bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pernicious liaisons: antibiotic-depressed immune response of a livestock micropredator, the common vampire bat (Desmodus rotundus)
Authors: Cabrera-Campos Iván , Flores Rafael Ávila , Rivera-Ruiz David Alfonso , Herrera M. L. Gerardo 
Published: September 2023

AbstractAntibiotics are pharmaceutical products that have the potential to affect the immune performance of wildlife. Wildlife species might incorporate antibiotic residues in their system by feeding on livestock treated with these chemicals. One of the most important interactions of livestock with wildlife is that established with the common vampire bat (Desmodus rotundus). We used vampire bats as an ecologically relevant model to test the effect of antibiotics on wildlife immune response. We tested the effect of clindamycin on the humoral and cellular acquired immune responses of common vampire bats captured in the wild in southern Mexico. We expected that both cellular and humoral acquired immune responses would be negatively affected after bats were exposed to clindamycin for several days. We measured local inflammation and serum immunoglobulin concentration (IgG) after the repeated application of phytohemagglutinin. We expected that antibiotic-exposed bats would present a weaker inflammatory response to a second injection of PHA and that their IgG serum levels did not increase to the same rate after the third PHA injection.Antibiotic-treated vampire bats exhibited weaker inflammatory response to the repeated PHA treatment: induced swelling was ∼30% larger after the second injection than that after the first injection, whereas swelling after the second injection in antibiotic-treated bats was ∼10% lower than after the first injection. There was an increase of IgG serum levels following three consecutive PHA injections but it occurred only in vampires that did not receive the antibiotic: IgG serum levels of control individuals increased ∼90% over pre-injection values, whereas this value was ∼15% lower in vampires treated with antibiotic. Our study adds to previous evidence pointing to the negative effect that exposure to anthropogenic chemicals generates in wildlife capacity to maintain a healthy immune system and warrants further work on the relationship of potential antibiotic-induced changes in gut microbiota and immune response.
X-chromosomal diversity may reflect climate (when considering human expansion from Africa)
Authors: Cenac Zarus 
Published: September 2023

AbstractA decreasing of diversity with increasing distance from Africa has been interpreted as a signal of modern humans having expanded (across the globe) from Africa. Research is consistent with a climatic signal being present in mitochondrial diversity, but not in other genetic diversities (e.g., X-chromosomal) or cranial diversity. Some of that research involved adjusting diversity for distance from Africa, and seeing whether this adjusted diversity is associated with climate. The choice of African location which the distance from Africa is measured from may affect whether adjusted diversity appears to be related to climate. To bypass this potential effect of location, some analyses in the present study featured only populations outside of Africa. Other analyses included African populations. The present study used diversities, distances, and minimum temperatures from beforehand. Autosomal, X-chromosomal, and cranial diversities were adjusted for distance from Africa. Y-chromosomal diversity was adjusted for distance from Asia because previous research suggested that Y-chromosomal microsatellite heterozygosity offers more support to expansion from Asia (than Africa). Whether populations were worldwide or only outside of Africa, adjusted X-chromosomal diversity increased with minimum temperature. Other adjusted diversities were not related to minimum temperature. Perhaps previous research found no indication of a climatic signal in X-chromosomal diversity because of two populations, one of which likely had an atypical adjusted diversity for their minimum temperature. These populations may have led to heteroscedasticity and the climatic signal being obscured.
FGF19 and its analog Aldafermin cooperate with MYC to induce aggressive hepatocarcinogenesis
Authors: Ursic-Bedoya José , Desandré Guillaume , Chavey Carine , Marie Pauline , Polizzi Arnaud , Rivière Benjamin , Guillou Hervé , Assenat Eric , Hibner Urszula , Gregoire Damien 
Published: September 2023

AbstractFGF19 hormone has pleiotropic metabolic functions, notably the modulation of insulin sensitivity, glucose/lipid metabolism and energy homeostasis. On top of its physiological metabolic role, FGF19 has been identified as a potentially targetable oncogenic driver, notably in hepatocellular carcinoma (HCC). Nevertheless, FGF19 remained an attractive candidate for treatment of metabolic disease, prompting the development of analogs uncoupling its metabolic and tumor-promoting activities.Using pre-clinical mice models of somatic mutation driven HCC, we assessed the oncogenicity of FGF19 in combination with frequent HCC tumorigenic alterations: p53 inactivation, CTNNB1 mutation, CCND1 or MYC overexpression. Our data revealed a strong oncogenic cooperation between FGF19 and MYC. Most importantly, we show that this oncogenic synergy is conserved with a FGF19-analog Aldafermin (NGM282), designed to solely mimic the hormone’s metabolic functions. In particular, even a short systemic treatment with recombinant proteins triggered rapid appearance of proliferative foci of MYC-expressing hepatocytes.The fact that FGF19 analog Aldafermin is not fully devoid of the hormone’s oncogenic properties raises concerns in the context of its potential use for patients with damaged, mutation-prone liver.
Converting genetic information to non-equilibrium cellular thermodynamics in enzyme-catalyzed reactions
Authors: Gatenby Robert A. 
Published: September 2023

AbstractLiving systems use genomic information to maintain a stable highly ordered state far from thermodynamic equilibrium but the specific mechanisms and general principles governing the interface of genetics and thermodynamics has not been extensively investigated. Genetic information is quantified in unitless bits termed “Shannon entropy”, which does not directly relate to thermodynamic entropy or energy. Thus, it is unclear how the Shannon entropy of genetic information is converted into thermodynamic work necessary to maintain the non-equilibrium state of living systems. Here we investigate the interface of genetic information and cellular thermodynamics in enzymatic acceleration of a chemical reaction S+E→ES→E+P, where S and E are substrate and enzyme, ES is the enzyme substrate complex and P product. The rate of any intracellular chemical reaction is determined by probability functions at macroscopic (Boltzmann distribution of the reactant kinetic energies governed by temperature) or microscopic (overlap of reactant quantum wave functions) scales - described, respectively, by the Arrhenius and Knudsen equations. That is, the reaction rate, in the absence of a catalyst, is governed by temperature which determines the kinetic energy of the interacting molecules. Genetic information can act upon a when the encoded string of amino acids folds into a 3-deminsional structure that permits a lock/key spatial matching with the reactants. By optimally superposing the reactants’ wave functions, the information in the enzyme increases the reaction rate by up to15 orders of magnitude under isothermal conditions. In turn, the accelerated reaction rate alters the intracellular thermodynamics environment as the products are at lower Gibbs free energy which permits thermodynamic work (Wmax= −ΔG). Mathematically and biologically, the critical event that allows genetic information to produce thermodynamic work is the folding of the amino acid string specified by the gene into a 3-dimensional shape determined by its lowest energy state. Biologically, this allows the amino acid string to bind substrate and place them in an optimal spatial orientation. These key-lock are mathematically characterized by Kullback-Leibler Divergence and the interactions with the reaction channel now represent Fisher Information (the second derivative Kullback-Leibler divergence), which can take on the units of the process to which it is applied. Interestingly, Shannon is typically derived by “coarse graining” Shannon information. Thus, living system, by acting at a quantum level, “fine grain” Shannon information
Entering new circles: Expansion of the LC8/DYNLL1 interactome in the ciliary-centrosomal network through system-driven motif evolution
Authors: Pajkos Mátyás , Szaniszló Tamás , Fülöp Máté , Dosztányi Zsuzsanna 
Published: September 2023

AbstractLC8 is a eukaryotic hub protein that presents a highly conserved interface recognized by short linear motifs (SLiMs) in partner proteins. LC8 was originally associated with the dynein motor complex and was also suggested to promote dimerization of partner proteins. However, the growing list of validated partners with diverse functions suggests that LC8 plays a more general cellular role which is still not fully understood. In this work, we combined computational and experimental approaches in order to gain insights into the LC8 interaction network at the system level. Our machine-learning based pipeline together with functional enrichment analysis revealed that LC8 plays a central role in the ciliary-centrosomal system with several partners involved in various types of ciliopathies. By integrating proteomic data and functional annotations, we identified a high confidence, ciliary-centrosomal specific LC8 partner list of 57 proteins, 15 of which are central to centriole life-cycle organization. Validated binding motifs and the detailed characterization of the interaction with protein OFD1 emphasized the important role of LC8, which was confirmed by confocal microscopy. OFD1, which is a central player in this system, also stood out as an early and highly conserved LC8 partner. However, additional partners showed a more recent evolutionary origin featuring novel proteins as well as novel motifs. Altogether, our results highlight that LC8 plays a major role in the ciliary-centrosomal system and its interaction network underwent a major expansion. This system driven motif evolution contributed to the increased complexity of the organization and regulation of the ciliary-centrosomal system.
Head-related transfer functions of rabbits within the front horizontal plane
Authors: Day Mitchell L. 
Published: September 2023

AbstractThe head-related transfer function (HRTF) is the direction-dependent acoustic filtering by the head that occurs between a source signal in free-field space and the signal at the tympanic membrane. HRTFs contain information on sound source location via interaural differences of their magnitude or phase spectra and via the shapes of their magnitude spectra. The present study characterized HRTFs for source locations in the front horizontal plane for nine rabbits, which are a species commonly used in studies of the central auditory system. HRTF magnitude spectra shared several features across individuals, including a broad spectral peak at 2.6 kHz that increased gain by 12 to 23 dB depending on source azimuth; and a notch at 7.6 kHz and peak at 9.8 kHz visible for most azimuths. Overall, frequencies above 4 kHz were amplified for sources ipsilateral to the ear and progressively attenuated for frontal and contralateral azimuths. The slope of the magnitude spectrum between 3 and 5 kHz was found to be an unambiguous monaural cue for source azimuths ipsilateral to the ear. Average interaural level difference (ILD) between 5 and 16 kHz varied monotonically with azimuth over ±31 dB despite a relatively small head size. Interaural time differences (ITDs) at 0.5 kHz and 1.5 kHz also varied monotonically with azimuth over ±358 μs and ±260 μs, respectively. Remeasurement of HRTFs after pinna removal revealed that the large pinnae of rabbits were responsible for all spectral peaks and notches in magnitude spectra and were the main contribution to high-frequency ILDs, whereas the rest of the head was the main contribution to ITDs and low-frequency ILDs. Lastly, inter-individual differences in magnitude spectra were found to be small enough that deviations of individual HRTFs from an average HRTF were comparable in size to measurement error. Therefore, the average HRTF may be acceptable for use in neural or behavioral studies of rabbits implementing virtual acoustic space when measurement of individualized HRTFs is not possible.
Automated Maternal Behavior during Early life in Rodents (AMBER) pipeline
Authors: Lapp Hannah E. , Salazar Melissa G. , Champagne Frances A. 
Published: September 2023

AbstractMother-infant interactions during the early postnatal period are critical for infant survival and the scaffolding of infant development. Rodent models are used extensively to understand how these early social experiences influence neurobiology across the lifespan. However, methods for measuring postnatal dam-pup interactions typically involve time-consuming manual scoring, vary widely between research groups, and produce low density data that limits downstream analytical applications. To address these methodological issues, we developed the Automated Maternal Behavior during Early life in Rodents (AMBER) pipeline for quantifying home-cage maternal and mother-pup interactions using open-source machine learning tools. DeepLabCut was used to track key points on rat dams (32 points) and individual pups (9 points per pup) in postnatal day 1-10 video recordings. Pose estimation models reached key point test errors of approximately 4.1–10 mm (14.39 pixels) and 3.44-7.87 mm (11.81 pixels) depending on depth of animal in the frame averaged across all key points for dam and pups respectively. Pose estimation data and human-annotated behavior labels from 38 videos were used with Simple Behavioral Analysis (SimBA) to generate behavior classifiers for dam active nursing, passive nursing, nest attendance, licking and grooming, self-directed grooming, eating, and drinking using random forest algorithms. All classifiers had excellent performance on test frames, with F1scores above .886. Performance on hold-out videos remained high for nest attendance (F1=.990), active nursing (F1=.828), and licking and grooming (F1=.766) but was lower for eating, drinking, and self-directed grooming (F1=.534-.554). A set of 242 videos was used with AMBER and produced behavior measures in the expected range from postnatal 1-10 home-cage videos. This pipeline is a major advancement in assessing home-cage dam-pup interactions in a way that reduces experimenter burden while increasing reproducibility, reliability, and detail of data for use in developmental studies without the need for special housing systems or proprietary software.
The hydrogen sulfide donor sodium thiosulfate limits inflammation but aggravate smooth muscle cells apoptosis and aneurysm progression in a mouse model of abdominal aortic aneurysm
Authors: Bechelli Clémence , Macabrey Diane , Caloz Florian , Urfer Severine , Lambelet Martine , Allagnat Florent , Déglise Sébastien 
Published: September 2023

AbstractIntroThe prevalence of abdominal aortic aneurysm (AAA) is constantly progressing with the aging of the global population. AAA rupture has a devastating 80% mortality rate and there is no treatment to slow-down AAA progression. Hydrogen sulfide (H2S) is a ubiquitous redox-modifying gasotransmitter produced in the cardiovascular system via the reverse trans-sulfuration pathway by cystathionine γ-lyase (CSE). H2S has protective properties on the cardiovascular system, including anti-inflammatory and antioxidant effects. Here, we hypothesized that sodium thiosulfate (STS), a clinically relevant source of H2S, would limit AAA growth.Methods8-12 weeks old male WT or Cse-/-mice on a C57BL/6J genetic background were submitted to a model of AAA by topical elastase application on the abdominal aorta and β-aminopropionitrile fumarate treatment in the drinking water for 2 weeks post-op. Sodium thiosulfate (STS) was given via the drinking water post-op until aorta collection.In vitroexperiments were conducted to assess the effect of STS and pro-inflammatory cytokines interleukin-1 β and 6 and tumor necrosis factor α on primary human vascular smooth muscle cell (VSMC).ResultsSurprisingly, STS increased elastin degradation, AAA size and rupture, despite reducing infiltration of macrophages, antigen-presenting cells and lymphocytes in WT mice. Conversely, Cse-/-mice with impaired H2S production developed smaller AAA than WT mice despite increased infiltration of immune cells. STS reduced VSMC coverage, possibly lowered VSMC proliferation, and promoted VSMC loss and extracellular matrix (ECM) breakdown. In vitro, STS aggravated pro-inflammatory cytokine-induced VSMCs apoptosis.ConclusionSTS has a paradoxical effect on AAA growth, reducing inflammation while simultaneously impeding favorable vascular remodeling, resulting in bigger AAA in a model of periadventitial elastase. This study identifies a negative effect of H2S on VSMC in this environment, highlighting the complex role of H2S in AAA progression. The deleterious effect of STS on AAA progression is significant, especially given the growing use of STS in clinical settings for various indications.
Amyloids “at the border”: deep mutagenesis and random sequence extension reveal an incomplete amyloid-forming motif in Bri2 that turns amyloidogenic upon C-terminal extension
Authors: Martín Mariano , Bolognesi Benedetta 
Published: September 2023

AbstractStop-loss mutations cause over twenty different diseases. The effects of stop-loss mutations can have multiple consequences that are, however, hard to predict. Stop-loss inITM2B/BRI2results in C-terminal extension of the encoded protein and, upon furin cleavage, in the production of two 34 amino acid long peptides, ADan and ABri, that accumulate as amyloids in the brains of patients affected by familial Danish and British Dementia. To systematically explore the consequences of Bri2 C-terminal extension, here, we measure amyloid formation for 676 ADan substitutions and identify the region that forms the putative amyloid core of ADan fibrils, located between positions 20 and 26, where stop-loss occurs. Moreover, we measure amyloid formation for ∼18,000 random C-terminal extensions of Bri2 and find that ∼32% of these sequences can nucleate amyloids. We find that the amino acid composition of these nucleating sequences varies with peptide length and that short extensions of 2 specific amino acids (Aliphatics, Aromatics and Cysteines) are sufficient to generate novel amyloid cores. Overall, our results show that the C-terminus of Bri2 contains an incomplete amyloid motif that can turn amyloidogenic upon extension. C-terminal extension with de novo formation of amyloid motifs may thus be a widespread pathogenic mechanism resulting from stop-loss, highlighting the importance of determining the impact of these mutations for other sequences across the genome.
Why are spontaneous bio photons observed only in living organisms? The key role of the proton current in ultra-weak photon emission
Authors: Langer Jerzy J. , Langer Marcin 
Published: September 2023

AbstractLight emission from living things is still at the centre of scientific interest. Ultra-weak photon emission (UPE) in the range from 300 to 900 nm has been discovered in living cells and organisms, including the human body1. In general, so-called bio photons are attributed to life.Our recent studies on protonic p-n junction formation and light emission from electrically powered protonic p-n junction systems suggest, that UPE can be generated by excitations owing to proton current flow in living cells and sub-cellular structures (e.g. mitochondria), just like it is done in the case of laboratory protonic light-emitting diodes (H+LED)2,3.While the emission of higher energy bio photons (above 3 eV, 200-420 nm wavelength) is mainly caused by radicals and reactive oxygen species (ROS)1, 21, 32, 36, 37, 38, lower energy bio photons (below 3 eV, at 420 -1000 nm wavelength) should be associated with the excitation of the protonic system as a result of the flow of the proton current (discussed in this paper). We expect this to have important biomedical implications for diagnosis and therapy using UPE36, 37. The similarity of H+LED and UPE spectra (Fig. 2) allows the use of protonic H+LED as a new broadband light source, ideally suited to mitochondria-oriented low-intensity light therapy37.Our results explain why spontaneous biophotons (UPE) are observed only in living organisms, tissues and cells21. This is due to the constant flow of protons in the active ATP synthase/ATPase23and in the mitochondria in general25-28, which is necessary both for life and for the emission of light (observed as bio photons).
The interferon/STAT1 signaling axis is a common feature of tumor-initiating cells in breast cancer
Authors: Souto Eric P. , Gong Ping , Landua John D. , Srinivasan R. Rajaram , Ganesan Abhinaya , Dobrolecki Lacey E. , Purdy Stephen C. , Pan Xingxin , Zeosky Michael , Chung Anna , Yi S. Stephen , Ford Heide L. , Lewis Michael T. 
Published: September 2023

ABSTRACTA tumor cell subpopulation of tumor-initiating cells (TIC), or “cancer stem cells”, are associated with therapeutic resistance, as well as both local and distant recurrence. Enriched populations of TIC are identified by markers including aldehyde dehydrogenase (ALDH1) activity, the cell surface marker combination CD44+/CD24−, or fluorescent reporters for signaling pathways that regulate TIC function. We showed previously thatSignalTransducer andActivator ofTranscription (STAT)-mediated transcription allows enrichment for TIC in claudin-low models of human triple-negative breast cancer using a STAT-responsive reporter. However, the molecular phenotypes of STAT TIC are not well understood, and there is no existing method to lineage-trace TIC as they undergo cell state changes. Using anewSTAT-responsive lineage-tracing (LT) system in conjunction with our original reporter, we enriched for cells with enhanced mammosphere-forming potential in some, but not all, basal-like triple-negative breast cancer (TNBC) xenograft models (TNBC) indicating TIC-related and TIC-independent functions for STAT signaling. Single-cell RNA sequencing (scRNAseq) of reporter-tagged xenografts and clinical samples identified a common interferon (IFN)/STAT1-associated transcriptional state, previously linked to inflammation and macrophage differentiation, in TIC. Surprisingly, most of the genes we identified are not present in previously published TIC signatures derived using bulk RNA sequencing. Finally, we demonstrated that bone marrow stromal cell antigen 2 (BST2), is a cell surface marker of this state, and that it functionally regulates TIC frequency. These results suggest TIC may exploit the IFN/STAT1 signaling axis to promote their activity, and that targeting this pathway may help eliminate TIC.SignificanceTIC differentially express interferon response genes, which were not previously reported in bulk RNA sequencing-derived TIC signatures, highlighting the importance of coupling single-cell transcriptomics with enrichment to derive TIC signatures.