bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adipocyte-specific deletion of Dbc1 does not recapitulate healthy obesity phenotype but suggests regulation of inflammation signaling
Authors: Santos Leonardo , Fort Rafael Sebastián , Schlapp Geraldine , Cal Karina , Perez-Torrado Valentina , Meikle Maria Noel , Mulet Ana Paula , Sotelo-Silveira José R. , Verdes Jose M , Contreras Paola , Calliari Aldo J. , Crispo Martina , Badano Jose L. , Escande Carlos 
Published: September 2024

AbstractThe protein Deleted in Breast Cancer 1 (DBC1), a regulator of several transcription factors and epigenetic modulators, plays determinant roles in metabolism regulation, obesity and aging-related processes. Knockout mice for Dbc1, develop morbid obesity but are protected against liver steatosis, insulin resistance and atherosclerosis. We have proposed that this healthy obesity phenotype was mainly due to the expansion of adipose tissue, avoiding free-fatty acid spillover and metabolic damage in peripheral tissues. To gain more insight about the role of Dbc1 in adipose cells during obesity and its impact on metabolic dysregulation, we generated a conditionalDbc1KO mouse and backcrossed it withCRE-AdipoQtransgenic mice, aiming to abrogate Dbc1 expression in all mature adipocytes (cAT-Dbc1). cAT-Dbc1 mice showed deletion of Dbc1 specifically in mature adipocytes in different fat depots. We tested the effect of Dbc1 deletion in adipocytes on different aspects of metabolic regulation in male and female mice fed in normal chow and high-fat diets. We found that deletion of Dbc1 in mature adipocytes had no effect on weight gain, glucose tolerance and other markers of metabolic dysregulation, regardless sex. However, Dbc1 KO adipocytes displayed an mRNA expression profile consistent with increased inflammation during obesity. Our results suggest that the healthy phenotype displayed in the whole body Dbc1 KO obese mice is not due to the protein function in mature adipocytes and might involve other cell types present in adipose tissue. Instead, the specific deletion of Dbc1 in mature adipocytes highlights a novel role of Dbc1 in inflammation signaling during obesity.
β2-Adrenergic Biased Agonist Nebivolol Inhibits the Development of Th17 and the Response of Memory Th17 Cells in an NF-κB-Dependent Manner
Authors: Hajiaghayi Mehri , Gholizadeh Fatemeh , Han Eric , Little Samuel R. , Rahbari Niloufar , Ardila Isabella , Naranjo Carolina Lopez , Tehranimeh Kasra , Shih Steve C.C. , Darlington Peter J. 
Published: September 2024

AbstractIntroductionAdrenergic receptors regulate metabolic, cardiovascular and immunological functions in response to the sympathetic nervous system. The effect of β2-adrenergic receptor (AR) as a high-expression receptor on different subpopulations of T cells is complex and varies depending on the type of ligand and context. While traditional β2-AR agonists generally suppress T cells, they potentially enhance IL-17A production by Th17 cells. The effects of pharmacological drugs that count as biased agonists of AR like nebivolol are not completely understood. We investigated the impact of nebivolol on human memory CD4+ T (Th1, Th2, Th17) cells and polarized naïve Th17 cells highlighting its potential for IL-17A suppression via a non-canonical β2AR cell-signaling pathway.MethodsThe effects of nebivolol were tested on healthy human peripheral blood mononuclear cells, purified memory Th cells, and polarized naïve Th17 cells activated with antiCD3/antiCD28/antiCD2 ImmunoCult reagent. IFN-γ, IL-4, and IL-17A which are primarily derived from Th1, Th2, and Th17 cells respectively, were quantified by ELISA and flow cytometry. IL-10 was measured by ELISA. Gene expression of RORC, ADRB1, ADRB2, and ADRB3 was evaluated by qPCR. The ADRB2 gene was knocked out in memory Th cells using CRISPR/Cas9. Protein expression of phosphorylated-serine133-CREB and phosphorylated-NF-κB p65 was assessed by Western blot. Proliferation was assessed by fluorescent dye loading and flow cytometry.ResultsNebivolol treatment decreased IL-17A and IFN-γ secretion by activated-memory Th cells and elevated IL-4 levels. Nebivolol reduced the proportion of IL-17A+ Th cells and downregulated RORC expression. Unlike the β2-AR agonist terbutaline, nebivolol inhibited the shift of naïve CD4+ T cells towards the Th17 phenotype. IL-10 and proliferation index remained unchanged. Nebivolol-treated β2-knockout memory Th cells showed significant inhibition of β2AR-mediated signaling, evidenced by the absence of IL-17A suppression compared to controls. Phosphorylation of the NF-κB p65 subunit was inhibited by nebivolol, but CREB phosphorylation was not changed, suggesting a selective transcriptional control.ConclusionsThe findings demonstrate that nebivolol acts through a β2-AR-mediated signaling pathway, as a distinctive anti-inflammatory agent capable of selectively shifting Th17 cells and suppressing phosphorylation of NF-κB. This highlights nebivolol’s potential for therapeutic interventions in chronic autoimmune conditions with elevated IL-17A levels.
Estimating adequate contact rates and time of Highly Pathogenic Avian Influenza virus introduction into individual United States commercial poultry flocks during the 2022/24 epizootic
Authors: Ssematimba Amos , Malladi Sasidhar , Bonney Peter J. , St. Charles Kaitlyn M. , Hutchinson Holden C. , Schoenbaum Melissa , Marusak Rosemary , Culhane Marie R. , Cardona Carol J. 
Published: September 2024

AbstractFollowing confirmation of the first case of the ongoing U.S. HPAI H5N1 epizootic in commercial poultry on February 8, 2022, the virus has continued to devastate the U.S. poultry sector and the pathogen has since managed to cross over to livestock and a few human cases have also been reported. Efficient outbreak management benefits greatly from timely detection and proper identification of the pathways of virus introduction and spread.In this study, using changes in mortality rates as a proxy for HPAI incidence in a layer, broiler and turkey flock, mathematical modeling techniques, specifically the Approximate Bayesian Computation algorithm in conjunction with a stochastic within-flock HPAI transmission model, were used to estimate the time window of pathogen introduction into the flock (TOI) and adequate contact rate (ACR) based on the daily mortality and diagnostic test results. The estimated TOI was then used together with the day when the first positive sample was collected to calculate the most likely time to first positive sample (MTFPS) which reflects the time to HPAI detection in the flock.The estimated joint (i.e., all species combined) median of the MTFPS for different flocks was six days, the joint median most likely ACR was 6.8 newly infected birds per infectious bird per day, the joint medianR0was 13 and the joint median number of test days per flock was two. These results were also grouped by species and by epidemic phase and discussed accordingly.We conclude that findings from this and related studies are beneficial for the different stakeholders in outbreak management and combining TOI analysis with complementary approaches such as phylogenetic analyses is critically important for improved understanding of disease transmission pathways. The estimated parameters can also inform models used for surveillance design, risk analysis, and emergency preparedness.
Distinct modes of coupling between VCP, an essential unfoldase, and deubiquitinases
Authors: Vostal Lauren E. , Dahan Noa E. , Zhang Wenzhu , Reynolds Matthew J. , Chait Brian T. , Kapoor Tarun M. 
Published: September 2024

AbstractErrors in proteostasis, which requires regulated degradation and recycling of diverse proteins, are linked to aging, cancer and neurodegenerative disease (1). In particular, recycling proteins from multiprotein complexes, organelles and membranes is initiated by ubiquitylation, extraction and unfolding by the essential mechanoenzyme VCP (2–4), and ubiquitin removal by deubiquitinases (DUBs), a class of ∼100 ubiquitin-specific proteases in humans (5, 6). As VCP’s substrate recognition requires ubiquitylation, the removal of ubiquitins from substrates for recycling must follow extraction and unfolding. How the activities of VCP and different DUBs are coordinated for protein recycling or other fates is unclear. Here, we employ a photochemistry-based approach to profile proteome-wide domain-specific VCP interactions in living cells (7). We identify DUBs that bind near the entry, exit, or both sites of VCP’s central pore, the channel for ATP-dependent substrate translocation (8–10). From this set of DUBs, we focus on VCPIP1, required for organelle assembly and DNA repair (11–13), that our chemical proteomics workflow indicates binds the central pore’s entry and exit sites. We determine a ∼3Å cryo-EM structure of the VCP-VCPIP1 complex and find up to 3 VCPIP1 protomers interact with the VCP hexamer. VCPIP1’s UBX-L domain binds VCP’s N-domain in a ‘down’ conformation, linked to VCP’s ADP-bound state (2, 14), and the deubiquitinase domain is positioned at the central pore’s exit site, poised to remove ubiquitin following substrate unfolding. We find that VCP stimulates VCPIP1’s DUB activity and use mutagenesis and single-molecule mass photometry assays to test the structural model. Together, our data suggest that DUBs bind VCP at distinct sites and reveal how the two enzyme activities can be coordinated to achieve specific downstream outcomes for ubiquitylated proteins.
Collaborative forecasting of influenza-like illness in Italy: the Influcast experience
Authors: Fiandrino Stefania , Bizzotto Andrea , Guzzetta Giorgio , Merler Stefano , Baldo Federico , Valdano Eugenio , Mateo Urdiales Alberto , Bella Antonino , Celino Francesco , Zino Lorenzo , Rizzo Alessandro , Li Yuhan , Perra Nicola , Gioannini Corrado , Milano Paolo , Paolotti Daniela , Quaggiotto Marco , Rossi Luca , Vismara Ivan , Vespignani Alessandro , Gozzi Nicolò 
Published: September 2024

AbstractCollaborative hubs that integrate multiple teams to generate ensemble projections and forecasts for shared targets are now regarded as state-of-the-art in epidemic predictive modeling. In this paper, we introduce Influcast, Italy’s first epidemic forecasting hub for influenza-like illness. During the 2023/2024 winter season, Influcast provided 20 rounds of forecasts, involving five teams and eight models to predict influenza-like illness incidence up to four weeks in advance at the national and regional administrative level. The individual forecasts were synthesized into an ensemble and bench-marked against a baseline model. The ensemble forecasts consistently outperformed both individual models and baseline forecasts, demonstrating superior accuracy at national and sub-national levels across various metrics. Despite a decline in absolute performance over longer horizons, the ensemble model outperformed the baseline in all considered time frames. These findings underscore the importance of multimodel forecasting hubs in producing consistent short-term influenza-like illnesses forecasts that can inform public health preparedness and mitigation strategies.
A Nerve-Fibroblast Axis in Mammalian Lung Fibrosis
Authors: Ishikawa Genta , Peng Xueyan , Ghincea Alexander , McGovern John , Zielonka Jana , Jeevanandam Advait , Shao Shuai , Woo Samuel , Okuno Daisuke , Yu Sheeline , Lee Chris J. , Liu Angela , Saber Tina , Hu Buqu , Sun Ying , Gao Ruijuan , Jumaily Karam Al , Homer Robert , Hinchcliff Monique , Feghali-Bostwick Carol , Sumida Tomokazu S. , Sauler Maor , Gomez Jose L. , Sun Huanxing , Ryu Changwan , Herzog Erica L. 
Published: September 2024

ABSTRACTFibrosis contributes to incurable pathologies in vital organs including the lung. Myofibroblasts are fibrogenic effector cells that accumulate via incompletely understood mechanisms. We discovered that α1-adrenoreceptor expressing myofibroblasts receive sympathetic nerve-derived noradrenergic inputs in fibrotic mouse and human lungs. We combined optical clearing, whole lung imaging, cell-specific gene deletion in sympathetic nerves and myofibroblasts, pharmacologic interventions, sympathetic nerve co-culture and precision-cut lung slices, with analysis of bronchoalveolar lavage fluid, lung tissues, single-cell RNA sequencing datasets, and isolated lung fibroblasts from patients with diverse forms of pulmonary fibrosis to characterize a fibrogenic unit comprised of aberrantly patterned sympathetic nerves and α1-adrenoreceptor subtype D expressing myofibroblasts. The discovery of this previously undefined nerve-fibroblast axis that is conserved across species demonstrates the pivotal contribution of nerves to tissue remodeling and heralds a novel paradigm in fibrosis research.
Three-dimensional analysis of mitochondria in a patient-derived xenograft model of triple negative breast cancer reveals mitochondrial network remodeling following chemotherapy treatments
Authors: Berner Mariah J. , Beasley Heather K. , Vue Zer , Lane Audra , Vang Larry , Baek Mokryun L. , Marshall Andrea G. , Killion Mason , Zeleke Faben , Shao Bryanna , Parker Dominque , Peterson Autumn , Rhoades Julie Sterling , Scudese Estevão , Dobrolecki Lacey E. , Lewis Michael T. , Hinton Antentor , Echeverria Gloria V. 
Published: September 2024

ABSTRACTMitochondria are hubs of metabolism and signaling and play an important role in tumorigenesis, therapeutic resistance, and metastasis in many cancer types. Various laboratory models of cancer demonstrate the extraordinary dynamics of mitochondrial structure, but little is known about the role of mitochondrial structure in resistance to anticancer therapy. We previously demonstrated the importance of mitochondrial structure and oxidative phosphorylation in the survival of chemotherapy-refractory triple negative breast cancer (TNBC) cells. As TNBC is a highly aggressive breast cancer subtype with few targeted therapy options, conventional chemotherapies remain the backbone of early TNBC treatment. Unfortunately, approximately 45% of TNBC patients retain substantial residual tumor burden following chemotherapy, associated with abysmal prognoses. Using an orthotopic patient-derived xenograft mouse model of human TNBC, we compared mitochondrial structures between treatment-naïve tumors and residual tumors after conventional chemotherapeutics were administered singly or in combination. We reconstructed 1,750 mitochondria in three dimensions from serial block-face scanning electron micrographs, providing unprecedented insights into the complexity and intra-tumoral heterogeneity of mitochondria in TNBC. Following exposure to carboplatin or docetaxel given individually, residual tumor mitochondria exhibited significant increases in mitochondrial complexity index, area, volume, perimeter, width, and length relative to treatment-naïve tumor mitochondria. In contrast, residual tumors exposed to those chemotherapies given in combination exhibited diminished mitochondrial structure changes. Further, we document extensive intra-tumoral heterogeneity of mitochondrial structure, especially prior to chemotherapeutic exposure. These results highlight the potential for structure-based monitoring of chemotherapeutic responses and reveal potential molecular mechanisms that underlie chemotherapeutic resistance in TNBC.
Interaction with AK2A links AIFM1 to cellular energy metabolism
Authors: Rothemann Robin Alexander , Pavlenko Egor , Mondal Mrityunjoy , Gerlich Sarah , Grobushkin Pavel , Mostert Sebastian , Racho Julia , Weiss Konstantin , Stobbe Dylan , Stillger Katharina , Lapacz Kim , Salscheider Silja Lucia , Petrungaro Carmelina , Ehninger Dan , Nguyen Thi Hoang Duong , Dengjel Jörn , Neundorf Ines , Bano Daniele , Pöpsel Simon , Riemer Jan 
Published: September 2024

ABSTRACTApoptosis inducing factor 1 (AIFM1) is a flavoprotein essential for mitochondrial function and biogenesis. Its interaction with MIA40, the central component of the mitochondrial disulfide relay, accounts for some, but not all effects of AIFM1 loss. Our high-confidence AIFM1 interactome revealed novel interaction partners of AIFM1. For one of these interactors, adenylate kinase 2 (AK2), an essential enzyme maintaining cellular adenine nucleotide pools, AIFM1 binding specifically stabilized the isoform AK2A via interaction with its C-terminus. High resolution cryo-EM and biochemical analyses showed that both, MIA40 and AK2A bind AIFM1’s C-terminal β-strand, enhancing NADH oxidoreductase activity by locking an active, dimer conformation and, in the case of MIA40, affecting the cofactor binding site. The AIFM1-AK2A interaction is crucial during respiratory conditions. We further identified ADP/ATP translocases and the ATP synthase as AIFM1 interactors, emphasizing its important regulatory role as a central, organizing platform in energy metabolism.
Redistribution of ancestral functions underlies the evolution of venom production in marine predatory snails
Authors: Zancolli Giulia , Modica Maria Vittoria , Puillandre Nicolas , Kantor Yuri , Barua Agneesh , Campli Giulia , Robinson-Rechavi Marc 
Published: September 2024

AbstractVenom-secreting glands are highly specialised organs evolved throughout the entire animal kingdom to synthetise and secrete toxins for predation and defence. Venom is extensively studied for its toxin components and application potential; yet, how animals become venomous remains poorly understood. Venom systems therefore offer a unique opportunity to understand the molecular mechanisms underlying functional innovation. Here, we conducted a multi-species multi-tissue comparative transcriptomics analysis of 12 marine predatory gastropods, including species with venom glands and species with homologous non-venom producing glands, to examine how specialised functions evolve through gene expression changes. We found that while the venom gland specialised for the mass production of toxins, its homologous glands retained the ancestral digestive functions. The functional divergence and specialisation of the venom gland was achieved through a redistribution of its ancestral digestive functions to other organs, specifically the oesophagus. This entailed concerted expression changes and accelerated transcriptome evolution across the entire digestive system. The increase in venom gland secretory capacity was achieved through the modulation of an ancient secretory machinery, particularly genes involved in endoplasmic reticulum stress and unfolded protein response. This study shifts the focus from the well-explored evolution of toxins to the lesser-known evolution of the organ and mechanisms responsible for venom production. As such, it contributes to elucidating the molecular mechanisms underlying organ evolution at a fine evolutionary scale, highlighting the specific events that lead to functional divergence.
Mycobacterial Topoisomerase I Energetically Suffers From C-Terminal Deletions
Authors: Balthrop Dillon , Sigdel Deepesh , Mao Chunfeng , Tse-Dinh Yuk-Ching , Mills Maria 
Published: September 2024

AbstractType IA topoisomerases relieve torsional stress in DNA by a strand-passage mechanism, using the strain in the DNA to drive relaxation. The topoisomerase IAs of the Mycobacterium genus have distinct C-terminal domains which are crucial for successful strand-passage. We used single-molecule magnetic tweezers to observe supercoil relaxation by wild typeMycobacterium smegmatistopoisomerase IA and two C-terminal truncation mutants. We recorded distinct behaviors from each truncation mutant. We calculated the free energy stored in the DNA as it is twisted under force to examine the differences between the proteins. Based on our results, we propose a modified model of the strand-passage cycle.
Distributional learning drives statistical suppression and deafening
Authors: Luthra Sahil , Luor Austin , Tierney Adam T. , Dick Frederic , Holt Lori L. 
Published: September 2024

AbstractHumans and other animals use information about how likely it is for something to happen. The absolute and relative probability of an event influences a remarkable breadth of behaviors, from foraging for food to comprehending linguistic constructions -- even when these probabilities are learned implicitly. It is less clear how, and under what circumstances, statistical learning of simple probabilities might drive changes in perception and cognition. Here, across a series of 29 experiments, we probe listeners’ sensitivity to task-irrelevant changes in the probability distribution of tones’ acoustic frequency across tone-in-noise detection and tone duration decisions. We observe that the task-irrelevant frequency distribution influences the ability to detect a sound and the speed with which perceptual decisions are made. The shape of the probability distribution, its range, and a tone’s relative position within that range impact observed patterns of suppression and enhancement of tone detection and decision making. Perceptual decisions are also modulated by a newly discovered perceptual bias, with lower frequencies in the distribution more often and more rapidly perceived as longer, and higher frequencies as shorter. Perception is sensitive to rapid distribution changes, but distributional learning from previous probability distributions also carries over. In fact, massed exposure to a single point along the dimension results in a sustained ’statistical deafening’ along a range of subsequently encountered frequencies. This seemingly maladaptive loss of sensitivity - occurring entirely in the absence of feedback or reward - points to a gain mechanism that suppresses sensitivity to regions along a perceptual dimension that are less likely to be encountered.Significance StatementOrganisms as diverse as honeybees and humans pick up on probabilities in the world around them. People implicitly learn the likelihood of a color, price range, or even syntactic structure. How does statistical learning affect how we detect events and make decisions, especially when probabilities are completely irrelevant to the task at hand, and can change without warning? We find that people learn and track changes in perceptual probabilities irrelevant to a task and that this learning drives dynamic shifts in perception characterized by graded effects of enhancement – and primarily – suppression across acoustic frequency. This can result in a remarkably long- lived ’statistical deafening’ that seems maladaptive but may instead reflect use of likelihood to guide and sharpen perception.
b¯c
susceptibilities from fully relativistic lattice QCD
Authors: Harrison Judd 
Published: September 2024

We compute the h¯c (pseudo)scalar, (axial-)vector and (axial-)tensor susceptibilities as a function of u=mc/mh between u=mc/mb and u=0.8 using fully relativistic lattice QCD, employing nonperturbative current renormalization and using the second generation 2+1+1 MILC HISQ gluon field configurations. We include ensembles with a≈0.09, 0.06, 0.045, and 0.033 fm and we are able to reach the physical b-quark on the two finest ensembles. At the physical mh=mb point we find m¯b2χ1+=0.720(34)×10−2, m¯b2χ1−=1.161(54)×10−2, χ0−=2.374(33)×10−2, and χ0+=0.609(14)×10−2. Our results for the (pseudo)scalar, vector, and axial vector are compatible with the expected small size of nonperturbative effects at u=mc/mb. We also give the first nonperturbative determination of the tensor susceptibilities, finding m¯b2χT=0.891(44)×10−2 and m¯b2χAT=0.441(33)×10−2. Our value of m¯b2χAT is in good agreement with the O(αs) perturbation theory, while our result for m¯b2χT is in tension with the O(αs) perturbation theory at the level of 2σ. These results will allow for dispersively bounded parametrizations to be employed using lattice inputs for the full set of h→c semileptonic form factors in future calculations, for heavy-quark masses in the range 1.25×mc≤mh≤mb.

Published by the American Physical Society
2024