bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nanoscale Phosphoinositide Distribution on Cell Membranes of Mouse Cerebellar Neurons
Authors: Eguchi Kohgaku , Le Monnier Elodie , Shigemoto Ryuichi 
Published: May 2023

Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) plays an essential role in neuronal activities through interaction with various proteins involved in signaling at membranes. However, the distribution pattern of PI(4,5)P2and the association with these proteins on the neuronal cell membranes remain elusive. In this study, we established a method for visualizing PI(4,5)P2by SDS-digested freeze-fracture replica labeling (SDS-FRL) to investigate the quantitative nanoscale distribution of PI(4,5)P2in cryo-fixed brain. We demonstrate that PI(4,5)P2forms tiny clusters with a mean size of ∼1000 nm2rather than randomly distributed in cerebellar neuronal membranes in male C57BL/6J mice. These clusters show preferential accumulation in specific membrane compartments of different cell types, in particular, in Purkinje cell (PC) spines and granule cell (GC) presynaptic active zones. Furthermore, we revealed extensive association of PI(4,5)P2with CaV2.1 and GIRK3 across different membrane compartments, whereas its association with mGluR1α was compartment specific. These results suggest that our SDS-FRL method provides valuable insights into the physiological functions of PI(4,5)P2in neurons.SIGNIFICANCE STATEMENTIn this study, we established an electron microscopic method to visualize and analyze the quantitative distribution pattern of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) on cell membranes using cryo-fixed brain tissues and SDS-digested freeze-fracture replica labeling. PI(4,5)P2interacts with various ion channels and receptors to regulate membrane signaling but its nanoscale distribution and association with these proteins remain elusive. This method revealed PI(4,5)P2clusters preferentially accumulated in specific membrane compartments and its distinct associations with CaV2.1, GIRK3, and mGluR1α in the mouse cerebellum. These results demonstrate usefulness of the method for gaining insights into the physiological functions of PI(4,5)P2.
Prior Movement of One Arm Facilitates Motor Adaptation in the Other
Authors: Gippert Magdalena , Leupold Saskia , Heed Tobias , Howard Ian Spencer , Villringer Arno , Nikulin Vadim V. , Sehm Bernhard 
Published: May 2023

Many movements in daily life are embedded in motion sequences that involve more than one limb, demanding the motor system to monitor and control different body parts in quick succession. During such movements, systematic changes in the environment or the body might require motor adaptation of specific segments. However, previous motor adaptation research has focused primarily on motion sequences produced by a single limb, or on simultaneous movements of several limbs. For example, adaptation to opposing force fields is possible in unimanual reaching tasks when the direction of a prior or subsequent movement is predictive of force field direction. It is unclear, however, whether multilimb sequences can support motor adaptation processes in a similar way. In the present study (38 females, 38 males), we investigated whether reaches can be adapted to different force fields in a bimanual motor sequence when the information about the perturbation is associated with the prior movement direction of the other arm. In addition, we examined whether prior perceptual (visual or proprioceptive) feedback of the opposite arm contributes to force field-specific motor adaptation. Our key finding is that only active participation in the bimanual sequential task supports pronounced adaptation. This result suggests that active segments in bimanual motion sequences are linked across limbs. If there is a consistent association between movement kinematics of the linked and goal movement, the learning process of the goal movement can be facilitated. More generally, if motion sequences are repeated often, prior segments can evoke specific adjustments of subsequent movements.SIGNIFICANCE STATEMENTMovements in a limb's motion sequence can be adjusted based on linked movements. A prerequisite is that kinematics of the linked movements correctly predict which adjustments are needed. We show that use of kinematic information to improve performance is even possible when a prior linked movement is performed with a different limb. For example, a skilled juggler might have learned how to correctly adjust his catching movement of the left hand when the right hand performed a throwing action in a specific way. Linkage is possibly a key mechanism of the human motor system for learning complex bimanual skills. Our study emphasizes that learning of specific movements should not be studied in isolation but within their motor sequence context.
Neural α Oscillations and Pupil Size Differentially Index Cognitive Demand under Competing Audiovisual Task Conditions
Authors: Kraus Frauke , Tune Sarah , Obleser Jonas , Herrmann Björn 
Published: May 2023

Cognitive demand is thought to modulate two often used, but rarely combined, measures: pupil size and neural α (8–12 Hz) oscillatory power. However, it is unclear whether these two measures capture cognitive demand in a similar way under complex audiovisual-task conditions. Here we recorded pupil size and neural α power (using electroencephalography), while human participants of both sexes concurrently performed a visual multiple object-tracking task and an auditory gap detection task. Difficulties of the two tasks were manipulated independent of each other. Participants' performance decreased in accuracy and speed with increasing cognitive demand. Pupil size increased with increasing difficulty for both the auditory and the visual task. In contrast, α power showed diverging neural dynamics: parietal α power decreased with increasing difficulty in the visual task, but not with increasing difficulty in the auditory task. Furthermore, independent of task difficulty, within-participant trial-by-trial fluctuations in pupil size were negatively correlated with α power. Difficulty-induced changes in pupil size and α power, however, did not correlate, which is consistent with their different cognitive-demand sensitivities. Overall, the current study demonstrates that the dynamics of the neurophysiological indices of cognitive demand and associated effort are multifaceted and potentially modality-dependent under complex audiovisual-task conditions.SIGNIFICANCE STATEMENTPupil size and oscillatory α power are associated with cognitive demand and effort, but their relative sensitivity under complex audiovisual-task conditions is unclear, as is the extent to which they share underlying mechanisms. Using an audiovisual dual-task paradigm, we show that pupil size increases with increasing cognitive demands for both audition and vision. In contrast, changes in oscillatory α power depend on the respective task demands: parietal α power decreases with visual demand but not with auditory task demand. Hence, pupil size and α power show different sensitivity to cognitive demands, perhaps suggesting partly different underlying neural mechanisms.
The Anterior Cingulate Cortex Promotes Long-Term Auditory Cortical Responses through an Indirect Pathway via the Rhinal Cortex in Mice
Authors: Liang Ye , Li Jing , Tian Yu , Tang Peng , Liu Chunhua , Chen Xi 
Published: May 2023

Sensory cortical areas are robustly modulated by higher-order cortices. Our previous study shows that the anterior cingulate cortex (ACC) can immediately and transiently enhance responses in the mouse auditory cortex (ACx). Here, we further examined whether strong activation of ACC neurons can induce long-term effects in mice of both sexes. To our surprise, only stimulation of cell bodies in the ACC, but not ACC-to-ACx terminal activation, induced long-term enhancement of auditory responses in the ACx. Anatomical examination showed that the ACC indirectly projects to the ACx via the rhinal cortex (RCx). High-frequency stimulation of ACC-projecting terminals to the RCx or RCx-projecting terminals to the ACx induced a similar effect as the cell body activation of ACC neurons, whereas silencing the RCx blocked this long-term enhancement. High-frequency stimulation of ACC projections to the RCx also induced long-term augmentation of sound-evoked flight behavior in male mice. These results show that the ACC promotes the long-term enhancement of auditory responses in the ACx through an indirect pathway via the RCx.SIGNIFICANCE STATEMENTIn this study, we demonstrate that the anterior part of the anterior cingulate cortex (ACC) evokes long-term enhancement of auditory responses in the auditory cortex (ACx) when it is strongly activated. Importantly, instead of a direct projection, we show that the ACC implements this effect via an indirect pathway through the lateral rhinal cortex using a series of physiological, optogenetic, anatomic, and behavioral experiments. Along with a short-term effect, this long-term enhancement induced by an indirect ACC-to-ACx projection could increase the odds of survival when animals are faced with threats after a significant event.
Hypothalamic Corticotropin-Releasing Hormone Contributes to Hypertension in Spontaneously Hypertensive Rats
Authors: Zhang Hua , Zhou Jing-Jing , Shao Jian-Ying , Sheng Zhao-Fu , Wang Jingxiong , Zheng Peiru , Kang Xunlei , Liu Zhenguo , Cheng Zixi Jack , Kline David D. , Li De-Pei 
Published: May 2023

Corticotropin-releasing hormone (CRH) is a neuropeptide regulating neuroendocrine and autonomic function. CRH mRNA and protein levels in the hypothalamic paraventricular nucleus (PVN) are increased in primary hypertension. However, the role of CRH in elevated sympathetic outflow in primary hypertension remains unclear. CRHR1 proteins were distributed in retrogradely labeled PVN presympathetic neurons with an increased level in the PVN tissue in adult spontaneously hypertensive rats (SHRs) compared with age-matched male Wistar–Kyoto (WKY) rats. CRH induced a more significant increase in the firing rate of PVN-rostral ventrolateral medulla (RVLM) neurons and sympathoexcitatory response in SHRs than in WKY rats, an effect that was blocked by preapplication of NMDA receptors (NMDARs) antagonist AP5 and PSD-95 inhibitor, Tat-N-dimer. Blocking CRHRs with astressin or CRHR1 with NBI35965 significantly decreased the firing rate of PVN-RVLM output neurons and reduced arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) in SHRs but not in WKY, whereas blocking CRHR2 with antisauvagine-30 did not. Furthermore, Immunocytochemistry staining revealed that CRHR1 colocalized with NMDARs in PVN presympathetic neurons. Blocking CRHRs significantly decreased the NMDA currents in labeled PVN neurons. PSD-95-bound CRHR1 and PSD-95-bound GluN2A in the PVN were increased in SHRs. These data suggested that the upregulation of CRHR1 in the PVN is critically involved in the hyperactivity of PVN presympathetic neurons and elevated sympathetic outflow in primary hypertension.SIGNIFICANCE STATEMENTOur study found that corticotropin-releasing hormone receptor (CRHR)1 protein levels were increased in the paraventricular nucleus (PVN), and CRHR1 interacts with NMDA receptors (NMDARs) through postsynaptic density protein (PSD)-95 in the PVN neurons in primary hypertension. The increased CRHR1 and CRHR1-NMDAR-PSD-95 complex in the PVN contribute to the hyperactivity of the PVN presympathetic neurons and elevated sympathetic vasomotor tone in hypertension in SHRs. Thus, the antagonism of CRHR1 decreases sympathetic outflow and blood pressure in hypertension. These findings determine a novel role of CRHR1 in elevated sympathetic vasomotor tone in hypertension, which is useful for developing novel therapeutics targeting CRHR1 to treat elevated sympathetic outflow in primary hypertension. The CRHR1 receptor antagonists, which are used to treat health consequences resulting from chronic stress, are candidates to treat primary hypertension.
Oxidative stress enhances the therapeutic action of a respiratory inhibitor in MYC‐driven lymphoma
Authors: Donati Giulio , Nicoli Paola , Verrecchia Alessandro , Vallelonga Veronica , Croci Ottavio , Rodighiero Simona , Audano Matteo , Cassina Laura , Ghsein Aya , Binelli Giorgio , Boletta Alessandra , Mitro Nico , Amati Bruno 
Published: May 2023

AbstractMYC is a key oncogenic driver in multiple tumor types, but concomitantly endows cancer cells with a series of vulnerabilities that provide opportunities for targeted pharmacological intervention. For example, drugs that suppress mitochondrial respiration selectively kill MYC‐overexpressing cells. Here, we unravel the mechanistic basis for this synthetic lethal interaction and exploit it to improve the anticancer effects of the respiratory complex I inhibitor IACS‐010759. In a B‐lymphoid cell line, ectopic MYC activity and treatment with IACS‐010759 added up to induce oxidative stress, with consequent depletion of reduced glutathione and lethal disruption of redox homeostasis. This effect could be enhanced either with inhibitors of NADPH production through the pentose phosphate pathway, or with ascorbate (vitamin C), known to act as a pro‐oxidant at high doses. In these conditions, ascorbate synergized with IACS‐010759 to kill MYC‐overexpressing cells in vitro and reinforced its therapeutic action against human B‐cell lymphoma xenografts. Hence, complex I inhibition and high‐dose ascorbate might improve the outcome of patients affected by high‐grade lymphomas and potentially other MYC‐driven cancers.
Untargeted metabolomics reveal sex-specific and non-specific redox-modulating metabolites in kidneys following binge drinking
Authors: Rafferty Daniel , Martins de Carvalho Luana , Sutter Mason , Heneghan Katlyn , Nelson Victoria , Leitner Megan , Bolch Charlotte , Lasek Amy W , Puthanveetil Prasanth 
Published: May 2023

Graphical abstract

Abstract
Binge drinking is a growing health concern among all age groups. The ability of individuals to handle ethanol in their systems differs not due to differences in enzyme expression but also due to other factors. Vital organs including brain, liver, heart, and kidneys are at high risk following repeated exposure to high concentrations of ethanol from binge drinking. The impact of chronic binge drinking on kidneys is not well studied. Using a mouse model of chronic binge drinking, we have identified major metabolic alterations that could set the stage for detrimental effects in the kidneys of male and female mice. We have deciphered that even though there are pathway overlaps, the different sexes exhibited unique and divergent metabolic pathway dysregulations as per the metabolite panels following binge drinking. We have reported that binge drinking could negatively influence renal redox homeostasis in both sexes through the regulation of different metabolite clusters. In male mice by downregulation of pantothenic acid and riboflavin synthesis, and in female mice by upregulation of α-aminoadipic acid and formyl kynurenine level. Interestingly, the uric acid biosynthesis pathway has been upregulated independent of the sex-specific effects, portraying the significance of uric acid as a potential marker for binge drinking-induced injury in both sexes. Thus, by altering renal metabolome, binge drinking sets the stage for renal damage by disturbing renal redox balance. Our data has high translational potential and will aid in finding ideal therapeutics in a sex-specific manner for subjects exposed to binge drinking- induced renal injury.
Adverse Childhood Experiences Among US Adolescents Over the Course of the COVID-19 Pandemic
Authors: Hertz Marci , Heim Viox Melissa , Massetti Greta M. , Anderson Kayla N. , Bacon Sarah , Fordyce Erin , Mercado Melissa C. , Verlenden Jorge V. 
Published: May 2023

BACKGROUND AND OBJECTIVE
A national, longitudinal survey of US adolescents assessed adverse childhood experiences (ACEs) twice during the COVID-19 pandemic. Adolescents with more Wave 1 ACEs were expected to be more likely to experience additional ACEs at Wave 2.

METHODS
Adolescents aged 13 to 18 (n = 727, Fall 2020; n = 569, Spring 2021) recruited via a national, probability-based panel (survey completion rate Wave 1, 62.1%; Wave 2, 78.3%) responded to questions about household challenges, violence or neglect, and community ACE exposure at Wave 1 and Wave 2 (since Wave 1). Unweighted frequencies and 95% confidence intervals of demographic characteristics and individual ACEs were calculated by using weighted data. Odds ratios examined associations between ACEs by Wave 1 and Wave 2.

RESULTS
Among respondents of both survey waves (n = 506), 27.2% experienced violence or abuse, 50.9% experienced a household challenge, and 34.9% experienced a community ACE by Wave 1. By Wave 2, 17.6% experienced 1 new ACE, 6.1% experienced 2 new ACEs and 2.7% experienced 4 or more new ACEs. Those with ≥4 ACEs by Wave 1 were 2.71 times as likely as those with none to report a new ACE at Wave 2 (confidence interval: 1.18–6.24).

CONCLUSIONS
This nationwide, longitudinal study of US adolescents measured exposure to ACEs early in and during the COVID-19 pandemic. Nearly one-third of adolescents experienced a new ACE between survey waves. Prevention and trauma-informed approaches in clinical, school, and community settings may be helpful.
Acciones estatales para el desarrollo de las regiones Atlántico/Caribe y Chorotega de Costa Rica: una comparación de intenciones y resultados. 1950-2009
Authors: Blanco Obando Edgar Eduardo 
Published: May 2023

En el presente artículo se analizan las principales acciones estatales dirigidas al desarrollo de los sistemas productivos en las regiones Atlántico/Caribe y Chorotega de Costa Rica, así como a la expansión de los principales servicios para el bienestar de la población.
Mediante la revisión de numerosos documentos oficiales, estadísticos, científicos y técnicos se demuestra que, el Estado costarricense ha dirigido importante y continua inversión para incorporar a las regiones en el modelo económico nacional y asegurar a su población el acceso a los servicios esenciales. Sin embargo, dichas acciones no han sido suficientes para revertir las condiciones regionales de pobreza y desigualdad.
High seroprevalence of hepatitis E virus (HEV) in South Transdanubia, Hungary (2010–2022)
Authors: Balázs Benigna , Boros Ákos , Pankovics Péter , Reuter Gábor 
Published: May 2023

AbstractHepatitis E virus (HEV) is an increasingly recognized etiological agent of acute, chronic and extrahepatic human infections with primarily zoonotic origin in Europe. Limited numbers of comprehensive population-based studies are available related to HEV seroepidemiology, especially from Central Europe.The aim of this study was to investigate the seroprevalence and trends of total and IgM antibodies against HEV in different age groups in the population of South Transdanubia, Hungary, within a thirteen years long period between the years 2010 and 2022.We retrospectively analysed the serological test results of HEV total and HEV IgM antibodies carried out by ELISA technique using Dia.Pro (Diagnostic Bioprobes, Italy) kit from serum samples collected from patients with or without hepatitis between January 1, 2010 and December 31, 2022.The number of tested samples (∑6,996 for total antibody and ∑6,582 for IgM) increased during the study period. The average HEV total and the IgM antibody seropositivities were 33% (2,307/6,996 samples) and 9.6% (642/6,582 samples), respectively, in the study population. The HEV total antibody seropositivity varied in different age groups between 3.9% (age group 1–5 years) and 58.6% (86–90 years) and showed an increasing positivity by age. At the age groups >50 years, nearly half (43%) of the population had antibodies against HEV. The HEV IgM positivity had an increasing trend of up to 13.9% in the age group 81–85 years.High HEV total and IgM antibody seroprevalence were detected in South Transdanubia, Hungary, confirming that this region is highly endemic for HEV infections in Europe.
Expressing pain from the Antiquities to the Middle Ages: Heu as a part of speech
Authors: Cotugno Francesca 
Published: May 2023

AbstractThe interjection was recognised as a part of speech by the Latin grammarians, replacing the lack of the article class in the Greek system and maintaining the eight parts of speech. However, it is noteworthy that the definition of interjection among the different scholars and grammarians is not stable and wavers between the need to identify its role as a part of speech – whether it was an adverb or not – and its pragmatic function, identifying to what extent it was connected to emotions. The scholarly discussion over the interjection entangled and disentangled itself during the centuries, and its theoretical status has been verified in the present paper, which shows how the classical and non-classical evidence reconnects this part of speech to its most rhetorical function. This paper delves into this debate, focusing on the interjection heu and providing a history of the interjection, covering the classical period and the Middle Ages, according to the linguistic perspective and highlighting how Latin grammarians considered it in their linguistic framework.
Finite-Frequency Delay Times of Phase Segments for Body Waves
Authors: Jiang Yan , Chen Xiaofei 
Published: May 2023

ABSTRACT
We propose a new way of measuring the delay times of body waves, based on the time differences between short segments of a phase. Using this proposed methodology, which we call the delay time of phase segments (DTPSs) method, we believe it is possible to (1) optimize the reduction mode that reduces finite-frequency kernels to ray-theoretical kernels, (2) reduce computation and memory storage costs by reducing the volume of finite-frequency sensitivity kernels, and (3) achieve greater linearity between delay times and velocity variations for larger velocity perturbations up to ±30%. The DTPS kernel can also be used in adjoint methods. Theory and our calculations indicate that the width of the DTPS kernel decreases as the length of the phase segment decreases from the length of the entire phase. The scattering caused by inhomogeneity is more likely to complicate the latter parts of a phase more than its beginning. For this reason, the DTPS method using a phase segment in the first quarter of a phase is robust for velocity perturbations up to ±30% from the initial model, whereas traditional methods using the entire phase are only robust for velocity perturbations up to ±10%. The DTPS method may reduce computation times by up to 70% because the size of the DTPS kernels is smaller than that of other methods by up to 70%. Synthetic tests indicate that the DTPS method produces inverse models nearly as accurate as generalized seismological data functionals.