bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of sex-biased miRNA markers informative of heat-past events
Authors: van Gelderen Tosca A. , Montfort Jerome , Álvarez-Dios José Antonio , Piferrer Francesc , Bobe Julien , Ribas Laia 
Published: January 2024

AbstractElevated temperatures during early developmental stages play a pivotal role in the fate of the final sexual phenotype of fish populations, particularly towards male-skewed sex ratios. This is the case with European sea bass (Dicentrarchus labrax), one of the most important European species in the aquaculture industry. To unveil informative markers of the past thermal events, we investigated changes in the miRNome within the gonads of this species. Consequently, we exposed European sea bass to elevated temperatures during early development and conducted miRNA-sequencing analysis in the ovaries and testes one year post-heat treatment. The examination of miRNA expression levels identified three and twelve miRNAs in ovaries and testes, respectively, reflecting past thermal events. To assess the evolutionary conservation of these identified miRNAs in gonads, we cross-referenced our data with miRNome public information from ovaries and testes in nine additional fish species. This analysis uncovered 43 potential sex-biased markers present in at least five studied species along the evolutionary timeline. For instance, miR-155, miR-429, and miR-140 were female-skewed while miR-184, miR-499, and miR-135 were male-skewed. In addition, among these markers, eight conserved sex-skewed miRNAs proved informative regarding past thermal events in both the ovaries (e.g., miR-192-5p and miR-143-3p) and testes (miR-129-5p, miR-2187a-3p, miR-724-5p, miR-143-3p, miR-194a-5p and miR-223-3p). Notably, miR-223-3p and miR-194a-5p were conserved female-skewed, but showed upregulation in males exposed to high temperature. These miRNAs could serve as markers of heat-induced masculinization of genetic female-prone fish. The current research broadens the inventory of sex-specific miRNAs along evolution in fish and, elucidates thermosensitive miRNAs in the gonads. These findings hold promise as potential tools for predicting historical environmental events associated with masculinization due to high-temperature treatments in cultured species but also perhaps for natural populations exposed to a climate change scenario.
p66Shc Mediates SUMO2-induced Endothelial Dysfunction
Authors: Kumar Jitendra , Uppulapu Shravan K. , Kumari Sujata , Sharma Kanika , Paradee William , Yadav Ravi Prakash , Kumar Vikas , Kumar Santosh 
Published: January 2024

AbstractBackgroundSumoylation is a post-translational modification that can regulate different physiological functions. Increased sumoylation, specifically conjugation of SUMO2/3 (small ubiquitin-like modifier 2/3), is detrimental to vascular health. However, the molecular mechanism mediating this effect is poorly understood.MethodsWe used cell-based assays and mass spectrometry to show that p66Shc is a direct target of SUMO2 and SUMO2 regulates p66Shc function via lysine-81 modification. To determine the effects of SUMO2-p66ShcK81 on vascular function, we generated p66ShcK81R knockin mice and crossbred to LDLr-/-mice to induce hyperlipidemia. Next, to determine p66ShcK81-SUMO2ylation-induced changes in endothelial cell signaling, we performed mass spectrometry followed by Ingenuity Pathway Analysis.ResultsOur data reveal that p66Shc mediates the effects of SUMO2 on endothelial cells. Mass spectrometry identified that SUMO2 modified lysine-81 in the unique collagen homology-2 domain of p66Shc. SUMO2ylation of p66Shc increased phosphorylation at serine-36, causing it to translocate to the mitochondria, a step critical for oxidative function of p66Shc. Notably, sumoylation-deficient p66Shc (p66ShcK81R) was resistant to SUMO2-induced p66ShcS36 phosphorylation and mitochondrial translocation. P66ShcK81R knockin mice were resistant to endothelial dysfunction induced by SUMO2ylation and hyperlipidemia. Ingenuity Pathway Analysis revealed multiple signaling pathways regulated by p66ShcK81-SUMO2ylation in endothelial cells, highlighting Rho-GTPase as a major pathway affected by SUMO2-p66ShcK81.ConclusionsCollectively, our work reveals SUMO2-p66Shc signaling as a fundamental regulator of vascular endothelial function. We discovered that p66ShcK81 is an upstream modification regulating p66Shc signaling and mediates hyperlipidemia-induced endothelial dysfunction and oxidative stress.
Peripheral monocyte transcriptomics associated with immune checkpoint blockade outcomes in metastatic melanoma
Authors: Cooper Rosalin A , Taylor Chelsea A , Watson Robert A , Tong Orion , Nassiri Isar , Sharma Piyush Kumar , Little Martin , Ye Weiyu , Koturan Surya , Danielli Sara , Middleton Mark , Fairfax Benjamin P 
Published: January 2024

ABSTRACTClinical responses to immune checkpoint blockade (ICB) for metastatic melanoma (MM) are variable, with patients frequently developing immune related adverse events (irAEs). The role played by myeloid populations in modulating responses to ICB remains poorly defined. We explored the effect of MM and the response to ICB across a cohort of patients with MM (n=116) and healthy donors (n=45) using bulk and single cell RNA-seq, and flow cytometry. Monocytes from patients with MM exhibit highly dysregulated baseline transcriptional profiles, whilst ICB treatment elicits induction of interferon signaling, MHC class II antigen presentation and CXCR3 ligand expression. Although both combination (cICB - anti-PD-1 and anti-CTLA) and single-agent (sICB - anti-PD1) ICB therapy modulates a shared set of genes, cICB displays a markedly greater magnitude of transcriptional effect. Notably, we find increased baseline monocyte counts correlate with a monocyte proliferation signature and risk of early death, whilst a gene-signature corresponding to a subset of platelet-binding classical monocytes conversely associates with improved outcome. This work demonstrates a central role for monocytes in the modulation of treatment response to ICB, providing insights into inter-individual variation in immune responses to ICB and further highlighting the multifarious immunological consequences of ICB treatment.
Longitudinal progression of blood biomarkers reveals a key role of astrocyte reactivity in preclinical Alzheimer’s disease
Authors: Varma VR , An Y , Kac PR , Bilgel M , Moghekar A , Loeffler T , Amschl D , Troncoso J , Blennow K , Zetterberg H , Ashton NJ , Resnick SM , Thambisetty M 
Published: January 2024

AbstractDefining the progression of blood biomarkers of Alzheimer’s disease (AD) is essential for targeting treatments in patients most likely to benefit from early intervention. We delineated the temporal ordering of blood biomarkers a decade prior to the onset of AD symptoms in participants in the Baltimore Longitudinal Study of Aging. We show that increased astrocyte reactivity, assessed by elevated glial fibrillary acidic protein (GFAP) levels is an early event in the progression of blood biomarker changes in preclinical AD. In AD-converters who are initially cognitively unimpaired (N=158, 377 serial plasma samples), higher plasma GFAP levels are observed as early as 10-years prior to the onset of cognitive impairment due to incident AD compared to individuals who remain cognitively unimpaired (CU, N=160, 379 serial plasma samples). Plasma GFAP levels in AD-converters remain elevated 5-years prior to and coincident with the onset of cognitive impairment due to AD. In participants with neuropathologically confirmed AD, plasma GFAP levels are elevated relative to cognitively normal individuals and intermediate in those who remain cognitively unimpaired despite significant AD pathology (asymptomatic AD). Higher plasma GFAP levels at death are associated with greater severity of both neuritic plaques and neurofibrillary tangles. In the 5XFAD transgenic model of AD, we observed greater GFAP levels in the cortex and hippocampus of transgenic mice relative to wild-type prior to the development of cognitive impairment. Reactive astrocytosis, an established biological response to neuronal injury, may be an early initiator of AD pathogenesis and a promising therapeutic target.
Characterisation of laminar and vascular spatiotemporal dynamics of CBV and BOLD signals using VASO and ME-GRE at 7T in humans
Authors: Dresbach Sebastian , Huber Renzo , Gulban Omer Faruk , Pizzuti Alessandra , Trampel Robert , Ivanov Dimo , Weiskopf Nikolaus , Goebel Rainer 
Published: January 2024

AbstractInterpretation of cortical laminar functional magnetic resonance imaging (fMRI) activity requires detailed knowledge of the spatiotemporal haemodynamic response across vascular compartments due to the well-known vascular biases (e.g. the draining veins). Further complications arise from the spatiotemporal hemodynamic response that differs depending on the duration of stimulation. This information is crucial for future studies using depth-dependent cerebral blood volume (CBV) measurements, which promise higher specificity for the cortical microvasculature than the blood oxygenation level dependent (BOLD) contrast. To date, direct information about CBV dynamics with respect to stimulus duration, cortical depth and vasculature is missing in humans. Therefore, we characterized the cortical depth-dependent CBV-haemodynamic responses across a wide set of stimulus durations with 0.9 mm isotropic spatial and 0.785 seconds effective temporal resolution in humans using slice-selective slabinversion vascular space occupancy (SS-SI VASO). Additionally, we investigated signal contributions from macrovascular compartments using fine-scale vascular information from multiecho gradient-echo (ME-GRE) data at 0.35 mm isotropic resolution. In total, this resulted in>7.5h of scanning per participant (n=5). We have three major findings: (I) While we could demonstrate that 1 second stimulation is viable using VASO, more than 12 seconds stimulation provides better CBV responses in terms of specificity to microvasculature, but durations beyond 24 seconds of stimulation may be wasteful for certain applications. (II) We observe that CBV responses show dilation patterns across the cortex. (III) While we found increasingly strong BOLD signal responses in vessel-dominated voxels with longer stimulation durations, we found increasingly strong CBV signal responses in vessel-dominated voxels only until 4 second stimulation durations. After 4 seconds, only the signal from non-vessel dominated voxels kept increasing. This might explain why CBV responses are more specific to the underlying neuronal activity for long stimulus durations.
BBSome-dependent ciliary Hedgehog signaling governs cell fate in the white adipose tissue
Authors: Sieckmann Katharina , Winnerling Nora , Silva Ribeiro Dalila Juliana , Kardinal Ronja , Steinheuer Lisa Maria , Schermann Geza , Klausen Christina , Blank-Stein Nelli , Schulte-Schrepping Jonas , Osei-Sarpong Collins , Becker Matthias , Bonaguro Lorenzo , Beyer Marc , Thurley Kevin , May-Simera Helen Louise , Zurkovic Jelena , Thiele Christoph , Ruiz de Almodovar Carmen , Mass Elvira , Wachten Dagmar 
Published: January 2024

AbstractThe primary cilium has emerged as critical in regulating whole-body energy metabolism, as reflected in the Bardet-Biedl syndrome (BBS), where primary cilia dysfunction leads to obesity due to hyperphagia and white adipose tissue (WAT) remodeling. The regulation of cell fate and differentiation of adipocyte precursor cells (APCs) is key to maintaining WAT homeostasis during obesity. Using mice that recapitulated the BBS patient phenotype (Bbs8−/−), we demonstrate that primary cilia dysfunction reduces the stem-cell-like P1 APC subpopulation by inducing a phenotypic switch into a fibrogenic progenitor state, characterized by extracellular matrix (ECM) remodeling and upregulation of CD9. Single-cell RNA sequencing revealed a direct transition of stem-cell-like P1 cells into fibrogenic progenitors, bypassing the committed P2 cells. Ectopic ciliary Hedgehog signaling upon loss of BBS8 emerged as a central driver of the molecular changes inBbs8−/−APCs, altering differentiation into adipocytes and lipid uptake. These findings unravel a novel role for primary cilia in governing APC fate, determining the delicate balance between adipogenesis and fibrogenesis. The identified molecular mechanisms provide insights into potential therapeutic targets for obesity.
Oviposition status and sugar availability influence measures of transmission potential in malaria-infected mosquitoes
Authors: Shiau Justine C. , Garcia-Diaz Nathan , Kyle Dennis E. , Pathak Ashutosh K. 
Published: January 2024

ABSTRACTBackgroundLike other oviparous organisms, the gonotrophic cycle of mosquitoes is not complete until they have selected a suitable habitat to oviposit. In addition to the evolutionary constraints associated with selective oviposition behavior, the physiological demands relative to an organism’s oviposition status also influences their nutrient requirement from the environment. Yet, studies that measure transmission potential (vectorial capacity or competence) of mosquito-borne parasites rarely consider if the rates of parasite replication and development could be influenced by these constraints resulting from whether mosquitoes have completed their gonotrophic cycle.MethodsAnopheles stephensimosquitoes were infected withPlasmodium bergheithe rodent analog of human malaria and maintained on 1% or 10% dextrose and either provided oviposition sites (‘oviposited’ herein) to complete their gonotrophic cycle or forced to retain eggs (‘non-oviposited’). Transmission potential in the four groups was measured up to 27 days post-infection as 1) the rates of vector survival, 2) rates of sporozoite migration to the salivary glands (‘extrinsic incubation period’ or EIP), and 3), sporozoite densities.ResultsIn the two groups of oviposited mosquitoes, rates of sporozoite migration and densities in the salivary glands were clearly higher in mosquitoes fed 10% dextrose. In non-oviposited mosquitoes however, rates of sporozoite migration and densities were independent of sugar concentrations, although both measures were slightly lower than oviposited mosquitoes fed 10% dextrose. Rates of vector survival were higher in non-oviposited mosquitoes.ConclusionsTaken together, these results suggest vectorial capacity for malaria parasites may be dependent on nutrient availability and oviposition/gonotrophic status and as such, argue for more careful consideration of this interaction when estimating transmission potential; costs to parasite fitness and vector survival were buffered against changes in nutritional availability from the environment in non-oviposited mosquitoes, but not oviposited mosquitoes. In general, however, these patterns suggest parasite fitness may be dependent on complex interactions between physiological (nutrition) and evolutionary (egg-retention) trade-offs in the vector, with potential implications for disease transmission and management. For instance, while reducing availability of oviposition sites and environmental sources of nutrition are key components of integrated vector management strategies, their abundance and distribution is under strong selection pressure from the patterns associated with climate change.Graphical abstract
Branch-specific clustered parallel fiber input controls dendritic computation in Purkinje cells
Authors: Cirtala Gabriela , Schutter Erik De 
Published: January 2024

SummaryMost central neurons have intricately branched dendritic trees that integrate massive numbers of synaptic inputs. Intrinsic active mechanisms in dendrites can be heterogenous and be modulated in a branch-specific way. However, it remains poorly understood how heterogenous intrinsic properties contribute to processing of synaptic input. We propose the first computational model of the cerebellar Purkinje cell with dendritic heterogeneity, in which each branch is an individual unit and is characterized by its own set of ion channel conductance densities. When simultaneously activating a cluster of parallel fiber synapses, we measure the peak amplitude of a response (PAR) and observe how changes in P-type calcium channel conductance density shift PAR from a linear one to a bimodal one including dendritic calcium spikes and vice-versa. These changes relate to the morphology of each branch. We show how dendritic calcium spikes propagate and how Kv4 channels block spreading depolarization to nearby branches.
A senescence-specific lncRNA controls metabolic rewiring of senescent cells
Authors: Grossi Elena , Marchese Francesco P. , González Jovanna , Goñi Enrique , Amadoz Alicia , Herranz Nicolás , Montes Marta , Huarte Maite 
Published: January 2024

ABSTRACTDespite the classical view of senescence as passive growth arrest, it is an active process with profound implications for cellular homeostasis. Senescent cells remain metabolically active to be able to cope with the energetic demand of the senescence program, although the precise mechanisms underlying this metabolic reprogramming are just beginning to emerge. Here we have identifiedsin-lncRNA,a previously uncharacterized lncRNA, highly specific of senescent cells, and transcriptionally induced by C/EBPβ, the master regulator of the senescence-associated secretory phenotype (SASP). While being strongly activated in senescence,sin-lncRNAknockdown reinforces the senescence program by affecting oxidative phosphorylation and mitochondrial function.sin-lncRNAinteracts with the TCA enzyme dihydrolipoamide S-succinyltransferase (DLST) to facilitate its proper. sin-lncRNAdepletion increases DLST nuclear translocation, favoring a metabolic shift from oxidative phosphorylation to a glycolytic phenotype. Moreover, whilesin-lncRNAexpression remains low in highly proliferative cancer cells, it is strongly induced upon cisplatin-induced senescence. Knockdown ofsin-lncRNAin ovarian cancer cells results in deficient oxygen consumption and increased extracellular acidification, sensitizing the cells to cisplatin treatment. Altogether, these results indicate thatsin-lncRNAis specifically induced in cellular senescence to maintain metabolic homeostasis. Our findings reveal a new regulatory mechanism in which a lncRNA contributes to the adaptive metabolic changes in senescent cells, unveiling the existence of an RNA-dependent metabolic network specific to senescent cells.
Generation and characterization of CRISPR-Cas9-MediatedXPCGene Knockout in Human Skin Cells
Authors: Nasrallah Ali , Rezvani Hamid-Reza , Kobaisi Farah , Hammoud Ahmad , Rambert Jérôme , Smits Jos P.H. , Sulpice Eric , Rachidi Walid 
Published: January 2024

AbstractXeroderma pigmentosum group C (XPC) is a versatile protein, crucial for sensing DNA damage in the global genome nucleotide excision repair (GG-NER) pathway. This pathway is vital for mammalian cells, acting as their essential approach for repairing DNA lesions stemming from interactions with environmental factors, such as exposure to ultraviolet (UV) radiation from the sun. Loss-of-function mutations in theXPCgene confer a photosensitive phenotype in XP-C patients with the accumulation of unrepaired UV induced DNA damage. This remarkable increase in DNA damage tends to elevate by 10,000-fold the risk of developing melanoma and non-melanoma skin cancers. To date, creating accurate and reproducible models to study human XP-C disease has been an important challenge. To tackle this, we used CRISPR-Cas9 technology in order to knockoutXPCgene in various human skin cells (keratinocytes, fibroblasts, and melanocytes). After validation of theXPCknockout in these edited skin cells, we showed that they recapitulate the major phenotypes of XPC mutations: photosensitivity and the impairment of UV induced DNA damage repair. Moreover, these mutated cells demonstrated a reduced proliferative capacity compared to their respective wild-type controls. Finally, to better mimic the disease environment, we built a 3D reconstructed skin using these XPC knockout skin cells. This model exhibited an abnormal behavior, showing an extensive remodeling of its extracellular matrix compared to normal skin. Analyzing the composition of the fibroblasts secretome revealed a significant augmented shift in the inflammatory response following XPC knockout. Our innovative “disease on a dish” approach can provide valuable insights into the molecular mechanisms underlying XP-C disease, paving the way to design novel preventive and therapeutic strategies to alleviate the disease phenotype. Also, given the high risk of skin cancer onset in XP-C disease, our new approach can also serve as a link to draw novel insights towards this elusive field.
TRESK background potassium channel in MrgprA3+pruriceptors regulates acute and chronic itch
Authors: Llimós-Aubach Júlia , Andres-Bilbe Alba , Pujol-Coma Anna , Pallás Irene , de Anta Josep Maria , Soler Concepció , Comes Núria , Callejo Gerard , Gasull Xavier 
Published: January 2024

AbstractTRESK (K2P18.1) is a background K+channel expressed in sensory neurons, where it modulates the resting membrane potential, action potential firing and neuronal excitability. A subset of these sensory neurons, which express specific TRPs and Mas-related G protein-coupled receptors (Mrgprs), are activated by pruritogens and mediate itch sensations. Because TRESK is involved in somatosensation and pain transduction, we evaluated the contribution of this channel to pruritic sensitivity and its potential as a target for the treatment of chronic itch pathologies. By combining RNA in situ hybridization, calcium imaging, electrophysiological and behavioral approaches, we found that TRESK is involved in the modulation of non-histaminergic itch. TRESK is coexpressed with MrgprD+and MrgprA3+in sensory neurons and MrgprA3+neurons from TRESK-/-animals display an enhanced firing compared to WT counterparts. Interestingly, acute itch to intradermal injection of chloroquine is significantly enhanced in the absence of TRESK but not the response to histamine, BAM8-22 or LTC4. TRESK deletion also enhanced chronic itch in mice models of Allergic Contact Dermatitis and Dry Skin. In the mouse model imiquimod-induced psoriasiform dermatitis, the absence of TRESK produced a significantly enhanced scratching behavior, which developed earlier and was more robust. Finally, enhancing TRESK function with the channel activator cloxyquin diminished both acute and chronic itch in WT mice but not in KO animals. In summary, our data indicates that TRESK is involved in regulating the excitability of a subset of sensory neurons that mediate histaminergic-independent itch. Enhancing the channel function with specific activators constitutes a novel anti-pruritic therapeutic method that can be combined with other compounds for the treatment of non-histaminergic itch, for which appropriate treatments are lacking.