bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peptidergic neurons with extensive branching orchestrate the internal states and energy balance of maleDrosophila melanogaster
Authors: Song Yutong , Zhang Tianmu , Zhang Xiaoli , Ryu Tae Hoon , Wong Kyle , Wu Zekun , Wei Yanan , Schweizer Justine , Nguyen Khoi-Nguyen Ha , Kwan Alex , Yu Kweon , Kim Woo Jae 
Published: June 2024

ABSTRACTNeuropeptide SIFamide (SIFa) neurons inDrosophila melanogasterhave been characterized by their exceptionally elaborate arborization patterns, which extend from the brain into the ventral nerve cord (VNC). SIFa neurons are equipped to receive signals that integrate both internal physiological cues and external environmental stimuli. These signals enable the neurons to regulate energy balance, sleep patterns, metabolic status, and circadian timing. These peptidergic neurons are instrumental in orchestrating the animal’s internal states and refining its behavioral responses, yet the precise molecular underpinnings of this process remain elusive. Here we demonstrate that SIFa neurons coordinate a range of behavioral responses by selectively integrating inputs and outputs in a context-dependent manner. These neurons engage in a feedback loop with sNPF neurons in the ventral nerve cord, modifying behaviors such as long mating duration (LMD) and shorter mating duration (SMD). Furthermore, SIFa neurons receive essential inputs from neuropeptides Dsk, sNPF, and dilp2, which regulate interval timing behaviors. Activating SIFa neurons leads to reduced mating duration and increased food intake, while deactivating them reduces food intake. Overall, these findings demonstrate the importance of SIFa neurons in absorbing inputs and turning them into behavioral outputs, shedding light on animal’s intricate behavioral orchestration.
Phylogenetic divergence of GABABreceptor signalling in neocortical networks over adult life
Authors: Wilson Max A. , Taylor Lewis W. , Meftah Soraya , McGeachan Robert I. , Modebadze Tamara , Jayasekera B. Ashan P. , Cowie Christopher J. A. , LeBeau Fiona E. N. , Liaquat Imran , Durrant Claire S. , Brennan Paul M. , Booker Sam A. 
Published: June 2024

SummaryCortical circuit activity is controlled by GABA-mediated inhibition in a spatiotemporally restricted manner. Much is known about fast GABA currents, GABABreceptor (GABABR) signalling exerts powerful slow inhibition that controls synaptic, dendritic and neuronal activity. However, little is known about how GABABRs contribute to circuit-level inhibition over the lifespan of rodents and humans. In this study, we quantitatively determine the functional contribution of GABABR signalling to pre- and postsynaptic domains in rat and human cortical principal cells (PC). We find that postsynaptic GABABR differentially control pyramidal cell activity within the cortical column as a function of age and species, and that these receptors contribute to co-ordination of local information processing in a layer- and species-dependent manner. These data directly increase our knowledge of translationally relevant local circuit dynamics, with direct impact on understanding the role of GABABRs in the treatment of seizure disorders.HighlightsGABABreceptor signalling displays age and species differences in cortexGABABreceptor presynaptic inhibition is stronger in humans than rodentsIn vitrooscillations in human cortex are strongly regulated by GABABRsLevetiracetam enhances endogenous GABABR signalling in human cortex
Altered dynamics of ATP synthase cause functional irregularities in senescent hiPS-cardiomyocytes
Authors: Morris Silke , Molina-Riquelme Isidora , Barrientos Gonzalo , Schmelter Frank , Peischard Stefan , Seebohm Guiscard , Eisner Verónica , Busch Karin B. 
Published: June 2024

AbstractHeart disease is the leading cause of death in the elderly population and the heart is a highly energy-consuming tissue. Aging-related heart failure is often driven by energy depletion in cardiomyocytes (CM), which rely on their abundant, cristae-dense mitochondria for ATP production. ATP synthase, localized along the cristae rims, plays a critical role in energy conversion, but the connection between its organization and function remains unclear. Here, we explored the spatiotemporal organization of ATP synthase in senescent CM at the level of individual complexes. Using single-molecule localization and tracking microscopy, we observed reduced enzyme mobility within the cristae, coinciding with decreased ATP synthase activity, despite a stable resting mitochondrial membrane potential. This reduction in activity was independent of changes in ATP synthase expression or dimerization. Electron tomography revealed an increased prevalence of curved inner membranes and fenestrated cristae in senescent CM, explaining the reduced enzyme mobility. Senescent CM displayed irregular autonomous and paced beating patterns. These abnormalities suggest that impaired cardiac function is directly driven by disrupted energy metabolism, rooted in the suboptimal organization and function of ATP synthase in altered cristae.
Microscopy analysis of delayed co-transcriptional splicing in highly expressed thyroglobulin gene
Authors: Ullrich Simon , Nadelson Iliya , Krebs Stefan , Blum Helmut , Leonhardt Heinrich , Solovei Irina 
Published: June 2024

ABSTRACTTranscription of the majority of eukaryotic genes is accompanied by splicing, a process that depends on the assembly of the spliceosome on introns. The timing of spliceosome assembly varies significantly between introns, transcripts, genes and species. While quick co-transcriptional intron removal has been demonstrated for many mammalian genes, most splicing events do not occur immediately after intron synthesis. In this study, we utilized the highly expressedTggene, which forms exceptionally long transcription loops (Leidescher et al., 2022), providing a convenient model for studying splicing dynamics using advanced light microscopy. Our single-cell oligopainting-based analysis revealed a delay in splicing several tens of kilobases downstream of a transcribed intron, a finding further supported by standard cell population analyses. We speculate that this phenomenon is due to the abnormally high transcription rate of theTggene, which may lead to a localized deficiency in splicing factors and, consequently, delayed spliceosome assembly on thousands of nascent transcripts decorating the gene. Additionally, we found that, in contrast to short introns (<10 kb), longTgintron (>50 kb) is spliced promptly, providing further support for the idea that intron length may modulate splicing speed.
Horn size is linked to Sertoli cell efficiency and sperm size homogeneity during sexual development in common eland (Taurotragus oryx)
Authors: Pintus Eliana , Kotrba Radim , Ros-Santaella José Luis 
Published: June 2024

AbstractBackgroundIn polygynous species, the development of secondary sexual characters is usually decisive for male reproductive success. However, our understanding about the links between the growth of these traits and reproductive efficiency is still elusive. Most research efforts in this topic have been also focused on adult males, although the development of some secondary sexual characters, like bovid horns, typically starts after birth, continues during the puberty and in some species, such as the common eland, slows or even stops during adulthood. In this study, we investigated the relationships between horn size and testicular function during sexual development in common elands using a comprehensive approach that considers both spermatogenic and sperm parameters.MethodsTwenty-two non-sexually mature common elands were analyzed for the present study. Horn size was estimated by performing a principal component analysis of horn length, spiral length, and basal circumference. In addition, body mass, testes mass, and gonadosomatic index were assessed. Spermatogenic activity was assessed by cytological and histological analyses. Sperm concentration, morphology, morphometry, and intramale variation in sperm size were evaluated on epididymal sperm samples.ResultsWe found that bigger horns are associated with increased Sertoli cell efficiency and reduced intramale variation in sperm size. Both parameters were not related to one another while they have shown to be associated with enhanced sperm quality in ungulates. Moreover, horn size was positively linked to the testis mass, sperm concentration, and testicular investment in the seminiferous epithelium. Surprisingly, horn size did not correlate to the percentage of the spermatozoa over the germ cell population nor the percentage of those with normal morphology, which typically increase throughout the male sexual development. It is also remarkable to note that the spiral length and basal circumference were the horn traits most strongly correlated with spermatogenic and sperm parameters as well as those responsible for the sexual dimorphism in this species.ConclusionsTaken together, our results indicate that horn size can be regarded as a good index of male reproductive potential during sexual development and provide insights into the role of secondary sexual characters in sexual selection dynamics.
Borg3 controls septin recruitment for primary cilia formation
Authors: Schampera Janik N. , Lehmann Friederike , Meléndez Ana Valeria , Schwan Carsten 
Published: June 2024

SummarySeptin GTPases form linear hexa- or octameric rods that polymerize into higher order structures. They are incorporated into the cytoskeleton and involved in vital cellular functions. Among these, they play a role in the formation of primary cilia. Primary cilia are evolutionary conserved cellular signaling hubs. While it is accepted that septins localize to primary cilia and are involved in their formation and function, the regulation of septin assembly in the confined ciliary compartment remains elusive. Here we show, that Borg3, also known as Cdc42 effector protein 5 (Cdc42EP5), is an essential component of primary cilia. Specific Borg3 localization is facilitated by switching the Rho-GTPase Cdc42 between an inactive- and active state at the base of the primary cilium. The active form of Cdc42 has a defined localization restricted to the base of the primary cilium. Knockout of Borg3 as well as dysregulation of Cdc42 reduces septin dynamics at cilia and consequently, the formation of cilia.The study demonstrates that Borg3 is a novel and essential regulator of ciliogenesis through the spatiotemporal control of septin dynamics downstream of Cdc42.
CHRFAM7Aoverexpression in human iPSC-derived Interneurons dysregulates α7- nAChR surface expression and alters response to oligomeric β-amyloid peptide
Authors: Llach Pou Maria , Thiberge Camille , Pons Stéphanie , Maskos Uwe , Cloëz-Tayarani Isabelle 
Published: June 2024

AbstractThe α7 neuronal nicotinic receptor (α7-nAChR) gene,CHRNA7, is widely expressed within the brain and at the periphery. It plays various important roles in cognition and immune functions. Decreased expression of α7-nAChR has been associated with Alzheimer’s disease (AD) triggered by the accumulation of the 42-amino acid beta-amyloid peptide (Aβ1-42). The interactions of this peptide with α7-nAChR may represent a pivotal mechanism that is involved in pathogenesis of AD. The regulation ofCHRNA7is a complex process. Normal function of α7-nAChR in mammalian cells requires the co-expression of chaperone proteins such as RIC3 and NACHO which facilitate the formation of cell surface receptors. In humans,CHRNA7regulation also involves the specific chimericCHRFAM7Agene product dupα7, which may assemble with α7 subunits and lead to dominant negative regulation of α7-nAChR function. To further elucidate the complex interplay betweenCHRFAM7Agene product (dupα7), α7-nAChRs and Aβ1-42, we used human induced pluripotent stem cells (iPSC)-derived interneurons (INs). Four iPSC lines were analyzed for the presence ofCHRFAM7Acopies. Among them, a cell line with a null genotype was selected for the lentiviral overexpression ofCHRFAM7A. Our data show that overexpression ofCHRFAM7Aled to a reduction in the surface detection of α7-nAChR ligand binding sites in iPSC-derived INs. INs expressing the α7-dupα7 subunit (α7-dupα7-INs) exhibited lower levels of RIC3 and NACHO. Upon agonist treatment by nicotine, an up-regulation of α7-nAChR ligand binding sites was observed in α7-dupα7-INs as compared to non-transduced INs (α7-INs). At low levels of Aβ treatment, α7-INs displayed a significant reduction in production of reactive oxygen species (ROS), while high levels resulted in a slight increase. In contrast, α7-dupα7-INs exhibited lower baseline levels of ROS that remained unaltered by Aβ treatment. ROS are known to exacerbate AD pathogenesis. We hypothesize that such effects may also be triggered by α7-dupα7-INs in the brain of patients. Further investigations are currently undertaken to confirm this hypothesis.
E cadherin appears to be an essential on/off switch for initiating bile canaliculi formation
Authors: Chevallet Mireille , Rabilloud Thierry , Diemer Hélène , Bertile Fabrice , Fuchs Alexandra , Deniaud Aurélien 
Published: June 2024

AbstractThe mechanisms underlying cell polarization are fundamental in biology, yet they are not fully understood. This is particularly true for hepatocytes, which exhibit a complex polarization, enabling the formation of the bile canaliculi (BCs) network that is essential for liver excretion functions. To identify key proteins involved in hepatocyte polarization and BC formation, we performed a proteomic approach to compare the human hepatocyte cell line HepG2 to its sub clone HepG2/C3A which shows much greater efficiency in forming mature BCs. We localized LimA1 and Espin to the BC for the first time, suggesting their important role there, and confirmed the presence of NHE-RF1. Using a protein repression strategy directed against selected proteins, we highlighted the essential role of E cadherin in the initiation of BC formation. Our data showed, for the first time, that in absence of E cadherin, hepatocytes lose their ability to form BCs.
At the onset of active whisking, the input layer of barrel cortex exhibits a 24 h window of increased excitability that depends on prior experience
Authors: Shallow Molly C. , Tian Lucy , Lin Hudson , Lefton Katheryn B , Chen Siyu , Dougherty Joseph D. , Culver Joe P. , Lambo Mary E. , Hengen Keith B. 
Published: June 2024

AbstractThe development of motor control over sensory organs is a critical milestone in sensory processing, enabling active exploration and shaping of the sensory environment. However, whether the onset of sensory organ motor control directly influences the development of corresponding sensory cortices remains unknown. Here, we exploit the late onset of whisking behavior in mice to address this question in the somatosensory system. Using ex vivo electrophysiology, we discovered a transient increase in the intrinsic excitability of excitatory neurons in layer IV of the barrel cortex, which processes whisker input, precisely coinciding with the onset of active whisking at postnatal day 14 (P14). This increase in neuronal gain was specific to layer IV, independent of changes in synaptic strength, and required prior sensory experience. Strikingly, the effect was not observed in layer II/III of the barrel cortex or in the visual cortex upon eye opening, suggesting a unique interaction between the development of active sensing and the thalamocortical input layer in the somatosensory system. Predictive modeling indicated that changes in active membrane conductances alone could reliably distinguish P14 neurons in control but not whisker-deprived hemispheres. Our findings demonstrate an experience-dependent, lamina-specific refinement of neuronal excitability tightly linked to the emergence of active whisking. This transient increase in the gain of the thalamic input layer coincides with a critical period for synaptic plasticity in downstream layers, suggesting a role in facilitating cortical maturation and sensory processing. Together, our results provide evidence for a direct interaction between the development of motor control and sensory cortex, offering new insights into the experience-dependent development and refinement of sensory systems. These findings have broad implications for understanding the interplay between motor and sensory development, and how the mechanisms of perception cooperate with behavior.
The synergy between cannabidiol and probiotics curtails the glycemic indicators, enhances insulin production, and alleviates the symptoms of type 2 diabetes
Authors: Naeini Sahar Emami , Bhandari Bidhan , Rogers Hannah M , Gouron Jules , Chagas Pablo Shimaoka , Maciel Lívia Maria , Shimaoka Chagas Henrique Izumi , Yu Jack C , Seyyedi Mohammad , Salles Évila Lopes , Fields Mark , Baban Babak , Wang Lei P 
Published: June 2024

AbstractDiabetes continues to challenge healthcare system as one of the most growing epidemics with staggering economic burden. It is estimated that 783 million by 2045 will live with diabetes worldwide, 90% of those cases are type 2 diabetes (T2D). T2D is a multifaceted disease, its treatment requires a holistic approach, beyond single target medications with high efficacy. There is a dire need to explore and invent new and effective therapeutic modalities for T2D.In this study we tested whether a combined formulation of cannabidiol (CBD) and probiotics could control glycemic indices and alleviate symptoms of T2D. We used a mouse model of T2D, replaced their drinking water with a combination of CBD and probiotics formulated as a commercially available beverage.Our findings demonstrated that combination of CBD and probiotics not only reduced the glycemic indices (HbA1c & FBG), but also altered the microbiome profile, promoted beneficial bacteria. Further, the CBD/probiotic combination reduced peripheral inflammatory cytokines and enhanced insulin production in pancreatic islets.In conclusion, our results suggest that consumption of combined CBD and probiotics could be used as a natural, practical, affordable, and safe alternative and complementary therapeutic modality to treat T2D.
Diverse toxins exhibit a common binding mode to the Nicotinic Acetylcholine Receptors revealing a new molecular determinant
Authors: Do Hung N. , Kubicek-Sutherland Jessica Z. , Gnanakaran S. 
Published: June 2024

AbstractNicotinic acetylcholine receptors (nAChRs) are critical ligand-gated ion channels in the human nervous system. They are targets for various neurotoxins produced by algae, plants, and animals. While there have been many structures of nAChRs bound by neurotoxins published, the binding mechanism of toxins to the nAChRs remains uncleared. In this work, we have performed extensive Gaussian accelerated molecular dynamics simulations on severalAplysia californica(AC) nAChRs in complex with α-conotoxins, strychnine, and pinnatoxins, as well as human nAChRs in complex with α-bungarotoxin and α-conotoxin for a total of 60 μs of simulation time to determine the binding and dissociation pathways of the toxins to the nAChRs and the associated effects. We uncovered two common binding and dissociation pathways shared by toxins and nAChRs. In the primary binding pathway, the toxins diffused from the bulk solvent to first bind a region near the extracellular pore before moving downwards along the nAChRs to the nAChR orthosteric pocket. The second binding pathway involved a direct diffusion of the toxins from the bulk solvent into the nAChR orthosteric pocket. The dissociation pathways were the reverse of the observed binding pathways. We also found that the toxins enacted their toxicity upon binding by restricting the necessary movements required by the nAChRs to open their extracellular and intracellular pores for the ions to pass through. Notably, the electrostatically bipolar interactions between nAChR orthosteric pocket and toxins provides a molecular level explanation for the common binding mode shared by diverse toxins and serve as a key determinant for toxicity.
Cooperation between Intrinsically Disordered Regions regulates CBP condensate behaviour
Authors: Gelder Katie L. , Carruthers Nicola A. , Ball Sophie , Dunning Mark , Craggs Timothy D. , Twelvetrees Alison E. , Bose Daniel A. 
Published: June 2024

AbstractCreb binding protein(CBP) andEP300(p300) are transcription coactivators that bind atcis-regulatory elements and regulate gene expression in multicellular organisms. They contain large intrinsically disordered regions (IDRs), and form biomolecular condensates that are important for transcription regulation. However, little is known about how different IDRs work together to contribute to the behaviour of CBP condensates, knowledge which is essential to fully understand their biological function. Here, we show that endogenous CBP forms fluid-like condensates in the nucleus, and that properties of CBP condensates depend on IDRs dispersed throughout its sequence. Adjacent IDRs in the C-terminus form a regulatory module that balances positive and negative contributions, to ensure that CBP condensates are responsive to other IDRs and to post translational lysine acetylation. These distinct behaviours also change the characteristics of endogenous CBP condensates, including changing patterns of chromatin localisation and altering behaviours in live cell imaging. Cooperation between different IDRs therefore ensures that CBP condensates are poised to respond to their environment, allowing CBP to effectively integrate signalling events and control diverse transcriptional outputs.
Tetra hydroxy ethyl disulfate disodium: a novel non-resistant antibacterial chelating agent
Authors: Audah KA , Jogia GE , Kustaryono D , Amsyir J , Amalda SA , Darmadi J , Himawan S , Saidin S , Tejo BA , Budiman C , Singh S K , Thekkiniath J 
Published: June 2024

AbstractDiscovery of novel antibacterial drugs is urgently required as common antibiotics have numerous side effects and are becoming less effective due to antibiotic resistance occurrences. Developing a novel class of antibacterial compounds without inducing the prevalence of resistance when used repeatedly against bacterial pathogens is presumably one of the best approaches to overcome this problem. Tetra hydroxy ethyl disulfate disodium (THES) is a novel antibacterial agent, capable of disrupting cell activity without any need for drug influx. In this study, the molecular interaction between THES, Gram-positive, and Gram-negative bacteria was investigated. It was suggested that THES possessed the desirable characteristics of a non-resistant bacterial agent with bactericidal properties. Additionally, the non-resistant characteristics of THES were validated as a novel antibacterial agent. The unique feature of THES was the property of chelation with its strong binding ability to target ligands. This binding played a major role in bacterial peptidoglycan porosity enlargement, resulting in lysis and cell death. The bacterial cell membrane porosity enlargement was confirmed by Scanning Electron Microscopy, Transmission Electron Microscopy, as well as Atomic Force Microscopy. These findings were further supported by the results fromin silicoanalysis which showed that THES formed favorable interactions with peptidoglycan with a binding affinity of −4.7 kcal/mol. The minimum inhibitory concentration value against multidrug-resistant (MDR) bacteria was notably low, between 0.05 - 0.1%. Furthermore, the analysis of resistance over a seven-month course showed thatStaphylococcus aureusdid not develop resistant characteristics to repeated treatment to THES treatment. This study has also shown that bactericidal characteristics can be easily manipulated and modified for more preferable antibacterial activities, whilst yielding desirable pharmacokinetic/pharmacodynamics (PK/PD) properties. There are several advantages of THES as compared to common antibiotics, including its flexibility in the killing capacity of different microbial strains. The simplicity, efficacy, and non-resistant properties of THES make it a promising drug candidate or compound to combat the outbreak of MDR bacteria in the future.