrated that RAMP2 differentially modulates G protein activation by PTH1R in a ligand-dependent manner, with PTH (1-34) and PTHrP (1-34) inducing distinct patterns of G protein subtype activation.

These findings highlight the complex role of RAMPs in regulating PTH1R signalling and trafficking, revealing differential effects of RAMP2 and RAMP3 on receptor function. The data suggest that targeting the PTH1R/RAMP2 complex may be a promising strategy for developing novel bone anabolic therapies by leveraging biased agonism and functional selectivity. Further research using physiologically relevant models is needed to elucidate the therapeutic potential of this approach.
Wampee chromosome-level reference genome elucidates fruit sugar-acid metabolism
Authors: Chen Huiqiong , Wang Jingxuan , Wang Xiangfeng , Peng Cheng , Chang Xiaoxiao , Chen Zhe , Yang Bowen , Wang Xinrui , Qiu Jishui , Guo Li , Lu Yusheng
Published: April 2024

Wampee (Clausena lansium) is an economically significant subtropical fruit tree widely cultivated in Southern China. High-quality genomic resources are unavailable, but they are essential for functional genomics and germplasm enhancement of wampee. Here, we provide a chromosome-level genome sequence for the wampee cultivar JinFeng and a population genomic analysis of 266 accessions. The 297.1 Mb wampee genome, containing nine chromosomes with a scaffold N50 of 29.2 Mb and encoding 23,468 protein-coding genes, showed a significant improvement over the previous version. We dissected the wampee population structure and genetic differentiation in China using population genomic analysis, which detected 110 and 671 genes under a selective sweep associated with sour and sweet wampee evolution in domesticated clones, respectively. Homozygous non-synonymous single nucleotide polymorphisms are likely associated with fruit flavor differentiation. A genome-wide association study identified 220 remarkable marker-trait associations for total acid content, harboring 289 genes encoding transcription factors, transporters, and enzymes involved in sugar and acid metabolism, which are potentially useful for sour and sweet taste development in wampee fruit. Furthermore, the ethylene response factor family geneClERF061and the SWEET family geneClSWEET7were identified. Linkage assessment between the relative expression levels ofClERF061orClSWEET7and the total acid/total sugar contents implied their potential involvement in sugar-acid metabolism in wampee fruits. High-quality genome resources are valuable for expediting wampee research and genome-assisted breeding.
Protein-ligand binding affinity prediction: Is 3D binding pose needed?
Authors: Wu Ming-Hsiu , Xie Ziqian , Zhi Degui
Published: April 2024

Accurate protein-ligand binding affinity prediction is crucial in drug discovery. Existing methods are predominately docking-free, without explicitly considering atom-level interaction between proteins and ligands in scenarios where crystallized protein-ligand binding conformations are unavailable. Now, with breakthroughs in deep learning AI-based protein folding and binding conformation prediction, can we improve binding affinity prediction? This study introduces a framework, Folding-Docking-Affinity (FDA), which folds proteins, determines protein-ligand binding conformations, and predicts binding affinities from three-dimensional protein-ligand binding structures. Our experiments demonstrate the feasibility of our FDA framework and its superiority over state-of-the-art docking-free models, showcasing the potential of explicit modeling of three-dimensional binding conformations for enhancing binding affinity prediction accuracy.
Massively parallel jumping assay decodesAluretrotransposition activity
Authors: Matharu Navneet , Zhao Jingjing , Sohota Ajuni , Deng Linbei , Hung Yan , Li Zizheng , Sims Jasmine , Rattanasopha Sawitree , Meyer Josh , Carbone Lucia , Kircher Martin , Ahituv Nadav
Published: April 2024

The human genome contains millions of retrotransposons, several of which could become active due to somatic mutations having phenotypic consequences, including disease. However, it is not thoroughly understood how nucleotide changes in retrotransposons affect their jumping activity. Here, we developed a novel massively parallel jumping assay (MPJA) that can test the jumping potential of thousands of transposonsen masse. We generated nucleotide variant library of selected fourAluretrotransposons containing 165,087 different haplotypes and tested them for their jumping ability using MPJA. We found 66,821 unique jumping haplotypes, allowing us to pinpoint domains and variants vital for transposition. Mapping these variants to theAlu-RNA secondary structure revealed stem-loop features that contribute to jumping potential. Combined, our work provides a novel high-throughput assay that assesses the ability of retrotransposons to jump and identifies nucleotide changes that have the potential to reactivate them in the human genome.
A systematic bi-genomic split-GFP assay illuminates the mitochondrial matrix proteome and protein targeting routes
Authors: Bykov Yury S. , Zuttion Solène , Senger Bruno , Klein Ofir , Asraf Yeynit , Meyer Hadar , Becker Hubert D. , Kucharczyk Róża , Schuldiner Maya
Published: April 2024

The majority of mitochondrial proteins are encoded in the nuclear genome and often lack clear targeting signals. Therefore, what constitutes the entire mitochondrial proteome is still unclear. We here build on our previously developed bi-genomic (BiG) split-GFP assay (Bader et al. 2020) to solidify the list of matrix and inner membrane mitochondrial proteins. The assay relies on one fragment (GFP1-10) encoded in the mitochondrial DNA enabling specific visualization of only the proteins tagged with a smaller fragment, GFP11, and localized to the mitochondrial matrix or the inner membrane. We used the SWAp-Tag (SWAT) strategy to tag every protein with GFP11and mated them with the BiG GFP strain. Imaging the collection in six different conditions allowed us to visualize almost 400 mitochondrial proteins, 50 of which were never visualized in mitochondria before, and many are poorly studied dually localized proteins. We also show how this data can be applied to study mitochondrial inner membrane protein topology and sorting. This work brings us closer to finalizing the mitochondrial proteome and the freely distributed library of GFP11-tagged strains will be a useful resource to study protein localization, biogenesis and interactions.
Discovery and Synthesis of GS-7682, a Novel Prodrug of a 4′-CN-4-Aza-7,9-DideazaadenosineC-Nucleoside with Broad-Spectrum Potency Against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys
Authors: Siegel Dustin S. , Hui Hon C. , Pitts Jared , Vermillion Meghan S. , Ishida Kazuya , Rautiola Davin , Keeney Michael , Irshad Hammad , Zhang Lijun , Chun Kwon , Chin Gregory , Goyal Bindu , Doerffler Edward , Yang Hai , Clarke Michael O. , Palmiotti Chris , Vijjapurapu Arya , Riola Nicholas C. , Stray Kirsten , Murakami Eisuke , Ma Bin , Wang Ting , Zhao Xiaofeng , Xu Yili , Lee Gary , Marchand Bruno , Seung Minji , Nayak Arabinda , Tomkinson Adrian , Kadrichu Nani , Ellis Scott , Barauskas Ona , Feng Joy Y. , Perry Jason K. , Perron Michel , Bilello John P. , Kuehl Philip J. , Subramanian Raju , Cihlar Tomas , Mackman Richard L.
Published: April 2024

Acute respiratory viral infections (ARVI), such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 (1) a novel phosphoramidate prodrug of a 4′-CN-4-aza-7,9-dideazaadenosineC-nucleoside GS-646089 (2) with broad antiviral activity against RSV EC50= 3-46 nM, human metapneumovirus (hMPV) EC50= 210 ± 50 nM, human rhinovirus (RV) EC50= 54-61 nM, and enterovirus (EV) EC50= 83-90 nM. Prodrug optimization for cellular potency and lung cell metabolism identified the 5’-methyl((S)-hydroxy(phenoxy)phosphoryl)-L-alaninate in combination with 2’,3’-diisobutyrate promoieties as optimal for high intracellular triphosphate formation in vitro and in vivo.1demonstrated significant reductions of viral loads in the lower respiratory tract of RSV-infected African green monkeys when administered once daily via intratracheal nebulized aerosol. Together these finding support additional evaluation of1and its analogs as a potential therapeutic for pneumo- and picornaviruses.
RESIST ACINETO test for the rapid detection of NDM and OXA acquired carbapenemases directly from blood culture inAcinetobacterspecies
Authors: Potron Anaïs , Daniel Marion , Bay Mila , Choulet Pauline , Garrigos Thomas , Sababadichetty Loïk , Belmonte Olivier , Fournier Damien , Jeannot Katy , Miltgen Guillaume
Published: April 2024

The immunochromatographic assay RESIST ACINETO (Coris BioConcept) was evaluated on a collection of 121Acinetobacterspp. clinical isolates, including 104 carbapenemase producers. The strains producing carbapenemases OXA-23, -40, -58, or/and NDM were accurately detected from bacterial cultures and directly from blood cultures, with the exception of an OXA-23/NDM-1-positiveA. radioresistensisolate (only detected through standard culture). The performance of the RESIST ACINETO test was excellent (sensitivity 99%, specificity 100%) on this collection of isolates.
A variant prioritization tool leveraging multiple instance learning for rare Mendelian disease genomic testing
Authors: Kim Ho Heon , Baek Ju Yeop , Han Heonjong , Jeong Won Chan , Kim Dong-Wook , Kwon Kisang , Song Yongjun , Lee Hane , Seo Go Hun , Lee Jungsul , Lee Kyoungyeul
Published: April 2024

Background

Genomic testing such as exome sequencing and genome sequencing is being widely utilized for diagnosing rare Mendelian disorders. Because of a large number of variants identified by these tests, interpreting the final list of variants and identifying the disease-causing variant even after filtering out likely benign variants could be labor-intensive and time-consuming. It becomes even more burdensome when various variant types such as structural variants need to be considered simultaneously with small variants. One way to accelerate the interpretation process is to have all variants accurately prioritized so that the most likely diagnostic variant(s) are clearly distinguished from the rest.

Methods

To comprehensively predict the genomic test results, we developed a deep learning based variant prioritization system that leverages multiple instance learning and feeds multiple variant types for variant prioritization. We additionally adopted learning to rank (LTR) for optimal prioritization. We retrospectively developed and validated the model with 5-fold cross-validation in 23,115 patients with suspected rare diseases who underwent whole exome sequencing. Furthermore, we conducted the ablation test to confirm the effectiveness of LTR and the importance of permutational features for model interpretation. We also compared the prioritization performance to publicly available variant prioritization tools.

Results

The model showed an average AUROC of 0.92 for the genomic test results. Further, the model had a hit rate of 96.8% at 5 when prioritizing single nucleotide variants (SNVs)/small insertions and deletions (INDELs) and copy number variants (CNVs) together, and a hit rate of 95.0% at 5 when prioritizing CNVs alone. Our model outperformed publicly available variant prioritization tools for SNV/INDEL only. In addition, the ablation test showed that the model using LTR significantly outperformed the baseline model that does not use LTR in variant prioritization (p=0.007).

Conclusion

A deep learning model leveraging multiple instance learning precisely predicted genetic testing conclusion while prioritizing multiple types of variants. This model is expected to accelerate the variant interpretation process in finding the disease-causing variants more quickly for rare genetic diseases.
Comparative Analysis of COVID-19 Serological testing methods to Polymerase Chain Reaction: A systematic review and meta-analysis
Authors: Chisompola David , Maleti Alex , Tembo Kingsley , Banda Tioni , Chishinji George , Phiri Richard
Published: April 2024

Background

Accurate and reliable diagnosis of COVID-19 is essential for effective disease management and public health interventions. SARS-CoV-2 antibody/antigen tests play a crucial role in identifying covid-19 infections and assessing immunity in populations. This systematic review aimed to evaluate the sensitivity, specificity, and accuracy of SARS-CoV-2 antibody tests in diagnosing COVID-19.

Method

A comprehensive systematic review of the literature was conducted using prominent scientific databases, including PubMed, Google Scholar, Cochrane, and Scopus to search studies published from January 2020 to May 2023. The review followed the PRISMA-DTA framework to ensure transparency and rigor in the selection and evaluation of studies. The QUADAS-2 tool was utilized to assess study quality and risk of bias. This review was registered on PROSPERO (registration number CRD 42023445695).

Results

The pooled sensitivity of SARS-CoV-2 antibody/antigen tests was found to be 73% (95% CI: 60–86), with individual studies reporting a wide range from 30% to 100%. The pooled specificity was 98% (95% CI: 97–100), with values ranging from 85.9% to 100%. The pooled accuracy was 88%, showing variation from 50% to 100% across different studies.

Conclusion

This review highlights the moderate to high sensitivity and specificity of SARS-CoV-2 antibody/antigen tests for COVID-19 diagnosis. The substantial variability in test performance necessitates the standardization of testing protocols and further research to improve accuracy and reliability. These findings offer valuable insights for clinical decision-making and the formulation of effective public health strategies related to COVID-19 diagnosis.