bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transpulmonary proteome gradients identify pathways involved in the development of pulmonary vascular disease in heart failure
Authors: Melenovsky Vojtech , Jarolim Petr , Kutilkova Eva , Jenca Dominik , Binova Jana , Al-Hiti Hikmet , Franekova Janka , Kikerlova Sona , Adamova Marketa , Miklovic Matus , Borlaug Barry A. 
Published: February 2025

Background and AimsSome, but not all, patients with heart failure (HF) develop pulmonary vascular disease (PVD), which contributes to poor prognosis. Mechanisms leading to PVD in HF are poorly understood. Unbiased analysis of transpulmonary gradients may identify mediators of PVD by finding proteins consumed or elaborated across the lungs.Methods21 controls and 160 HFrEF patients underwent pulmonary artery (PA) catheterization with blood sampling from postcapillary (wedged balloon) and precapillary (unwedged) position to obtain transpulmonary gradients. The samples from controls and HF from the highest (Q4, n=40) and lowest quartile (Q1, n=40) of pulmonary vascular resistance (PVR) were analyzed using proteomic proximity extension assay (Olink) of 275 proteins. Venous blood concentrations or transpulmonary gradients were analyzed to identify biomarkers or mediators of PVD.ResultsComparison of Q1 and Q4 of PVR identified Surfactant protein-D (PSP-D) as a marker of PVD. Examination of gradients across the lungs in high PVR HF revealed significant uptake of 18 mediators, mostly associated with inflammation (chemokines, oncostatin-M, MMP9) or with TGF/activin pathway (GDF2/BMP9), and release of 5 mediators, notably IL-6 and IL-33. In contrast, these protein gradients were negligible in controls and low PVR HF patients.ConclusionsThe lungs of patients with HF and high PVR, display abnormal uptake and release of proinflammatory cytokines from IL6/gp130 family (IL6, IL33, Oncostatin-M), along with increased transpulmonary uptake of GDF2/BMP9. The study shows that proteins orchestrating inflammation or pulmonary vessel remodeling in group 1 PH, are also operating in patients with PVD due to HF.Structured graphical abstractKey questionCan transpulmonary gradients of regulatory peptides, measured by unbiased proteomic assay, provide a hint on mechanisms of increased pulmonary vascular resistance (PVR) in patients with heart failure (HF)?Key findingsIn striking contrast to Controls (n=21) and HF with low PVR (n=40), the lungs of patients with HF and high PVR (n=40) display abnormal release of proinflammatory cytokines (IL6, IL33), along with increased transpulmonary uptake of chemokines, BNP, Oncostatin M and GDF2/BMP9, a key ligand of BMPRII receptor.Take home messageThe study shows that proteins orchestrating inflammation or pulmonary vessel remodeling in group 1 pulmonary hypertension, are also operating in patients with pulmonary vascular disease due to HF.
Differences in stomatal conductance between leaf shape genotypes ofIpomoea hederaceasuggest divergent ecophysiological strategies
Authors: Singhal Yash Kumar , Boyle Julia Anne , Stinchcombe John R. 
Published: February 2025

AbstractIntraspecific variation in leaf shape affects many physiological processes but its impact on plant distribution is underexplored. Using a common garden, we studied daytime thermoregulation of lobed and entire leaf genotypes ofIpomoea hederacea, which displays a latitudinal leaf shape cline. Both leaf shapes maintained similar temperatures but entire leaf genotypes had significantly increased stomatal conductance in warmer/sunnier weather. With less potential water loss, lobed genotypes may have advantages in drier conditions. Lobed genotypes are more common in the north of the species’ range, which receives less summer precipitation, suggesting water availability as a potential clinally varying selective agent.
Environment and weight class linked to skin microbiome structure of juvenile Eastern hellbenders (Cryptobranchus alleganiensis alleganiensis) in human care
Authors: Aplasca Andrea C. , Johantgen Peter B. , Madden Christopher , Soares Kilmer , Junge Randall E. , Hale Vanessa L. , Flint Mark 
Published: February 2025

AbstractAmphibian skin is integral to promoting normal physiological processes in the body and promotes both innate and adaptive immunity against pathogens. The amphibian skin microbiota is comprised of a complex assemblage of microbes and is shaped by internal host characteristics and external influences. Skin disease is a significant source of morbidity and mortality in amphibians, and increasing research has shown that the amphibian skin microbiota is an important component in host health. The Eastern hellbender (Cryptobranchus alleganiensis alleganiensis) is a giant salamander declining in many parts of its range, and captive-rearing programs are important to hellbender recovery efforts. Survival rates of juvenile hellbenders in captive-rearing programs are highly variable, and mortality rates are overall poorly understood. Deceased juvenile hellbenders often present with low body condition and skin abnormalities. To investigate potential links between the skin microbiota and body condition, we collected skin swab samples from 116 juvenile hellbenders and water samples from two holding tanks in a captive-rearing program. We used 16s rRNA gene sequencing to characterize the skin and water microbiota and observed significant differences in the skin microbiota by weight class and tank. The skin microbiota of hellbenders that were housed in tanks in close proximity were generally more similar than those housed physically distant. A single taxa,Parcubacteria, was differentially abundant by weight class only and observed in higher abundance in low weight hellbenders. These results suggest a true association between this taxa and Low weight hellbenders. Additional research is needed to investigate how husbandry factors and potential pathogenic organisms, such asParcubacteria, impact the skin microbiota of hellbenders and ultimately morbidity and mortality in the species.
The number of immune defense and counter-defense systems sustained in the arms race between procaryotes and viruses
Authors: Ispolatov Yaroslav , Lekontseva Anna , Severinov Konstantin 
Published: February 2025

AbstractProkaryotes have evolved various mechanisms to counter viruses, which in their turn developed numerous strategies to avoid defenses of the hosts. Dozens of such defense and counter-defense mechanisms have recently been discovered, yet the number of such systems held by a given virus or its host is limited. Here, we present numerical and theoretical arguments for the existence of the maximal number of ecologically and evolutionary sustainable defense and counter-defense systems maintained by both sides at any time of the never-ending evolutionary arms race. We find that the number of such systems is of the order of 10 for a broad range of assumptions about the costs and benefits of defense and counter-defense mechanisms and their specificity. This optimum in the number of defense and counter-defense systems appears as a result of a compromise between the metabolic and autoimmune costs of adding a new layer of defense and the benefits it conveys.1Significance statementAlmost all living creatures are either predators or prey (and many are both). At all scales of life, from single cells to largest mammals, prey evolve defenses against predators and predators in their turn evolve counter-defense mechanisms. As a result of this ever-lasting arms race, each organism usually possesses multilayer defense and counter-defense arsenals. Is there a limit to the size of these arsenals? In this work we present a proof-of-principle argument that such a limit indeed exists. Using for definity an example of prokaryotes as the prey and their viruses as predators, we show that the number of distinct defense and counter-defense system that the prey and predators possess is limited by a number of the order of 10 and is only weakly dependent on the ecology of predator-prey interactions. Similar principles and limits likely emerge universally in various antagonistic conflicts such as crime and law enforcement or real arms race.
Dual-targeting strategy to repurpose Cetuximab with HFn nanoconjugates for immunotherapy of triple-negative breast cancer
Authors: Barbieri Linda , Salvioni Lucia , Banfi Andrea , Garbujo Stefania , Fiandra Luisa , Baioni Chiara , Giustra Marco , Morelli Lucia , Frascotti Gianni , Colombo Miriam , Innocenti Metello , Prosperi Davide 
Published: February 2025

AbstractTriple-negative breast cancer (TNBC) is a highly aggressive and treatment-resistant malignancy, characterized by the lack of targeted therapies and poor clinical outcomes. Here, we present a dual-targeting strategy combining the anti-EGFR monoclonal antibody Cetuximab (CTX) with H-ferritin (HFn), a nanoparticle targeting transferrin receptor 1 (TfR1), for potential immunotherapy in CTX-resistant tumors. The HFn-CTX nanoconjugate exhibited favorable biophysical properties, including a hydrodynamic size of <30 nm, and significantly enhanced antibody-dependent cellular cytotoxicity (ADCC) in TNBC spheroids compared to CTX alone. Conversely, glioblastoma spheroids did not exhibit comparable reactivity. This effect correlated with elevated cell-surface EGFR expression and plasma-membrane lingering of the nanoconjugate in TNBC cells, facilitating robust immune activation. Biodistribution studies showed selective accumulation of the HFn-CTX nanoconjugate in TNBC tumors in vivo. These findings highlight the potential of HFn-CTX nanoconjugates to repurpose CTX for refractory cancers that express EGFR at high levels like TNBC, leveraging dual-receptor targeting to amplify immune-mediated cytotoxicity and overcome resistance.
Genes with disrupted connectivity in the architecture of schizophrenia gene co-expression networks highlight atypical neuronal-glial interactions
Authors: Radulescu Eugenia , Vértes Petra E. , Han Shizhong , Hyde Tom M. , Kleinman Joel E. , Bullmore Edward T. , Weinberger Daniel R. 
Published: February 2025

ABSTRACTDysconnectivity in schizophrenia is a pervasive trait across various levels of systems biology. To better understand disrupted patterns of molecular connectivity distinguishing schizophrenia from control non-clinical populations, we applied novel approaches to gene co-expression networks in large samples of postmortem brains from multiple regions relevant to schizophrenia: the dorso-lateral prefrontal cortex- (DLPFC) (Ndonors=297), hippocampus (Ndonors=250) and caudate (Ndonors=349). We identified differentially connected genes (DCGs) in schizophrenia networks that deviated from architectural relationships characteristic of control gene co-expression networks, by assessing three network metrics - total connectivity (K), clustering coefficient (C), and intra-module degree (kIn) determined by projecting the modular community structure of the control networks onto the schizophrenia co-expression networks. Genes showing significant absolute case-control differences for these metrics (i.e., irrespective of difference directionality) were then tested for their relationships with common genetic variants conferring risk of schizophrenia and their biological significance through post-GWAS analyses (stratified LDSC and MAGMA), gene ontology annotations and enrichment in schizophrenia-relevant gene sets.We identified multiple DCGs, with case-control differences of connectivity metrics, consistent across brain regions. When parsed by parameter specificity, these genes show shared and specific enrichment in schizophrenia genetic signal, biological ontologies and selected cell-type markers. Notably these findings revealed widespread disturbances in co-expression connectivity affecting both neuronal and glial cells, particularly oligodendrocytes.Overall, our results highlight disrupted co-expression network architecture in schizophrenia, implicating disrupted neuronal-glial crosstalk and its effect on synaptic transmission.
Broad-Spectrum Activity and Mechanisms of Action of SQ109 on a Variety of Fungi
Authors: Malwal Satish R. , Garcia-Rubio Rocio , Kordalewska Milena , Patterson Hoja , Zhang Chi , Calderin Jorge D. , Zhou Ruijie , Pandey Akanksha M. , Shor Erika , Perlin David S. , Wiederhold Nathan P. , Ostrosky-Zeichner Luis , Fratti Rutilio , Nacy Carol , Oldfield Eric 
Published: February 2025

ABSTRACTWe investigated the activity of the tuberculosis drug SQ109 against sixteen fungal pathogens:Candida albicans,C. auris,C. glabrata,C. guilliermondi,C. kefyr,C. krusei,C. lusitaniae,Candida parapsilosis,C. tropicalis, Cryptococcus neoformans,Rhizopusspp.,Mucorspp.,Fusariumspp.,Coccidioidesspp.,Histoplasma capsulatumandAspergillus fumigatus. MIC values varied widely (125 ng/mL to >64 µg/mL) but in many cases we found promising (MIC∼4 µg/mL) activity as well as MFC/MIC ratios of ∼2. SQ109 metabolites were inactive. The activity of 12 analogs of SQ109 againstSaccharomyces cerevisiaecorrelated with protonophore uncoupling activity, suggesting mitochondrial targeting, consistent with the observation that growth inhibition was rescued by agents which inhibit ROS species accumulation. SQ109 disrupted H+/Ca2+homeostasis inS. cerevisiaevacuoles, and there was synergy (FICI∼0.31) with pitavastatin, indicating involvement of isoprenoid biosynthesis pathway inhibition. SQ109 is, therefore, a potential antifungal agent with multi-target activity.
Residue conservation and solvent accessibility are (almost) all you need for predicting mutational effects in proteins
Authors: Tsishyn Matsvei , Hermans Pauline , Pucci Fabrizio , Rooman Marianne 
Published: February 2025

AbstractMotivationPredicting how mutations impact protein biophysical properties remains a significant challenge in computational biology. In recent years, numerous predictors, primarily deep learning models, have been developed to address this problem; however, issues such as their lack of interpretability and limited accuracy persist.ResultsWe showed that a simple evolutionary score, based on the log-odd ratio (LOR) of wild-type and mutated residue frequencies in evolutionary related proteins, when scaled by the residue’s relative solvent accessibility (RSA), performs on par with or slightly outperforms most of the benchmarked predictors, many of which are considerably more complex. The evaluation is performed on mutations from the ProteinGym deep mutational scanning dataset collection, which measures various properties such as stability, activity or fitness. This raises further questions about what these complex models actually learn and highlights their limitations in addressing prediction of mutational landscape.AvailabilityThe RSALOR model is available as a user-friendly Python package that can be installed from the PyPI repository. The code is freely available athttps://github.com/3BioCompBio/RSALOR.ContactMatsvei.Tsishyn@ulb.be,Fabrizio.Pucci@ulb.be
Channel-mediated astrocytic volume transient is required for synaptic plasticity and spatial memory
Authors: Woo Junsung , Drew Victor James , Lee Jung Moo , Koh Wuhyun , Won Joungha , Lee C. Justin 
Published: February 2025

AbstractAstrocytes, known for their support roles, are emerging as active participants in synaptic plasticity and cognitive functions. Astrocytes actively regulate synaptic plasticity and memory through dynamic volume transients. Our previous research identified several key molecules, including TREK-1, TRPA1, and Best1 ion channels, as well as the gliotransmitter BDNF, as critical components of astrocytic volume transients. However, the precise mechanisms by which these volume transients influence synaptic plasticity and memory remain poorly understood. In this study, we investigate the roles of TREK-1 and TRPA1 in astrocytic volume dynamics and their downstream effects. Using intrinsic optical signal imaging, electrophysiology, and behavioral assays, we demonstrate that neuronal stimulation induces astrocytic swelling, initiated by K+uptake through TREK-1 channels and regulated by Ca2+influx via TRPA1 channels. This swelling is closely associated short- and long-term potentiation, and is accompanied by the release of BDNF, which restores long-term potentiation under conditions of calcium sequestration during astrocytic calcium clamping experiments. Disruption of astrocytic volume transient associated ion channels results in significant deficits in spatial memory, as evidenced by impairments in object-place recognition and passive avoidance tasks. Furthermore, these channels were found to modulate the synaptic plasticity. These findings reveal astrocytic volume transients and BDNF as pivotal modulators of synaptic plasticity and memory, as well as potential therapeutic targets for addressing memory dysfunctions.
Separable Dorsal Raphe Dopamine Projections mediate the Facets of Loneliness-like state
Authors: Lee Christopher R. , Matthews Gillian A. , Lemieux Mackenzie E. , Wasserlein Elizabeth M. , Borio Matilde , Miranda Raymundo L. , Keyes Laurel R. , Schneider Gates P. , Jia Caroline , Tran Andrea , Aloboudi Faith , Chan May G. , Peroni Enzo , Pereira Grace S. , López-Moraga Alba , Pallé Anna , Kimchi Eyal Y. , Padilla-Coreano Nancy , Wichmann Romy , Tye Kay M. 
Published: February 2025

AbstractAffiliative social connections facilitate well-being and survival in numerous species. Engaging in social interactions requires positive or negative motivational drive, elicited through coordinated activity across neural circuits. However, the identity, interconnectivity, and functional encoding of social information within these circuits remains poorly understood. Here, we focus on downstream projections of dorsal raphe nucleus (DRN) dopamine neurons (DRNDAT), which we previously implicated in social motivation alongside an aversive affective state. We show that three prominent DRNDATprojections – to the bed nucleus of the stria terminalis (BNST), central amygdala (CeA), and posterior basolateral amygdala (BLP) – play separable roles in behavior, despite substantial collateralization. Photoactivation of the DRNDAT-CeA projection promoted social behavior and photostimulation of the DRNDAT-BNST projection promoted exploratory behavior, while the DRNDAT-BLP projection supported place avoidance, suggesting a negative affective state. Downstream regions showed diverse receptor expression, poising DRNDATneurons to act through dopamine, neuropeptide, and glutamate transmission. Furthermore, we showex vivothat the effect of DRNDATphotostimulation on downstream neuron excitability depended on region and baseline cell properties, resulting in excitatory responses in BNST cells and diverse responses in CeA and BLP. Finally,in vivomicroendoscopic cellular-resolution recordings in the CeA with DRNDATphotostimulation revealed a correlation between social behavior and neurons excited by social stimuli– suggesting that increased dopamine tone may recruit different CeA neurons to social ensembles. Collectively, these circuit features may facilitate a coordinated, but flexible, response in the presence of social stimuli that can be flexibly guided based on the internal social homeostatic need state of the individual.
Genetic evidence: zebrafishhoxbaandhoxbbclusters are essential for the anterior-posterior positioning of pectoral fins
Authors: Kikuchi Morimichi , Fujii Renka , Kobayashi Daiki , Kawabe Yuki , Kanno Haruna , Toyama Sohju , Tawakkal Farah , Yamada Kazuya , Kawamura Akinori 
Published: February 2025

AbstractVertebrate paired appendages, such as the pectoral fins in fish and the forelimbs in tetrapods, emerge at specific regions along the anterior-posterior axis of the body.Hoxgenes are considered prime candidates for determining the positioning of these paired appendages during development. Nevertheless, despite extensive phenotypic analyses of numerous single and compoundHoxknockout mice, no genetic studies have identified substantial defects in limb positioning, leaving questions unresolved. In a previous study, we generated seven distincthoxcluster-deficient mutants in zebrafish. Here, we provide genetic evidence that zebrafishhoxba;hoxbbcluster mutants specifically exhibit a complete absence of pectoral fins, accompanied by the absence oftbx5aexpression in pectoral fin buds. In these mutants,tbx5aexpression in the pectoral fin field of the lateral plate mesoderm fails to be induced at an early stage, suggesting a lack of pectoral fin precursor cells. Furthermore, the competence to respond to retinoic acid is lost inhoxba;hoxbbcluster mutants, indicating thattbx5aexpression cannot be induced in the pectoral fin bud. We also identifyhoxb4a, hoxb5a, and hoxb5bas pivotal genes underlying this process. Although the frameshift mutations in thesehoxgenes do not recapitulate the absence of pectoral fins, we demonstrate that deletion mutants at these genomic loci show the absence of pectoral fins, albeit with low penetrance. Our results suggest that the positioning of zebrafish pectoral fins is cooperatively determined byhoxb4a, hoxb5a, and hoxb5bwithinhoxbaandhoxbbclusters, which inducetbx5aexpression in the restricted pectoral fin field. Our findings also provide insights into the acquisition of paired appendages in vertebrates.
Demixing of simultaneously co-expressed four phase-separating proteins in the endoplasmic reticulum lumen
Authors: Hasegawa Haruki 
Published: February 2025

AbstractIntracellular protein crystallization represents an intriguing form of biomolecular self-assembly. While the list of such crystallizing proteins is growing and their physiological roles are beginning to be elucidated, the underlying requirements and processes for intracellular protein crystallogenesis remain largely unknown. This study examines how simultaneously co-expressed phase-separating proteins influence each other’s phase-separation event in the endoplasmic reticulum (ER) lumen by using four cargoes selected based on their ability to produce distinctive crystals and droplet inclusion bodies. The co-expressed model proteins independently reached their respective threshold concentrations and spontaneously phase-separated into inclusions in the ER without losing their signature morphologic characteristics. The fact that protein crystals and droplets continued to grow in size over time suggests that nascent cargo proteins were continuously synthesized and folded in the ER to fuel the growth of corresponding inclusion bodies. Namely, despite the highly crowded molecular environment, overexpressed cargoes find their mates by self-association and propagate into microscale structures in the ER. This study demonstrates that cells can accommodate up to four distinct phase separation events simultaneously in the ER lumen, and the phase separation events proceed without interfering with each other and without morphological or content mixing.