bluuebunny/crossref_metadata_2025_split huggingface dataset:
Natural variations in maternal behaviour shape trait anxiety and hippocampal neurogenesis in offspring
Authors: Grieco Fabio , van Gelderen Pauline , Larrieu Thomas , Toni Nicolas 
Published: September 2024

AbstractUnderstanding the early origins of emotional traits and baseline anxiety is crucial for the development of personalized medicine in mood disorders. While previous research primarily focused on extreme conditions like chronic maternal deprivation, in the present study, we investigated how natural variations in maternal care influence anxiety-related behaviour and neurogenesis in C57BL/6J offspring in a longitudinal manner. We observed that mothers engaging in low maternal care (LMC) displayed lower adult neurogenesis in both the olfactory bulb and the dentate gyrus of the hippocampus compared to high maternal care (HMC) mothers. We then observed that LMC-reared pups exhibited increased anxiety-related behaviour at postnatal day (PND) 5, 9, and 22. Furthermore, maternal behaviour induced the development of emotional individuality at early stage. This mood-related phenotype in LMC-reared offspring was associated with decreased neurogenesis after weaning at PND24. In another group of litters, we further examined neurogenesis at an earlier age (PND9) and already found a reduction in the population of adult neural progenitor cells and cell proliferation in the subgranular zone of the dentate gyrus of LMC-reared pups. These results highlight that natural variations in early life experiences such as maternal care, shape long-term brain plasticity and behaviour in offspring. This underscores the relevance of maternal care and adult neurogenesis in shaping personality-like traits related to mood disorders.
Stiffening Symphony of Aging: How Senescent Osteocytes Lose Their Elastic Rhythm
Authors: Tilton Maryam , Weivoda Megan , Potes Maria Astudillo , Gingery Anne , Liu Alan Y. , Tchkonia Tamara , Lu Lichun , Kirkland James L. 
Published: October 2024

AbstractSenescent osteocytes are key contributors to age-related bone loss and fragility; however, the impact of mechanobiological changes in these cells remains poorly understood. This study provides a novel analysis of these changes in primary osteocytes following irradiation-induced senescence. By integrating sub-cellular mechanical measurements with gene expression analyses, we identified significant, time-dependent alterations in the mechanical properties of these cells. Increases in SA-β-Gal activity and p16Ink4a expression levels confirmed the senescence status post-irradiation. Key findings include a time-dependent increase in cytoskeletal Young’s modulus and altered viscoelastic properties of the plasma membrane, affecting the contractility of primary osteocytes. Additionally, we observed a significant increase in Sclerostin (Sost) expression 21 days post-irradiation. These mechanobiological changes may impair osteocyte mechanosensation and mechanotransduction, contributing to bone fragility. This is the first study to time-map senescence-associated mechanical changes in the osteocyte cytoskeleton. Our findings highlight the potential of biophysical markers as indicators of cellular senescence, providing more specificity than traditional, variable biomolecular markers. We believe these results support biomechanical stimulation as a potential therapeutic strategy to rejuvenate aging osteocytes and enhance bone health.
Levodopa impairs lysosomal function in sensory neurons in vitro
Authors: Olaoye Oyedele J. , Aksoy Asya Esin , Hyytiäinen Santeri V. , Narits Aia A. , Hickey Miriam A. 
Published: October 2024

AbstractParkinson’s disease (PD) is the second-most common neurodegenerative disease world-wide. Patients are diagnosed based upon movement disorders, including bradykinesia, tremor and stiffness of movement. However, non-motor signs, including constipation, rapid eye movement sleep behavior disorder, smell deficits and pain are well recognized. Peripheral neuropathy is also increasingly recognized, as the vast majority of patients show reduced intraepidermal nerve fibers, and sensory nerve conduction and sensory function is also impaired. Many case studies in the literature show that high-dose levodopa, the primary drug used in the treatment of PD, may exacerbate neuropathy, thought to involve levodopa’s metabolism to homocysteine. Here, we treated primary cultures of dorsal root ganglia and a sensory neuronal cell line with levodopa to examine effects on cell morphology, mitochondrial content and physiology, and lysosomal function. High-dose levo-dopa reduced mitochondrial membrane potential. At concentrations observed in the patient, levo-dopa enhanced immunoreactivity to beta III tubulin. Critically, levodopa reduced lysosomal content and also reduced the proportion of lysosomes that were acidic while homocysteine tended to have the opposite effect. Levodopa is a critically important drug for the treatment of PD. However, our data suggests that at concentrations observed in the patient, it has deleterious effects on sensory neurons that are not related to homocysteine.Simple SummaryParkinson’s disease (PD) is one of the most common chronic, degenerative brain diseases worldwide. Patients are diagnosed on the basis of slowness of movement and/or tremor and/or stiffness. However, many symptoms that are not movement related are now well recognized. Patients show changes in skin sensation, and the vast majority of patients show loss of sensory neurites, which enable sensation in skin. These changes in skin sensation occur prior to diagnosis; however, sensory issues may also be exacerbated by levodopa, an important drug used in the treatment of PD. Undoubtedly, levodopa is critical for the treatment of PD, but at high doses, it has repeatedly been shown to impair sensation in PD patients. Here, we show for the first time that high-dose levodopa impairs function of sensory neurons. Importantly, we also show for the first time that lysosomes, a critical organelle involved in recycling, are impaired by levodopa concentrations observed in patients. These data are important given the well-known lysosomal dysfunction observed in PD. Our data sheds light on how levodopa, the most important drug in the treatment of PD, may contribute to sensory deficits in PD.
Efficacy and safety of an mRNA-based RSV preF vaccine in preclinical studies
Authors: Bai Huarong , Li Qin , Gao Yue , Zhao Yubin , Yu Xueliang , Hu Rongkuan 
Published: October 2024

AbstractThe transmembrane fusion (F) protein of RSV plays important roles in RSV pathogenesis as it mediates the fusion between virus and the target cell membrane. During the fusion process, F protein transits from a metastable state (prefusion, preF) to a stable state after merging of virus and cell membranes (postfusion, postF). The majority of highly neutralizing antibodies induced by natural infection or immunization targets the preF form, making it the preferred antigen for vaccine development. Here, we evaluate the mRNA vaccine candidate, STR-V003, which encapsulates the modified mRNA encoding the preF protein in lipid nanoparticles (LNPs). This vaccine demonstrated robust immunogenic in both mice and cotton rats. STR-V003 induced high levels of neutralizing antibodies and RSV preF-specific IgG antibodies, and significantly reduced the RSV viral loads in the lung and nose tissue of challenged animals. In addition, STR-V003 did not have obvious enhancement of lung pathology without causing vaccine enhanced disease (VED). The repeated dose general toxicology studies and local tolerance studies of STR-V003 were evaluated in rats. Therefore, STR-V003 has an acceptable safety profile and robust protective immunity against RSV, and has been approved by the FDA to enter phase I clinical study (NCT06344975).
WITHDRAWN: Tartrazine cannot make live tissues transparent
Authors: Inagaki Shigenori , Imai Takeshi 
Published: September 2024

Withdrawal StatementThe authors have withdrawn their manuscript because one of the conclusions was wrong. The authors sincerely apologize to Ou et al. and the research community for the confusion. In this preprint, the authors performed an abdominal skin clearing experiment following the methods section in Ou et al. (ref. 1) and observed only a marginal clearing effect. In this condition (Figure 1), the authors detected tartrazine only in the stratum corneum (SC) of the skin, where only dead cells are present (Figure 1E, F). However, following a more detailed protocol with additional tips kindly provided by Ou et al. (ref. 1), the abdominal skin became more transparent. It seems that mechanical damage to the SC barrier is critical for successful clearing. In this condition, the authors detected strong tartrazine signals under the SC, including the dermis where live cells are located. We are still concerned about the issue of osmolality and toxicity to live cells; cleared cells must be under hypertonic conditions (Figure 3 and 4). However, since Figure 1 (especially Figure 1E, F) no longer stands, and the title can be misinterpreted as if the original results (ref. 1) were irreproducible, the authors believe it is best to withdraw this preprint. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Phagocytosis is differentially regulated by LPS in M1- and M2-like macrophages via PGE2formation and EP4 signaling
Authors: Kirchhoff Rebecca , Chromik Michel André , Schebb Nils Helge 
Published: October 2024

AbstractPhagocytosis is a key process in human innate immune response. Human macrophages are important phagocytes engulfing and neutralizing pathogens and cell debris. In addition, they modulate the inflammatory process by releasing cytokines and lipid mediators. However, the link between oxylipins and phagocytosis in different macrophage phenotypes remains poorly understood.In order to better understand the link between phagocytosis and the arachidonic acid (ARA) cascade, we established a phagocytosis assay in primary human ‘inflammatory’ M1- and ‘anti-inflammatory’ M2-like macrophages from PBMCs, representing extremes of macrophage phenotypes. The branches of the ARA cascade were investigated by quantitative targeted proteomics and metabolomics.M1-like macrophages show a higher abundance of cyclooxygenase (COX)-2 and its products particularly after LPS stimulus compared to M2-like macrophages. LPS increased phagocytosis in M2-like, but not in M1-like macrophages. We demonstrate that the COX product PGE2modulates the differential effects of LPS on phagocytosis: Via the EP4 receptor PGE2signaling suppresses phagocytosis in primary human macrophages. Thus, blockage of COX, e.g. by NSAID, leads to an increase of phagocytosis also in ‘inflammatory’ M1-like macrophages and may shift the macrophages towards a more pro-resolving phenotype. This supports the well-described anti-inflammatory effects of these drugs.
Mitochondria-centered metabolomic map of inclusion body myositis: sex-specific alterations in central carbon metabolism
Authors: Naddaf Elie , Shammas Ibrahim , Dasari Surendra , Petterson Xuan-Mai T. , Trushina Eugenia , Lanza Ian R. 
Published: October 2024

ABSTRACTBackgroundInclusion body myositis (IBM) is a disease of aging characterized by progressive muscle loss. Despite its positioning at the intersection of aging, mitochondrial dysfunction and chronic inflammation, limited studies have evaluated the underlying metabolic disturbances in IBM.ObjectiveTo investigate the mitochondria-centered metabolomic map of IBM in muscle tissue, highlighting sex-specific differences, and to determine the correlation of the changes in metabolites and gene expression with clinical parameters.Methods37 IBM patients and 22 controls without a myopathy were included. All participants had bulk RNA sequencing performed previously. Clinical parameters included age at biopsy, disease duration, manual motor test (MMT) score, and modified Rankin scale (MRS). A complementary battery of metabolomics platforms was used, including untargeted metabolomics, Agilent dMRM Database and Method platform, and targeted metabolomics. Metabolite levels and RNA-metabolomics integrated modules were correlated with clinical parameters.ResultsMuscle samples from IBM patients had elevated TCA cycle intermediates with concomitant increase in anaplerotic amino acids, suggesting increased anaplerosis into the cycle. There was a decrease in upper glycolysis intermediates and an increase in most of the pentose phosphate pathway (PPP) metabolites. The PPP is the main source of NAPDH, a main antioxidant, and ribose-5-P a precursor of nucleic acids. There were marked sex-specific differences in the acylcarnitine profile, with a decrease in short-chain acylcarnitines only in males. Lastly, there was an increase in nucleic acid bases and a decrease in nucleotides. Several metabolites from various pathways had significant correlations with various clinical parameters, with the most pronounced sex-specific differences observed in correlations with acylcarnitines. RNA-metabolomics integration identified 4 modules, with the strongest correlation observed between one module and sex. The MMT score, an indicator of disease severity, showed a strong correlation with 3 modules. There were major sex specific differences with males having relatively similar correlation to the grouped (both sexes) analysis, while females had no significant correlation with any of the modules.ConclusionTaken together, our findings identified clinically significant alterations in central carbon metabolism in IBM, with major differences between males and females. Future studies are needed to determine the role of the detected metabolic alterations in IBM pathogenesis and track the changes longitudinally over the disease course.
Imprecise counting of observations in averaging tasks predicts primacy and recency effects
Authors: Prat-Carrabin Arthur , Woodford Michael 
Published: October 2024

AbstractPrimacy and recency effects — wherein early and recent observations exert disproportionate influence on judgments — have long been noted in cognitive tasks involving the sequential presentation of information. In studies where human subjects make decisions based on the average of a sequence of numbers, recency effects are typically modeled phenomenologically through exponential discounting, while primacy effects are neglected altogether. Here, we exhibit the prevalence of both effects in such tasks, and propose that they result from the observer’s imprecision in their running tally of how many pieces of information they have received. If their approximate counting follows a central tendency — a typical Bayesian pattern — then past information is overweighted near the beginning of the sequence, while new numbers are overweighted towards the end of the sequence. Thus both primacy and recency effects are simultaneously predicted by this single mechanism. The model moreover nests exponential discounting as a special case in which the observer has no information about the count. The behavioral data suggests that subjects indeed misestimate the count of observations, with biases similar to those observed in numerosity-estimation tasks. Finally, we present evidence that the central tendency of subjects shifts towards lower counts in tasks with shorter sequence lengths, consistent with a Bayesian estimation of the counts. These findings provide new insights into the cognitive processes underlying serial-position effects in averaging tasks, with broader implications for other cognitive domains.
HNF4α-TET2-FBP1 axis contributes to gluconeogenesis and type 2 diabetes
Authors: Li Hongchen , Zhang Xinchao , Liang Xiaoben , Li Shuyan , Cui Ziyi , Zhao Xinyu , Wang Kai , Zha Bingbing , Ma Haijie , Xu Ming , Lv Lei , Xu Yanping 
Published: October 2024

AbstractThe control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, and TET2 knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4α, contributing to the demethylation of FBP1 promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4α on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4α-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D.
Leveraging CRISPR activation for rapid assessment of gene editing products in human pluripotent stem cells
Authors: Wu Youjun , Zhong Aaron , Evangelisti Alessandro , Sidharta Mega , Studer Lorenz , Zhou Ting 
Published: October 2024

AbstractVerification of genome editing in human pluripotent stem cells (hPSCs), particularly in silent locus is desirable but challenging because it often requires complex and time-intensive lineage-specific or tissue-specific differentiation to induce their expression. Here, we establish a rapid and effective workflow for the verification of hPSC lines with genome editing in unexpressed genes using CRISPR-mediated transcriptional activation (CRISPRa). We systematically compared the efficiency of various CRISPRa systems in hPSCs, identifying the SAM system as the most potent for activating silent genes in hPSCs. Furthermore, we demonstrated enhanced gene activation by combining the SAM system with TET1, a demethylation module. By inducing targeted gene activation in undifferentiated hPSCs using CRISPRa, we successfully verified single and dual reporter hPSC lines and conducted functional tests of dTAG knock-ins and silent gene knockouts within 48 hours. This approach eliminates the need for cell differentiation to access genes only expressed by differentiated cells, offering a handy assay for verifying gene editing in hPSCs.
Impaired speaking-induced suppression predicts degraded agency and hallucination severity in schizophrenia
Authors: Tan Songyuan , Jia Yingxin , Mathew Miriam , Jariwala Namasvi , Pongos Alvincé , Brent Kurtis , Ford Judith , Mathalon Daniel , Houde John , Nagarajan Srikantan , Subramaniam Karuna 
Published: October 2024

AbstractBackgroundAgency is the awareness of being the originator of one’s own thoughts and actions. Patients with schizophrenia (SZ) show deficits in agency that contribute to distortions in reality-monitoring (distinguishing self-generated from externally-produced information) and result in psychotic symptoms. Agency is also critical for speech-monitoring (monitoring what we hear ourselves say while speaking). For example, disruptions in agency that manifest as hallucinations are thought to result from the misattribution of the source of patients’ inner thoughts/speech as external voices.MethodsWe used magnetoencephalography (MEG) to assay assess agency during reality-monitoring (RM) and speech-monitoring (SM) tasks. In healthy controls (HC) during SM, the auditory cortical (A1) response is smaller while speaking (speak condition) compared to listening to the same speech (listen condition). This is known as speaking-induced suppression (SIS) M100 response which is measured using MEG 100ms after speech onset.ResultsDuring RM, SZ (N=30) showed impairments in both self-agency (identification of self-generated information) and external-agency (identification of externally-produced information), compared to HC (N=30). During SM, SZ failed to enhance M100 A1 responses during the listen condition and suppress M100 A1 responses while speaking, revealing impaired SIS. Weakened SIS predicted worsening hallucination severity.ConclusionsSZ showed degraded neural M100 responses in A1 during the listen condition which drove impaired suppression of M100 SIS during highly-predictable self-generated speech. Impaired SIS induced noisier auditory sensory predictions, making it more likely for SZ to misattribute the source of inner thoughts/speech as externally-derived, giving rise to disruptions in agency during RM and more severe hallucinations.
Spatiotemporal properties of cortical excitatory and inhibitory neuron activation by sustained and bursting electrical microstimulation
Authors: Hughes Christopher L , Stieger Kevin A , Chen Keying , Vazquez Alberto L , Kozai Takashi DY 
Published: October 2024

AbstractIntracortical microstimulation (ICMS) of sensory cortices produces artificial sensation yet the neural mechanisms underlying evoked responses, particularly among inhibitory subpopulations, remain unclear. We investigated how long durations (30 s) of ICMS shape spatiotemporal patterns in excitatory and inhibitory network activation using two-photon imaging of visual cortex in transgenic mice. Inhibitory neurons were more likely to facilitate (increase in activation) across 30 s of ICMS, whereas excitatory neurons were more likely to adapt (decrease in activation) and exhibit post-ICMS depression. Different temporal profiles led to preferential activation of excitatory or inhibitory neurons, with theta-burst stimulation driving the strongest inhibitory response and 10-Hz burst patterns driving the strongest peak excitatory response. Neurons located farther from the electrode exhibited more diverse responses to ICMS, highlighting synaptic recruitment dynamics such as inhibition and disinhibition. This study reveals how ICMS differentially influences excitatory and inhibitory neuron activity across long durations of ICMS and suggests temporal patterning can be used to potentially target neuronal subpopulations and drive desirable activity patterns.
Promiscuous and multivalent interactions between Eps15 and partner protein Dab2 generate a complex interaction network
Authors: Papagiannoula Andromachi , Vedel Ida Marie , Motzny Kathrin , Tengo Maud , Saiti Arbesa , Milles Sigrid 
Published: October 2024

AbstractClathrin-mediated endocytosis depends on complex protein interactions. Eps15 plays a key role through interactions of its three EH domains with Asn-Pro-Phe (NPF) motifs in intrinsically disordered regions (IDRs) of other endocytic proteins. Using nuclear magnetic resonance spectroscopy, we investigate the interaction between Eps15’s EH domains and a highly disordered Dab2 fragment (Dab2₃₂₀₋₄₉₅). We find that the EH domains exhibit binding promiscuity, recognizing not only the NPF motif of Dab2 but also other phenylalanine containing motifs. This promiscuity enables interactions with Eps15’s own IDR (Eps15IDR), which lacks NPF motifs, suggesting an self-inhibitory state that promotes liquid-liquid phase separation. Despite competing for the same EH domain binding sites, Eps15IDRand Dab2₃₂₀₋₄₉₅ can bind EH123 simultaneously, forming a highly dynamic interaction network that facilitates the recruitment of Dab2₃₂₀₋₄₉₅ into Eps15 condensates. Our findings provide molecular insights into the competitive interactions shaping the early stages of clathrin-mediated endocytosis.