bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thermo- and photoreceptors of eyes as regulators of circadian rhythm and glymphatic system
Authors: Kholmanskiy Alexander 
Published: September 2023

AbstractThe dynamics of hydrogen bonds in bulk and hydrated water affected the activation energies of temperature dependence of ion currents of voltage-dependent channels that regulate communication and trophic bonds in the neuropil of the cortical parenchyma. The physics of minimizing of isobaric heat capacity of water made it possible to explain stabilization and functional optimization of thermodynamics of eyeball fluids at 34.5 °C and human brain during sleep at 36.5 °C. At these temperatures, thermoreceptors of cornea and cells of ganglionic layer of the retina, through connections with suprachiasmatic nucleus and pineal gland, switch brain metabolism from daytime to nighttime modes. The phylogenesis of circadian rhythm was reflected in dependence of duration of nighttime sleep of mammals on diameter of eyeball, mass of pineal gland, and density of neurons in parenchyma of cortex. The activity of all nerves of eyeball led to division of nocturnal sleep into slow and fast phases. These phases correspond to two modes of glymphatic system - electrochemical and dynamic. The first is responsible for relaxation processes of synaptic plasticity and chemical neutralization of toxins with participation of water and melatonin. Rapid eye movement and an increase in cerebral blood flow in second mode increase water exchange in parenchyma and flush out toxins into venous system.
PD-1 Mediated Regulation of Unique Activated CD8+T Cells by NK Cells in the Submandibular Gland
Authors: Borys Samantha M. , Reilly Shanelle P. , Magill Ian , Zemmour David , Brossay Laurent 
Published: September 2023

SummaryThe increasing utilization of anti-PD-1 immune checkpoint blockade (ICB) has led to the emergence of immune-related adverse events (irAEs), including sicca syndrome. Interestingly, we found that the submandibular gland (SMG) of PD-1 deficient mice harbors a large population of CD8+T cells, reminiscing ICB induced sicca. This phenotype was also observed in the SMG of both NK cell-depleted C57BL/6 animals and NK cell-deficient animals. Mechanistically, using mice conditionally deficient for PD-L1 in the NK cell lineage, we discovered that NK cells regulate CD8+T cell homeostasis via the PD-1/PD-L1 axis in this organ. Importantly, single-cell RNA sequencing of PD-1 deficient SMG CD8+T cells reveals a unique transcriptional profile consistent with TCR activation. These cells have limited TCR diversity and phenotypically overlap with GzmK+CD8+T autoimmune cells identified in primary Sjögren’s syndrome patients. These insights into NK cell immunoregulation in the SMG, and the consequences of disrupted CD8+T cell homeostasis, provide opportunities for preventing the development of irAEs.HighlightsElevated CD8+T cells in the submandibular gland (SMG) of PD-1 deficient mice parallel sicca-like irAEs seen in ICB patients.In addition to their previously described hyporesponsive phenotype, NK cells in the SMG regulate CD8+T cell homeostasis through the PD-L1/PD-1 axis.PD-1 deficient SMG CD8+T cells display unique transcriptional profiles associated with proinflammatory functions, TCR activation, interferon stimulation, and exhaustion.Oligoclonal expansion and similarities in TCR sequences indicate T cell activation and a preference for recognizing specific antigens.
Adenine methylation is very scarce in the drosophila genome and not erased by the Ten Eleven Translocation dioxygenase
Authors: Boulet Manon , Gilbert Guerric , Renaud Yoan , Schmidt-Dengler Martina , Plantié Emilie , Bertrand Romane , Nan Xinsheng , Jurkowski Tomasz , Helm Mark , Vandel Laurence , Waltzer Lucas 
Published: September 2023

AbstractN6-methyladenine (6mA) DNA modification has recently been described in metazoans, including in drosophila, for which the erasure of this epigenetic mark has been ascribed to the Ten Eleven Translocation (TET) enzyme. Here, we re-evaluated 6mA presence and TET impact on drosophila genome. Using axenic or conventional breeding conditions, we found traces of 6mA by LC-MS/MS and no significant increase in 6mA levels in the absence of TET, suggesting that this modification is present at very low levels in the drosophila genome but not regulated by TET. Consistent with this latter hypothesis, further molecular and genetic analyses showed that TET does not demethylate 6mA but acts essentially in an enzymatic-independent manner. Our results call for further caution concerning the role and regulation of 6mA DNA modification in metazoans and underline the importance of TET non-enzymatic activity for fly development.
Sulfatase 2 Inhibition Sensitizes Triple-Negative Breast Cancer Cells to Chemotherapy Through Augmentation of Extracellular ATP
Authors: Manouchehri Jasmine M , Marcho Lynn , Cherian Mathew A 
Published: September 2023

ABSTRACTBackgroundBreast cancer is the leading cause of cancer-related death among women worldwide. Patients diagnosed with triple-negative breast cancer (TNBC) have limited therapeutic options that produce durable responses. Hence, a diagnosis of TNBC is associated with a poor prognosis compared to other types of breast cancer. As a result, there is a critical need for novel therapies that can deepen and prolong responses.We previously found that chemotherapy causes the release of extracellular adenosine triphosphate (eATP). Augmenting eATP release can boost the response of TNBC cells to chemotherapy and cause increased cell death. However, eATP concentrations are limited by several families of extracellular ATPases, which complicates the design of compounds that attenuate eATP degradation.In this study, we hypothesized that heparan sulfate (HS) would inhibit extracellular ATPases and accentuate chemotherapy-induced cytotoxicity in TNBC by augmenting eATP. HS can be desulfated by sulfatase 1 and 2; sulfatase 2 is consistently highly expressed in a variety of cancers including breast cancer, whereas sulfatase 1 is not. We hypothesized that the sulfatase 2 inhibitor OKN-007 would exacerbate chemotherapy-induced eATP release and TNBC cell death.MethodsTNBC cell lines and nontumorigenic immortal mammary epithelial cells were treated with paclitaxel in the presence of heparan sodium sulfate and/or OKN-007; eATP content and cell viability were evaluated. In addition, protein and cell surface expression of sulfatases 1 and 2 were determined in all examined cell lines via ELISA, Western blot, and flow cytometry analyses.ResultsSulfatase 2 was highly expressed in TNBC cell lines and human breast cancer samples but not in immortal mammary epithelial cells and much less so in normal human breast tissue and ductal carcinoma in situ samples. OKN-007 exacerbated chemotherapy-induced eATP release and chemotherapy-induced TNBC cell death. When combined with chemotherapy, OKN-007 attenuated cells with a cancer-initiating cell phenotype.ConclusionsThese results suggest that sulfatase 2 inhibitors in combination with chemotherapy attenuate the viability of TNBC cells more than chemotherapy alone by exacerbating eATP release. These effects, as well as their capacity to attenuate the cancer-initiating cell fraction, may translate into combination therapies for TNBC that induce deeper and more durable responses.
Unravelling Paralog-Specific Notch Signaling through Ternary Complex Stability and Transcriptional Activation Measurements Using Chimeric Receptors
Authors: Ramsey Kristen M. , Barrick Doug 
Published: September 2023

SummaryNotch signaling is mediated by four paralogous receptors with conserved architectures and overlapping yet non-redundant functions. Notch signaling generates a transcriptional activation complex (NTC) wherein the N-terminal RAM and ankyrin repeat (ANK) regions of the Notch intracellular domain (NICD) bind transcription factor CSL and recruit co-activator Mastermind-like (MAML). To better understand paralog-specific differences in Notch signaling, we analyzed the thermodynamics of binary and ternary NTCs for all four Notch paralogues and chimeric constructs. We find that RAMANK:CSL stability (ΔGRA) is primarily determined by the RAM region while MAML binding to preformed RAMANK:CSL complexes (ΔGMAML) is largely determined by the ANK region. We determined transcriptional activation data for the paralogous and chimeric NICDs and analyzed the data with an independent multiplicative model. This analysis shows ternary complex stability (ΔGTC, where ΔGTC= ΔGRA+ΔGMAML) correlates well with transcriptional activations and provides insights into contributions of RAM, ANK and the C-terminal regions to Notch signaling.
Mapping the Changing Neural Architecture of Narrative Processing Using Naturalistic Stimuli: an fMRI Study
Authors: Haines Christina , Sullivan KiAnna , Klamer Keva , Craig Joshua , Ekstrand Chelsea 
Published: September 2023

AbstractA narrative is a coherent representation of actual or fictional events designed to connect experiences. Narratives provide a unique opportunity to investigate brain functions in scenarios more closely resembling real-world experiences. However, most neuroimaging studies examining narrative formation have utilized static stimuli that fail to capture the intricacies of narrative construction in everyday life, particularly how cognitive demands change over the course of narrative processing. The current research uses functional magnetic resonance imaging (fMRI) to examine dynamic narrative processing over the course of a full-length audiovisual narrative. We examined changes in neural synchrony (as quantified by intersubject correlations) in areas related to semantic memory, episodic memory, and visuospatial attention between the beginning, middle, and end of the narrative. Results from two experiments identified two core narrative processing networks responsible for constructing coherent representations across extended timescales. The first network is associated with the early narrative construction, and includes the right intraparietal sulcus/superior parietal lobule, bilateral angular gyrus, bilateral precuneus, and left fusiform gyrus. The second network consists of the right ventral frontal cortex and bilateral parahippocampal cortices, and is associated with longer term narrative integration. Together, these regions provide the framework for successful narrative processing during naturalistic stimuli.
The impact of Parkinson’s disease on striatal network connectivity and cortico-striatal drive: an in-silico study
Authors: Carannante Ilaria , Scolamiero Martina , Hjorth J. J. Johannes , Kozlov Alexander , Bekkouche Bo , Guo Lihao , Kumar Arvind , Chachólski Wojciech , Hellgren Kotaleski Jeanette 
Published: September 2023

ABSTRACTStriatum, the input stage of the basal ganglia, is important for sensory-motor integration, initiation and selection of behaviour, as well as reward learning. Striatum receives glutamatergic inputs from mainly cortex and thalamus. In rodents, the striatal projection neurons (SPNs), giving rise to the direct and the indirect pathway (dSPNs and iSPNs, respectively), account for 95% of the neurons and the remaining 5% are GABAergic and cholinergic interneurons. Interneuron axon terminals as well as local dSPN and iSPN axon collaterals form an intricate striatal network. Following chronic dopamine depletion as in Parkinson’s disease (PD), both morphological and electrophysiological striatal neuronal features have been shown to be altered in rodent models. Our goal with thisin-silicostudy is twofold: a) to predict and quantify how the intrastriatal network connectivity structure becomes altered as a consequence of the morphological changes reported at the single neuron level, and b) to investigate how the effective glutamatergic drive to the SPNs would need to be altered to account for the activity level seen in SPNs during PD. In summary we predict that the richness of the connectivity motifs in the striatal network is significantly decreased during PD, while at the same time a substantial enhancement of the effective glutamatergic drive to striatum is present.AUTHOR SUMMARYThisin-silicostudy predicts the impact that the single cell neuronal morphological alterations will have on the striatal microcircuit connectivity. We find that the richness in the topological striatal motifs is significantly reduced in Parkinson’s disease, highlighting that just measuring the pairwise connectivity between neurons gives an incomplete description of network connectivity. Moreover, we predict how the resulting electrophysiological changes of SPN excitability together with their reduced number of dendritic branches affect their response to the glutamatergic drive from cortex and thalamus. We find that the effective glutamatergic drive is likely significantly increased in PD, in accordance with the hyperglutamatergic hypothesis.
Effects of dim light at night in C57BL/6J mice on recovery after spinal cord injury
Authors: Aldrich John C. , Scheinfeld Ashley R. , Lee Sydney E. , Dusenbery Kalina J. , Mahach Kathryn M. , Van de Veire Brigid C. , Fonken Laura K. , Gaudet Andrew D. 
Published: September 2023

AbstractSpinal cord injury (SCI) can cause long-lasting locomotor deficits, pain, and mood disorders. Anatomical and functional outcomes are exacerbated by inflammation after SCI, which causes secondary damage. One promising target after SCI is manipulating the circadian system, which optimizes biology and behavior for time of day – including neuroimmune responses and mood- related behaviors. Circadian disruption after SCI is likely worsened by a disruptive hospital environment, which typically includes dim light-at-night (dLAN). Here, we hypothesized that mice subjected to SCI, then placed in dLAN, would exhibit worsened locomotor deficits, pain- like behavior, and anxiety-depressive-like symptoms compared to mice maintained in light days with dark nights (LD). C57BL/6J mice received sham surgery or moderate T9 contusion SCI, then were placed permanently in LD or dLAN. dLAN after SCI did not worsen locomotor deficits; rather, SCI-dLAN mice showed slight improvement in open-field locomotion at the final timepoint. Although dLAN did not alter SCI-induced heat hyperalgesia, SCI-dLAN mice exhibited an increase in mechanical allodynia at 13 days post-SCI compared to SCI-LD mice. SCI-LD and SCI-dLAN mice had similar outcomes using sucrose preference (depressive-like) and open-field (anxiety-like) tests. At 21 dpo, SCI-dLAN mice had reduced preference for a novel juvenile compared to SCI-LD, implying that dLAN combined with SCI may worsen this mood-related behavior. Finally, lesion size was similar between SCI-LD and SCI-dLAN mice. Therefore, newly placing C57BL/6J mice in dLAN after SCI had modest effects on locomotor, pain-like, and mood-related behaviors. Future studies should consider whether clinically-relevant circadian disruptors, alone or in combination, could be ameliorated to enhance outcomes after SCI.
Unveiling the phenology and associated floral regulatory pathways ofHumulus lupulusL. in subtropical conditions
Authors: Gutiérrez Robert Márquez , de Oliveira Raphael Ricon , Ribeiro Thales Henrique Cherubino , de Oliveira Kellen Kauanne Pimenta , Silva João Victor Nunes , Alves Tamires Caixeta , do Amaral Laurence Rodrigues , Gomes Marcos de Souza , Gomes Matheus de Souza , Chalfun-Junior Antonio 
Published: September 2023

AbstractTheHumulus lupulusL. (hops) is traditionally produced in temperate regions, historically attributed to the belief that vernalization was necessary for reproductive transition. Nevertheless, recent studies have revealed the potential for hop plants to flower in tropical and subtropical climates, thereby reshaping cultivation prospects once the developmental disparities are understood and adapted for optimized production. Here, we delved into the hop phenological cycle and the underlying floral regulatory pathways ultimately, seeking to devise strategies to modulate development and enhance production in regions with low latitudes. In contrast to cultivation in temperate regions, hops grown in the subtropical climate of Minas Gerais, Brazil, flower multiple times throughout the year, independently of the season. Hop is a short-day plant, and in Brazil, the photoperiod is consistently inductive due to daylight hours always being below the described threshold (16,5 h of light critical point). We observed that the reproductive transition of hop initiates after a specific number of nodes, 25 to 28, leading us to hypothesize that this process is primarily controlled by endogenous factors. To explore this issue, we first identified in the hop genome families of miRNAs related to reproductive transition, such as the families MIR156 and MIR172, and the PEBP family which includes the FLOWERING LOCUS T (FT). The expression of miR156 decreased along development inversely to miR172 and in synchrony with the upregulation of HlFT3 and HlFT5. These findings strongly support that the reproductive transition in hops under inductive photoperiodic conditions is primarily regulated by endogenous factors related to development and aging throughout the miRNA and FT-associated pathways. Thus, our study shedded light on the intricate molecular mechanisms that underlie hop floral development paving the way for potential advancements in hop production on a global scale.
Robust and scalable single-molecule protein sequencing with fluorosequencing
Authors: Mapes James H. , Stover Julia , Stout Heather D. , Folsom Tucker M. , Babcock Emily , Loudwig Sandra , Martin Christopher , Austin Mariah J. , Tu Fan , Howdieshell Casey J. , Simpson Zachary B. , Blom Thomas , Weaver Daniel , Winkler Daniel , Velden Kent Vander , Ossareh Parham M. , Beierle John M , Somekh Talli , Bardo Angela M. , Anslyn Eric V. , Marcotte Edward M. , Swaminathan Jagannath 
Published: September 2023

ABSTRACTThe need to accurately survey proteins and their modifications with ever higher sensitivities, particularly in clinical settings with limited samples, is spurring development of new single molecule proteomics technologies. Fluorosequencing is one such highly parallelized single molecule peptide sequencing platform, based on determining the sequence positions of select amino acid types within peptides to enable their identification and quantification from a reference database. Here, we describe substantial improvements to fluorosequencing, including identifying fluorophores compatible with the sequencing chemistry, mitigating dye-dye interactions through the use of extended polyproline linkers, and developing an end-to-end workflow for sample preparation and sequencing. We demonstrate by fluorosequencing peptides in mixtures and identifying a target neoantigen from a database of decoy MHC peptides, highlighting the potential of the technology for high sensitivity clinical applications.
Exponentially decreasing exposure of antigen generates anti-inflammatory T-cell responses
Authors: Esrafili Arezoo , Kupfer Joshua , Thumsi Abhirami , Sekhar Jaggarapu Madhan Mohan Chandra , Suresh Abhirami P. , Talitckii Aleksandr , Khodaei Taravat , Swaminathan Srivatsan J. , Mantri Shivani , Peet Matthew M , Acharya Abhinav P. 
Published: September 2023

AbstractRheumatoid Arthritis (RA) is a chronic debilitating disease characterized by auto-immune reaction towards self-antigen such as collagen type II. In this study, we investigated the impact of exponentially decreasing levels of antigen exposure on pro-inflammatory T cell responses in the collagen-induced arthritis (CIA) mouse model. Using a controlled delivery experimental approach, we manipulated the collagen type II (CII) antigen concentration presented to the immune system. We observed that exponentially decreasing levels of antigen generated reduced pro-inflammatory T cell responses in secondary lymphoid organs in mice suffering from RA. Specifically, untreated mice exhibited robust pro-inflammatory T cell activation and increased paw inflammation, whereas, mice exposed to exponentially decreasing concentrations of CII demonstrated significantly reduced pro-inflammatory T cell responses, exhibited lower levels of paw inflammation, and decreased arthritis scores in right rear paw. The data also demonstrate that the decreasing antigen levels promoted the induction of regulatory T cells (Tregs), which play a crucial role in maintaining immune tolerance and suppressing excessive inflammatory responses. Our findings highlight the importance of antigen concentration in modulating pro-inflammatory T cell responses in the CIA model. These results provide valuable insights into the potential therapeutic strategies that target antigen presentation to regulate immune responses and mitigate inflammation in rheumatoid arthritis and other autoimmune diseases. Further investigations are warranted to elucidate the specific mechanisms underlying the antigen concentration-dependent modulation of T cell responses and to explore the translational potential of this approach for the development of novel therapeutic interventions in autoimmune disorders.
Humanin vivomidtarsal and subtalar joint kinematics during walking, running, and hopping
Authors: Behling Anja-Verena , Welte Lauren , Kelly Luke , Rainbow Michael J 
Published: September 2023

AbstractThe interaction among joints of the midtarsal complex and subtalar joint is essential role for locomotor function; however, its complexity poses substantial challenges in quantifying their motions. We determine the mobility of these joints across locomotion tasks and investigate their alignment with individual talus morphology.Utilizing highly accurate biplanar videoradiography, three-dimensional bone kinematics were captured during walking, running, and hopping. We calculated the axis of rotation of each midtarsal and subtalar joint for the landing and push-off phases, respectively. A comparison was made between these rotation axes and the morphological subtalar axis. Measurement included total rotation about, the orientation of the rotation axes in the direction of the subtalar joint and its deviation via spatial angles for both phases.The rotation axes of all three bones relative to the talus closely align with the morphological subtalar axis. This suggests that the midtarsal and subtalar joints’ motions might be described by one commonly oriented axis. Despite having such axis, the location of axes and ranges of motion differed among the bones.Our results provide a novel perspective of healthy foot function across different sagittal plane-dominant locomotion tasks underscoring the importance of midtarsal and subtalar motion with respect to subject-specific talus morphology.