bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanistic insights into ligand dissociation from the SARS-CoV-2 spike glycoprotein
Authors: Hasse Timothy , Mantei Esra , Shahoei Rezvan , Pawnikar Shristi , Wang Jinan , Miao Yinglong , Huang Yu-ming M.
Published: December 2023

The COVID-19 pandemic, driven by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spurred an urgent need for effective therapeutic interventions. The spike glycoprotein of the SARS-CoV-2 is crucial for infiltrating host cells, rendering it a key candidate for drug development. By interacting with the human angiotensin-converting enzyme 2 (ACE2) receptor, the spike initiates the infection of SARS-CoV-2. Linoleate is known to bind the spike glycoprotein, subsequently reducing its interaction with ACE2. However, the detailed kinetics underlying the protein-ligand interaction remains unclear. In this study, we characterized the pathways of ligand dissociation and the conformational changes associated with the spike glycoprotein by using ligand Gaussian accelerated molecular dynamics (LiGaMD). Our simulations resulted in eight complete ligand dissociation trajectories, unveiling two distinct ligand unbinding pathways. The preference between these two pathways depends on the gate distance between two α-helices in the receptor binding domain (RBD) and the position of the N-linked glycan at N343. Our study also highlights the essential contributions of K417, N121 glycan, and N165 glycan in ligand unbinding, which are equally crucial in enhancing spike-ACE2 binding. We suggest that the presence of the ligand influences the motions of these residues and glycans, consequently reducing accessibility for spike-ACE2 binding. These findings enhance our understanding of ligand dissociation from the spike glycoprotein and offer significant implications for drug design strategies in the battle against COVID-19.
Reconstructing oral cavity tumor evolution through brush biopsy
Authors: John Evit R. , Lesluyes Tom , Baker Toby M. , Tarabichi Maxime , Gillenwater Ann , Wang Jennifer R. , Van Loo Peter , Zhao Xiao
Published: December 2023

Oral premalignant lesions (OPLs) with genomic alterations have a heightened risk of evolving into oral squamous cell carcinoma (OSCC). Currently, genomic data are obtained through invasive tissue biopsy. Brush biopsy has been utilized for diagnosing dysplasia but its effectiveness in reflecting the complete genomic landscape of OPLs remains uncertain. This study investigates the potential of brush biopsy samples in accurately reconstructing the genomic profile of OPLs. We analyzed single nucleotide variants (SNVs), copy number aberrations (CNAs), and subclonal structures in paired tissue and brush biopsy samples from a patient with both OPL and OSCC lesions. The results showed that brush biopsy can effectively reflect about 90% of SNVs and similar CNA profiles as those found in tissue biopsies. It was specific, as normal oral epithelium didn’t share these genomic alterations. Interestingly, brush biopsy revealed shared SNVs and CNAs between the distinct OPL and OSCC lesions, indicating a common ancestral origin. Subclonal reconstruction confirmed this shared ancestry, followed by divergent evolution of the lesions. These findings highlight the potential of brush biopsies in accurately representing the genomic profile of OPL and OSCC, proving useful in understanding tumor evolution.
Auditory associative word learning in adults: the effects of musical experience and stimulus ordering
Authors: Cosper Samuel H. , Männel Claudia , Mueller Jutta L.
Published: December 2023

Evidence for sequential associative word learning in the auditory domain has been identified in infants, but adults have proven to have difficulties in this type of word learning. To investigate the role of auditory expertise and auditory stimuli salience in the association of auditory objects and their labels, we tested in the first experiment auditorily-trained musicians versus athletes as a high-level control group and in the second experiment stimulus ordering, contrasting object-label versus label-object presentation. Learning was evaluated from electrophysiological (EEG) recordings during training and subsequent testing phases, as well as accuracy-judgement responses during test. Results revealed for musicians a late positive component in the EEG during testing, neither N400 nor behavioral effects were found at test, while athletes did not show any effect of learning. Moreover, the object-label-ordering group only exhibited emerging association effects during training, while the label-object-ordering group showed an EEG effect during test as well as above chance accuracy-judgement scores. Thus, our results suggest an advantage of musical expertise and more salient label-object-ordering in auditory associative word learning in adults. Implications with respect to developmental differences in auditory word learning are discussed.
Regions of Inflammation in mouse asthma correspond to regions of heme-free soluble guanylyl cyclase and can be tracked by marked expression of heme-oxygenase-1
Authors: Sumi Mamta , Westcott Rosemary , Stuehr Eric , Ghosh Chaitali , Stuehr Dennis J. , Ghosh Arnab
Published: December 2023

Asthma is characterized by airway remodeling and hyperreactivity. Our earlier studies determined that the Nitric Oxide (NO)-soluble Guanylyl Cyclase (sGC)-cGMP pathway plays a significant role in human lung bronchodilation. However this bronchodilation is dysfunctional in asthma due to high NO levels which cause sGC to become heme-free and desensitized to its natural activator, NO. In order to determine how asthma impacts the various lung segments/lobes we mapped the inflammatory regions of lungs to determine whether such regions coincided with molecular signatures of sGC dysfunction. We demonstrate using models of mouse asthma (OVA, CFA/HDM) that the inflammed segments of the mouse asthma lungs can be tracked by upregulated expression of HO1 and these regions in-turn overlap with regions of heme-free sGC as evidenced by a decreased sGC-α1β1 heterodimer and an increased response to heme-independent sGC activator, BAY 60-2770 relative to naïve uninflamed regions. We also find that NO generated from iNOS upregulation in the inflamed segments has a higher impact in developing heme-free sGC as increasing iNOS activity correlates linearly with elevated heme-independent sGC activation. This excess NO works by affecting the epithelial lung hemoglobin (Hb) to become heme-free in asthma thereby causing the Hb to lose its NO scavenging function and exposing the underlying smooth muscle sGC to excess NO, which in-turn becomes heme-free. Recognition of these specific lung segments enhance our understanding of the inflammed lungs in asthma with the ultimate aim to evaluate potential therapies and suggests that regional and not global inflammation impacts lung function in asthma.
Predicting hypersensitivity and comorbid depressive-like behavior in late stages of joint disease using early weight bearing deficit
Authors: Hestehave Sara , Florea Roxana , Fedorec Alexander J.H. , Jevic Maria , Mercy Lucile , Wright Annia , Morgan Oakley B. , Brown Laurence A. , Peirson Stuart N. , Géranton Sandrine M.
Published: December 2023

Chronic pain is a hallmark of joint diseases and is often accompanied by negative affective symptoms such as low mood, anxiety and memory dysfunction. Whether these may be the results of the more obvious sensory and functional symptoms of joint pain is poorly understood and this likely contributes to the difficulty in adequately managing this condition. Here, we have used two mouse models to address this lack of knowledge. Using a model of ankle inflammation and a model of knee osteoarthritis, we found that these models of joint pain induced weight bearing deficits of different magnitude but relatively similar mechanical allodynia that lasted at least 3 months. However, the models were accompanied by very different affective outcomes, as only the model of knee osteoarthritis, that led to significant early changes in activity and sleep patterns, was accompanied by an increase in negative affective behaviors, including cognitive impairments and depressive-like behavior. The models also had different molecular profiles at both spinal and hippocampal levels. Importantly, the functional outcomes measured in the early stages of the disease stage strongly correlated with sensory and emotional profiles at 3 months, suggesting that early functional measures may be used as predictors of the long-term symptoms associated with persistent joint pain. In conclusion, the predictive value of early measures of functional impact of joint disease could prove useful in the clinics for adapted therapeutic approaches for the prevention of emotional comorbidities and better pain management for patients with joint pain.
The ventral hippocampus and nucleus accumbens as neural substrates for cocaine contextual memory reconsolidation
Authors: Rivera Carolina Caban , Price Rachael , Fortuna Ricardo P. , Li Chen , Do Chau , Shinkle Justin , Ghilotti Marco G. , Shi Xiangdang , Kirby Lynn G. , Smith George M. , Unterwald Ellen M.
Published: December 2023

Drug craving triggered by cues that were once associated with drug intoxication is a major contributor to continued drug-seeking behaviors. Addictive drugs engage molecular pathways of associative learning and memory. Reactivated memories are vulnerable to disruption by interference with the process of reconsolidation, hence targeting reconsolidation could be a strategy to reduce cue-induced drug craving and relapse. Here we examined the circuitry of cocaine contextual memory reconsolidation and explored neuroplasticity following memory reactivation. Mice underwent chemogenetic inhibition of either nucleus accumbens (NA) neurons or the glutamatergic projection neurons from the ventral hippocampus (vHPC) to NA using inhibitory designer receptors exclusively activated by designer drugs (iDREADD). Mice underwent cocaine conditioned place preference followed by reactivation of the cocaine contextual memory. Clozapine-N-oxide (CNO) was administered after memory reactivation to inhibit either NA neurons or the accumbens–projecting vHPC neurons during the reconsolidation period. When retested 3 days later, a significant reduction in the previously established preference for the cocaine context was found in both conditions. FosTRAP2-Ai14 mice were used to identify neurons activated by cocaine memory recall and to evaluate plasticity in NA medium spiny neurons (MSNs) and vHPC pyramidal neurons upon recall of cocaine memories. Results indicate a significant increase in dendritic spine density in NA MSNs activated by cocaine memory recall, particularly of the thin spine type. Sholl analysis indicated longer dendritic length and more branching of NA MSNs after cocaine memory recall than without memory reactivation. vHPC neurons showed increased spine density, with the most robust change in stubby spines. These results implicate a circuit involving glutamatergic projections from the vHPC onto NA neurons which is necessary for the reconsolidation of cocaine memories. Interruption of cocaine memory reconsolidation reduced drug-seeking behavior.
Spatiotemporal Rhythmic Seizure Sources Can be Imaged by means of Biophysically Constrained Deep Neural Networks
Authors: Sun Rui , Sohrabpour Abbas , Joseph Boney , Worrell Gregory , He Bin
Published: December 2023

Noninvasive dynamic brain imaging of neural oscillations provides valuable insights into both physiological and pathological brain states. Yet, challenges remain due to the ill-posed nature of the problem and high complexity of the solution space, which can be alleviated by advanced computational models. Here, we investigated the capability of a novel deep learning-based source imaging framework (DeepSIF) for imaging ictal activities from high-density electroencephalogram (EEG) recordings in drug-resistant focal epilepsy patients. The neural mass model of ictal oscillations was adopted to generate synthetic training data with spatio-temporal-spectra features similar to ictal dynamics. We rigorously validated the trained DeepSIF model using computer simulations and in a cohort of 33 drug-resistant focal epilepsy patients. The DeepSIF ictal source imaging was compared with interictal source imaging and three conventional imaging methods as benchmark comparisons. Our findings show that the trained DeepSIF model outperforms other methods in estimating the spatial and temporal information of ictal sources. It achieves a high spatial specificity of 96% and a low spatial dispersion of 3.80 ± 5.74 mm when compared to the resection region. The noninvasive source imaging results also demonstrate good coverage of seizure-onset-zone (SOZ), with an average distance of 10.89 ± 10.14 mm (from the SOZ to the reconstruction). These promising results suggest that DeepSIF has significant potential for advancing noninvasive imaging of ictal activities in patients with focal epilepsy. By providing valuable insights into the spatiotemporal dynamics of seizure activity, DeepSIF promises to help guide clinical decisions and improve treatment outcomes for epilepsy patients.
Scalable Incident Detection via Natural Language Processing and Probabilistic Language Models
Authors: Walsh Colin G. , Wilimitis Drew , Chen Qingxia , Wright Aileen , Kolli Jhansi , Robinson Katelyn , Ripperger Michael A. , Johnson Kevin B. , Carrell David , Desai Rishi J. , Mosholder Andrew , Dharmarajan Sai , Adimadhyam Sruthi , Fabbri Daniel , Stojanovic Danijela , Matheny Michael E. , Bejan Cosmin A.
Published: December 2023

Post marketing safety surveillance depends in part on the ability to detect concerning clinical events at scale. Spontaneous reporting might be an effective component of safety surveillance, but it requires awareness and understanding among healthcare professionals to achieve its potential. Reliance on readily available structured data such as diagnostic codes risk under-coding and imprecision. Clinical textual data might bridge these gaps, and natural language processing (NLP) has been shown to aid in scalable phenotyping across healthcare records in multiple clinical domains. In this study, we developed and validated a novel incident phenotyping approach using unstructured clinical textual data agnostic to Electronic Health Record (EHR) and note type. It’s based on a published, validated approach (PheRe) used to ascertain social determinants of health and suicidality across entire healthcare records. To demonstrate generalizability, we validated this approach on two separate phenotypes that share common challenges with respect to accurate ascertainment: 1) suicide attempt; 2) sleep-related behaviors. With samples of 89,428 records and 35,863 records for suicide attempt and sleep-related behaviors, respectively, we conducted silver standard (diagnostic coding) and gold standard (manual chart review) validation. We showed Area Under the Precision-Recall Curve of ∼ 0.77 (95% CI 0.75-0.78) for suicide attempt and AUPR ∼ 0.31 (95% CI 0.28-0.34) for sleep-related behaviors. We also evaluated performance by coded race and demonstrated differences in performance by race were dissimilar across phenotypes and require algorithmovigilance and debiasing prior to implementation.
Dual role of FOXG1 in regulating gliogenesis in the developing neocortex via the FGF signalling pathway
Authors: Bose Mahima , Talwar Ishita , Suresh Varun , Mishra Urvi , Biswas Shiona , Yadav Anuradha , Suryavanshi Shital T. , Hippenmeyer Simon , Tole Shubha
Published: December 2023

In the developing vertebrate central nervous system, neurons and glia typically arise sequentially from common progenitors. Here, we report that the transcription factor Forkhead Box G1 (Foxg1) regulates gliogenesis in the mouse neocortex via distinct cell-autonomous roles in progenitors and in postmitotic neurons that regulate different aspects of the gliogenic FGF signalling pathway. We demonstrate that loss ofFoxg1in cortical progenitors at neurogenic stages causes premature astrogliogenesis. We identify a novel FOXG1 target, the pro-gliogenic FGF pathway componentFgfr3, that is suppressed by FOXG1 cell-autonomously to maintain neurogenesis. Furthermore, FOXG1 can also suppress premature astrogliogenesis triggered by the augmentation of FGF signalling. We identify a second novel function of FOXG1 in regulating the expression of gliogenic cues in newborn neocortical upper-layer neurons.

Loss of FOXG1 in postmitotic neurons non-autonomously enhances gliogenesis in the progenitors via FGF signalling. These results fit well with the model that newborn neurons secrete cues that trigger progenitors to produce the next wave of cell types, astrocytes. If FGF signalling is attenuated inFoxg1null progenitors, they progress to oligodendrocyte production. Therefore, loss of FOXG1 transitions the progenitor to a gliogenic state, producing either astrocytes or oligodendrocytes depending on FGF signalling levels. Our results uncover how FOXG1 integrates extrinsic signalling via the FGF pathway to regulate the sequential generation of neurons, astrocytes, and oligodendrocytes in the cerebral cortex.
A chromosome-level, haplotype-resolved genome assembly and annotation for the Eurasian minnow (Leuciscidae: Phoxinus phoxinus) provide evidence of haplotype diversity
Authors: Oriowo Temitope Opeyemi , Chrysostomakis Ioannis , Martin Sebastian , Kukowka Sandra , Brown Thomas , Winkler Sylke , Myers Eugene W , Boehne Astrid , Stange Madlen
Published: December 2023

In this study we present an in-depth analysis of the Eurasian minnow (Phoxinus phoxinus) genome, highlighting its genetic diversity, structural variations, and evolutionary adaptations. We generated an annotated haplotype-phased, chromosome-level genome assembly (2n = 50) by integrating high-fidelity (HiFi) long reads and chromosome conformation capture data (Hi-C). We achieved a haploid size of 940 Megabase pairs (Mbp) for haplome one and 929 Mbp for haplome two with high scaffold N50 values of 36.4 Mb and 36.6 Mb and BUSCO scores of 96.9% and 97.2%, respectively, indicating a highly complete genome assembly. We detected notable heterozygosity (1.43%) and a high repeat content (approximately 54%), primarily consisting of DNA transposons, which contribute to genome rearrangements and variations. We found substantial structural variations within the genome, including insertions, deletions, inversions, and translocations. These variations affect genes enriched in functions such as dephosphorylation, developmental pigmentation, phagocytosis, immunity, and stress response. In the annotation of protein-coding genes, 30,980 mRNAs and 23,497 protein-coding genes were identified with a high completeness score, which further underpins the high contiguity of our genome assemblies. We performed a gene family evolution analysis by comparing our proteome to ten other teleost species, which identified immune system gene families that prioritise histone-based disease prevention over NLR-based immune responses. Additionally, demographic analysis indicates historical fluctuations in the effective population size of P. phoxinus, likely correlating with past climatic changes. This annotated, phased reference genome provides a crucial resource for resolving the taxonomic complexity within the genus Phoxinus and highlights the importance of haplotype-phased assemblies in understanding haplotype diversity in species characterised by high heterozygosity.
Structural mechanism of HP1α-dependent transcriptional repression and chromatin compaction
Authors: Sokolova Vladyslava , Miratsky Jacob , Svetlov Vladimir , Brenowitz Michael , Vant John , Lewis Tyler , Dryden Kelly , Lee Gahyun , Sarkar Shayan , Nudler Evgeny , Singharoy Abhishek , Tan Dongyan
Published: December 2023

Heterochromatin protein 1 (HP1) plays a central role in establishing and maintaining constitutive heterochromatin. However, the mechanisms underlying HP1-nucleosome interactions and their contributions to heterochromatin functions remain elusive. In this study, we employed a multidisciplinary approach to unravel the interactions between human HP1α and nucleosomes. We have elucidated the cryo-EM structure of an HP1α dimer bound to an H2A.Z nucleosome, revealing that the HP1α dimer interfaces with nucleosomes at two distinct sites. The primary binding site is located at the N-terminus of histone H3, specifically at the trimethylated K9 (K9me3) region, while a novel secondary binding site is situated near histone H2B, close to nucleosome superhelical location 4 (SHL4). Our biochemical data further demonstrates that HP1α binding influences the dynamics of DNA on the nucleosome. It promotes DNA unwrapping near the nucleosome entry and exit sites while concurrently restricting DNA accessibility in the vicinity of SHL4. This study offers a model that explains how HP1α functions in heterochromatin maintenance and gene silencing, particularly in the context of H3K9me-dependent mechanisms. Additionally, it sheds light on the H3K9me-independent role of HP1 in responding to DNA damage.
The historical ecological background of West Nile virus in Portugal provides One Health opportunities into the future
Authors: Geraldes Martim Afonso , Cunha Mónica V. , Godinho Carlos , Faustino de Lima Ricardo , Giovanetti Marta , Lourenço José
Published: December 2023

West Nile (WNV) is a zoonotic arbovirus with an expanding geographical range and epidemic activity in Europe. Not having yet experienced a human-associated epidemic, Portugal remains an outlier in the Mediterranean basin. In this study, we apply ecological niche modelling informed by WNV historical evidence (1969-2022) and a multitude of environmental variables from across Portugal. We identify that ecological backgrounds compatible with WNV historical circulation are mostly restricted to the south, characterized by a warmer and drier climate, high avian diversity, specific avian species and land types. We estimate WNV ecological suitability across the country, identifying overlaps with the distributions of the three relevant hosts (humans, birds, equines) for public and animal health. From this, we propose a category-based spatial framework providing first of a kind valuable insights for future WNV surveillance under the One Health nexus. We also forecast that climate trends alone will contribute to pushing adequate WNV ecological suitability northwards, toward regions with higher human density. This unique perspective on the past, present and future ecology of WNV addresses existing national knowledge gaps, enhances our understanding of the evolving emergence of WNV, and offers opportunities to prepare and respond to the first human-associated epidemic in Portugal.
Spatiotemporal Metabolic Responses to Water Deficit Stress in Distinct Leaf Cell-types of Poplar
Authors: Balasubramanian Vimal Kumar , Velickovic Dusan , Rubio Wilhelmi Maria Del Mar , Anderton Christopher R , Stewart C. Neal , DiFazio Stephen , Blumwald Eduardo , Ahkami Amir H.
Published: December 2023

The impact of water-deficit (WD) stress on plant metabolism has been predominantly studied at the whole tissue level. However, plant tissues are made of several distinct cell types with unique and differentiated functions, which limits whole tissue ‘omics’-based studies to determine only an averaged molecular signature arising from multiple cell types. Advancements in spatial omics technologies provide an opportunity to understand the molecular mechanisms underlying plant responses to WD stress at distinct cell-type levels. Here, we studied the spatiotemporal metabolic responses of two poplar leaf cell types-palisade and vascular cells-to WD stress using matrix-assisted laser desorption Ionization-mass spectrometry imaging (MALDI-MSI). We identified unique WD stress-mediated metabolic shifts in each leaf cell type when exposed to early and prolonged WD and recovery from stress. During stress, flavonoids and phenolic metabolites were exclusively accumulated in leaf palisade cells. However, vascular cells mainly accumulated sugars during stress and fatty acids during recovery conditions, highlighting a possibility of interconversion between sugars and fatty acids under stress and recovery conditions in vascular cells. By comparing our MALDI-MSI metabolic data with whole leaf tissue gas chromatography-mass spectrometry (GC-MS)-based metabolic profile, we identified only a few metabolites that showed a similar accumulation trend at both cell-type and whole leaf tissue levels. Overall, this work highlights the potential of the MSI approach to complement the whole tissue-based metabolomics techniques and provides a novel spatiotemporal understanding of plant metabolic responses to WD stress. This will help engineer specific metabolic pathways at a cellular level in strategic perennial trees like poplars to help withstand future aberrations in environmental conditions and to increase bioenergy sustainability.
High-Throughput Evolution Unravels Landscapes of High-Level Antibiotic Resistance Induced by Low-Level Antibiotic Exposure
Authors: Wang Hanqing , Lu Hui , Jiang Chao , Zhu Lizhong , Lu Huijie
Published: December 2023

Potential pathogens exposed to low-level environmental antibiotics could develop high-level clinically relevant antibiotic resistance detrimental to the health of the general population. However, the underlying evolutionary landscapes remain poorly understood. We conducted a high-throughput experimental evolution study by exposing an environmentally isolated pathogenicEscherichia colistrain to 96 typical antibiotics at 10 μg l−1for 20 days. Antibiotic resistance phenotypic (IC90against 8 clinically used antibiotics) and genetic changes of the evolved populations were systematically investigated, revealing a universal increase in antibiotic resistance (up to 349-fold), and mutations in 2,432 genes. Transposon sequencing was further employed to verify genes potentially associated with resistance. A core set of mutant genes conferring high-level resistance was analyzed to elucidate their resistance mechanisms by analyzing the functions of interacted genes within the gene co-fitness network and performing gene knockout validations. We developed machine-learning models to predict antibiotic resistance phenotypes from antibiotic structures and genomic mutations, enabling the resistance predictions for another 569 antibiotics. Importantly, 14.6% of the 481 key mutations were observed in clinical and environmentalE. coliisolates retrieved from the NCBI database, and several were over-represented in clinical isolates. Deciphering the evolutionary landscapes underlying resistance exposed to low-level environmental antibiotics is crucial for evaluating the emergence and risks of environment-originated clinical antibiotic resistance.
A PhyloFisher utility for nucleotide-based phylogenomic matrix construction;nucl_matrix_constructor.py
Authors: Jones Robert E. , Jones Erin P. , Tice Alexander K. , Brown Matthew W.
Published: December 2023

Phylogenies built from multiple genes have become a common component of evolutionary biology studies. Molecular phylogenomic matrices used to build multi-gene phylogenies can be built from either nucleotide or protein matrices. Nucleotide-based analyses are often more appropriate for addressing phylogenetic questions in evolutionarily shallow timescales (i.e., less than 100 million years) while protein-based analyses are often more appropriate for addressing deep phylogenetic questions. PhyloFisher is a phylogenomic software package written in Python3. The manually curated PhyloFisher database contains 240 protein-coding genes from 304 eukaryotic taxa. Here we presentnucl_matrix_constructor.py, an expansion of the PhyloFisher starting database, and an update to PhyloFisher that maintains DNA sequences. This combination will allow users the ability to easily build nucleotide phylogenomic matrices while retaining the benefits of protein-based pre-processing used to identify contaminants and paralogy.
Cortical sensory aging is layer-specific
Authors: Liu Peng , Doehler Juliane , Henschke Julia U. , Northall Alicia , Serian Angela , Loaiza-Carvajal Laura C. , Budinger Eike , Schwarzkopf Dietrich S. , Speck Oliver , Pakan Janelle M.P. , Kuehn Esther
Published: December 2023

The segregation of processes into cortical layers is a convergent feature in animal evolution. However, how changes in the cortical layer architecture interact with sensory system function and dysfunction remains unclear. We conducted functional and structural layer-specific in-vivo 7T-MRI of the primary somatosensory cortex in two cohorts of healthy younger and older adults. Input layer IV is enlarged and more myelinated in older adults, and associated with extended sensory input signals. Age-related cortical thinning is driven by deep layers, and accompanied by altered functional modulation and preserved inhibition. Calcium imaging and histology in younger and older mice reveal increased sensory-evoked neuronal activity accompanied by increased parvalbumin expression as a potential inhibitory balance, with dynamic changes in layer-specific myelination across age groups. Using multimodal imaging, we demonstrate that middle and deep layers show specific vulnerability to aging across species.
A Mouse Model of the Protease Activated Receptor 4 (PAR4) Pro310Leu Variant has Reduced Platelet Reactivity
Authors: Han Xu , Knauss Elizabeth A. , de la Fuente Maria , Li Wei , Conlon Ronald A , LePage David F. , Jiang Weihong , Renna Stephanie A. , McKenzie Steven E. , Nieman Marvin T.
Published: December 2023

Background

Protease activated receptor 4 (PAR4) mediates thrombin signaling on platelets and other cells. Our recent structural studies demonstrated a single nucleotide polymorphism in extracellular loop 3 (ECL3), PAR4-P310L (rs2227376) leads to a hypo-reactive receptor.

Objectives

The goal of this study was to determine how the hypo-reactive PAR4 variant in ECL3 impacts platelet function in vivo using a novel knock-in mouse model (PAR4-322L).

Methods

A point mutation was introduced into the PAR4 gene, F2rl3, via CRISPR/Cas9 to create PAR4-P322L, the mouse homolog to human PAR4-P310L. Platelet response to PAR4 activation peptide (AYPGKF), thrombin, ADP, and convulxin was monitored by αIIbβ3 integrin activation and P-selectin translocation using flow cytometry or platelet aggregation. In vivo responses were determined by the tail bleeding assay and the ferric chloride-induced carotid artery injury model.

Results

PAR4-P/L and PAR4-L/L platelets had a reduced response to AYPGKF and thrombin measured by P-selectin translocation or αIIbβ3 activation. The response to ADP and convulxin was unchanged among genotypes. In addition, both PAR4-P/L and PAR4-L/L platelets showed a reduced response to thrombin in aggregation studies. There was an increase in the tail bleeding time for PAR4-L/L mice. The PAR4-P/L and PAR4-L/L mice both showed an extended time to arterial thrombosis.

Conclusions

PAR4-322L significantly reduced platelet responsiveness to AYPGKF and thrombin, which is in agreement with our previous structural and cell signaling studies. In addition, PAR4-322L had prolonged arterial thrombosis time. Our mouse model provides a foundation to further evaluate the role of PAR4 in other pathophysiological contexts.

Essentials

A mouse model was created to represent the PAR4-P310L sequence variant.

PAR4-P322L leads to reduced platelet reactivity in response to PAR4-activation peptide and thrombin, while the ADP and GPVI signaling pathways were unaffected.

The PAR4-P322L mutation decreases time to occlusion in a mouse model of arterial thrombosis.

The PAR4-P322L mouse model provides a foundation to further explore the role of PAR4 in hemostasis and thrombosis.
Epithelial organoid supports resident memory CD8 T cell differentiation
Authors: Ulibarri Max R. , Lin Ying , Ramprashad Julian R. , Han Geongoo , Hasan Mohammad H. , Mithila Farha J. , Ma Chaoyu , Gopinath Smita , Zhang Nu , Milner J. Justin , Beura Lalit K.
Published: December 2023

Resident Memory T cells (TRM) play a vital role in regional immune defense in barrier organs. Although laboratory rodents have been extensively used to study fundamental TRM biology, poor isolation efficiency, sampling bias and low cell survival rates have limited our ability to conduct TRM-focused high-throughput assays. Here, we engineered a murine vaginal epithelial organoid (VEO)-CD8 T cell co-culture system that supports CD8 TRM differentiationin vitro. The three-dimensional VEOs established from murine adult stem cells resembled stratified squamous vaginal epithelium and induced gradual differentiation of activated CD8 T cells into epithelial TRM. Thesein vitrogenerated TRM were phenotypically and transcriptionally similar toin vivoTRM, and key tissue residency features were reinforced with a second cognate-antigen exposure during co-culture. TRM differentiation was not affected even when VEOs and CD8 T cells were separated by a semipermeable barrier, indicating soluble factors’ involvement. Pharmacological and genetic approaches showed that TGF-β signaling played a crucial role in their differentiation. We found that the VEOs in our model remained susceptible to viral infections and the CD8 T cells were amenable to genetic manipulation; both of which will allow detailed interrogation of antiviral CD8 T cell biology in a reductionist setting. In summary, we established a robust model which captures bonafide TRM differentiation that is scalable, open to iterative sampling, and can be subjected to high throughput assays that will rapidly add to our understanding of TRM.
Embryonic Stem Cell Gene Targeting and Chimera Production in Mice
Authors: Papaioannou Virginia E. , Behringer Richard R.
Published: December 2023

Producing a custom gene mutation in embryonic stem (ES) cells, whether through homologous recombination or CRISPR–Cas gene editing, is the first step along the way to getting the mutation into live mice. However, there are a number of additional steps along the way, each presenting technical challenges. Here, we provide a guide for troubleshooting when the results are not as expected and to distinguish technical problems from possible biological effects of the mutation. From the isolation of clonal lines of targeted ES cells through the production of ES cell chimeras with the targeted ES cell clone, we discuss common technical problems and their most likely causes and solutions. We also provide guidance for situations where the mutation has a phenotype in the form of a dominant effect on ES cells or in chimeras.
Immersive capability and spatial presence in virtual reality photo-based tours: implications for distance education
Authors: Figueroa Jr Roberto Bacani
Published: December 2023

Purpose

The purpose of this study is to describe an educational virtual reality (VR) photo-based tour used in an online course and investigate the influence of immersive capability on the dimensions of spatial presence and their relationship with learning-related variables.

Design/methodology/approach

The study employs a descriptive and an experimental methodological approach. The research objectives were achieved using a two-group (n1 = 29 and n2 = 30) experiment, employing descriptive statistics, t-test and correlation analysis.

Findings

The t-test revealed that the immersive capability had a significant effect on the sense of physical space (SP) , Engagement (EN) and negative effects (NE) dimensions. Correlations between the dimensions of spatial presence were found to confirm reports from the literature. Furthermore, some of the dimensions were found to be correlated with motivational and learning variables.

Research limitations/implications

The study reported the results of a one-off experiment among 59 participants. While the results were promising, a longitudinal qualitative study could confirm the results in an actual distance learning context.

Practical implications

The study confirmed that adding VR photo-based tours as learning activities may enhance the learning experience of distance learners.

Social implications

The study shared a case of a learning activity that can be employed for flexible education. Virtual tours can support the need for context-based learning that the geographical or political constraints may limit.

Originality/value

While the paper confirms previous reports on the benefits of using VR photo-based tours as learning activities, this paper has empirically shown the relationship between the dimensions of spatial presence and immersive capability in this specialized context.
The influence of home-country resources and state ownership on subsidiary’s performance: a multilevel perspective
Authors: Alcântara Juciara Nunes de , Calegario Cristina Lelis Leal , Viglioni Marco Túlio Dinali , Carneiro Jorge
Published: December 2023

Purpose

Although emerging markets are distinctly known for the rapid growth and international expansion of their state-owned enterprises, little is known about the influence of parent resource advantages and mixed state ownership on a subsidiary’s performance. Using the resource-based view, this study aims to investigate how resource advantages from the parent company and state ownership influence the performance of subsidiaries.

Design/methodology/approach

This study included a unique data set of 207 subsidiaries from 33 large Brazilian multinationals located in 32 countries from 2000 to 2015. The authors used a hierarchical linear modeling and a multilevel structure based on data at different levels to analyze the influence of home-country parent resource advantages and state ownership on host-country subsidiary’s performance.

Findings

This study illustrates that state ownership can alleviate the resource advantages of parent companies. Evidence is presented, indicating that low and medium degrees of state ownership have a negative impact on the resource advantages of the parent company, consequently reducing the subsidiary’s performance. Moreover, this study highlights that low and medium degrees of state ownership lead to conflicting interests between state ownership and parent resource advantages, resulting in an overall decline in subsidiary performance.

Originality/value

This research contributes new evidence regarding state ownership and resource advantages to the field of international business studies and the domain of Latin American multinational enterprises, Multilatinas. The results suggest that low and medium levels of state ownership diminish the influx of resources from parent companies, thereby restricting the subsidiary’s performance.
Extraction of effective cycles on reducing patients’ depression in the design of treatment spaces
Authors: Faghiholislam Marziyeh , Azemati Hamidreza , Keshmiri Hadi , Pourbagher Somayeh
Published: December 2023

Purpose

The most common reaction to an acute physical illness is anxiety, which may be followed by depression. In patients with chronic diseases, the prevalence of anxiety disorders and depression is almost twice as high as in other diseases. This study aims to extract prominent components in the design of treatment spaces on reducing hospitalized patients’ depression from both experts and patients/users’ point of views. A final model is also presented based on the findings.

Design/methodology/approach

This research used an exploratory mixed method. The effective components were extracted through the administration of two Likert-scale researcher-made questionnaires in two phases. Q factor analysis was conducted to reach the components. A total of 205 patients were admitted to Namazi Hospital in Shiraz, and 20 architecture and psychology experts participated in the survey. Final modeling of the data was done through path analysis.

Findings

Six factors were found to be effective by experts in reducing depression in therapeutic spaces: nature-oriented space, targeted social space, diverse space, visual comfort, logical process and safe space. On the part of patients, seven components were deemed to be effective: visual perception, naturalism, functionalism, physical security, logical process, psychological safety and diversity. Also, four main cycles were extracted from the final model with the direct effect of diversity and the other five cycles were mediated by naturalism.

Research limitations/implications

A total of 15 interviews with architects and psychologists, who were available at the time of the study, were conducted in January 2018. The only general question during interviews was “In your opinion, what factors are effective in reducing the level of depression of patients in the design of treatment spaces?” This may have limited the range of factors that could be surveyed in the study. After collecting the effective factors from the aforementioned expert’s points of view, the questionnaire of experts was designed (Appendix). The expert questionnaires were distributed and edited in two stages in January 2019 among 20 architect experts who were available at the time of the study. The one-year interval between designing and administering the questionnaires occurred because of the limitations posed by the COVID-19 pandemic situation. However, the interval did not pose methodological obstacles for the study.

Originality/value

Evidence-based investigation of the effectiveness of proper design components of therapeutic spaces in reducing the symptoms of patients with chronic secondary depression has received little attention in the literature. Using a “conceptual model,” the present study brought the issue into its focus so as to find effective components in the design of treatment spaces that can alleviate depression symptoms in chronically hospitalized patients.
Governance mechanism to improve sustainability report quality: the impact on information risk and stock market participation
Authors: Justina Dormauli , Lantara I Wayan Nuka
Published: December 2023

Purpose

This study aims to examine the effect of sustainability report quality (SRQ) on information risk. This research also aims to examine the effect of SRQ on stock market participation through information risk.

Design/methodology/approach

The research sample includes 120 firm-years listed on the Sri Kehati Index period of 2017–2021. The hypothesis test uses firm and industry effect regression analysis. SRQ is measured by the existence of a sustainability committee and external assurance. The information risk is measured by bid-ask spread. Stock market participation is measured by volume of stock trading.

Findings

Based on the data analysis, this investigation finds that SRQ reduces information risk. This research also finds that SRQ improves stock market participation by reducing information risk.

Originality/value

First, this examination gives new evidence of SRQ to promote information environment improvement. Second, this examination contributes to providing the role of SRQ in an emerging market, such as Indonesia. Third, this examination contributes to providing the evaluation standard for sustainability reporting quality in Indonesia, since Indonesia has no specific standard for the sustainability report. Fourth, this examination contributes to filling the previous gap.
Exploring the effect of family control on debt financing within large firms: a transnational study in emerging markets
Authors: Boumlik Zouhair , Oulhadj Badia , Colot Olivier
Published: December 2023

Purpose

This paper aims to analyze the effect of family control and influence dimension of the socioemotional wealth (SEW) on capital structure of large listed firms in the North African region.

Design/methodology/approach

The study uses panel data of the top 98 largest listed firms in the North African capital markets over the period from 2018 to 2022. The analysis is conducted employing random effects models.

Findings

Findings suggest that large listed firms in North African region rely on more use of equity rather than debt financing. Further, results show that family control and influence dimension of the SEW, has no significant impact on the capital structure of North African large listed firms. This implies that the financing behavior of large firms listed in the North African countries is driven by financial and rationale factors rather than non-economic considerations. Indeed, findings support assumptions of the pecking order theory.

Originality/value

This transnational study provides new insights into relevancy of socioemotional theory in explaining capital structure decisions within large family businesses in emerging markets. Findings have the potential to enhance analysts', investors' and practitioners' understanding of financing decisions by large listed firms in this region. This, in turn, can aid in conceiving adapted financing solutions.
Managing multi-sided platforms in an emerging country: challenges, critical success factors and contrasts with traditional companies
Authors: Nobrega Julio Henrique Costa , Sigahi Tiago F.A.C. , Rampasso Izabela Simon , Minatogawa Vinicius Luiz Ferraz , Moraes Gustavo Hermínio Salati Marcondes de , Ávila Lucas Veiga , Anholon Rosley
Published: December 2023

Purpose

This paper aims to analyze the main challenges and critical success factors (CSFs) in managing multi-sided platforms (MSP) in Brazil, as well as to understand the differences between this management model and traditional companies.

Design/methodology/approach

Semi-structured interviews were conducted with experienced professionals in the field, focusing on challenges, CSFs and difficulties in managing MSP businesses. The data were analyzed using a mixed-method approach, involving content analysis for qualitative data and grey relational analysis and sensitivity analysis for quantitative data.

Findings

The experts identified eight CSFs, seven key differences between traditional businesses and MSPs, and five technology-related challenges in managing MSPs. They assessed the main difficulties reported in the literature and ranked them, with the most critical challenges being competition with companies adopting MSP models in the same sector (product/service niche) and the necessity for ongoing process adjustments to accommodate scalability.

Originality/value

This study enhances understanding of CSF, disparities between traditional and MSPs and technology-related challenges in this management model. The results can assist managers in emerging nations in enhancing the performance of MSP operations and can be a resource for researchers studying various contexts and creating company guidelines.