bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma proteomic profiles of UK Biobank participants with Multiple Sclerosis
Authors: Jacobs Benjamin M , Vickaryous Nicola , Giovannoni Gavin , Proitsi Petroula , Waters Sheena , Dobson Ruth
Published: July 2023

Abstract

Objective

We aimed to describe plasma protein biomarkers of Multiple Sclerosis risk and to explore protein biomarkers of disease severity using radiological outcome measures.

Methods

Multiple Sclerosis cases and controls were identified in UK Biobank, a longitudinal cohort study of ∼500,000 British adults. Plasma proteins were assayed in ∼50,000 UK Biobank participants using the Olink proximity extension assay. We performed case-control association testing to examine the association between 2911 proteins and Multiple Sclerosis, using linear models adjusted for confounding covariates. Associations with radiological lesion burden and brain volume were determined in a subset of the cohort with available magnetic resonance imaging, using normalised T2-hyperintensity volume or whole brain volume as the outcome measure.

Results

407 prevalent Multiple Sclerosis cases and 39,979 healthy controls were included. We discovered 72 proteins associated with Multiple Sclerosis at a Bonferroni-adjusted p-value of 0.05, including established markers such as Neurofilament Light Chain and Glial Fibrillary Acidic Protein. We observed a decrease in plasma Granzyme A, a marker of T cell and NK cell degranulation, which was specific to Multiple Sclerosis. Higher levels of plasma proteins involved in coagulation were associated with lower T2 lesion burden and preserved brain volume.

Interpretation

We report the largest plasma proteomic screen of Multiple Sclerosis, replicating important known associations and suggesting novel markers, such as the reduction in granzyme A. While these findings require external validation, they demonstrate the power of biobank-scale datasets for discovering new biomarkers for Multiple Sclerosis.
Oral health vulnerability and its associated risk factors among tribal elderly people in Bangladesh: a pilot study
Authors: Barua Shomrita , Bosu Sunanda , Haque Mohammad Farhadul , Bosak Liza , Rashid Md Rezowan , Zaman Shaikh Riaduz , Rahman Md. Foyzur , Rahman Mohammad Meshbahur
Published: July 2023

Background

Tribal elderly is a vulnerable population due to their geographic location and lack of access to healthcare services. This study aims to assess the oral health status of tribal elderly in Bangladesh and identify any associated risk factors.

Methods

This cross-sectional pilot survey was conducted among 280 tribal elderlies aged 60 years and above residing in the main tribal residing region in Bangladesh. The data was collected through cluster sampling methods using a semi-structured questionnaire and oral examination. Different statistical tools including frequency distribution, Chi-square association test and multivariable logistic regression model were performed in data analysis.

Results

The results showed that 25.35% of the tribal elderly had high DMFT score, indicating poor oral health. Respondents’ age, sex, marital status, occupational status, sweet eater, tobacco, and alcohol consumption were significantly associated with oral health. The major oral clinical sign and symptoms were dental carries, teeth sensitivity, loose teeth, broken teeth, calculus and staining in teeth, tongue pain and bad breath. The logistic regression analysis suggested that elderly aged 80 and above had 3.33 times more, males were 4.6 time less, tobacco user (smoked/smokeless) were 2.03 times more and alcohol consumers were 6.83 times more likely to experienced poor oral health condition than their counterparts.

Conclusions

Elderly individuals were found to be more likely to suffer from poor oral health condition than younger individuals, and certain lifestyle factors such as tobacco and alcohol consumption, meal frequency, and sweet consumption can further increase the risk of poor oral health condition.
Patterns of social-affective responses to trauma exposure and their relation to psychopathology
Authors: Thomas Sarah , Schäfer Judith , Kanske Philipp , Trautmann Sebastian
Published: July 2023

Introduction

Traumatic event exposure is an important risk factor for the development and maintenance of psychopathology. Social-affective responses to trauma exposure (e.g. shame, guilt, revenge, social alienation) could moderate this relationship, but little is known about their relevance for different types of psychopathology. Moreover, the interplay of different social-affective responses in predicting psychopathology is poorly understood.

Methods

In a sample ofN=1321 trauma-exposed German soldiers, we examined cross-sectional associations of trauma-related social alienation, revenge, guilt and shame with both categorical (depressive disorder, alcohol use disorder, posttraumatic stress disorder) and dimensional (depression, anxiety) measures of psychopathology. Latent class analysis was conducted to identify possible patterns of trauma-related social-affective responses, and their relation to psychopathology.

Results

All trauma-related social-affective responses predicted the presence of posttraumatic stress disorder, depressive disorder, alcohol use disorder and higher depressive and anxiety symptoms. Three latent classes were identified that fitted the data best, reflecting groups with (1) low, (2) moderate and (3) high risk for social-affective responses. The low-risk group demonstrated the lowest expressions on all psychopathology measures. Compared to the moderate-risk group, the high-risk group demonstrated no increased psychopathology.

Conclusions

Trauma-related social alienation, shame, guilt, and revenge are characteristic of individuals with posttraumatic stress disorder, depressive disorder, alcohol use disorder, as well as with higher anxiety and depressive symptoms. There was little evidence for distinctive patterns of social-affective responses despite variation in the overall proneness to show trauma-related social-affective responses. Trauma-related social-affective responses could represent promising treatment targets which might be included in both cognitive and emotion-focused interventions.
Treatment of Acute Myocardial Infarction and Cardiogenic Shock: Outcomes of the RECOVER III Post-Approval Study by SCAI Shock Stage
Authors: Hanson Ivan , Rusia Akash , Palomo Andres , Tawney Adam , Pow Timothy , Dixon Simon R. , Meraj Perwaiz , Sievers Eric , Johnson Michael , Wohns David , Ali Omar , Kapur Navin , Grines Cindy , Burkhoff Daniel , Anderson Mark , Lansky Alexandra , Naidu Srihari S. , Basir Mir B , O’Neill William
Published: July 2023

Background

The Society for Cardiovascular Angiography and Interventions (SCAI) proposed a staging system (A-E) to predict prognosis in cardiogenic shock. Herein, we report clinical outcomes of the RECOVER III study for the first time, according to SCAI shock classification.

Methods

RECOVER III is an observational, prospective, multicenter, single-arm, post-approval study of patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) undergoing percutaneous coronary intervention (PCI) with Impella support. Patients enrolled in RECOVER III were assigned a baseline SCAI shock stage. Staging was then repeated within 24 hours after initiation of Impella. Kaplan-Meier survival curve analyses were conducted to assess survival across SCAI shock stages at both timepoints.

Results

At baseline assessment, 16.5%, 11.4%, and 72.2% were classified as Stage C, D, and E, respectively. At ≤24 hour assessment, 26.4%, 33.2%, and 40.0% were Stage C, D, and E respectively. Thirty-day survival amongst patients with Stage C, D and E shock at baseline was 59.7%, 56.5% and 42.9%, respectively (p=0.003). Survival amongst patients with Stage C, D and E shock at ≤24 hours was 65.7%, 52.1% and 29.5%, respectively (p<0.001). After multivariate analysis of impact of shock stage classifications at baseline and ≤ 24 hours, only Stage E classification at ≤24 hours was a significant predictor of mortality (OR 4.8, p<0.001).

Conclusions

In a real-world cohort of patients with AMICS undergoing PCI with Impella support, only Stage E classification at ≤ 24 hours was significantly predictive of mortality, suggesting that response to therapy may be more important than clinical severity of shock at presentation.

Clinical Perspective

Many patients with AMICS treated with Impella present in SCAI Stage E shock, but may improve to a more favorable shock stage within 24 hours of their presentation.

In-hospital and 30-day outcomes correlate with SCAI shock stage at presentation, but the correlation is more robust upon repeat assessment within 24 hours after Impella initiation.

The SCAI shock staging system may be a useful clinical tool to guide in-hospital management of patients with AMICS, especially within the first 24 hours, and to provide prognostic information to patients and/or their families.
Reversion of the inflammatory markers in patients with chronic limb threatening ischaemia
Authors: Ferreira Joana , Roque Susana , Carneiro Alexandre Lima , Longatto-Filho Adhemar , Vila Isabel , Cunha Cristina , Silva Cristina , Mesquita Amílcar , Cotter Jorge , Correia-Neves Margarida , Mansilha Armando , Cunha Pedro
Published: July 2023

Introduction

Peripheral arterial disease (PAD) affects over 202 million individuals worldwide, with 1.3% suffering from chronic limb-threatening ischaemia (CLTI). Atherosclerosis, characterized by intense inflammation, is the primary cause of PAD. Inflammation is linked to higher mortality rates, especially in CLTI patients. This study aims to compare the evolution of inflammatory markers between claudication and CLTI patients over three, six, and twelve months.

Methods

A prospective, single-center observational study was conducted from January 2018 to July 2022. A PAD cohort was observed at admission and at three, six, and twelve months, with data on clinical, analytical, and inflammatory markers collected. The analyzed markers included positive acute phase proteins (C-reactive protein - CRP and fibrinogen) and negative acute phase proteins (albumin, total cholesterol, and high-density lipoprotein - HDL).

Results

The study involved 119 subjects (mean age: 67.58 ± 9.60 years; 79.80% males), with 65 patients having claudication and 54 with CLTI. At admission, CLTI patients exhibited significantly higher serum levels of CRP and fibrinogen (positive acute phase proteins) and lower levels of albumin, total cholesterol, and HDL (negative acute phase proteins) compared to claudication patients. Three months after CLTI resolution, negative acute phase proteins increased, and positive acute phase proteins decreased. However, no significant changes in inflammatory proteins were observed in patients with claudication over time.

Conclusion

CLTI patients demonstrate an inflammatory state, which may have deleterious consequences and be partially reversible after the resolution of the ischemic process. Recognizing the potential for reversibility through revascularization/amputation underscores the significance of timely intervention.
Modulation of prefrontal couplings by prior belief-related responses in ventromedial prefrontal cortex
Authors: Wang Bin A. , Drammis Sabrina , Hummos Ali , Halassa Michael M. , Pleger Burkhard
Published: July 2023

Humans and animals can maintain constant payoffs in an uncertain environment by steadily re-evaluating and flexibly adjusting current strategy, which largely depends on the interactions between the prefrontal cortex (PFC) and mediodorsal thalamus (MD). While the ventromedial PFC (vmPFC) represents the level of uncertainty (i.e., prior belief about external states), it remains unclear how the brain recruits the PFC-MD network to re-evaluate decision strategy based on the uncertainty. Here, we leverage nonlinear dynamic causal modeling on fMRI data to test how prior belief-dependent activity in vmPFC gates the information flow in the PFC-MD network when individuals switch their decision strategy. We show that the prior belief-related responses in vmPFC had a modulatory influence on the connections from dorsolateral PFC (dlPFC) to both, lateral orbitofrontal (lOFC) and MD. Bayesian parameter averaging revealed that only the connection from the dlPFC to lOFC surpassed the significant threshold, which indicates that the weaker the prior belief, the less was the inhibitory influence of the vmPFC on the strength of effective connections from dlPFC to lOFC. These findings suggest that the vmPFC acts as a gatekeeper for the recruitment of processing resources to re-evaluate the decision strategy in situations of high uncertainty.

Author Summary

Prefrontal cortex (PFC) together with the mediodorsal thalamus (MD) jointly establish computations critical for behavioral adaptations. While the task uncertainty (i.e., prior belief) was represented by the ventromedial PFC (vmPFC), it remains unclear how the PFC-MD network reallocates the processing resources to re-evaluate decision strategy under uncertainty. Here we filled this gap by leveraging the Bayesian hierarchical modelling and nonlinear dynamic causal modelling in an associative learning task. We found that in situations of high uncertainty, the prior belief-related responses in vmPFC significantly strengthened effective connectivity from the dorsolateral PFC to the orbitofrontal cortex, but not to the MD. The findings provide evidence for the role of vmPFC in driving the re-evaluation of the decision strategy during behavioral adaptations in situations of uncertainty.
The Nucleoporin Nup153 Is the Anchor for Kif1a during Basal Nuclear migration in Brain Progenitor Cells
Authors: Falnikar Aditi , Quintremil Sebastian , Helmer Paige , Vallee Richard B.
Published: July 2023

Radial glial progenitors (RGPs) are highly elongated epithelial cells that give rise to most stem cells, neurons, and glia, in the vertebrate cerebral cortex. During development the RGP nuclei exhibit a striking pattern of cell cycle-dependent oscillatory movements known as interkinetic nuclear migration (INM), which we previously found to be mediated during G1 by the kinesin Kif1a, and during G2 by cytoplasmic dynein, recruited to the nuclear envelope by the nucleoporins RanBP2 and Nup133. We now identify Nup153 as a nucleoporin anchor for Kif1a, responsible for G1-specific basal nuclear migration, providing a complete model for the mechanisms underlying this basic, but mysterious behavior, with broad implications for understanding brain development.
GRouNdGAN: GRN-guided simulation of single-cell RNA-seq data using causal generative adversarial networks
Authors: Zinati Yazdan , Takiddeen Abdulrahman , Emad Amin
Published: July 2023

We introduce GRouNdGAN, a gene regulatory network (GRN)-guided causal implicit generative model for simulating single-cell RNA-seq data,in-silicoperturbation experiments, and benchmarking GRN inference methods. Through the imposition of a user-defined GRN in its architecture, GRouNdGAN simulates steady-state and transient-state single-cell datasets where genes are causally expressed under the control of their regulating transcription factors (TFs). Training on three experimental datasets, we show that our model captures non-linear TF-gene dependences and preserves gene identities, cell trajectories, pseudo-time ordering, and technical and biological noise, with no user manipulation and only implicit parameterization. Despite imposing rigid causality constraints, it outperforms state-of-the-art simulators in generating realistic cells. GRouNdGAN learns meaningful causal regulatory dynamics, allowing sampling from both observational and interventional distributions. This enables it to synthesize cells under conditions that do not occur in the dataset at inference time, allowing to performin-silicoTF knockout experiments. Our results show thatin-silicoknockout of cell type-specific TFs significantly reduces cells of that type being generated. Interactions imposed through the GRN are emphasized in the simulated datasets, resulting in GRN inference algorithms assigning them much higher scores than interactions not imposed but of equal importance in the experimental training dataset. Benchmarking various GRN inference algorithms reveals that GRouNdGAN effectively bridges the existing gap between simulated and biological data benchmarks of GRN inference algorithms, providing gold standard ground truth GRNs and realistic cells corresponding to the biological system of interest. Our results show that GRouNdGAN is a stable, realistic, and effective simulator with various applications in single-cell RNA-seq analysis.
The components of an electrical synapse as revealed by expansion microscopy of a single synaptic contact
Authors: Cárdenas-García Sandra P. , Ijaz Sundas , Pereda Alberto E.
Published: July 2023

Most nervous systems combine both transmitter-mediated and direct cell-cell communication, known as ‘chemical’ and ‘electrical’ synapses, respectively. Chemical synapses can be identified by their multiple structural components. Electrical synapses are, on the other hand, generally defined by the presence of a ‘gap junction’ (a cluster of intercellular channels) between two neuronal processes. However, while gap junctions provide the communicating mechanism, it is unknown whether electrical transmission requires the contribution of additional cellular structures. We investigated this question at identifiable single synaptic contacts on the zebrafish Mauthner cells, at which gap junctions coexist with specializations for neurotransmitter release and where the contact defines the anatomical limits of a synapse. Expansion microscopy of these contacts revealed a detailed map of the incidence and spatial distribution of proteins pertaining to various synaptic structures. Multiple gap junctions of variable size were identified by the presence of their molecular components. Remarkably, most of the synaptic contact’s surface was occupied by interleaving gap junctions and components of adherens junctions, suggesting a close functional association between these two structures. In contrast, glutamate receptors were confined to small peripheral portions of the contact, indicating that most of the synaptic area works as an electrical synapse. Thus, our results revealed the overarching organization of an electrical synapse that operates with not one, but multiple gap junctions, in close association with structural and signaling molecules known to be components of AJs. The relationship between these intercellular structures will aid in establishing the boundaries of electrical synapses found throughout animal connectomes and provide insight into the structural organization and functional diversity of electrical synapses.
How Veeries vary: Whole genome sequencing resolves fine-scale genetic structure in a long-distance migratory bird,Catharus fuscescens
Authors: Kimmitt Abigail A. , Pegan Teresa M. , Jones Andrew W. , Winker Kevin , Winger Benjamin M.
Published: July 2023

Fine-scale resolution of spatial genetic structure is important for understanding a species’ evolutionary history and contemporary genetic diversity. For high-latitude species with high dispersal ability, such as long-distance migratory birds, populations typically exhibit little genetic structure due to high gene flow and recent postglacial expansion. Some migratory birds, however, show high breeding site fidelity, which might reduce gene flow such that population genetic structure could be detectable with sufficient genomic data. We sequenced over 120 low-coverage whole genomes from across the breeding range of a long-distance migratory bird, the Veery (Catharus fuscescens). As this species’ breeding range extends across both historically glaciated and unglaciated regions in North America, we evaluated whether contemporary patterns of structure and genetic diversity are consistent with historical population isolation in glacial refugia. We found strong evidence for isolation by distance across the breeding range, as well as significant population structure between southern Appalachian and northern populations. However, patterns of genetic diversity did not support southern Appalachia as a glacial refugium. Resolution of isolation by distance across the breeding range was sufficient to assign likely breeding origins of individuals sampled in this species’ poorly understood South American nonbreeding range, demonstrating the potential to assess migratory connectivity in this species using genomic data. Overall, our findings suggest that isolation by distance yields subtle associations between genetic structure and geography across the breeding range even in the absence of obvious historical vicariance or contemporary barriers to dispersal.
Molecular characterization of nodose ganglia development reveals a novel population of Phox2b+ glial progenitors in mice
Authors: Lowenstein Elijah D. , Misios Aristotelis , Buchert Sven , Ruffault Pierre-Louis
Published: July 2023

The vagal ganglia, comprised of the superior (jugular) and inferior (nodose) ganglia of the vagus nerve, receive somatosensory information from the head and neck, or viscerosensory information from the inner organs, respectively. Developmentally, the cranial neural crest gives rise to all vagal glial cells and to neurons of the jugular ganglia, while the epibranchial placode gives rise to neurons of the nodose ganglia. Crest-derived nodose glial progenitors can additionally generate autonomic neurons in the peripheral nervous system, but how these progenitors generate neurons is unknown. Here, we found that some Sox10+ neural crest-derived cells in, and surrounding, the nodose ganglion transiently expressed Phox2b, a master regulator of autonomic nervous system development, during early embryonic life. Our genetic lineage tracing analysis revealed that despite their common developmental origin and extreme spatial proximity a substantial proportion of glial cells in the nodose, but not in the neighboring jugular ganglia, have a history of Phox2b expression. Lastly, we used single cell RNA-sequencing (scRNA-seq) to demonstrate that these progenitors give rise to all major glial subtypes in the nodose ganglia, including Schwann cells, satellite glia and glial precursors, and mapped their spatial distribution byin situhybridization. Our work demonstrates that these crest- derived nodose glial progenitors transiently express Phox2b, give rise to the entire complement of nodose glial cells and display a transcriptional program that may underlie their bipotent nature.

Significance statement

The nodose ganglia contain sensory neurons that innervate many inner organs and play key roles in homeostatic behaviors such as digestion, regulation of blood pressure and heart rate, and breathing. Nodose sensory neurons are supported by nodose glial cells, which are understudied compared to their neuronal neighbors. Specifically, the genetic program governing their development is not fully understood. Here, we uncover a transcriptional program unique to nodose glial cells (transient expression of Phox2b) that resolves the 40-year-old finding that nodose glial progenitors can also give rise to autonomic neurons (whose development depends on Phox2b expression). Lastly, we leveraged single cell RNA-sequencing to identify the four major subtypes of nodose glial cells and used subtype specific marker genes to map their spatial distribution.
Emotional state dynamics impacts temporal memory
Authors: Wang Jingyi , Lapate Regina C.
Published: July 2023

Emotional fluctuations are ubiquitous in everyday life, but precisely how they sculpt the temporal organization of memories remains unclear. Here, we designed a novel task—the Emotion Boundary Task—wherein participants viewed sequences of negative and neutral images surrounded by a color border. We manipulated perceptual context (border color), emotional valence, as well as the direction of emotional-valence shifts (i.e., shifts from neutral-to-negative and negative-to-neutral events) to create encoding events comprised of image sequences with a shared perceptual and/or emotional context. We measured memory for temporal order and subjectively remembered temporal distances for images processedwithinandacrossevents. Negative images processed within events were remembered as closer in time compared to neutral ones. In contrast, temporal distance was remembered as longer for images spanning neutral-to-negative shifts— suggesting temporal dilation in memory with the onset of a negative event following a previously-neutral state. The extent of this negative-picture induced temporal dilation in memory correlated with dispositional negativity across individuals. Lastly, temporal order memory was enhanced for recently presented negative (compared to neutral) images. These findings suggest that emotional-state dynamics matters when considering emotion-temporal memory interactions: While persistent negative events may compress subjectively remembered time, dynamic shifts from neutral to negative events produce temporal dilation in memory, which may be relevant for adaptive emotional functioning.
Interferon-γ lowers tumour growth by increasing glycolysis and lactate production in a nitric oxide-dependent manner: implications for cancer immunotherapy
Authors: Chattopadhyay Avik , Jagdish Sirisha , Karhale Aagosh Kishore , Ramteke Nikita S. , Zaib Arsha , Nandi Dipankar
Published: July 2023

Interferon-gamma (IFN-γ), the sole member of the type-II interferon family, is well known to protect the host from infectious diseases as well as mount anti-tumour responses. The amounts of IFN-γ in the tumour microenvironment determine the host responses against tumours; however, several tumours employ evasive strategies by responding to low IFN-γ signalling. In this study, the response of various tumour cell lines to IFN-γ was studiedin vitro. IFN-γ-activation increases glycolytic flux and reduces mitochondrial function in a nitric oxide (NO)- and reactive oxygen species (ROS)-dependent manner in the H6 hepatoma tumour cell line. The higher glycolysis further fuelled NO and ROS production, indicating a reciprocal regulation. These processes are accompanied by Hypoxia inducing factor (HIF)-1αstabilization and HIF-1α-dependent augmentation of the glycolytic flux. The IFN-γ enhancement of lactate production also occurred in other NO-producing cell lines: RAW 264.7 monocyte/macrophage and Renca renal adenocarcinoma. However, two other tumour cell lines, CT26 colon carcinoma and B16F10 melanoma, did not produce NO and lactate upon IFN-γ-activation. HIF-1α stabilization upon IFN-γ-activation led to lower cell growth of B16F10 but not CT26 cells. Importantly, the IFN-γ-activation of both CT26 and B16F10 cells demonstrated significant cellular growth reduction upon metabolic rewiring by exogenous administration of potassium lactate. Clinical studies have shown the crucial roles of IFN-γ for successful cancer immunotherapies involving checkpoint inhibitors and chimeric antigen receptor T cells. The positive implications of this study on the metabolic modulation of IFN-γ activation on heterogeneous tumour cells are discussed.
The impact of incidental anxiety on the neural signature of mentalizing
Authors: Chang Li-Ang , Engelmann Jan B.
Published: July 2023

While the effects of anxiety on various cognitive processes, including memory, attention, and learning, have been relatively well documented, the neurobiological effects of anxiety on social cognitive processes remain largely unknown. We address this gap using threat-of-shock to induce incidental anxiety while participants performed two false-belief tasks, a standard and an economic-games version. During belief formation and belief inferences, regions in a canonical social cognition network showed activation reflecting mentalizing, including the temporoparietal junction (TPJ), precuneus, and dorsomedial prefrontal cortex (dmPFC). At the same time, we found threat-related suppression of social cognition regions during belief inferences. A conjunction analysis confirmed that a network of regions was simultaneouslyengagedduring mentalizing andsuppressedby anxiety: bilateral TPJ, bilateral IFG, and putamen. We examined how threat impacted the connectivity between seed regions from the conjunction analyses and its targets. During belief formation, we found that anxiety suppressed the connectivity between the precuneus seed and two key mentalizing nodes, the dmPFC and right TPJ. Moreover, during belief inferences threat specificallty suppressed belief-based connectivity between putamen and its targets in IPS and dlPFC, and dispositional distress significantly modulated threat-related suppression of connectivity between the left TPJ seed and left IPS. Our results highlight important effects of incidental and dispositional anxiety on specific nodes of the social cognition network. Taken together, our study uncovers novel interactions between the reward, social cognition, and attentional systems, indicating that social cognitive processes rely on support from other large-scale networks, and that these network interactions are disrupted under incidental anxiety.
ZBTB48 is a pioneer factor regulating B-cell-specific CIITA expression
Authors: Rane Grishma , Kuan Vivian L. S. , Wang Suman , Huang Mok Michelle Meng , Khanchandani Vartika , Hansen Julia , Norvaisaite Ieva , Yong Wai Khang , Jahn Arne , Mukundan Vineeth , Shi Yunyu , Osato Motomi , Li Fudong , Kappei Dennis
Published: July 2023

CIITA is the master regulator of MHC II gene expression and hence the adaptive immune response. CIITA expression itself is tightly regulated by three cell type-specific promoters, pI, pIII, and by pIV, and can also be induced by IFNγ in non-immune cells. While key regulatory elements have been identified within these promoters, knowledge of transcription factors regulating CIITA is incomplete. Here, we demonstrate that the telomere-binding protein and transcriptional activator ZBTB48 directly binds to both the critical activating elements within CIITA pIII and is essential for its gene expression. ZBTB48 establishes open chromatin at CIITA pIII upstream of activating H3K4me3 modifications both priming CIITA transcription for IFNγ-induction and ensuring constitutive expression in primary murine B cells. Hence, ZBTB48 acts as a molecular on-off-switch for B-cell-specific CIITA expression.
Motor, somatosensory, and executive cortical areas directly modulate firing activity in the auditory midbrain
Authors: Gartside Sarah E , Rees Adrian , Olthof Bas MJ
Published: July 2023

We have recently reported that the central nucleus of the inferior colliculus (the auditory midbrain) is innervated by glutamatergic pyramidal cells originating not only in auditory cortex (AC) but also in multiple ‘non-auditory’ regions of the cerebral cortex. Using optogenetics and electrical stimulation, we investigated the functional properties of these descending connections in vivo in anaesthetised rats. A retrograde virus encoding green fluorescent protein (GFP) and channelrhodopsin (ChR2) injected into the central nucleus of the inferior colliculus (ICC), labelled discrete groups of cells in multiple areas of the cerebral cortex. Light stimulation of AC and M1 caused local activation of cortical neurones and increased the firing rate of neurones in ICc indicating a direct excitatory input from AC and M1 to ICC. Electrical stimulation of M1, secondary motor, somatosensory and prefrontal cortical regions evoked short, fixed latency firing events in ICC as well as longer latency, longer duration increases in firing activity. The short latency events were singular spikes of consistent shape and size likely resulting from monosynaptic excitation of individual ICC units. The longer latency responses comprised multiple units and spikes occurred with significant temporal jitter suggesting polysynaptic activation of local circuits within the ICC. The probability of the monosynaptic event, the magnitude of the polysynaptic response, and the area of ICC affected were dependent on the stimulus current. Our data are consistent with cortical regions exerting an important excitatory direct and indirect regulation of ICc neurones.

Significance statement

We have recently described inputs from motor, somatosensory, and executive cortices to the inferior colliculus (IC, auditory midbrain). Here we provide functional evidence for such connections. Optogenetics, using a retrograde virus encoding channelrhodopsin injected into IC revealed a direct excitatory influence of neurones in auditory and motor cortices on firing in IC. Electrical stimulation of discrete cortical regions revealed that multiple non-auditory cortical regions have a direct monosynaptic excitatory influence on neurones in the IC which, in turn, activates local circuits increasing the firing probability of multiple neurones in the IC. This is the first evidence for circuitry by which auditory processing can be influenced at an early stage by activity in the sensory, motor and executive domains.
Negative selection on aSOD1mutation limits canine degenerative myelopathy while avoiding inbreeding
Authors: Ukawa Hisashi , Akiyama Noriyoshi , Yamamoto Fumiko , Ohashi Ken , Ishihara Genki , Matsumoto Yuki
Published: July 2023

Several hundred disease-causing mutations are currently known in domestic dogs. Breeding management is therefore required to minimize their spread. Recently, genetic methods such as direct-to-consumer testing have gained popularity; however, their effects on dog populations are unclear. Here, we aimed to evaluate the influence of genetic testing on the frequency of mutations responsible for canine degenerative myelopathy (DM) and assess the changes in the genetic structure of a Pembroke Welsh corgi population from Japan. Genetic testing of 5,512 dogs for the causative mutation in superoxide dismutase 1 (SOD1) (c.118G>A (p.E40K)) uncovered a recent decrease in frequency, plummeting from 14.5% (95/657) in 2019 to 2.9% (24/820) in 2022. Weir and Cockerham population differentiation (FST) and simulation-based genome-wide single-nucleotide polymorphism (SNP) analysis of 117 selected dogs revealed 143 candidate SNPs for selection. The SNP with the highestFSTvalue was located in the intron ofSOD1adjacent to the c.118G>A mutation, supporting a strong selection signature onSOD1. Further genome-wide SNP analyses revealed no obvious changes in inbreeding levels and genetic diversity between the 2019 and 2022 populations. Our study highlights that genetic testing can help inform improved mating choices in breeding programs to reduce the frequency of risk variants and avoid inbreeding. This combined strategy could decrease the genetic risk of canine DM, a fatal disease, within only a few years.

Significance statement

Genetic breeding methods using direct-to-consumer testing have gained popularity, but their effects on dog populations remain unclear. In this study, the effect of direct-to-consumer genetic testing onSOD1mutation, the causative element of canine degenerative myelopathy, in a domestic dog population (Pembroke Welsh corgi) from Japan was investigated. Our analyses revealed that since the expansion of genetic testing in 2019, breeders used these tests to artificially select against theSOD1mutation, considerably decreasing its occurrence in the corgi population within only a few years (2019 versus 2022). Our study makes a substantial contribution to existing literature by providing empirical evidence that direct-to-consumer genetic testing can have rapid influence on pet genetics, noticeable in a span of 2–3 years.
Cell type-specific consequences of mosaic structural variants in hematopoietic stem and progenitor cells
Authors: Grimes Karen , Jeong Hyobin , Amoah Amanda , Xu Nuo , Niemann Julian , Raeder Benjamin , Hasenfeld Patrick , Stober Catherine , Rausch Tobias , Benito Eva , Jann Johann-Christoph , Nowak Daniel , Emini Ramiz , Hoenicka Markus , Liebold Andreas , Ho Anthony , Shuai Shimin , Geiger Hartmut , Sanders Ashley D. , Korbel Jan O.
Published: July 2023

The functional impact and cellular context of mosaic structural variants (mSVs) in normal tissues is understudied. Utilizing Strand-seq, we sequenced 1,133 single cell genomes from 19 human donors of increasing age, revealing a heterogeneous mSV landscape in hematopoietic stem and progenitor cells (HSPCs). While mSV clonal expansions are confined to individuals over 60,de novomSV formation occurs consistently across age, frequently leading to megabase-scale segmental aneuploidies. Cells harboring subclonal mosaicism show evidence for increased mSV formation. To enable high-resolution cell-typing of each Strand-seq library, we generated single-cell MNase-seq reference datasets for eight distinct HSPCs. Subclonal mSVs frequently exhibit enrichment in myeloid progenitors, and single-cell multiomic analysis suggests that these mSVs result in recurrent dysregulation of pathways related to proliferation and metabolism, including Ras signaling and lipid metabolism. The comprehensive mSV landscape identified in this study implicates mSVs in cell type-specific molecular phenotypes, establishing a foundation for deciphering links between mSVs, aging, and disease risk.
Lesions in a songbird vocal circuit increase variability in song syntax
Authors: Koparkar Avani , Warren Timothy L. , Charlesworth Jonathan D. , Shin Sooyoon , Brainard Michael S. , Veit Lena
Published: July 2023

Complex motor skills like speech and dance are composed of ordered sequences of simpler elements, but the neuronal basis for syntactic ordering of individual actions into sequences is poorly understood. Birdsong is a learned vocal behavior composed of syntactically ordered sequences of individual syllables. Activity in song premotor nucleus HVC (proper name) has been linked to the control of syllable sequencing, but sequencing may also be affected by its recurrent inputs. We here test the contribution of one of HVC’s inputs, mMAN (medial magnocellular nucleus of the anterior nidopallium), to the variable songs of adult male Bengalese finches (Lonchura striata domestica). The syntax of Bengalese song includes several patterns: 1)chunks, where syllables follow stereotypical order 2)branch points, where a given syllable can be followed by two or more different syllables in a probabilistic manner and 3)repeat phrases, where an individual syllable is repeated a variable number of times. We found that after bilateral lesions of mMAN, the acoustic structure of syllables remained largely intact, but sequencing became more variable for each of these patterns, seen by ‘breaks’ in previously stereotyped chunks, increased uncertainty at branch points and increased variability of repeat numbers. This increase in sequencing variability highlights the potential importance of regions projecting to HVC in the ordering of vocal elements. Previous studies on zebra finches found little effect of mMAN lesions on their relatively stereotyped adult song. In contrast, our results suggest that mMAN contributes to sequencing the variable songs of Bengalese finches and highlight the utility of species with more complex song syntax in investigating neuronal control of ordered motor sequences.
The Role of Vision and Lateral Line Sensing for Schooling in Giant Danios (Devario Aequipinnatus)
Authors: Tidswell Ben , Veliko-Shapko Annushka , Tytell Eric
Published: July 2023

To protect themselves from predators, fishes often form schools with other fish. Previous work has identified abstract “rules” of schooling – attraction to neighbours that are far away, repulsion from neighbours that are too close, and alignment with neighbours at the correct distance – but we do not understand well how these rules emerge from the sensory physiology and behaviour of individual fish. In particular, fish use both vision and their lateral lines to sense other fish, but it is unclear how they integrate information from these sensory modalities to coordinate schooling behaviour. To address this question, we studied how the schooling of giant danios (Devario aequipinnatus) changes when they are either unable to see or unable to use their lateral lines. We found that giant danios were able to school normally without their lateral lines, but did not school in darkness. Surprisingly, giant danios in darkness had the same attraction and alignment properties as fish in light, potentially indicating that they do not feel as much risk in darkness. Overall, we suggest that differences among schooling species in sensory integration between vision and lateral line may depend on their natural predators and environment.
Dopaminoceptive D1 and D2 neurons in ventral hippocampus arbitrate approach and avoidance in anxiety
Authors: Godino Arthur , Salery Marine , Minier-Toribio Angelica M. , Patel Vishwendra , Fullard John F. , Parise Eric M. , Martinez-Rivera Freddyson J. , Morel Carole , Roussos Panos , Blitzer Robert D. , Nestler Eric J.
Published: July 2023

The hippocampus1–7, as well as dopamine circuits8–11, coordinate decision-making in anxiety-eliciting situations. Yet, little is known about how dopamine modulates hippocampal representations of emotionally-salient stimuli to inform appropriate resolution of approachversusavoidance conflicts. We here study dopaminoceptive neurons in mouse ventral hippocampus (vHipp), molecularly distinguished by their expression of dopamine D1 or D2 receptors. We show that these neurons are transcriptionally distinct and topographically organized across vHipp subfields and cell types. In the ventral subiculum where they are enriched, both D1 and D2 neurons are recruited during anxiogenic exploration, yet with distinct profiles related to investigation and behavioral selection. In turn, they mediate opposite approach/avoidance responses, and are differentially modulated by dopaminergic transmission in that region. Together, these results suggest that vHipp dopamine dynamics gate exploratory behaviors under contextual uncertainty, implicating dopaminoception in the complex computation engaged in vHipp to govern emotional states.
A dual target molecular MRI probe for noninvasive profiling of pathologic alpha-synuclein and microgliosis in a mouse model of Parkinson’s disease
Authors: Sun Xianwei , Badachhape Andrew , Chin Jeannie , Annapragada Ananth , Tanifum Eric
Published: July 2023

Parkinson’s disease is characterized progressive deposition of pathologic alpha-synuclein (α-syn) aggregates, neuroinflammation, and death of dopaminergic neurons in the substantia nigra projecting to the striatum. Noninvasivein vivoprofiling of α-syn aggregate accumulation and microgliosis by molecular imaging can provide insights on the underlying mechanisms of disease progression, facilitating the development of effective treatment. However, no classical imaging methods have been successful, despite several attempts. We demonstrate a novel method to noninvasivein vivoprofiling of pathologic α-syn in combination with microgliosis using molecular magnetic resonance imaging (MRI), by targeting oligomeric α-syn in cerebrospinal fluid with nano scavengers (T) bearing a T1-relaxive Gd(III) payload. In this proof-of-concept report we demonstrate,in vitro,that microglia and neuroblastoma cell lines internalize cross-linkedT/oligomeric α-syn agglomerates. Delayedin vivoT1-weighted MRI scans following intravenous administration in the M83 α-syn transgenic mouse line show statistically significant T1 signal enhancement in test mice versus controls. Thein vivodata was validated byex-vivoimmunohistochemical analysis which showed a strong correlation betweenin vivoMRI signal enhancement, Lewy pathology distribution, and microglia activity in the treated brain tissue. Furthermore, neuronal, and microglial cells in brain tissue from treated mice displayed strong cytosolic signal originating fromT, confirmingin vivocell uptake of the nano scavengers.
3D electronic implants in subretinal space: long-term follow-up in rodents
Authors: Bhuckory Mohajeet , Wang Bing-Yi , Chen Zhijie Charles , Shin Andrew , Pham-Howard Davis , Shah Sarthak , Monkongpitukkul Nicharee , Galambos Ludwig , Kamins Theodore , Mathieson Keith , Palanker Daniel
Published: July 2023

Photovoltaic subretinal prosthesis (PRIMA) enables restoration of sight via electrical stimulation of the interneurons in degenerated retina, with resolution limited by the 100 μm pixel size. Since decreasing the pixel size below 75 μm in the current bipolar geometry is impossible, we explore the possibility of using smaller pixels based on a novel 3-dimensional honeycomb-shaped design. We assessed the long-term biocompatibility and stability of these arrays in rats by investigating the anatomical integration of the retina with flat and 3D implants and response to electrical stimulation over lifetime – up to 9 months post-implantation in aged rats. With both flat and 3D implants, VEP amplitude decreased after the day of implantation by more than 3-fold, and gradually recovered over about 3 months. With 25 μm high honeycomb walls, the majority of bipolar cells migrate into the wells, while amacrine and ganglion cells remain above the cavities, which is essential for selective network-mediated stimulation of the second-order neurons. Retinal thickness and full-field stimulation threshold with 40 μm-wide honeycomb pixels were comparable to those with planar devices – 0.05 mW/mm2with 10ms pulses. However, fewer cells from the inner nuclear layer migrated into the 20 μm-wide wells, and stimulation threshold increased over 5 months, before stabilizing at about 0.08 mW/mm2. Such threshold is significantly lower than 1.8 mW/mm2with a previous design of flat bipolar pixels, confirming the promise of the 3D honeycomb-based approach to high resolution subretinal prosthesis.
Modular Splicing is Linked to Evolution in the Synapse-Specificity Molecule Kirrel3
Authors: Traenkner Dimitri , Shennib Omar , Johnson Alyssa , Weinbrom Adam , Taylor Matthew R. , Williams Megan E.
Published: July 2023

Kirrel3 is a cell-adhesion molecule that instructs the formation of specific synapses during brain development in mouse and Kirrel3 variants may be risk factors for autism and intellectual disabilities in humans. Kirrel3 is predicted to undergo alternative splicing but brain isoforms have not been studied. Here, we present the first in-depth characterization of Kirrel3 isoform diversity in brain using targeted, long-read mRNA sequencing of mouse hippocampus. We identified 19 isoforms with predicted transmembrane and secreted forms and show that even rare isoforms generate detectable protein in the brain. We also analyzed publicly-available long-read mRNA databases from human brain tissue and found 11 Kirrel3 isoforms that, similar to mouse, encode transmembrane and secreted forms. In mice and humans, Kirrel3 diversity arises from alternative, independent use of protein-domain coding exons and alternative early translation-stop signals. Intriguingly, the alternatively spliced exons appear at branch points in the chordate phylogenetic tree, including one exon only found in humans and their closest living relatives, the great apes. Together, these results validate a simple pipeline for analyzing isoform diversity in genes with low expression and suggest that Kirrel3 function is fine-tuned by alternative splicing and may play a role in brain evolution.

Significance Statement

Kirrel3 is an important molecule for synapse and circuit formation with gene variants that are associated with neurodevelopmental disorders, yet Kirrel3 function remains largely unknown. Here, we report new isoforms of mouse and human Kirrel3, including secreted and transmembrane forms, that suggest a diverse repertoire of Kirrel3 actions. Importantly, we identified a new Kirrel3 exon only present in humans and the other great apes with potential to play an important role in circuit formation unique to these species.