bluuebunny/crossref_metadata_2025 huggingface dataset:
Differentiation and migration of hematopoietic stem and progenitor cells cross multiple tissues
Authors: Yu Shiya , Li Hui , Wang Xuefei , Chen Guanming , Huang Hongwen , Hong Ni , Song You-Qiang , Zhang Xuegong , Jin Wenfei
Published: September 2023

Hematopoiesis requires the coordinated differentiation of hematopoietic stem cells and progenitor cells (HSPCs) in multiple tissues. Although differentiation of HSPCs in bone marrow (BM) has been well-studied, our knowledge about the migration and differentiation of HSPCs cross tissues is limited. Here, we collected and integrated single-cell RNA-seq data of human CD34+ cells, which represent HSPCs, from BM, peripheral blood (PB), thymus and mobilized PB (mPB), to investigate the hematopoiesis cross tissues. We constructed a cell atlas of HSPCs cross tissues and found most HSPC subsets in BM had counterparts in PB, indicating migration of HSPCs from BM to PB has a much broad spectrum. We found B progenitors highly expressedCXCR4for anchoring in BM, while cells with low expression ofCXCR4facilitate their migration out of BM. Among the HSPC subsets from thymus, we only found the counterparts of the earliest thymic progenitors (ETPs) in BM and PB, potentially indicating that ETPs were the subsets that migrated from BM to PB and thymus. We found interaction signaling includingCD99-CD99,CXCL12-CXCR4andCCL19-CCR7played important roles in ETP homing to thymus. Briefly, these data provided a single unified developmental spectrum of hematopoiesis cross different tissues, connected by cell migration.
Assessing the environmental impacts of conventional and organic scenarios of rainbow trout farming in France
Authors: Pouil Simon , Besson Mathieu , Phocas Florence , Aubin Joël
Published: September 2023

In France, rainbow trout (Oncorhynchus mykiss) farming traditionally used flow-through systems, which raised concerns about environmental impacts, including limited freshwater availability, and the use of ingredients from intensive agriculture and fishing. To address the growing demand for sustainable food products, there is an increasing interest in organic aquaculture. In this study, we employed an attributional life cycle assessment (LCA) to analyse the environmental impacts of rainbow trout production. We simulated conventional and organic production practices in a hypothetical fish farm to evaluate the differences in environmental impacts at the farm level. The potential impacts were calculated using a product-based functional unit (one tonne of trout) under the two production scenarios and were also expressed using a surface-based functional unit (m2y). Our life cycle impact assessment revealed that organic farming significantly reduced environmental impacts per tonne of trout in seven out of the nine selected impact categories. Notably, freshwater ecotoxicity exhibited the greatest difference, with organic systems showing a 55% decrease. The only exceptions were freshwater eutrophication and water dependence, where organic production led to higher impacts per tonne of trout. In conventional farming, emissions amounted to 14 kg of P eq./tonne, whereas in organic farming, the emissions were slightly higher (15 kg of P eq./tonne). For water dependence, one tonne of trout production in the conventional system mobilized 128 103m3vs. 185 103m3in the organic system. The environmental benefits of organic production were even more marked when using a surface-based functional unit (m2y). We demonstrated the benefits of organic trout production from an environmental perspective. However, our findings highlight the caution needed when interpreting LCA comparisons of such production systems that can be highly influenced by methodological choices such as the functional unit used.
Rendering protein mutation movies with MutAmore
Authors: Weissenow Konstantin , Rost Burkhard
Published: September 2023

The success ofAlphaFold2in reliable protein three-dimensional (3D) structure prediction, assists the move of structural biology toward studies of protein dynamics and mutational impact on structure and function. This transition needs tools that qualitatively assess alternative 3D conformations. We introduceMutAmore, a bioinformatics tool that renders individual images of protein 3D structures for, e.g., sequence mutations into a visually intuitive movie format.MutAmorestreamlines a pipeline casting single amino-acid variations (SAVs) into a dynamic 3D mutation movie providing a qualitative perspective on the mutational landscape of a protein. By default, the tool first generates all possible variants of the sequence reachable through SAVs (L*19 for proteins with L residues). Next, it predicts the structural conformation for all L*19 variants using state-of-the-art models. Finally, it visualizes the mutation matrix and produces a color-coded 3D animation. Alternatively, users can input other types of variants, e.g., from experimental structures.MutAmoresamples alternative protein configurations to study the dynamical space accessible from SAVs in the post-AlphaFold2 era of structural biology. As the field shifts towards the exploration of alternative conformations of proteins,MutAmoreaids in the understanding of the structural impact of mutations by providing a flexible pipeline for the generation of protein mutation movies using current and future structure prediction models.
Widespread position-dependent transcriptional regulatory sequences in plants
Authors: Voichek Yoav , Hristova Gabriela , Mollá-Morales Almudena , Weigel Detlef , Nordborg Magnus
Published: September 2023

Much of what we know about eukaryotic transcription stems from animals and yeast, however, plants have evolved separately for 1.6 billion years, leaving ample time for divergence in transcriptional regulation. Here, we set out to elucidate fundamental properties of cis-regulatory sequences in plants. Using massively parallel reporter assays across four plant species, we demonstrate the central role of sequences downstream of the transcription start site (TSS) in transcriptional regulation. Unlike animal enhancers that are position-independent, plant regulatory elements depend on their position, as altering their location relative to the TSS significantly affects transcription. We highlight the importance of the region downstream of the TSS in regulating transcription by identifying a DNA motif that is conserved across vascular plants and is sufficient to enhance gene expression in a dose-dependent manner. The identification of a large number of position-dependent enhancers points to fundamental differences in gene regulation between plants and animals.
The evolution of transposable elements inBrachypodium distachyonis governed by purifying selection, while neutral and adaptive processes play a minor role
Authors: Horvath Robert , Minadakis Nikolaos , Bourgeois Yann , Roulin Anne C.
Published: September 2023

Understanding how plants adapt to changing environments and the potential contribution of transposable elements (TEs) to this process is a key question in evolutionary genomics. While TEs have recently been put forward as active players in the context of adaptation, few studies have thoroughly investigated their precise role in plant evolution. Here we used the wild Mediterranean grassBrachypodium distachyonas a model species to identify and quantify the forces acting on TEs during the adaptation of this species to various conditions, across its entire geographic range. Using sequencing data from more than 320 naturalB. distachyonaccessions and a suite of population genomics approaches, we reveal that putatively adaptive TE polymorphisms are rare in wildB. distachyonpopulations. After accounting for changes in past TE activity, we show that only a small proportion of TE polymorphisms evolved neutrally (< 10%), while the vast majority of them are under moderate purifying selection regardless of their distance to genes. TE polymorphisms should not be ignored when conducting evolutionary studies, as they can be linked to adaptation. However, our study clearly shows that while they have a large potential to cause phenotypic variation inB. distachyon, they are not favored during evolution and adaptation over other types of mutations (such as point mutations) in this species.
Ultrastructural localization of calcium homeostasis modulator 1 in the taste buds of mouse circumvallate papillae
Authors: Ikuta Rio , Kakinohana Yuu , Hamada Shun
Published: September 2023

Taste receptor cells are morphologically classified as types II and III. These two types of cells transduce different taste modalities and form morphologically distinct synapses with afferent nerve fibers. Type III cells form conventional chemical synapses, whereas type II cells form a unique type of synapses referred to as channel synapses, which release adenosine triphosphate (ATP) as a neurotransmitter through voltage-gated channels comprising calcium homeostasis modulator (CALHM) 1 and CALHM3. Further, channel synapses are associated with large mitochondria with tubular cristae known as atypical mitochondria, which are believed to produce ATP for neurotransmission. Herein, we aimed to generate a monoclonal antibody against CALHM1 and examine its localization in taste buds using immunoelectron microscopy. CALHM1 was detected along the plasma membrane apposed to atypical mitochondria, indicating that CALHM1 is localized at the presynaptic membrane of channel synapses. Additionally, CALHM1 was detected along the plasma membrane lined by subsurface cisternae at sites apposed to afferent nerve fibers.
Autoturbo-DNA: Turbo-Autoencoders for the DNA data storage channel
Authors: Welzel Marius , Dreßler Hagen , Heider Dominik
Published: September 2023

DNA, with its high storage density and long-term stability, is a potential candidate for a next-generation storage device. The DNA data storage channel, comprised of synthesis, amplification, storage, and sequencing, exhibits error probabilities and error profiles specific to the components of the channel. Here, we present Autoturbo-DNA, a PyTorch framework for training error-correcting, overcomplete autoencoders specifically tailored for the DNA data storage channel. It allows training different architecture combinations and using a wide variety of channel component models for noise generation during training. It further supports training the encoder to generate DNA sequences that adhere to user-defined constraints.
Multifunctional evolution of palm squirrel coat colour and pattern
Authors: Nivetha M , D’Souza Senan , Shijisha AC , Ligon Russell A. , Nandini R
Published: September 2023

Complex colour pattern traits often evolve in response to multiple selective pressures, emphasizing the need for their investigation in an integrative framework. We use museum specimens (n=718) to study the evolution of coat colouration in three palm squirrel species (Funambulusspp.) in the Indian subcontinent, with climate, vegetation, and predators as the potential selective forces. Our results indicate a strong geographical trend in coat colour distribution within and across species, with darker individuals in the southern and lighter individuals in the northern regions. We find significant darkening of coat colouration in more humid, densely vegetated regions with dark soils. Fine-scale intra-specific analyses suggest that species respond differently to multiple abiotic selective pressures. Investigation of stripe pattern elements suggests that the colour-based elements are more visible to raptors, while luminance-based elements are more visible to ferrets. We also find that squirrel species are darker in areas with denser and taller canopies, with low-contrast stripes specific to each predator’s vision. Overall, squirrel coat colouration evolves in response to multiple abiotic factors, including climate and habitat, and specific stripe elements provide particular visual effects on predators depending on the habitat.
Forsythoside A blocks the infection of Avian Infectious Bronchitis Virus through binding S1 subunit
Authors: Shen Ruiting , Liu Xuewei , Yin Peng , Li Xu , Chu Jun , Yao Hua , Hou Xiaolin
Published: September 2023

Avian infectious bronchitis (IB) is an acute highly contagious respiratory infectious disease caused by avian infectious bronchitis virus (IBV), causing serious economic losses to poultry industry. Forsythiaside A (FTA) is a phenylethanol glycoside compound in the fruit ofForsythia suspensa, which is widely used for inflammatory respiratory tract disease, including viral infected inflammation. In this study, the mechanism of FTA against IBV was researched. To determine the inhibitory effect of FTA on IBV infection and the interaction between FTA and IBV particles, immunofluorescence assay, plaque assay, RT-qPCR and enzyme-linked immunosorbent assay (ELISA) were performed and it was discovered that FTA inhibited IBV infection and viral attachment to host receptor under non-cytotoxic concentrations, and FTA may bind to virus particles. Then ELISA and isothermal titration calorimetry (ITC) were employed to further study the interaction between FTA and S protein. The results indicated that FTA bound to S1 subunit rather S2 subunit. Besides, the molecular docking showed that FTA form hydrogen bonds with eight amino acids in the S1 subunit. When these amino acids were mutated. the affinity disappeared between the S1 mutant and FTA. In conclusion, FTA prevents IBV infection by blocking viral attachment and contacts with the S1, but not the S2 subunit of IBV. At last, the bind sites were identified by comparing the affinity of wild S1 and mutant S1.
Accurate Bayesian inference of sex chromosome karyotypes and sex-linked scaffolds from low-depth sequencing data
Authors: Caduff Madleina , Eckel Raphael , Leuenberger Christoph , Wegmann Daniel
Published: September 2023

1

The identification of sex-linked scaffolds and the genetic sex of individuals, i.e. their sex karyotype, is a fundamental step in population genomic studies. If sex-linked scaffolds are known, single individuals may be sexed based on read counts of next-generation sequencing data. If both sex-linked scaffolds as well as sex karyotypes are unknown, as is often the case for non-model organisms, they have to be jointly inferred. For both cases, current methods rely on arbitrary thresholds, which limits their power for low-depth data. In addition, most current methods are limited to euploid sex karyotypes (XX and XY). Here we developBeXY, a fully Bayesian method to jointly infer the posterior probabilities for each scaffold to be autosomal, X-or Y-linked and for each individual to be any of the sex karyotypes XX, XY, X0, XXX, XXY, XYY and XXYY. If the sex-linked scaffolds are known, it also identifies autosomal trisomies and estimates the sex karyotype posterior probabilities for single individuals. As we show with downsampling experiments,BeXYhas higher power than all existing methods. It accurately infers the sex karyotype of ancient human samples with as few as 20,000 reads and accurately infers sex-linked scaffolds from data sets of just a handful of samples or with highly imbalanced sex ratios, also in the case of low-quality reference assemblies. We illustrate the power ofBeXYby applying it to both whole-genome shotgun and target enrichment sequencing data of ancient and modern humans, as well as several non-model organisms.
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

Antibiotics 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.
Community metabolic modeling of host-microbiota interactions through multi-objective optimization
Authors: Lambert Anna , Budinich Marko , Mahé Maxime , Chaffron Samuel , Eveillard Damien
Published: September 2023

The human gut microbiota comprises various microorganisms engaged in intricate interactions among themselves and with the host, affecting its health. While advancements in omics technologies have led to the inference of clear associations between microbiome composition and health conditions, we usually lack a causal and mechanistic understanding of these associations. For modeling mechanisms driving the interactions, we simulated the organism’s metabolism usingin silicoGenome-Scale Metabolic Models (GEMs). We used multi-objective optimization to predict and explain metabolic interactions among gut microbes and an intestinal epithelial cell. We developed a score integrating model simulation results to predict the type (competition, neutralism, mutualism) and quantify the interaction between several organisms. This framework uncovered a potential cross-feeding for choline, explaining the predicted mutualism betweenLactobacillus rhamnosusGG and the epithelial cell. Finally, we analyzed a five-organism ecosystem, revealing that a minimal microbiota can favor the epithelial cell’s maintenance.
X-chromosomal diversity may reflect climate (when considering human expansion from Africa)
Authors: Cenac Zarus
Published: September 2023

A 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

FGF19 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

Living 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

LC8 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

The 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

Mother-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

Intro

The 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.

Methods

8-12 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).

Results

Surprisingly, 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.

Conclusion

STS 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

Stop-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

Light 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

A 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.

Significance

TIC 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.
Structure-Activity Relationship Studies of Novel Gut-derived Lantibiotics Against Human Gut Commensals
Authors: Zhang Zhenrun J. , Wu Chunyu , Dorantes Darian , Pappas Téa , Sundararajan Anitha , Lin Huaiying , Pamer Eric G. , van der Donk Wilfred A.
Published: September 2023

Recent advances in sequencing techniques unveiled the vast potential of ribosomally synthesized and post-translationally modified peptides (RiPPs) encoded in microbiomes. Class I lantibiotics such as nisin A, widely used as a food preservative, have been investigated for their efficacy in killing pathogens. However, the impact of nisin and nisin-like class I lantibiotics on commensal bacteria residing in the human gut remains unclear. Here, we report six gut-derived class I lantibiotics that are close homologs of nisin, four of which are novel. We applied an improved lantibiotic expression platform to produce and purify these lantibiotics for antimicrobial assays. We determined their minimal inhibitory concentration (MIC) against both Gram-positive human pathogens and gut commensals, and profiled the lantibiotic resistance genes in these pathogens and commensals. SAR studies with variants revealed key regions and residues that impact their antimicrobial properties. Our characterization and SAR studies of nisin-like lantibiotics against both pathogens and human gut commensals could shed light on the future development of lantibiotic-based therapeutics and food preservatives.
The association between cortical gyrification and sleep in adolescents and young adults
Authors: Santos João Paulo Lima , Hayes Rebecca , Franzen Peter L. , Goldstein Tina R. , Hasler Brant P. , Buysse Daniel J. , Siegle Greg J. , Dahl Ronald E. , Forbes Erika E. , Ladouceur Cecile D. , McMakin Dana L. , Ryan Neal D. , Silk Jennifer S. , Jalbrzikowski Maria , Soehner Adriane M
Published: September 2023

Study objectives

Healthy sleep is important for adolescent neurodevelopment, and relationships between brain structure and sleep can vary in strength over this maturational window. Although cortical gyrification is increasingly considered a useful index for understanding cognitive and emotional outcomes in adolescence, and sleep is also a strong predictor of such outcomes, we know relatively little about associations between cortical gyrification and sleep.

Methods

Using Local gyrification index (lGI) of 34 bilateral brain regions and regularized regression for feature selection, we examined gyrification-sleep relationships in the Neuroimaging and Pediatric Sleep databank (252 participants; 9-26 years; 58.3% female) and identified developmentally invariant (stable across age) or developmentally specific (observed only during discrete age intervals) brain-sleep associations. Naturalistic sleep characteristics (duration, timing, continuity, and regularity) were estimated from wrist actigraphy.

Results

For most brain regions, greater lGI was associated with longer sleep duration, earlier sleep timing, lower variability in sleep regularity, and shorter time awake after sleep onset. lGI in frontoparietal network regions showed associations with sleep patterns that were stable across age. However, in default mode network regions, lGI was only associated with sleep patterns from late childhood through early-to-mid adolescence, a period of vulnerability for mental health disorders.

Conclusions

We detected both developmentally invariant and developmentally specific ties between local gyrification and naturalistic sleep patterns. Default mode network regions may be particularly susceptible to interventions promoting more optimal sleep during childhood and adolescence.
Mechanistic Regulation of Planarian Shape During Growth and Degrowth
Authors: Ko Jason M. , Reginato Waverly , Lobo Daniel
Published: September 2023

Adult planarians can grow when fed and degrow (shrink) when starved while maintaining their whole-body shape with correct proportions. Different planarian morphogens are expressed at the anterior-posterior poles, medio-lateral border, and midline to provide positional information signals for the specification of different tissues at the right locations. However, it is currently unknown how these signals are coordinated together during feeding or starvation and how they modulate the differential tissue growth or degrowth necessary to form correct whole-body shapes. Here we investigate the dynamics of planarian shape during growth and degrowth together with a theoretical study to evaluate the mechanisms that regulate whole-body proportions and shape. We found that the planarian body proportions scale isometrically following similar linear rates during growth and degrowth, but that fed worms are significantly wider than starved worms. By combining a descriptive model of planarian shape and size with a mechanistic model of anterior-posterior and medio-lateral signaling calibrated with a novel machine learning methodology, we demonstrate that the feedback loop between these positional information signals and the shape they control can regulate the planarian whole-body shape during growth. Furthermore, the model can predict the correct shape and size dynamics during degrowth due to an increase in apoptosis rate and pole signal during starvation. These results offer mechanistic insights into planarian shape and size dynamics and the regulation of whole-body morphologies.
Mapping the interaction sites of Influenza A viruses and human complement Factor H
Authors: Rabeeah Iman , Billington Elizabeth , Nal-Rogier Beatrice , Sadeyen Jean-Remy , Pathan Ansar , Iqbal Munir , Temperton Nigel , Zipfel Peter F. , Skerka Christine , Kishore Uday , Shelton Holly
Published: September 2023

The complement system is an innate immune mechanism against microbial infection. It involves a cascade of effector molecules that is activated via classical, lectin and alternative pathways. Consequently, many pathogens bind to or incorporate in their structures host negative regulators of the complement pathways as an evasion mechanism. Factor H (FH) is a negative regulator of the complement alternative pathway that protects “self” cells of the host from non-specific complement attack. Viruses including human influenza A viruses (IAVs) have been shown to bind to FH. Here we show that IAVs of both human and avian origin can bind directly to human FH and the interaction is mediated via the IAV surface glycoprotein haemagglutinin (HA). HA bound to common pathogen binding footprints on the FH structure, complement control protein modules, CCP 5-7 and CCP 15-20. The FH binding to H1 and H3 showed that the interaction overlapped with the receptor binding site of both HAs but the footprint was more extensive for the H3 HA than the H1 HA. The HA - FH interaction impeded the initial entry of H1N1 and H3N2 IAV strains but its impact on viral multicycle replication in human lung cells was strain specific. The H3N2 virus binding to cells was significantly inhibited by preincubation with FH, whereas there was no alteration in replicative rate and progeny virus release for human H1N1 or avian H9N2 and H5N3 IAV strains. We have mapped the interaction between IAV and FH, the significance of which for the virus or host is yet to be elucidated.