bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activity of estrogen receptor beta expressing neurons in the medial amygdala regulates preference towards receptive females in male mice
Authors: Takenawa Satoshi , Nagasawa Yutaro , Go Kim , Chérasse Yoan , Mizuno Seiya , Sano Kazuhiro , Ogawa Sonoko 
Published: March 2023

AbstractThe processing of information regarding the sex and reproductive state of conspecific individuals is critical for successful reproduction and survival in males. Generally, male mice exhibit a preference towards sexually receptive (RF) over non-receptive females (XF) or gonadally intact males (IM). Previous studies suggested the involvement of estrogen receptor beta (ERβ) expressed in the medial amygdala (MeA) in male preference towards RF. To further delineate the role played by ERβ in the MeA in the neuronal network regulating male preference, we developed a new ERβ-iCre mouse line using the CRISPR-Cas9 system. Fiber-photometry Ca2+imaging revealed that ERβ expressing neurons in the postero-dorsal part of the MeA (MeApd-ERβ+neurons) were more active during social investigation towards RF compared to copresented XF or IM mice in a preference test. Chemogenetic inhibition of MeApd-ERβ+neuronal activity abolished a preference to RF in “RF vs. XF”, but not “RF vs. IM”, tests. Analysis with cre-dependent retrograde tracing viral vectors identified the principal part of the bed nucleus of stria terminalis (BNSTp) as a primary projection site of MeApd-ERβ+neurons. Fiber-photometry recording in the BNSTp during a preference test revealed that chemogenetic inhibition of MeApd-ERβ+neurons abolished differential neuronal activity of BNSTp cells as well as a preference to RF against XF but not against IM mice. Collectively, these findings demonstrate for the first time that MeApd-ERβ+neuronal activity is required for expression of receptivity-based preference (i.e., RF vs XF) but not sex-based preference (i.e., RF vs IM) in male mice.Significance StatementIn this study, by introducing a new Cre mice line for ERβ+cells, we described the function of MeApd-ERβ+neurons and characteristics of their neuronal activity during preference tests. Using fiber photometry and DREADD techniques we have found MeApd-ERβ+neurons have a specific role in receptivity-based (receptive female vs. non-receptive female) preference but not in sexbased (receptive female vs. intact male) preference in male mice. We have also described this specific role of MeApd-ERβ+neurons is achieved by regulating the neuronal activity of downstream BNSTp neurons during receptivity-based, but not sex-based, preference tests. Our findings contribute to a better understating of the function of estrogen receptor expressing neurons in the neuronal network for the male-typical reproductive behaviors.
Production of 130 diterpenoids by combinatorial biosynthesis in yeast
Authors: Bathe Ulschan , Schmidt Jürgen , Frolov Andrej , Soboleva Alena , Frank Oliver , Dawid Corinna , Tissier Alain 
Published: March 2023

AbstractDiterpenoids form a diverse group of natural products, many of which are or could become pharmaceuticals or industrial chemicals. However, low concentration, presence in complex mixtures and challenging synthesis often limit their exploitation. The modular character of diterpene biosynthesis and the substrate flexibility of the enzymes involved make combinatorial biosynthesis a promising approach. Here, we report on the assembly in yeast of 130 diterpenoids by pairwise combinations of ten diterpene synthases producing (+)-copalyl diphosphate-derived backbones and four cytochrome P450 enzymes (CYPs); 80 of these diterpenoids have not yet been reported. The CYPs accepted the majority of substrates they were given but remained regioselective. Our results bode well for the systematic exploration of diterpenoid chemical space using combinatorial assembly in yeast.
Predicting future conservation areas while avoiding competition in two alpine urodele amphibians severely threatened by climate change
Authors: Dubos Nicolas , Havard Antoine , Crottini Angelica , Seglie Daniele , Andreone Franco 
Published: March 2023

AbstractClimate change will cause important declines in species distributions, especially when living at high altitudes. The Critically EndangeredSalamandra lanzaifrom SW Alps may be severely exposed to future climate change effects and its suitable climate may shrink or shift. Another Alpine salamander (S. atra) is present in the region, which in case of spatial overlap may represent a competitor forS. lanzai. It is urgent to estimate the effect of future climate change on these species and identify priority areas for conservation while accounting for competition between both species. With a Species Distribution Modelling (SDM) approach, we projected the current and future climate suitability of both salamander species. We accounted for uncertainty related to the methods (model replicates) and climate projections (data source, global circulation model and scenario) to provide a consensus map for practitioners. This map also takes into account potential competition withS. atraby penalizing the suitability scores of S.lanzaiby the scores ofS. atra. We predict a severe effect of climate change on both species. Most of the current habitats are projected to become largely unsuitable by 2070, regardless of the climatology and scenario. We identified important spatial disagreements between projections based on different data sources, mostly due to precipitation projections and daily temperature variation. This highlights the need to account for multiple climatologies in mountainous environments. Both species’ habitats are highly fragmented, which is expected to prevent distributional shifts through natural dispersion. We suggest to explore the possibility of translocation for the most threatened populations and simultaneously develop captive breeding programs. Biotic interactions are rarely accounted for in SDMs, and we encourage the documentation of species with similar ecological requirements to improve the relevance of SDMs for future conservation planning.
The best of two worlds: Decoding and source-reconstructing M/EEG oscillatory activity with a unique model
Authors: Westner Britta U. , King Jean-Rémi 
Published: March 2023

AbstractThe application of decoding models to electrophysiological data has become standard practice in neuroscience. The use of such methods on sensor space data can, however, limit the interpretability of the results, since brain sources cannot be readily estimated from the decoding of sensor space responses. Here, we propose a new method that combines the common spatial patterns (CSP) algorithm with beamformer source reconstruction for the decoding of oscillatory activity. We compare this method to sensor and source space decoding and show that it performs equally well as source space decoding with respect to both decoding accuracy and source localization without the extensive computational cost. We confirm our simulation results on a real MEG data set. In conclusion, our proposed method performs as good as source space decoding, is highly interpretable in the spatial domain, and has low computational cost.
Wandering albatrosses exert high take-off effort only when both wind and waves are gentle
Authors: Uesaka Leo , Goto Yusuke , Naruoka Masaru , Weimerskirch Henri , Sato Katsufumi , Sakamoto Kentaro Q. 
Published: March 2023

AbstractThe relationship between the environment and marine animal small-scale behavior is not fully understood. This is largely due to the difficulty in obtaining environmental datasets with a high spatiotemporal precision. The problem is particularly pertinent in assessing the influence of environmental factors in rapid, high energy consuming behavior such as seabird take-off. To fill the gaps in the existing environmental datasets, we employed novel techniques using animal-borne sensors with motion records to estimate wind and ocean wave parameters and evaluated their influence on wandering albatross take-off patterns. Measurements revealed that wind speed and wave heights experienced by wandering albatrosses during take-off ranged from 0.7 ∼ 15.4 m/s and 1.6 ∼ 6.4 m, respectively. The four indices measured (flapping number, frequency, sea surface running speed, and duration) also varied with the environmental conditions (e.g., flapping number varied from 0 to over 20). Importantly, take-off was easier under higher wave conditions than under lower wave conditions at a constant wind speed, and take-off effort increased only when both wind and waves were gentle. Our data suggests that both ocean waves and winds play important roles for albatross take-off and advances our current understanding of albatross flight mechanisms.Impact statementWind and ocean wave conditions experienced by albatrosses were estimated using an animal-borne recorder and revealed that take-off was easier under higher wave conditions.
Shifting the selectivity of pyrido[2,3-d]pyrimidin-7(8H)-one inhibitors towards the salt-inducible kinase (SIK) subfamily
Authors: Rak Marcel , Tesch Roberta , Berger Lena M. , Shevchenko Ekaterina , Raab Monika , Tjaden Amelie , Zhubi Rezart , Balourdas Dimitrios-Ilias , Joerger Andreas C. , Poso Antti , Krämer Andreas , Elson Lewis , Lučić Aleksandar , Kronenberger Thales , Hanke Thomas , Strebhardt Klaus , Sanhaji Mourad , Knapp Stefan 
Published: March 2023

ABSTRACTSalt-inducible kinases 1-3 (SIK1-3) are key regulators of the LKB1-AMPK pathway and play an important role in cellular homeostasis. Dysregulation of any of the three isoforms has been associated with tumorigenesis in liver, breast, and ovarian cancers. We have recently developed the dual pan-SIK/group I p21-activated kinase (PAK) chemical probe MRIA9. However, inhibition of p21-activated kinases has been associated with cardiotoxicityin vivo, which complicates the use of MRIA9 as a tool compound. Here, we present a structure-based approach involving the back-pocket and gatekeeper residues, for narrowing the selectivity of pyrido[2,3-d]pyrimidin-7(8H)-one-based inhibitors towards SIK kinases, eliminating PAK activity. Optimization was guided by high-resolution crystal structure analysis and computational methods, resulting in a pan-SIK inhibitor, MR22, which no longer exhibited activity on STE group kinases and displayed excellent selectivity in a representative kinase panel. MR22-dependent SIK inhibition led to centrosome dissociation and subsequent cell-cycle arrest in ovarian cancer cells, as observed with MRIA9, conclusively linking these phenotypic effects to SIK inhibition. Taken together, MR22 represents a valuable tool compound for studying SIK kinase function in cells.
Constitutive expression of the Type VI secretion system carries no measurable fitness cost inVibrio cholerae
Authors: Zhang Christopher , Ratcliff William C. , Hammer Brian K. 
Published: March 2023

AbstractThe Type VI Secretion System (T6SS) is a widespread and highly effective mechanism of microbial warfare; it confers the ability to efficiently kill susceptible cells within close proximity. Due to its large physical size, complexity, and ballistic basis for intoxication it has widely been assumed to incur significant growth costs in the absence of improved competitive outcomes. In this study, we precisely examine the fitness costs of constitutive T6SS firing in the bacteriumVibrio cholerae. We find that, contrary to expectations, constitutive use of T6SS has a negligible impact on growth, reducing growth fitness by 0.025 ± 0.5% (95% CI) relative to a T6SS-control. Mathematical modeling of microbial populations demonstrates that, due to clonal interference, constitutive expression of the T6SS will often be neutral, with little impact on evolutionary outcomes. Our findings underscore the importance of precisely measuring the fitness costs of microbial social behaviors, and help explain the prevalence of the T6SS across Gram negative bacteria.
Elastomeric Pillar Cages Modulate Actomyosin Contractility of Epithelial Microtissues by Substrate Stiffness and Topography
Authors: Esser Lisann , Springer Ronald , Dreissen Georg , Lövenich Lukas , Konrad Jens , Hampe Nico , Merkel Rudolf , Hoffmann Bernd , Noetzel Erik 
Published: March 2023

AbstractCell contractility regulates epithelial tissue geometry development and homeostasis. The underlying mechanobiological regulation circuits are poorly understood and experimentally challenging. We developed an elastomeric pillar cage (EPC) array to quantify cell contractility as a mechanoresponse of epithelial microtissues to substrate stiffness and topography. The spatially confined EPC geometry consisted of 24 circularly arranged slender pillars (1.2 MPa, height: 50 μm, diameter: 10 μm, distance: 5 μm). These high-aspect-ratio pillars were confined at both ends by planar substrates with different stiffness (0.15 – 1.2 MPa). Analytical modeling and finite elements simulation retrieved cell forces from pillar displacements. For evaluation, highly contractile myofibroblasts and cardiomyocytes were assessed to demonstrate that the EPC device can resolve static and dynamic cellular force modes. Human breast (MCF10A) and skin (HaCaT) cells grew as adherence junction-stabilized 3D microtissues within the EPC geometry. Planar substrate areas triggered the spread of monolayered clusters with substrate stiffness-dependent actin stress fiber (SF)-formation and substantial single-cell actomyosin contractility (150 - 200 nN). Within same continuous microtissues, the pillar-ring topography induced bilayered cell tube growth. Here, low effective pillar stiffness overwrote local substrate stiffness sensing and induced SF-lacking roundish cell shapes with extremely low cortical actin tension (11 - 15 nN). This work introduced a versatile biophysical tool to explore mechanobiological regulation circuits driving low- and high-tensional states in developing and homeostatic microtissues. EPC arrays facilitate simultaneously analyzing the impact of planar substrate stiffness and topography on microtissue contractility hence microtissue geometry and function.
The complexity of micro-and nanoplastic research in the genusDaphnia– A systematic review of study variability and meta-analysis of immobilization rates
Authors: Brehm Julian , Ritschar Sven , Laforsch Christian , Mair Magdalena M. 
Published: March 2023

AbstractIn recent years, the number of publications on nano-and microplastic particles (NMPs) effects on freshwater organisms has increased rapidly. Freshwater crustaceans of the genusDaphniaare widely used in ecotoxicological research as model organisms for assessing the impact of NMPs. However, the diversity of experimental designs in these studies makes conclusions about the general impact of NMPs onDaphniachallenging. To approach this, we systematically reviewed the literature on NMP effects onDaphniaand summarized the diversity of test organisms, experimental conditions, NMP properties and measured endpoints to identify gaps in our knowledge of NMP effects onDaphnia.We use a meta-analysis on mortality and immobilization rates extracted from the compiled literature to illustrate how NMP properties and study parameters can impact outcomes in toxicity bioassays. In addition, we investigate the extent to which the available data can be used to predict the toxicity of untested NMPs based on the extracted parameters. Based on our results, we argue that focusing on a more diverse set of NMP properties combined with a more detailed characterization of the particles in future studies will help to fill current research gaps, improve predictive models and allow the identification of NMP properties linked to toxicity.HighlightsSystematic review of NMP effects on the model systemDaphniaOrganismic, experimental and NMP properties influence observed effectsIn silicoidentification of traits likely linked to NMP toxicity (immobilization)More detailed standardized characterization of NMP needed to improve predictions
High-Content Screening to Identify Inhibitors of Dengue Virus Replication
Authors: Hoffstadt Jillian G. , Wotring Jesse W. , Porter Sam , Halligan Benjamin , O’Meara Matthew J. , Tai Andrew W. , Sexton Jonathan Z. 
Published: March 2023

AbstractDengue Virus (DENV) causes dengue fever, a pandemic-potential disease with currently no FDA-approved antivirals. Additionally, the available vaccine for DENV can increase the risk of severe dengue fever for those who have never had a DENV infection due to antibody-dependent enhancements. Thus, there is an urgent need to identify dengue virus antivirals. Antivirals that target NS4B, the replication compartment forming protein of DENV and the flavivirus family, are a promising new drug class that minimize cytotoxic effects to host cells. Drug-repurposing and high-content screening were leveraged to efficiently identify antivirals likely to inhibit NS4B. Using high-content screening, we quantified the morphological patterns of NS4B and envelope (E) protein expression versus time and developed a viral pseudotime model that was able to predict the infection progression to enable drug screening. We then developed a single cell infection classifier for antiviral efficacy and performed high-throughput drug screening of 960 compounds. We identified four concentration-dependent inhibitors of DENV with nanomolar potencies including: Nexium, Pralatrexate, GW4064, and LY411575. LY411575, a gamma secretase inhibitor, exhibited an IC50of 72nM and reduced percent infection to levels indistinguishable from the mock infection control.
Inhibition of CD40-TRAF6 signaling protects against aneurysm development and progression
Authors: Ommer-Bläsius Miriam , Vajen Tanja , Elster Christin , Verheyen Sarah , Pfeiler Susanne , Quast Christine , Odendahl Julia , Lang Alexander , Kelm Malte , Lutgens Esther , Gerdes Norbert 
Published: March 2023

AbstractObjectiveInflammation is a critical process during the progressive development and complication of abdominal aortic aneurysm. The co-stimulatory dyad CD40-CD40L is a major driver of inflammation and modulates immune responses. This study evaluates the potential of a small molecule inhibitor, which blocks the interaction between CD40 and tumor necrosis factor (TNF) receptor-associated factor (TRAF)-6, referred to as TRAF-STOP, in the early and later phase during AAA progression.Methods and resultsAAAs were induced in C57BL/6J mice by infrarenal aortic porcine pancreatic elastase infusion for 7, 14 or 28 days. Inhibition of CD40 signaling by TRAF-STOP resulted in less severe AAA formation and reduced the incidence of AAA development. TRAF-STOP treatment attenuated aortic structural remodeling, characterized by a reduced elastic fiber degradation, lowered expression of matrix metalloproteinase (MMP)-2 and MMP9, as well as preserved collagen type IV content in aneurysmal tissue. Furthermore, this is accompanied by the reduction of key pro-inflammatory genes such as TNFα.ConclusionPharmacological inhibition of CD40-TRAF6 signaling protects from adverse aortic structural remodeling during the early phase of AAA progression representing a translational strategy to limit progression of human AAA disease.
Normal and cancer tissues are accurately characterised by intergenic transcription at RNA polymerase 2 binding sites
Authors: de Langen Pierre , Hammal Fayrouz , Guéret Elise , Spinelli Lionel , Ballester Benoit 
Published: March 2023

AbstractIntergenic transcription in normal and cancerous tissue is pervasive and incompletely understood. To investigate this activity at a global level, we constructed an atlas of over 180,000 consensus RNA Polymerase II (RNAP2) bound intergenic regions from more than 900 RNAP2 ChIP-seq experiments across normal and cancer samples. Using unsupervised analysis, we identified 51 RNAP2 consensus clusters, many of which map to specific biotypes and identify tissue-specific regulatory signatures. We developed a meta-clustering methodology to integrate our RNAP2 atlas with active transcription across 28,797 RNA-seq samples from TCGA, GTEx and ENCODE, which revealed strong tissue- and disease-specific interconnections between RNAP2 occupancy and transcription. We demonstrate that intergenic transcription at RNAP2 bound regions are novel per-cancer and pan-cancer biomarkers showing genomic and clinically relevant characteristics including the ability to differentiate cancer subtypes and are associated with overall survival. Our results demonstrate the effectiveness of coherent data integration to uncover and characterise intergenic transcriptional activity in both normal and cancer tissues.
Population-level antagonism between FGF and BMP signaling steers mesoderm differentiation in embryonic stem cells
Authors: Gattiglio Marina , Protzek Michelle , Schröter Christian 
Published: March 2023

AbstractThe mesodermal precursor populations for different internal organ systems are specified during gastrulation by the combined activity of extracellular signaling systems such as BMP, Wnt, Nodal, and FGF. The BMP, Wnt and Nodal signaling requirements for the differentiation of specific mesoderm subtypes in mammals have been mapped in detail, but how FGF shapes mesodermal cell type diversity is not precisely known. It is also not clear how FGF signaling integrates with the activity of other signaling systems involved in mesoderm differentiation. Here, we address these questions by analyzing the effects of targeted signaling manipulations in differentiating stem cell populations with single cell resolution. We identify opposing functions of BMP and FGF, and map FGF-dependent and -independent mesodermal lineages. Stimulation with exogenous FGF boosts the expression of endogenous Fgfs while repressing Bmp ligands. This positive autoregulation of FGF signaling, coupled to the repression of BMP signaling, may contribute to the specification of reproducible and coherent cohorts of cells with the same identity via a community effect, both in the embryo and in synthetic embryo-like systems.
Age-related variability in network engagement during music listening
Authors: Faber S. , Belden A.G. , Loui P. , McIntosh A.R. 
Published: March 2023

AbstractListening to music is an enjoyable behaviour that engages multiple networks of brain regions. As such, the act of music listening may offer a way to interrogate network activity, and to examine the reconfigurations of brain networks that have been observed in healthy aging. The present study is an exploratory examination of brain network dynamics during music listening in healthy older and younger adults. Network measures were extracted and analyzed together with behavioural data using a combination of hidden Markov modelling and partial least squares. We found age- and preference-related differences in fMRI data collected during music listening in healthy younger and older adults. Both age groups showed higher occupancy (the proportion of time a network was active) in a temporal-mesolimbic network while listening to self-selected music. Activity in this network was strongly positively correlated with liking and familiarity ratings in younger adults, but less so in older adults. Additionally, older adults showed a higher degree of correlation between liking and familiarity ratings consistent with past behavioural work on age-related dedifferentiation. We conclude that, while older adults do show network and behaviour patterns consistent with dedifferentiation, activity in the temporal-mesolimbic network is relatively robust to dedifferentiation. These findings may help explain how music listening remains meaningful and rewarding in old age.