bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological Enhancement of Adult Hippocampal Neurogenesis Improves Behavioral Pattern Separation in Young and Aged Mice
Authors: Chang Wei-li , Tegang Karly , Samuels Benjamin A. , Saxe Michael , Wichmann Juergen , David Denis J. , David Indira Mendez , Augustin Angélique , Fischer Holger , Golling Sabrina , Lamerz Jens , Roth Doris , Graf Martin , Zoffmann Sannah , Santarelli Luca , Jagasia Ravi , Hen René 
Published: February 2024

AbstractBACKGROUNDImpairments in behavioral pattern separation (BPS)—the ability to distinguish between similar contexts or experiences—contribute to memory interference and overgeneralization seen in many neuropsychiatric conditions, including depression, anxiety, PTSD, dementia, and age-related cognitive decline. While BPS relies on the dentate gyrus and is sensitive to changes in adult hippocampal neurogenesis (AHN), its significance as a pharmacological target has not been tested.METHODSIn this study, we applied a human neural stem cell high-throughput screening cascade to identify compounds that increase human neurogenesis. One compound with a favorable profile, RO6871135, was then tested in BPS in mice.RESULTSChronic treatment with RO6871135, 7.5 mg/kg increased AHN and improved BPS in a fear discrimination task in both young and aged mice. RO6871135 treatment also lowered innate anxiety-like behavior, which was more apparent in mice exposed to chronic corticosterone. Ablation of AHN by hippocampal irradiation supported a neurogenesis-dependent mechanism for RO6871135-induced improvements in BPS. To identify possible mechanisms of action, in vitro and in vivo kinase inhibition and chemical proteomics assays were performed. These tests indicated that RO6871135 inhibited CDK8, CDK11, CaMK2a, CaMK2b, MAP2K6, and GSK3b. An analog compound also demonstrated high affinity for CDK8, CaMK2a, and GSK3b.CONCLUSIONSThese studies demonstrate a method for empirical identification and preclinical testing of novel neurogenic compounds that can improve BPS, and points to possible novel mechanisms that can be interrogated for the development of new therapies to improve specific endophenotypes such as impaired BPS.
Distractor suppression operates exclusively in retinotopic coordinates
Authors: Ilksoy Yayla A. , van Moorselaar Dirk , Wang Benchi , Los Sander A. , Theeuwes Jan 
Published: February 2024

AbstractOur attention is influenced by past experiences, and recent studies have shown that individuals learn to extract statistical regularities in the environment, resulting in attentional suppression of locations that are likely to contain a distractor (high-probability location). However, little is known as to whether this learned suppression operates in retinotopic (relative to the eyes) or spatiotopic (relative to the world) coordinates. In the current study, two circular search arrays were presented side by side. Participants learned the high-probability location from a learning array presented on one side of the display (e.g., left). After several trials, participants shifted their gaze to the center of the other search array (e.g., located on the right side) and continued searching without any location probability (labelled as “test array”). Due to the saccade, the test array contained both a spatiotopic and a retinotopic matching location relative to the original high-probability location. The current findings show that, following saccadic eye movements, the learned suppression remained in retinotopic coordinates only, with no measurable transfer to spatiotopic coordinates. Even in a rich environment, attentional suppression still operated exclusively in retinotopic coordinates. We speculate that learned suppression may be resolved by changing synaptic weights in early visual areas.Significance statementIn our daily lives, attention is shaped by past experiences, guiding us to suppress locations that are likely to contain distractions. While this phenomenon has been studied extensively with static search displays, the real world is dynamic - we are constantly moving our eyes. This study addressed this issue by investigating what happens when we learn to suppress a likely distractor location while making eye movements. Do we suppress the same location in space (spatiotopic), or does the learned suppression persist relative to our eyes (retinotopic)? The current findings provide clear evidence of suppression in retinotopic coordinates only.
Neural substrates underlying the expectation of rewards resulting from effortful exertion
Authors: Kim Aram , Chib Vikram S. 
Published: February 2024

AbstractExpectations as a reference point shape our decisions to motivate effortful activity. Despite the important role of reference points in human performance, little is known about how the brain processes expectations to guide motivated exertion. Participants completed a reward-based effort task in an MRI scanner. During each trial, participants were presented with a risky option that would either result in a fixed monetary payment, regardless of their effort exertion, or a piece-rate payment where the payment was proportional to the amount of effort exerted. We found that participants exerted more effort as the fixed payment increased, suggesting that the fixed payment influenced the reference point for effort exertion. The strength of this reference-dependent behavior was correlated with neural activity in the ventral striatum, which was significantly modulated by the deviation from the payoff to reward expectations after effort exertion. Our results suggest that value-related brain areas, particularly the ventral striatum, encode expectations of reward as a reference point to motivate effort exertion.One-Sentence SummaryValue-related brain areas process reward expectations and how we evaluate outcomes based on that.
Suppression of ERK signalling promotes pluripotent epiblast in the human blastocyst
Authors: Simon Claire S. , McCarthy Afshan , Woods Laura , Staneva Desislava , Huang Qiulin , Linneberg-Agerholm Madeleine , Faulkner Alex , Papathanasiou Athanasios , Elder Kay , Snell Phil , Christie Leila , Garcia Patricia , Shaikly Valerie , Taranissi Mohamed , Choudhary Meenakshi , Herbert Mary , Brickman Joshua M. , Niakan Kathy K. 
Published: February 2024

AbstractStudies in the mouse demonstrate the importance of fibroblast growth factor (FGF) and extra-cellular receptor tyrosine kinase (ERK) in specification of embryo-fated epiblast and yolk-sac-fated hypoblast cells from uncommitted inner cell mass (ICM) cells prior to implantation. Molecular mechanisms regulating specification of early lineages in human development are comparatively unclear. Here we show that exogenous FGF stimulation leads to expanded hypoblast molecular marker expression, at the expense of the epiblast. Conversely, we show that specifically inhibiting ERK activity leads to expansion of epiblast cells functionally capable of giving rise to naïve human pluripotent stem cells. Single-cell transcriptomic analysis indicates that these epiblast cells downregulate FGF signalling and upregulate molecular markers associated with naïve pluripotency. Our functional study demonstrates for the first time the molecular mechanisms governing ICM specification in human development, whereby segregation of the epiblast and hypoblast lineages occurs during maturation of the mammalian embryo in an ERK signal-dependent manner.
Deep learning-based location decoding reveals that across-day representational drift is better predicted by rewarded experience than time
Authors: Freud Kipp , Lepora Nathan , Jones Matt W. , O’Donnell Cian 
Published: February 2024

ABSTRACTNeural representations of locational and spatial relations in the hippocampus and related brain areas change over timescales of days-weeks, even in familiar contexts and when behavior appears stable. It remains unclear how this ‘representational drift’ is driven by combinations of the passage of time, general experience or specific features of experience. We present a novel deep-learning approach for measuring network-level representational drift, quantifying drift as the rate of change in decoder error of deep neural networks as a function of train-test lag. Using this method, we analyse a longitudinal dataset of 0.5–475 Hz broadband local field potential (LFP) data recorded from dorsal hippocampal CA1, medial prefrontal cortex and parietal cortex of six rats over ∼30 days, during learning of a spatial navigation task in an initially unfamiliar environment. All three brain regions contained clear spatial representations which evolve and drift over training sessions. We find that the rate of drift slows for later training sessions. Finally, we find that drift is statistically better explained by task-relevant experiences within the maze, rather than the passage of time or number of sessions the animal spent on the maze. While previous research has focused on drift as a measure of the changes in spiking activities of units, here we examine drift as a measure of change in oscillatory activity of local field potentials; our approach of using of deep neural networks to quantify drift in broadband neural time series unlocks new possibilities for defining the drivers and functional consequences of representational drift.
NeuroTri2-VISDOT: An open-access tool to harness the power of second trimester human single cell data to inform models of Mendelian neurodevelopmental disorders
Authors: Clark Kelly J. , Lubin Emily E. , Gonzalez Elizabeth M. , Sangree Annabel K. , Layo-Carris Dana E. , Durham Emily L. , Ahrens-Nicklas Rebecca C. , Nomakuchi Tomoki T. , Bhoj Elizabeth J. 
Published: February 2024

AbstractWhole exome and genome sequencing, coupled with refined bioinformatic pipelines, have enabled improved diagnostic yields for individuals with Mendelian conditions and have led to the rapid identification of novel syndromes. For many Mendelian neurodevelopmental disorders (NDDs), there is a lack of pre-existing model systems for mechanistic work. Thus, it is critical for translational researchers to have an accessible phenotype- and genotype-informed approach for model system selection. Single-cell RNA sequencing data can be informative in such an approach, as it can indicate which cell types express a gene of interest at the highest levels across time. For Mendelian NDDs, such data for the developing human brain is especially useful. A valuable single-cell RNA sequencing dataset of the second trimester developing human brain was produced by Bhaduri et al in 2021, but access to these data can be limited by computing power and the learning curve of single-cell data analysis. To reduce these barriers for translational research on Mendelian NDDs, we have built the web-based tool,Neurodevelopment inTrimester2-VIsualization ofSingle cellDataOnlineTool (NeuroTri2-VISDOT), for exploring this single-cell dataset, and we have employed it in several different settings to demonstrate its utility for the translational research community.
Task-irrelevant phase but not contrast variability unlocks generalization in visual perceptual learning
Authors: Akkoyunlu Beyza , Schwiedrzik Caspar M. 
Published: February 2024

AbstractPerformance on visual tasks can be improved by practice, a process called visual perceptual learning. However, learning-induced performance improvements are often limited to the specific stimuli and visual field locations used during training. Recent research has shown that variability along task-irrelevant stimulus dimensions during training can reduce this specificity. This has been related to higher stages of visual processing that harbor neurons which are invariant to the task-irrelevant dimension. Here, we test whether task-irrelevant trial-by-trial variability in two visual features for which invariances arise at different stages of processing, contrast and spatial phase, results in different degrees of generalization in space in an orientation discrimination task. We find that randomizing spatial phase results in complete generalization of learning to a new spatial location, contrary to randomizing contrast. Our results thus suggest that the neural population undergoing plasticity in visual perceptual learning is determined by the training task, which, in turn, affects generalization. This lends further support to the hypothesis that task-irrelevant variability is an independent factor in determining the specificity of perceptual learning.
Vasopressin 1a receptor antagonist disrupts male-male affiliative relationships formed by triadic cohabitation in large-billed crows
Authors: Seguchi Akiko , Izawa Ei-Ichi 
Published: February 2024

AbstractSame-sex affiliative relationships are common in humans and some social animals, forming one of the bases of group living. The neuropeptide vasopressin (VP) and its receptors mediate these relationships and behaviours in mammals and birds with gregarious and colonial social structures. In some species, affiliative relationships between dominant and subordinate individuals can be maintained while still retaining strict dominance hierarchies where three or more individuals interact. However, it is unclear whether triadic interaction promotes these relationships, and whether the VP system is also involved in such affiliations due to the lack of suitable animal models and experimental settings. This study addresses these questions with two experiments. In Experiment 1, two-week cohabitation among three male crows facilitated affiliative relationships in particular dyads within each triad. In Experiment 2, vasopressin 1a receptor (V1aR) antagonism disrupted affiliative behaviours and led to the resurgence of agonistic behaviours in affiliated males but not in unaffiliated ones by peripherally administering a V1aR antagonist. These findings suggest that the VP system might universally mediate same-sex affiliative relationships, despite differences in inherent aggression levels among individuals. The triadic cohabitation paradigm established here could advance our understanding of animal societies and be applied across various species, sexes, and social structures.Impact statementThis study provides evidence that a triadic interactive environment facilitates the formation of affiliative relationship between specific dominant and subordinate males in large-billed crows, with crucial involvement of vasopressin 1a receptor in maintaining this affiliation.
A genetically modulated Toll-like-receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome
Authors: Khan Rehan , Ji Weizhen , Guzman-Rivera Jeisac , Madhvi Abhilasha , Andrews Tracy , Richlin Benjamin , Suarez Christian , Gaur Sunanda , Cuddy William , Singh Aalok R. , Bukulmez Hulya , Kaelber David , Kimura Yukiko , Ganapathi Usha , Michailidis Ioannis E. , Ukey Rahul , Moroso-Fela Sandra , Kuster John K. , Casseus Myriam , Roy Jason , Kleinman Lawrence C. , Horton Daniel B. , Lakhani Saquib A. , Gennaro Maria Laura 
Published: February 2024

AbstractDysregulated innate immune responses contribute to multisystem inflammatory syndrome in children (MIS-C), characterized by gastrointestinal, mucocutaneous, and/or cardiovascular injury occurring weeks after SARS-CoV-2 exposure. To investigate innate immune functions in MIS-C, we stimulatedex vivoperipheral blood cells from MIS-C patients with agonists of Toll-like receptors (TLR), key innate immune response initiators. We found severely dampened cytokine responses and elevated gene expression of negative regulators of TLR signaling. Increased plasma levels of zonulin, a gut leakage marker, were also detected. These effects were also observed in children enrolled months after MIS-C recovery. Moreover, cells from MIS-C children carrying rare genetic variants of lysosomal trafficking regulator (LYST) were less refractory to TLR stimulation and exhibited lysosomal and mitochondrial abnormalities with altered energy metabolism. Our results strongly suggest that MIS-C hyperinflammation and/or excessive or prolonged stimulation with gut-originated TLR ligands drive immune cells to a lasting refractory state. TLR hyporesponsiveness is likely beneficial, as suggested by excess lymphopenia among rareLYSTvariant carriers. Our findings point to cellular mechanisms underlying TLR hyporesponsiveness; identify genetic determinants that may explain the MIS-C clinical spectrum; suggest potential associations between innate refractory states and long COVID; and highlight the need to monitor long-term consequences of MIS-C.
Evaluating the causal impact of reproductive factors on breast cancer risk: a multivariable mendelian randomization approach
Authors: Prince Claire , Howe Laura D , Sanderson Eleanor , Sharp Gemma C , Fraser Abigail , Lloyd-Lewis Bethan , Richmond Rebecca C 
Published: February 2024

AbstractBackgroundObservational evidence proposes a protective effect of having children and an early age at first birth on the development of breast cancer, however the causality of this association remains uncertain. In this study we assess whether these reproductive factors impact breast cancer risk independently of age at menarche, age at menopause, adiposity measures and other reproductive factors that have been identified as being causally related to or genetically correlated with the reproductive factors of interest.MethodsWe used genetic data from UK Biobank (273,238 women) for reproductive factors, age at menarche and menopause, and adiposity measures, and the Breast Cancer Association Consortium for risk of overall, estrogen receptor (ER) positive and negative breast cancer as well as breast cancer subtypes. We applied univariable and multivariable Mendelian randomization (MR) to estimate direct effects of ever parous status, ages at first birth and last birth, and number of births on breast cancer risk.ResultsWe found limited evidence of an effect of age at first birth on overall or ER positive breast cancer risk in either the univariable or multivariable analyses. While the univariable analysis revealed an effect of later age at first birth decreasing ER negative breast cancer risk (Odds ratio (OR): 0.76, 95% confidence interval:0.61-0.95 per standard deviation (SD) increase in age at first birth), this effect attenuated with separate adjustment for age at menarche and menopause (e.g., OR 0.83, 0.62-1.06 per SD increase in age at first birth, adjusted for age at menarche). In addition, we found evidence for an effect of later age at first birth on decreased human epidermal growth factor receptor 2 enriched breast cancer risk but only with adjustment for number of births (OR 0.28 (0.11-0.57) per SD increase in age at first birth).We found little evidence for direct effects of ever parous status, age at last birth or number of births on breast cancer risk, however, analyses of ever parous status and age at last birth were limited by weak instruments in the multivariable analysis.ConclusionsThis study found minimal evidence of a protective effect of earlier age at first birth on breast cancer risk, while identifying some evidence for an adverse effect on ER negative breast cancer risk. However, multivariable MR of ever parous status and age at last birth is limited by weak instruments which might be improved in future studies with larger sample sizes and when additional genetic variants related to reproductive factors are identified.
Unreliability in Simulations of COVID-19 Cases and Deaths Based on Transmission Models
Authors: Kakeya Hideki , Itoh Makoto , Kamijima Yukari , Nitta Takeshi , Umeno Yoshitaka 
Published: February 2024

AbstractTwo papers authored by the same research group were published in academic journals in October 2023, both of which simulate counterfactual COVID-19 cases and deaths using transmission models. One paper estimates that the COVID-19 cases and deaths from Feb 17 to Nov 30, 2021 in Japan would have been as many as 63.3 million and 364 thousand respectively had the vaccination not been implemented, where the 95% confidence interval is claimed to be less than 1% of the estimated value. It also claims that the cases and deaths could have been reduced by 54% and 48% respectively had the vaccination been implemented 14 days earlier. The other paper estimates that the number of cases in early 2022, Tokyo would have been larger than the number of populations in the age group under 49 in the absence of the vaccination program. In this paper, we reexamine the results given by these papers to find that the simulation results do not explain the real-world data in Japan including prefectures with early/late vaccination schedules. The cause of discrepancy is identified as low reliability of model parameters that immensely affect the simulation results of case and death counts. Leaders of public healthcare are required to discern the reliability and credibility of simulation studies and to prepare for variety of possible scenarios when reliable predictions are not available.
Plasma proteomic evidence for increased Alzheimer’s disease-related brain pathology after SARS-CoV-2 infection
Authors: Duff Eugene P , Zetterberg Henrik , Heslegrave Amanda , Dehghan Abbas , Elliot Paul , Allen Naomi , Runz Heiko , Laban Rhiannon , Veleva Elena , Whelan Christopher D , Sun Benjamin B , Matthews Paul M 
Published: February 2024

AbstractPrior studies have suggested that systemic viral infections may increase risks of dementia. Whether this holds true for SARS-CoV-2 virus infections remains uncertain but is of great consequence for predicting future dementia rates. We examined this by comparing changes in plasma biomarkers in UK Biobank participants before and after serology confirmed SARS-CoV-2 infections. We discovered biomarker changes associated with increased AD risk within this population. SARS-CoV-2 infection was associated with reduced plasma Aβ42:Aβ40 concentration ratios, and in more vulnerable participants, lower plasma Aβ42 and higher plasma pTau-181. These biomarker changes, which have been associated with brain beta-amyloid accumulation in prodromal AD, were associated here with increased brain imaging signatures of AD, poorer cognitive scores, and worse assessments of overall health. Changes were greater in participants who had been hospitalised with COVID-19 or had previously reported hypertension. Our data provide evidence for the hypothesis that SARS-CoV-2 can be associated with accelerating brain pathology related to prodromal AD.
European Survey on Citizens’ Attitudes towards Personalized Medicine, Genetic Testing, and Health Data Sharing: Design and Delivery
Authors: Causio Francesco Andrea , Beccia Flavia , Kreeftenberg Loes Lindiwe , Calabrò Giovanna Elisa , Pastorino Roberta , Boccia Stefania , van El Carla 
Published: February 2024

AbstractPersonalized medicine leverages genetic, environmental, and lifestyle information to enhance the efficacy and safety of medical interventions. The shift from traditional one-size-fits-all approaches to a more individualized strategy signifies a major evolution in healthcare systems globally, promising improved patient outcomes and cost-effectiveness. A critical aspect of implementing personalized medicine is the role of public participation and their attitudes toward sharing health data. With growing concerns over data privacy, understanding and addressing public perceptions is essential. For this purpose, we designed and conducted a cross-sectional survey in Europe to gather public attitudes toward personalized medicine and health data sharing. The addressed issues range from knowledge and views to means of data sharing, e.g., via digital health instruments and electronic health care records. These insights are crucial for developing policies and practices that can help build trust and foster a secure environment for healthcare data sharing.