bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhalation of particulate matter containing environmentally persistent free radicals induces endothelial dysfunction mediated via AhR activation at the air-blood interface
Authors: Aryal Ankit , Harmon Ashlyn C , Varner Kurt J , Noël Alexandra , Cormier Stephania A , Nde Divine B , Mottram Peter , Maxie Jemiah , Dugas Tammy R 
Published: February 2024

Abstract
Particulate matter (PM) containing environmentally persistent free radicals (EPFR) is formed by the incomplete combustion of organic wastes, resulting in the chemisorption of pollutants to the surface of PM containing redox-active transition metals. In prior studies in mice, EPFR inhalation impaired endothelium-dependent vasodilation. These findings were associated with aryl hydrocarbon receptor (AhR) activation in the alveolar type-II (AT-II) cells that form the air-blood interface in the lung. We thus hypothesized that AhR activation in AT-II cells promotes the systemic release of mediators that promote endothelium dysfunction peripheral to the lung. To test our hypothesis, we knocked down AhR in AT-II cells of male and female mice and exposed them to 280 µg/m3 EPFR lo (2.7e + 16 radicals/g) or EPFR (5.5e + 17 radicals/g) compared with filtered air for 4 h/day for 1 day or 5 days. AT-II-AhR activation-induced EPFR-mediated endothelial dysfunction, reducing endothelium-dependent vasorelaxation by 59%, and eNOS expression by 50%. It also increased endothelin-1 mRNA levels in the lungs and peptide levels in the plasma in a paracrine fashion, along with soluble vascular cell adhesion molecule-1 and iNOS mRNA expression, possibly via NF-kB activation. Finally, AhR-dependent increases in antioxidant response signaling, coupled to increased levels of 3-nitrotyrosine in the lungs of EPFR-exposed littermate control but not AT-II AhR KO mice suggested that ATII-specific AhR activation promotes oxidative and nitrative stress. Thus, AhR activation at the air-blood interface mediates endothelial dysfunction observed peripheral to the lung, potentially via release of systemic mediators.
Exploring Parent Experiences With Early Palliative Care Practices in the NICU
Authors: Quinn Megan , Gephart Sheila , Crist Janice 
Published: February 2024

Background:
The anxiety and uncertain outcome of an admission of a seriously ill infant to the neonatal intensive care unit (NICU) can cause great stress for parents and contribute to poor mental health outcomes. Early implementation of family-centered palliative care (PC) may provide support for NICU parents. Key concepts of early PC in the NICU include shared decision-making, care planning, and support for coping with distress.

Purpose:
The purpose of this study was to explore parent experiences during their child's NICU admission with the early PC practices of shared decision-making, care planning, and coping with distress.

Methods:
Qualitative descriptive methodology was used. Strategies of reflexive journaling, peer debriefing, and data audits were used to enhance trustworthiness. Parents (N = 16) were interviewed, and data were analyzed by conventional content analysis. Targeted recruitment of fathers occurred to ensure they comprised 25% of sample.

Results:
Parents' descriptions of decision-making were contextualized in gathering information to make a decision, the emotional impact of the decision, and influences on their decision-making. In experiences with care planning, parents described learning to advocate, having a spectator versus participant role, and experiencing care planning as communication. Key themes expressed regarding parental coping were exposure to trauma, survival mode, and a changing support network.

Implications for Practice and Research:
These findings highlight key areas for practice improvement: providing more support and collaboration in decision-making, true engagement of parents in care planning, and encouraging peer support and interaction in the NICU and in online communities.
PackDock: a Diffusion Based Side Chain Packing Model for Flexible Protein-Ligand Docking
Authors: Zhang Runze , Jiang Xinyu , Cao Duanhua , Yu Jie , Chen Mingan , Fan Zhehuan , Kong Xiangtai , Xiong Jiacheng , Zhang Zimei , Zhang Wei , Ni Shengkun , Wang Yitian , Gao Shenghua , Zheng Mingyue 
Published: February 2024

AbstractStructure-based drug design (SBDD) relies on accurate knowledge of protein structure and ligand-binding conformations. However, most of the static conformations obtained by advanced methods such as structural biology and de novo protein folding algorithms often don’t meet the needs for drug design. We introduce PackDock, a flexible docking method that combines “conformation selection” and “induced fit” mechanisms in a two-stage docking pipeline. The core module of this method is PackPocket, which uses a diffusion model to explore the side-chain conformation space in ligand binding pockets, both with or without a ligand. We evaluate our method using several tests that reflect real-world application scenarios. (1) Side-chain packing and Re-docking experiments validate the ability of PackDock to predict accurate side-chain conformations and ligand conformations. (2) Cross-docking experiments withapoand non-homologous ligand-inducedholostructures align with real docking scenarios, demonstrating PackDock’s practical value. (3) Docking experiments with hypothetical models show that PackPocket can potentially conduct SBDD starting from protein sequence information only. Additionally, we found that PackDock can identify key amino acid conformation changes, which may provide insights for lead compound optimization. We demonstrate PackDock can accurately predict the complex conformations in various application scenarios, by combining the conformation selection theory and the induced fit theory, and by using the ability of PackPocket to accurately predict the side chain conformations in the pocket region. We believe this method can improve the usability of existing structures, providing a new perspective for the SBDD community.
Novel spirocyclic dimer, SpiD3, targets chronic lymphocytic leukemia survival pathways with potent preclinical effects
Authors: Eiken Alexandria P , Smith Audrey L , Skupa Sydney A , Schmitz Elizabeth , Rana Sandeep , Singh Sarbjit , Kumar Siddhartha , Mallareddy Jayapal Reddy , de Cubas Aguirre A , Krishna Akshay , Kalluchi Achyuth , Rowley M Jordan , D’Angelo Christopher R , Lunning Matthew A , Bociek R Gregory , Vose Julie M , Natarajan Amarnath , El-Gamal Dalia 
Published: February 2024

ABSTRACTChronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NF- κB signaling and the unfolded protein response (UPR). Malignant cells have higher basal levels of UPR posing a unique therapeutic window to combat CLL cell growth using pharmacological agents that induce accumulation of misfolded proteins. Frontline CLL therapeutics that directly target BCR signaling such as Bruton-tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) have enhanced patient survival. However, resistance mechanisms wherein tumor cells bypass BTK inhibition through acquired BTK mutations, and/or activation of alternative survival mechanisms have rendered ibrutinib ineffective, imposing the need for novel therapeutics. We evaluated SpiD3, a novel spirocyclic dimer, in CLL cell lines, patient-derived CLL samples, ibrutinib-resistant CLL cells, and in the Eµ-TCL1 mouse model. Our integrated multi-omics and functional analyses revealed BCR signaling, NF-κB signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR and inhibition of global protein synthesis in CLL cell lines and patient-derived CLL cells. In ibrutinib-resistant CLL cells, SpiD3 retained its anti-leukemic effects, mirrored in reduced activation of key proliferative pathways (e.g., PRAS, ERK, MYC). Translationally, we observed reduced tumor burden in SpiD3-treated Eµ-TCL1 mice. Our findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including NF-κB signaling and the UPR, culminating in profound anti-tumor properties independent of TME stimuli.STATEMENT OF SIGNIFICANCESpiD3 demonstrates cytotoxicity in CLL partially through inhibition of NF-κB signaling independent of tumor-supportive stimuli. By inducing the accumulation of unfolded proteins, SpiD3 activates the UPR and hinders protein synthesis in CLL cells. Overall, SpiD3 exploits critical CLL vulnerabilities (i.e., the NF-κB pathway and UPR) highlighting its use in drug-resistant CLL.VISUAL ABSTRACT
Family Leaders Communicate Risk During Cascade Screening after Sudden Cardiac Death in the Young
Authors: Dellefave-Castillo Lisa M. , Hinkamp Franceska , Shah Lisa , Scherr Courtney L. , Young Jennifer , Webster Gregory , Duquette Debra 
Published: February 2024

ABSTRACTIntroductionRelatives of a victim of sudden cardiac death in the young (SCDY) may be at risk for hereditary cardiomyopathies and arrhythmias. Family leaders are often responsible for communicating risk to surviving family at a difficult time.PurposeExplore barriers and facilitators to communication about cascade screening in families who have lost a family member to SCDYMethodsSemi-structured interviews (n = 14) were conducted with family members of a SCDY decedent. Participants were recruited from the Sudden Arrhythmia Death Syndrome advocacy group. Interviews were conducted until data saturation was reached. Interviews were audio recorded, transcribed, and analyzed using conventional content analysis.ResultsFive categories were identified from the interviews: 1. Participants understood fundamental risks but the clinical variability in arrhythmia and cardiomyopathy was difficult to interpret and convey; 2. Family leaders felt some family disregarded risk information; 3. Grief interfered with communication; 4. Communication aids were insufficient stand-alone interventions; 5. Families advocated for a “genetic family navigator”.ConclusionThe five categories provide practical strategies to improve clinical care and communication for families after a SCDY and emphasize the need for genetic family navigators to facilitate cascade screening.GRAPHICAL ABSTRACT
Humoral and cellular immune responses after 6 months of a heterologous SARS-CoV-2 booster with the protein-based PHH-1V vaccine in a phase IIb trial
Authors: Corominas Júlia , Garriga Carme , Prenafeta Antoni , Moros Alexandra , Cañete Manuel , Barreiro Antonio , González-González Luis , Madrenas Laia , Güell Irina , Clotet Bonaventura , Izquierdo-Useros Nuria , Raïch-Regué Dàlia , Gallemí Marçal , Blanco Julià , Pradenas Edwards , Trinité Benjamin , Prado Julia G , Pérez-Caballero Raúl , Bernad Laia , Plana Montserrat , Esteban Ignasi , Aurrecoechea Elena , Taleb Rachel Abu , McSkimming Paula , Soriano Alex , Nava Jocelyn , Anagua Jesse Omar , Ramos Rafel , Lluch Ruth Martí , Comes Aida Corpes , Romero Susana Otero , Martínez-Gómez Xavier , Camacho-Arteaga Lina , Molto Jose , Benet Susana , Bailón Lucía , Arribas Jose R , Borobia Alberto M , Parada Javier Queiruga , Navarro-Pérez Jorge , Giner Maria José Forner , Lucas Rafael Ortí , Jiménez María del Mar Vázquez , Fernández María Jesús López , Alvarez-Mon Melchor , Troncoso Daniel , Arana-Arri Eunate , Meijide Susana , Imaz-Ayo Natale , García Patricia Muñoz , de la Villa Sofía , Fernández Sara Rodríguez , Prat Teresa , Torroella Èlia , Ferrer Laura 
Published: February 2024

SummaryThe HIPRA-HH-2 was a multicentre, randomized, active-controlled, double-blind, non-inferiority phase IIb clinical trial to compare the immunogenicity and safety of a heterologous booster with PHH-1V adjuvanted recombinant vaccine versus a homologous booster with mRNA vaccine. Interim results showed a strong humoral and cellular immune response against the SARS-CoV-2 Wuhan-Hu-1 strain and the Beta, Delta, and Omicron BA.1 variants up to day 98 after dosing. Here we report that these humoral and cellular responses after PHH-1V dosing are sustained up to 6 months. These results are observed both when including or not participants who reported SARS-CoV-2 infection and in a high-risk population (≥65 years). Additional analysis revealed a non-inferiority of PHH-1V booster in eliciting neutralizing antibodies also for SARS-CoV-2 Omicron XBB.1.5 when compared to mRNA vaccine after 6 months. The PHH-1V vaccine provides long-lasting protection against a wide variety of SARS-CoV-2 emerging variants to prevent severe COVID-19.ClinicalTrials.govIdentifierNCT05142553
Enhancing mitochondrial pyruvate metabolism ameliorates myocardial ischemic reperfusion injury
Authors: Visker Joseph R. , Cluntun Ahmad A. , Velasco-Silva Jesse N. , Eberhardt David R. , Shankar Thirupura S. , Hamouche Rana , Ling Jing , Kwak Hyoin , Hillas Yanni , Aist Ian , Tseliou Eleni , Navankasattusas Sutip , Chaudhuri Dipayan , Ducker Gregory S. , Drakos Stavros G. , Rutter Jared 
Published: February 2024

SUMMARYThe established clinical therapy for the treatment of acute myocardial infarction is primary percutaneous coronary intervention (PPCI) to restore blood flow to the ischemic myocardium. PPCI is effective at reperfusing the ischemic myocardium, however the rapid re-introduction of oxygenated blood also can cause ischemia-reperfusion (I/R) injury. Reperfusion injury is the culprit for up to half of the final myocardial damage, but there are no clinical interventions to reduce I/R injury. We previously demonstrated that inhibiting the lactate exporter, monocarboxylate transporter 4 (MCT4), and re-directing pyruvate towards oxidation can blunt isoproterenol-induced hypertrophy. Based on this finding, we hypothesized that the same pathway might be important during I/R. Here, we establish that the pyruvate-lactate metabolic axis plays a critical role in determining myocardial salvage following injury. Post-I/R injury, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium following I/R injury. MPC loss in cardiomyocytes caused more cell death with less myocardial salvage, which was associated with an upregulation of MCT4 in the myocardium at risk of injury. We deployed a pharmacological strategy of MCT4 inhibition with a highly selective compound (VB124) at the time of reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (Δψ), and Ca2+, increased pyruvate entry to TCA cycle, and improved myocardial salvage and functional outcomes following I/R injury. Altogether, our data suggest that normalizing the pyruvate-lactate metabolic axis via MCT4 inhibition is a promising pharmacological strategy to mitigate I/R injury.GRAPHICAL ABSTRACT
Ready, set, yellow! Color Preference of Indian Free-ranging Dogs
Authors: Roy Anamitra , Lahiri Aesha , Nandi Srijaya , Manchalwar Aayush , Siddharth S , Abishek J V R , Bulhan Indira , Sengupta Shouvanik , Kumar Sandeep , Chakravarty Tushnim , Bhadra Anindita 
Published: February 2024

AbstractMost of the research on color vision related behaviors in dogs has involved training the dogs to perform visual discrimination tasks. We investigated the meaning of color to untrained Indian free-ranging dogs (FRDs). Using one-time multi-option choice tests for color preference in 134 adult dogs, we found the dogs to prefer yellow objects over blue or gray ones (p < 0.001, Cramer’s V = 0.433) while there was no preference between blue and gray (N = 102, p = 0.165). We next pitted a yellow object against a gray object that had food. Here, the dogs ignored the food to approach the yellow object first, both when the food was biscuit (N = 52, p < 0.001, Cramer’s V = 0.576) and chicken (N = 61, p < 0.001, Cramer’s V = 0.540), indicating the color preference to be quite strong. Color preference has previously been investigated in many other animals and has implications for behaviors like mate choice and foraging. Our study provides a new perspective into the ecology of Indian FRDs and might have implications for pet dogs as well, if they too show this preference.HighlightsIndian free-ranging dogs (FRDs) show preference toward the color yellow over blue and gray.Indian FRDs show no preference between blue and gray colors.Attraction towards a yellow object can be stronger than attraction towards food rewards for Indian FRDs.
Iron deficiency causes aspartate-sensitive metabolic and proliferative dysfunction in CD8+ T cells
Authors: Teh Megan R. , Gudgeon Nancy , Frost Joe N. , Sinclair Linda V. , Smith Alastair L. , Millington Christopher L. , Kronsteiner Barbara , Roberts Jennie , Marzullo Bryan P. , Preston Alexandra E. , Rehwinkel Jan , Milne Thomas A. , Tennant Daniel A. , Dunachie Susanna J. , Armitage Andrew E. , Dimeloe Sarah , Drakesmith Hal 
Published: February 2024

SummaryIron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people, causing symptoms including anaemia and impaired immunity. Nevertheless, precisely how iron deprivation impacts immune cell function remains poorly characterised. We therefore interrogated how physiologically low iron availability affected activated CD8+ T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation profoundly stalled proliferation without influencing cell viability, altered histone methylation status and disrupted mitochondrial membrane potential. Consistently, metabolism of glucose and glutamine in the TCA cycle was limited, indeed TCA cycle activity was partially reversed to a reductive trajectory. Previous studies have shown mitochondria-derived aspartate is crucial for proliferation of transformed cells. Surprisingly, we found aspartate was increased in stalled iron deficient CD8+ T-cells, but was not utilised cytosolically for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Conversely, exogenous aspartate, which directly accesses the cytosol, markedly rescued the clonal expansion of even severely iron-deficient CD8+ T-cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck impairing T-cells, which can be bypassed by resupplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8+ T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.
Excitation/Inhibition balance relates to cognitive function and gene expression in Temporal Lobe Epilepsy: an hdEEG assessment with aperiodic exponent
Authors: Duma Gian Marco , Cuozzo Simone , Wilson Luc , Danieli Alberto , Bonanni Paolo , Pellegrino Giovanni 
Published: February 2024

AbstractPatients with epilepsy are characterized by a dysregulation of excitation-inhibition balance (E/I). The assessment of E/I may inform clinicians during the diagnosis and therapy management, even though it is rarely performed. An accessible measure of the E/I of the brain represents a clinically relevant feature. Here we exploited the exponent of the aperiodic component of the power spectrum of EEG signal as a noninvasive and cost-effective proxy of the E/I balance. We recorded resting-state activity with high-density EEG from 65 patients with temporal lobe epilepsy (TLE) and 35 controls. We extracted the exponent of the aperiodic fit of the power spectrum from source-reconstructed EEG and tested differences between TLE and controls. Spearman’s correlation was performed between the exponent and clinical variables (age of onset, epilepsy duration and neuropsychology) and cortical expression of epilepsy-related genes derived from Human Allen Brain Atlas. Patients with TLE showed a significantly larger exponent, corresponding to an inhibition directed E/I balance, in bilateral frontal and temporal regions. Lower E/I in the left entorhinal, and bilateral dorsolateral prefrontal cortices corresponded to a lower performance of short term verbal memory. Limited to TLE, we detected a significant correlation between the exponent and the cortical expression of GABRA1, GRIN2A, GABRD, GABRG2, KCNA2and PDYN. EEG aperiodic exponent maps the E/I balance non-invasively in patients with epilepsy and reveals a tight relationship between altered E/I patterns, cognition and genetics.
Perceived association of mood and symptom severity in adults with mitochondrial diseases
Authors: Kelly Catherine , Junker Alex , Englestad Kris , Hirano Michio , Trumpff Caroline , Picard Martin 
Published: February 2024

AbstractIndividuals with genetic mitochondrial diseases suffer from multisystemic symptoms that vary in severity from day-to-day and week-to-week, but the underlying causes of symptomatic fluctuations are not understood. Based upon observations that: i) patients and their families frequently report that stressful life events either trigger exacerbations of existing symptoms or the onset of new symptoms, ii) psychological states and stress hormones influence mitochondrial energy production capacity, and iii) epidemiological reports document a robust connection between traumatic/stressful life events and various neurologic disorders, we hypothesized that mitochondrial disease symptom severity may vary according to participant’s mood. To investigate this we administered the Stress, Health and Emotion Survey (SHES) in 70 adults (majority white (84%) cisgender women (83%), ages 18-74) with self-reported mitochondrial diseases (MELAS, 18%; CPEO, 17%; Complex I deficiency, 13%). Participants rated the severity of each of their symptom(s) over the past year on either good or bad days. On days marked by more stress, sadness and other negative emotions, some but not all symptoms were reported to be worse, including fatigue, exercise intolerance, brain fog, and fine motor coordination. By contrast, on days marked by happiness and calmness, participants reported these and other symptoms to be better, or less severe. Other symptoms including diminished sweating, hearing problems, and dystonia were in general unrelated to mood. Thus, some individuals living with mitochondrial diseases, at times perceive a connection between their mood and symptom severity. These preliminary associative results constitute an initial step towards developing more comprehensive models of the factors that influence the clinical course of mitochondrial diseases.