bluuebunny/crossref_metadata_2025 huggingface dataset:
Delayed Diagnoses in Patients With Dizziness in the US Commonwealth of Virginia and the Tidewater Region
Authors: Walker Kendra N. , Guy Kevin M. , Volsky Peter G.
Published: December 2023

Objective:

In a region of approximately 1.7 million people (Tidewater, coastal Virginia), identify secondary diagnoses in persons with dizziness.

Methods:

This cross-sectional study utilizing TriNetX included individuals in the region of interest diagnosed with dizziness between 2010 and 2020. Subsequent diagnoses of vestibular disease or medical conditions possibly associated with dizziness in the same subjects were catalogued.

Results:

During the study period, 31,670 subjects were identified with diagnoses of dizziness as a symptom; 18,390 subjects were subsequently given a dizziness-related nonvestibular diagnosis, and 930 were given a subsequent vestibular disease diagnosis. The proportion of subjects diagnosed with vestibular disease (3%) after the dizziness diagnosis is far below expected norms (25%–34%) in the general population. There were greater proportions of delayed diagnoses of labyrinth dysfunction (odds ratio [OR], 4.8; P < 0.0001), superior semicircular canal dehiscence (OR, 3.1; P = 0.0023), otolith disease (OR, 3.1; P = 0.0023), among others, and a decreased proportion of delayed diagnosis of benign paroxysmal positional vertigo (OR, 0.56; P < 0.0001).

Conclusions:

The discrepancy between expected and observed prevalence in our region indicates that vestibular disease is likely underdiagnosed.
Early Cardiac Arrest Hemodynamics, End-Tidal Co 2, and Outcome in Pediatric Extracorporeal Cardiopulmonary Resuscitation: Secondary Analysis of the ICU-RESUScitation Project Dataset (2016–2021)*
Authors: Yates Andrew R. , Naim Maryam Y. , Reeder Ron W. , Ahmed Tageldin , Banks Russell K. , Bell Michael J. , Berg Robert A. , Bishop Robert , Bochkoris Matthew , Burns Candice , Carcillo Joseph A. , Carpenter Todd C. , Dean J. Michael , Diddle J. Wesley , Federman Myke , Fernandez Richard , Fink Ericka L. , Franzon Deborah , Frazier Aisha H. , Friess Stuart H. , Graham Kathryn , Hall Mark , Hehir David A. , Horvat Christopher M. , Huard Leanna L. , Maa Tensing , Manga Arushi , McQuillen Patrick S. , Morgan Ryan W. , Mourani Peter M. , Nadkarni Vinay M. , Notterman Daniel , Pollack Murray M. , Sapru Anil , Schneiter Carleen , Sharron Matthew P. , Srivastava Neeraj , Tilford Bradley , Viteri Shirley , Wessel David , Wolfe Heather A. , Yeh Justin , Zuppa Athena F. , Sutton Robert M. , Meert Kathleen L.
Published: December 2023

OBJECTIVES:

Cannulation for extracorporeal membrane oxygenation during active extracorporeal cardiopulmonary resuscitation (ECPR) is a method to rescue patients refractory to standard resuscitation. We hypothesized that early arrest hemodynamics and end-tidal Co2(ETco2) are associated with survival to hospital discharge with favorable neurologic outcome in pediatric ECPR patients.

DESIGN:

Preplanned, secondary analysis of pediatric Utstein, hemodynamic, and ventilatory data in ECPR patients collected during the 2016–2021 Improving Outcomes from Pediatric Cardiac Arrest study; the ICU-RESUScitation Project (ICU-RESUS; NCT02837497).

SETTING:

Eighteen ICUs participated in ICU-RESUS.

PATIENTS:

There were 97 ECPR patients with hemodynamic waveforms during cardiopulmonary resuscitation.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Overall, 71 of 97 patients (73%) were younger than 1 year old, 82 of 97 (85%) had congenital heart disease, and 62 of 97 (64%) were postoperative cardiac surgical patients. Forty of 97 patients (41%) survived with favorable neurologic outcome. We failed to find differences in diastolic or systolic blood pressure, proportion achieving age-based target diastolic or systolic blood pressure, or chest compression rate during the initial 10 minutes of CPR between patients who survived with favorable neurologic outcome and those who did not. Thirty-five patients had ETco2data; of 17 survivors with favorable neurologic outcome, four of 17 (24%) had an average ETco2less than 10 mm Hg and two (12%) had a maximum ETco2less than 10 mm Hg during the initial 10 minutes of resuscitation.

CONCLUSIONS:

We did not identify an association between early hemodynamics achieved by high-quality CPR and survival to hospital discharge with favorable neurologic outcome after pediatric ECPR. Candidates for ECPR with ETco2less than 10 mm Hg may survive with favorable neurologic outcome.
Celiac Disease and Intussusception
Authors: Aldaher Anwaar , Alali Mariam Mahmoud , Ourfali Nouri , AlJubab Abdulwahab , Ali Qamar , Bashir Muhammed Salman , Al-Hussaini Abdulrahman
Published: December 2023

Objectives

In young childhood, intestinal intussusception (IS) is the most common cause of small bowel obstruction. A lead point such as Meckel diverticulum, polyps, tumors, enlarged lymph nodes, cystic fibrosis, and Schoenlein-Henoch purpura are recognized causes. Association between celiac disease (CD) and IS has been well recognized in adults but rarely in children. Data on causes and outcome of intussusception among Saudi children are lacking in the literature. Our objectives were to characterize the pattern of IS among Saudi children and investigate the frequency, clinical presentation, and outcome of intussusception among children with CD.

Methods

We searched the hospital's picture archiving and communications system for abdominal imaging studies (ultrasound, magnetic resonance imaging, computed tomography scan, and barium contrast studies), performed between 2008 and 2019, using “intussusception” as a search key word. The hospital medical records of the identified cases of intussusception (aged 0–14 years) were then retrospectively reviewed to collect demographic, clinical, laboratory and imaging findings, management, and outcome.

Results

During the study period, 57 cases were identified as confirmed IS (31 boys, median age 1.95 years, range 0.33–11 years). Abdominal ultrasound was the diagnostic imaging study in 93%. An underlying cause (secondary IS) could be identified in 19 (33.3%) cases: CD in 6, malignancy and Henoch-Schoenlein purpura, 5 each, and Meckel diverticulum in 3; the remaining 38 (66.6%) cases of IS were idiopathic (primary IS). The presence of hypoalbuminemia and abdominal distension were significantly associated with secondary IS as compared with primary IS (P < 0.001, P = 0.006, respectively). All of the 6 cases of IS associated with CD resolved spontaneously, but 3 were recurrent.

Conclusions

Secondary causes contributed to a large proportion of IS in our study cohort (33%) as compared with 5% to 10% in the literature. Celiac disease is an underrecognized cause of IS among children. A child with IS and hypoalbuminemia, anemia, or chronic diarrhea needs to be investigated for CD to avoid unnecessary surgery.
Antibody-labelling correlative light electron microscopy
Authors: Doyle Nicole , Simpson Jennifer , Hawes Philippa C , Maier Helena J
Published: December 2023

In the intricate environment of a cell, many studies seek to discover the location of specific events or objects of interest. Advances in microscopy in recent years have allowed for high detail views of specific areas of cells of interest using correlative light electron microscopy (CLEM). While this powerful technique allows for the correlation of a specific area of fluorescence on a confocal microscope with that same area in an electron microscope, it is most often used to study tagged proteins of interest. This method adapts the correlative method for use with antibody labelling. We have shown that some cellular structures are more sensitive than others to this process and that this can be a useful technique for laboratories where tagged proteins or viruses, or dedicated CLEM instruments are not available.
Multi-omics integration of scRNA-seq time series data predicts new intervention points for Parkinson’s disease
Authors: Mihajlović Katarina , Ceddia Gaia , Malod-Dognin Noël , Novak Gabriela , Kyriakis Dimitrios , Skupin Alexander , Pržulj Nataša
Published: December 2023

Parkinson’s disease (PD) is a complex neurodegenerative disorder without a cure. The onset of PD symptoms corresponds to 50% loss of midbrain dopaminergic (mDA) neurons, limiting early-stage understanding of PD. To shed light on early PD development, we study time series scRNA-seq datasets of mDA neurons obtained from patient-derived induced pluripotent stem cell differentiation. We develop a new data integration method based on Non-negative Matrix Tri-Factorization that integrates these datasets with molecular interaction networks, producing condition-specific “gene embeddings”. By mining these embeddings, we predict 193 PD-related genes that are largely supported (49.7%) in the literature and are specific to the investigatedPINK1mutation. Enrichment analysis in Kyoto Encyclopedia of Genes and Genomes pathways highlights 10 PD-related molecular mechanisms perturbed during early PD development. Finally, investigating the top 20 prioritized genes reveals 12 previously unrecognized genes associated with PD that represent interesting drug targets.
Distinct effects of priming the brain using tDCS and observational practice: new evidence from brain effective connectivity
Authors: McLeod J. , Chavan A. , Lee H. , Sattari S. , Kurry S. , Wake M. , Janmohamed Z. , Hodges N.J. , Virji-Babul N.
Published: December 2023

Complex motor skills can be acquired while observing a model without physical practice. Transcranial direct-current stimulation (tDCS) applied to the primary motor cortex (M1) also facilitates motor learning. However, the effectiveness of observational practice for bimanual coordination skills is debated and there is little research on the effects of tDCS on acquiring bimanual skills and the underlying effective/causal brain connectivity. We compared the effect of primary motor cortex tDCS (M1-tDCS) to action-observation (AO) when acquiring a bimanual, two-ball juggling skill and characterized the brain causal connectivity patterns underlying each condition. Twenty healthy young adults with no juggling experience were randomly assigned to either video observation of a skilled juggler or anodal M1-tDCS. Thirty trials of juggling were performed and scored after the intervention. Resting-state EEG data were collected before and after the intervention. Information flow rate was applied to EEG source data to measure causal connectivity. Juggling scores were significantly higher in the AO group (p=.03). We found the strongest information exchange from (L) parietal to (R) parietal regions, strong bidirectional information exchange between (R) parietal and (R) occipital regions and an extensive network of activity that was (L) lateralized in the AO condition. In contrast, the M1-tDCS condition was characterized by bilateral long-range connections with the strongest information exchange from the (R) occipital region to the (R) temporal and (L) occipital regions. This study provides new results about the distinct network dynamics of priming the brain for skill acquisition using direct stimulation or indirect stimulation via action observation.
G6PD deficiency mediated impairment of iNOS and lysosomal acidification affecting phagocytotic clearance in microglia in response to SARS-CoV-2
Authors: Mondal Abir , Munan Subrata , Saxena Isha , Mukherjee Soumyadeep , Upadhyay Prince , Gupta Nutan , Dar Waseem , Samanta Animesh , Singh Shailja , Pati Soumya
Published: December 2023

The glucose-6-phosphate dehydrogenase (G6PD) deficiency is X-linked and is the most common enzymatic deficiency disorder globally. It is a crucial enzyme for the pentose phosphate pathway and produces NADPH, which plays a vital role in the regulation of oxidative stress of many cell types. The deficiency of G6PD causes hemolytic anemia, diabetes, cardiovascular and neurological disorders. Notably, the patient with G6PD deficiency was severely affected by SARS-CoV-2 and showed prolonged COVID-19 symptoms, neurological impacts, and high mortality. However, the mechanism of COVID-19 severity in G6PD deficient patients is still ambiguous. Here, using a CRISPR-edited G6PD deficient human microglia cell culture model, we observed a significant reduction in NADPH and an increase in basal reactive oxygen species (ROS) in microglia. Interestingly, the deficiency of the G6PD-NAPDH axis impairs induced nitric oxide synthase (iNOS) mediated nitric oxide (NO) production which plays a fundamental role in inhibiting viral replication. Surprisingly, we also observed that the deficiency of the G6PD-NADPH axis reduced lysosomal acidification, which further abrogates the lysosomal clearance of viral particles. Thus, impairment of NO production and lysosomal acidification as well as redox dysregulation in G6PD deficient microglia altered innate immune response, promoting the severity of SARS-CoV-2 pathogenesis.
Lumbosacral spinal cord functional connectivity at rest: From feasibility to reliability
Authors: Ricchi Ilaria , Kinany Nawal , Van De Ville Dimitri
Published: December 2023

In the past decade, exploration of spontaneous blood-oxygen-level-dependent (BOLD) signal fluctuations has expanded beyond the brain to include the spinal cord. While most studies have predominantly focused on the cervical region, the lumbosacral segments play a crucial role in motor control and sensory processing of the lower limbs. Addressing this gap, the aims of the current study were two-fold: first, confirming the presence and nature of organized spontaneous BOLD signals in the human lumbosacral spinal cord; second, systematically assessing the impact of various denoising strategies on signal quality and functional connectivity (FC) patterns. Given the susceptibility of spinal cord fMRI to noise, this step is pivotal to ensure the robustness of intrinsic FC. Our findings uncovered bilateral FC between the ventral horns. Importantly, these patterns were consistently observed across denoising methods and demonstrating fair to excellent reliability. Conversely, no other significant connectivity patterns were identified across the remaining horns. Importantly, the evaluation of diverse denoising strategies highlighted the efficacy of PNM-based pipelines in cleaning the signal while preserving the strength and reliability of connectivity estimates. Together, our results provide evidence of robust FC patterns in the lumbosacral spinal cord, thereby paving the way for future studies probing caudal spinal activity.
Adaptive LDA classifier enhances real-time control of an EEG Brain-computer interface for imagined-speech decoding
Authors: Wu Shizhe , Bhadra Kinkini , Giraud Anne-Lise , Marchesotti Silvia
Published: December 2023

Brain-Computer Interfaces (BCI) aim to establish a pathway between the brain and an external device without the involvement of the motor system, relying exclusively on neural signals. Such systems have the potential to provide a means of communication for patients who have lost the ability to speak due to a neurological disorder. Traditional methodologies for decoding imagined speech directly from brain signals often deploy static classifiers, that is, decoders that are computed once at the beginning of the experiment and that remain unchanged throughout the BCI use. However, this approach might be inadequate in effectively handling the non-stationary nature of electroencephalography (EEG) signals and the learning that accompanies BCI use as parameters are expected to change, all the more in a real-time setting. To address this limitation, we have developed an adaptive classifier that updates its parameters based on the incoming data in real time. We first identified optimal parameters (the update coefficient, UC) to be used in an adaptive Linear Discriminant Analysis (LDA) classifier, using a previously recorded EEG dataset, acquired while healthy participants controlled a binary BCI based on imagined syllable decoding. We subsequently tested the effectiveness of this optimization in a real-time BCI-control setting. Twenty healthy participants performed two BCI-control sessions based on the imagery of two syllables, using a static LDA and the other the adaptive LDA classifier, in randomized order. In this real-time BCI-control task, the adaptive classifier led to better performances than the static one. Furthermore, the optimal parameters for the adaptive classifier were closely aligned in both datasets acquired with the same syllable imagery task. These findings highlight the effectiveness and re-liability of adaptive LDA classifiers for real-time imagined speech decoding, and its interest for non-invasive EEG-based BCI notably characterized by low decoding accuracies.
Validation of a non-appetitive effort-based foraging task as a measure of motivational state in male mice
Authors: Xeni Foteini , Marangoni Caterina , Jackson Megan G
Published: December 2023

Motivational disorders such as apathy syndrome are highly prevalent across neurological disorders but do not yet have an agreed treatment approach. The use of translational behavioural models can provide a route through which to meaningfully screen novel drug targets. Methods that utilise food deprivation in contrived environments may lack the sensitivity to detect deficits in self-initiated or self-driven behaviour. Animals monitored in more naturalistic environments may display more ethologically-relevant behaviours of greater translational value. Here, we aimed to validate a novel, non-appetitive effort-based foraging task as a measure of motivational state in mice. In this task, the mouse can freely choose to exert effort to forage bedding material and shuttle it back to a safe and enclosed environment. The amount of bedding material foraged is used as a readout of motivational state. Acute dopaminergic modulation with haloperidol, amphetamine and methylphenidate, and two phenotypic models known to induce motivational deficits (healthy ageing and chronic administration of corticosterone) were used to validate this task. Consistent with other effort-based decision-making tasks we find that foraging behaviour is sensitive to acute modulation of dopaminergic transmission. We find that both phenotypic models induce differing deficits in various aspects of foraging behaviour suggesting that the task may be used to parse different behavioural profiles from distinct disease phenotypes. Thus, without requiring extended training periods or physiological deprivation, this task may represent a refined and translational preclinical measure of motivation.
Serine hydroxymethyl transferase is a binding target of caprylic acid: Uncovering a novel molecular target for a herbicide and for producing caprylic acid-tolerant crops
Authors: Li Zuren , Wang Mugui , Bai Haodong , Wang Hongzhi , Han Jincai , An Likun , Luo Dingfeng , Wang Yingying , Kuang Wei , Nie Xiaoyi , Bai Lianyang
Published: December 2023

Identification of new binding targets is essential for the development of herbicides and phytotoxin-tolerant crops. Caprylic acid (CAP) is a safe and non-selective bio-herbicide in uncultivated areas. However, the herbicidal action of CAP remains unclear. Herein, metabolomic and proteomic profiling indicated that a serine hydroxymethyl transferase inConyza canadensis(CcSHMT1) is a promising candidate binding targeted for CAP. The protein abundance and activity ofCcSHMT1 were decreased in a time- and dosage-dependent manners after CAP treatment. CAP competes with phenyl-serine at the binding sites, decreasing the enzymatic activity ofCcSHMT1. Overexpression ofCcSHMT1, AtSHMT1andOsSHMT1inArabidopsisor rice endowed plants with high tolerance to CAP treatment, whereas the knockout ofosshmt1led to death of plants under normal atmospheric conditions. Furthermore, T194A, T194A/ M195V and D209NOsshmt1mutant plants derived from base editing exhibited tolerance to CAP. CAP bound toCcSHMT1 with high affinity, and Ala191 in the key domains of N-terminus was identified to be critical for the binding site of CAP. Collectively, our findings demonstrate thatCcSHMT1 is a binding target for herbicidal activity of CAP. This study marks a key step in the druggability of SHMT inhibitors and represents an attractive target for phytotoxin-tolerant crops.
A modeling analysis of whole-body potassium regulation on a high potassium diet: Proximal tubule and tubuloglomerular feedback effects
Authors: Stadt Melissa M. , Layton Anita T.
Published: December 2023

Potassium (K+) is an essential electrolyte that plays a key role in many physiological processes, including mineralcorticoid action, systemic blood-pressure regulation, as well as hormone secretion and action. Indeed, maintaining K+balance is critical for normal cell function, as too high or too low K+levels can have serious and potentially deadly health consequences. K+homeostasis is achieved by an intricate balance between the intracellular and extracellular fluid as well as balance between K+intake and excretion. This is achieved via the coordinated actions of regulatory mechanisms such as the gastrointestinal feedforward effect, insulin and aldosterone upregulation of Na+-K+-ATPase uptake, and hormone and electrolyte impacts on renal K+handling. We recently developed a mathematical model of whole-body K+regulation to unravel the individual impacts of regulatory mechanisms. In this study, we extend our mathematical model to incorporate recent experimental findings that showed decreased fractional proximal tubule reabsorption under a high K+diet. We conducted model simulations and sensitivity analyses to unravel how these renal alterations impact whole-body K+regulation. Our results suggest that the reduced proximal tubule K+reabsorption under a high K+diet could achieve K+balance in isolation, but the resulting tubuloglomerular feedback reduces filtration rate and thus K+excretion. Model predictions quantify the sensitivity of K+regulation to various levels of proximal tubule K+reabsorption adaptation and tubuloglomerular feedback. Additionally, we predict that without the hypothesized muscle-kidney cross talk signal, intracellular K+stores can exceed normal range under a high K+diet.
III. Geometrical framework for thinking about globular proteins: turns in proteins
Authors: Škrbić Tatjana , Giacometti Achille , Hoang Trinh X. , Maritan Amos , Banavar Jayanth R.
Published: December 2023

We have shown recently that the notion of poking pairwise interactions along a chain provides a unifying framework for understanding the formation of both secondary and the tertiary protein structure based on symmetry and geometry. α-helices and β-sheets are found to be special geometries that have systematic poking contacts in a repetitive manner with the contacts being local along the α-helix and non-local along a pair of adjacent strands within a β-sheet. Pairwise poking interactions also govern tertiary structure formation, but they are weaker and there are no special geometrical constraints as in secondary structure formation. Here we demonstrate that protein turns, the most prevalent non-repetitive structural element in proteins, are instances of local (as in α-helices) and isolated (non-repetitive) poking pairwise contacts for which the geometrical constraints are partially relaxed. This simple and purely geometrical definition of protein turns (also sometimes known as reverse turns, β-turns, β-bends, hairpin bends, 310bends, kinks, widgets, …) provides a simple framework for unifying them. We present the results of a systematic analysis and identify their structural classes as well as their respective amino acid preferences.

Statement for broader audience

Poking interaction along a discrete chain signals the affinity of one part of the chain with another. It has been shown that a simple and purely geometrical model based on poking interactions is able to capture the essential features of complex protein chains, especially their building blocks and their assembly. We demonstrate that poking interactions also provide a simple framework to describe protein turns as isolated (not coordinated) local poking interactions. This framework allows one to comprehend the structural variety of protein turns that have been extensively studied in the past.
Genotype imputation in F2 crosses of inbred lines
Authors: Pierotti Saul , Welz Bettina , Lopez Mireia Osuna , Fitzgerald Tomas , Wittbrodt Joachim , Birney Ewan
Published: December 2023

Motivation

Crosses among inbred lines are a fundamental tool for the discovery of genetic loci associated with phenotypes of interest. In organisms for which large reference panels or SNP chips are not available, imputation from low-pass whole-genome sequencing is an effective method for obtaining genotype data from a large number of individuals. To date, a structured analysis of the conditions required for optimal genotype imputation has not been performed.

Results

We report a systematic exploration of the effect of several design variables on imputation performance in F2 crosses of inbred medaka lines using the imputation software STITCH. We determined that, depending on the number of samples, imputation performance reaches a plateau when increasing the per-sample sequencing coverage. We also systematically explored the trade-offs between cost, imputation accuracy, and sample numbers. We developed a computational pipeline to streamline the process, enabling other researchers to perform a similar cost-benefit analysis on their population of interest.

Availability and implementation

The source code for the pipeline is available athttps://github.com/birneylab/stitchimpute. While our pipeline has been developed and tested for an F2 population, the software can also be used to analyse populations with a different structure.
Transcription Factor NRF2 is Activated by Erythrophagocytosis of Oxidized Red Blood Cell Products and Suppresses the IL-12-IFNg-IL-10 Axis in a Murine Model of Hyperinflammatory Disease
Authors: Gallo Paul M. , Elliott Em , Ford Grace , Biswas Chhanda , Kim Jihwan , Wheaton Jadyn , Jiang Connie , Chu Niansheng , Kreiger Portia A. , Lambert Michele , Behrens Edward M.
Published: December 2023

Hyperinflammatory diseases including macrophage activation syndrome (MAS) and hemophagocytic lymphohistocytosis (HLH) are characterized by multi-lineage cytopenias, hypercytokinemia, and tissue hemophagocytosis. However, the mechanisms by which erythrophagocytosis mediates iron metabolism and regulates the hyperactive immune response remain unclear. The transcription factor NRF2 is an important sensor for inflammatory and redox distress. The targets of NRF2 are antioxidant response elements responsible for transcription of genes related to restoration of redox homeostasis within the cell. Here we demonstrate that mice with CpG-induced MAS have evidence of systemic oxidative and nitrosative distress – including increased serum nitric oxide and elevated systemic lipid peroxidation. In this model, NRF2 knockout mice develop significantly worse organomegaly, hypercytokinemia, and reticulocytosis. NRF2 knockout mice have unexpected exacerbation in the cytokines that are central to hyperinflammatory physiology – namely IL-12, IFN gamma (IFNg), and IL-10.In vitrowe demonstrate that oxidized red blood cell products and heme itself suppress IL-12 protein production and transcription from bone marrow derived dendritic cells in a NRF2-dependent manner. Together our studies demonstrate that erythrophagocytosis of oxidized red blood cell products suppresses the Il-12-IFNg-IL-10 axis which drives hyperinflammation in murine hyperinflammation.

Graphical abstract

Created with BioRender
Single-nucleotide-resolution genomic maps ofO6-methylguanine from the glioblastoma drug temozolomide
Authors: Büchel Jasmina , Mingard Cécile , Takhaveev Vakil , Reinert Patricia B. , Keller Giulia , Kloter Tom , Huber Sabrina M. , McKeague Maureen , Sturla Shana J.
Published: December 2023

Temozolomide kills cancer cells by formingO6-methylguanine (O6-MeG), which leads to apoptosis due to mismatch-repair overload. However,O6-MeG repair byO6-methylguanine-DNA methyltransferase (MGMT) contributes to drug resistance. Characterizing genomic profiles ofO6-MeG could elucidate howO6-MeG accumulation is influenced by repair, but there are no methods to map genomic locations ofO6-MeG. Here, we developed an immunoprecipitation- and polymerase-stalling-based method, termedO6-MeG-seq, to locateO6-MeG across the whole genome at single-nucleotide resolution. We analyzedO6-MeG formation and repair with regards to sequence contexts and functional genomic regions in glioblastoma-derived cell lines and evaluated the impact of MGMT.O6-MeG signatures were highly similar to mutational signatures from patients previously treated with temozolomide. Furthermore, MGMT did not preferentially repairO6-MeG with respect to sequence context, chromatin state or gene expression level, however, may protect oncogenes from mutations. Finally, we found an MGMT-independent strand bias inO6-MeG accumulation in highly expressed genes, suggesting an additional transcription-associated contribution to its repair. These data provide high resolution insight on howO6-MeG formation and repair is impacted by genome structure and regulation. Further,O6-MeG-seq is expected to enable future studies of DNA modification signatures as diagnostic markers for addressing drug resistance and preventing secondary cancers.

GRAPHICAL ABSTRACT
Differential developmental blueprints of organ-intrinsic nervous systems
Authors: Hsu I-Uen , Lin Yingxin , Guo Yunshan , Xu Qian J. , Shao Yuancheng , Wang Ruiqi L. , Yin Dominic , Zhao Jia , Young Lawrence H. , Zhao Hongyu , Zhang Le , Chang Rui B.
Published: December 2023

The organ-intrinsic nervous system is a major interface between visceral organs and the brain, mediating important sensory and regulatory functions in the body-brain axis and serving as critical local processors for organ homeostasis. Molecularly, anatomically, and functionally, organ-intrinsic neurons are highly specialized for their host organs. However, the underlying mechanism that drives this specialization is largely unknown. Here, we describe the differential strategies utilized to achieve organ-specific organization between the enteric nervous system (ENS)1and the intrinsic cardiac nervous system (ICNS)2, a neuronal network essential for heart performance but poorly characterized. Integrating high-resolution whole-embryo imaging, single-cell genomics, spatial transcriptomics, proteomics, and bioinformatics, we uncover that unlike the ENS which is highly mobile and colonizes the entire gastrointestinal (GI) tract, the ICNS uses a rich set of extracellular matrix (ECM) genes that match with surrounding heart cells and an intermediate dedicated neuronal progenitor state to stabilize itself for a ‘beads-on-the-necklace’ organization on heart atria. While ICNS- and ENS-precursors are genetically similar, their differentiation paths are influenced by their host-organs, leading to distinct mature neuron types. Co-culturing ENS-precursors with heart cells shifts their identity towards the ICNS and induces the expression of heart-matching ECM genes. Our cross-organ study thus reveals fundamental principles for the maturation and specialization of organ-intrinsic neurons.
Rv0687 a Putative Short-Chain Dehydrogenase is indispensable for pathogenesis ofMycobacterium tuberculosis
Authors: Bhargavi Gunapati , Mallakuntla Mohan Krishna , Kale Deepa , Tiwari Sangeeta
Published: December 2023

Mycobacterium tuberculosis (Mtb),a successful human pathogen, resides in host sentinel cells and combats the stressful intracellular environment induced by reactive oxygen and nitrogen species during infection.Mtbemploys several evasion mechanisms in the face of the host as a survival strategy, including detoxifying enzymes as short-chain dehydrogenases/ reductases (SDRs) to withstand host-generated insults. In this study, using specialized transduction we have generated a Rv0687 deletion mutant and its complemented strain and investigated the functional role of Rv0687, a member of SDRs family genes inMtbpathogenesis. Wildtype (WT) and mutantMtbstrain lacking Rv0687 (RvΔ0687) were tested forin-vitrostress response andin-vivosurvival in macrophages and mice models of infection. The study demonstrates that Rv0687 is crucial for sustaining bacterial growth in nutrition-limited conditions. The deletion of Rv0687 elevated the sensitivity ofMtbto oxidative and nitrosative stress-inducing agents. Furthermore, the lack of Rv0687 compromised the survival ofMtbin primary bone marrow macrophages and led to an increase in the levels of the secreted proinflammatory cytokines TNF-α, and MIP-1α. Interestingly, the growth of WT and RvΔ0687 was similar in the lungs of infected immunocompromised mice however, a significant reduction in RvΔ0687 growth was observed in the spleen of immunocompromised Rag-/-mice at 4 weeks post-infection. Moreover Rag-/-mice infected with RvΔ0687 survived longer compared to WTMtbstrain. Additionally, we observed significant reduction in bacterial burden in spleens and lungs of immunocompetent C57BL/6 mice infected with RvΔ0687 compared to complemented and WTMtbstrains. Collectively, this study reveals that Rv0687 plays a role inMtbpathogenesis.
Staphylococcus aureuscan use an alternative pathway to be internalized by osteoblasts in absence of β1 integrins
Authors: Mouton William , Tricou Léo-Paul , Cara Andréa , Trouillet-Assant Sophie , Bouvard Daniel , Laurent Frédéric , Diot Alan , Josse Jérôme
Published: December 2023

Staphylococcus aureusmain internalization mechanism in osteoblasts relies on a tripartite interaction between bacterial fibronectin-binding proteins, extracellular matrix soluble fibronectin, and osteoblasts’ β1 integrins. Caveolins, and particularly caveolin-1, have shown to limit the plasma membrane microdomain mobility, and consequently reduce the uptake ofS. aureusin keratinocytes. In this study, we aimed to deepen our understanding of the molecular mechanisms underlyingS. aureusinternalization in osteoblasts. Mechanistically,S. aureusinternalization requires endosomal recycling β1 integrins as well as downstream effectors such as Src, Rac1, and PAK1. Surprisingly, in β1 integrin deficient osteoblasts,S. aureusinternalization is restored when Caveolin-1 is absent and requires αvβ3/αvβ5 integrins as backup fibronectin receptors. Altogether, our data support that β1 integrins regulate the level of detergent-resistant membrane at the plasma membrane in a an endosomal and Caveolin-1 dependent manner.

SUMMARY STATEMENT

Staphylococcus aureuscan be internalized by osteoblasts via a different mechanism than the main α5β1/fibronectin/fibronectin-binding protein that likely involves αvβ3 or αvβ5 integrin.
Cell-Vision Fusion: A Swin Transformer-based Approach to Predicting Kinase Inhibitor Mechanism of Action from Cell Painting Data
Authors: Dee William , Sequeira Ines , Lobley Anna , Slabaugh Gregory
Published: December 2023

Image-based profiling of the cellular response to drug compounds has proven to be an effective method to characterize the morphological changes resulting from chemical perturbation experiments. This approach has been useful in the field of drug discovery, ranging from phenotype-based screening to identifying a compound’s mechanism of action or toxicity. As a greater amount of data becomes available however, there are growing demands for deep learning methods to be applied to perturbation data. In this paper we applied the transformer-based SwinV2 computer vision architecture to predict the mechanism of action of 10 kinase inhibitor compounds directly from raw images of the cellular response. This method outperforms the standard approach of using image-based profiles, multidimensional feature set representations generated by bioimaging software. Furthermore, we combined the best performing models for three different data modalities, raw images, image-based profiles and compound chemical structures, to form a fusion model, Cell-Vision Fusion (CVF). This approach classified the kinase inhibitors with 69.79% accuracy and 70.56% F1 score, 4.20% and 5.49% greater, respectively, than the best performing image-based profile method. Our work provides three techniques, specific to Cell Painting images, which enable the SwinV2 architecture to train effectively, and explores approaches to combat the significant batch effects present in large Cell Painting perturbation datasets.
Impacts of information asymmetry on users' payment rates: evidence from trading data of Chinese knowledge payment platform
Authors: Zhang Xing , Cai Yongtao , Li Yiwen , Zhou Yan
Published: December 2023

Purpose

This paper aims to clarify the impact of information asymmetry on users' payment rates and examine the role of perceived uncertainty (PU) and acceptable price (AP) in the relationship between information asymmetry and users' payment rates.

Design/methodology/approach

To test the influences of information asymmetry on users' payment rates, this paper collects 18,489 transaction data from the Chinese knowledge payment platform Zhihu with a Python crawler. This paper constructs a mediation model to define the relationship between information asymmetry and users' payment rates by introducing PU and AP as the mediators.

Findings

Information asymmetry negatively affects users' payment rates. In addition, PU and AP mediate the information asymmetry in users' payment rates bond.

Research limitations/implications

This study only explores the mediators of the information asymmetry users’ payment rates bond, ignoring the effect of potential moderators, which would be an important direction for future research.

Practical implications

The findings of this paper suggest that information communication is essential in knowledge market transactions. Knowledge providers, as well as knowledge platforms, should enhance information exchange with consumers in order to increase product sales.

Social implications

This paper provides a new perspective for understanding how information asymmetry affects users' payment rates and helps to guide suppliers to improve product quality. The research framework of this paper is universal to a certain extent.

Originality/value

This paper is one of the first to propose using PU and AP to construct a mediation model to study the information asymmetry between users' payment rates relationship. It provides a new perspective for understanding the channel of information asymmetry in customer behavior.
Strategic leadership and team innovation: a qualitative study from the lens of leader–member exchange
Authors: Singh Anjali , Jha Sumi
Published: December 2023

Purpose

This study aims to investigate the factors influencing team innovation from the perspective of strategic leaders. The study draws from the leader–member exchange (LMX) theory to propose that the quality of exchange the leaders perceive with the team members may provide a useful cue to identify the key elements and processes that may help drive team innovation.

Design/methodology/approach

A qualitative study using a hybrid approach was used, and a thematic analysis was performed. The data were based on 25 interviews collected from strategic leaders using the long interview technique.

Findings

The findings revealed themes and factors influencing innovation orientation among leaders and team members. Five themes were identified, namely modeling leadership behavior, autonomy and psychological safety for teams, organizational structure and technology, innovation and the decision-making process and innovation during times of uncertainty.

Research limitations/implications

Because of the purposefully chosen sample of only leaders who were involved in the innovation process, the research results may lack generalizability. Therefore, researchers are encouraged to corroborate the finding using a sample of teams involved in the innovation process.

Practical implications

A conceptual model is proposed with guidance for implementing innovation decisions and strategies in practice.

Originality/value

While the strategic leadership and team innovation literature emphasizes the interaction between leaders and team members, research on how these interactions unfold is still nascent. This paper fulfills these needs from a strategic leader’s perspective.
Memories that last: evaluating the impact of eco-tourism on children's future behaviour
Authors: Lestar Tamas , Hancock Jessica Clare
Published: December 2023

Purpose

This paper analyses children's experiences of school or family visits to Hare Krishna eco-farms in Europe. The article evaluates the extent to which these encounters enable retention and recollection of memories and, consequently, trigger change towards more sustainable behaviour.

Design/methodology/approach

Participatory research, qualitative observations and theories of childhood memory are used to explore the nature of children's environmental encounters on Hare Krishna eco-tours.

Findings

Findings reveal that Krishna eco-tours offer a conducive environment for cerebral registering and future reminiscing through the following components: experiential learning of sustainable practices which are radically different to mainstream alternatives, sensory experiences, nature play and entertainment and freedom from everyday constraints.

Originality/value

The emerging literature on children's eco-tourism has largely focussed on market-related aspects and farmers' needs. In contrast, the authors’ conceptual framework, based on contemporary research in childhood memories, offers a tool to evaluate the impacts of eco-tourism from a more holistic perspective.
Does cycle superposition amplify bank liquidity risk under different levels of financial openness? Empirical evidence from China
Authors: Jing Huimin , Zhu Yixin
Published: December 2023

Purpose

This paper aims to explore the impact of cycle superposition on bank liquidity risk under different levels of financial openness so that banks can better manage their liquidity risk. Meanwhile, it can also provide some ideas for banks in other emerging economies to better cope with the shocks of the global financial cycle.

Design/methodology/approach

Employing the monthly data of 16 commercial banks in China from 2005 to 2021 and based on the time-varying parameter vector autoregressive model with stochastic volatility (TVP-SV-VAR) model, the authors first examine whether the cycle superposition can magnify the impact of China's financial cycle on bank liquidity risk. Subsequently, the authors investigate the impact of different levels of financial openness on cycle superposition amplification. Finally, the shock of the financial cycle of the world's major economies on the liquidity risk of Chinese banks is also empirically analyzed.

Findings

Cycle superposition can magnify the impact of China's financial cycle on bank liquidity risk. However, there are significant differences under different levels of financial openness. Compared with low financial openness, in the period of high financial openness, the magnifying effect of cycle superposition is strengthened in the short term but obviously weakened in the long run. In addition, the authors' findings also demonstrate that although the United States is the main shock country, the influence of other developed economies, such as Japan and Eurozone countries, cannot be ignored.

Originality/value

Firstly, the cycle superposition index is constructed. Secondly, the authors supplement the literature by providing evidence that the association between cycle superposition and bank liquidity risk also depends on financial openness. Finally, the dominant countries of the global financial cycle have been rejudged.
Relationship between psoriasis and urolithiasis
Authors: Oğuz Işıl Deniz , Oğuz Ural , Usta Murat , Kulaklı Sevgi , Tosun Alptekin , Demirelli Erhan , Akşan Burak , Emecen Ömer , Yüzüak Erdem
Published: December 2023

The aim of the present study was to investigate whether patients with psoriasis are prone to urolithiasis. Prospective analysis of 67 patients diagnosed as psoriasis (PS group) and 65 volunteers who had never been diagnosed as psoriasis (NPS group) was performed. The levels of oxalate, citrate, calcium, uric acid, magnesium, creatinine, and sodium were evaluated by analyzing the 24‐h urine samples. Stone events were detected in 13 patients (19.4%) in the PS group and in five participants (7.7%) in the NPS group, respectively (P < 0.05). The median value of 24‐h citrate was significantly lower in the PS group than in the NPS group (P = 0.029). The median value of 24‐h urine uric acid was significantly higher in the PS group than the NPS group (P = 0.005). Hypernatriuria was significantly higher in the PS group (P = 0.027). Hyperuricosuria was detected in the 10.4% and 1.5% of patients who had severe and mild disease, respectively (P = 0.027). Patients with psoriasis are more prone to urolithiasis. Hypocitraturia, hyperuricosuria, and hypernatriuria were the main metabolic abnormalities detected in psoriasis. Hyperuricosuria has been associated with the severity of the disease.
Redefining Parent's Unpaid Labour: Distinguishing Errands from Housework for Targeted Mental Health Policy
Authors: Ilyushina Nataliya
Published: December 2023

Studies of the association between unpaid housework and wellbeing, especially for parents, has produced either negative or inconclusive results in previous studies. One potential oversight is that ‘housework’ often includes activities with a counteracting effect on mental health. By employing the Household, Income and Labour Dynamics in Australia (HILDA) data set that differentiates ‘housework’ from more routine tasks included in the ‘errands’ variable I illustrate the difference in the pattern of how these variables are linked to parents' mental health. By identifying specific groups of unpaid tasks that are most detrimental to mental health, policymakers can prioritise these areas, ensuring that negative associations are not wrongly attributed to all housework activities.
Emotional geographies of an urban forest: Insights from an email‐a‐tree initiative
Authors: Atchison Jennifer , Brennan‐Horley Chris , Phillips Catherine , Doyle Kim , Lewis Anna , Straughan Elizabeth
Published: December 2023

International and national policies are being used to prioritise increases in urban forest coverage and diversity, support equitable access to urban greenspaces, and advance sound environmental governance outcomes. Yet, the relationship between people’s feelings about urban trees and public policy remains under‐examined. Drawing on a unique dataset from an email‐a‐tree initiative, the objectives of this study were to identify how concern and connection for urban trees is expressed and determine how insights from the initiative might inform urban forest governance. We examined emails sent to trees using a mixed‐methods approach that included qualitative coding, VADER sentiment analysis, and statistical and spatial analyses. We identified and considered three themes based on emails sent by members of the public and municipal tree inventory data. Those themes were location, age and loss, and type. In accord with other studies, overall sentiment for urban trees was positive and underscored people’s strong connections with trees, often based on routine and repeated engagements. However, people noticed and were concerned about a limited range of trees and tree types in urban settings. Based in Melbourne, Australia, our case study shows how examining feelings for trees helps residents and researchers understand urban tree relationships and gauge how those designing public engagement programs might learn from such an initiative to create meaningful opportunities for active participation in governance.