bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium
Authors: Jiang Min-Zhi , Gaynor Sheila M. , Li Xihao , Van Buren Eric , Stilp Adrienne , Buth Erin , Wang Fei Fei , Manansala Regina , Gogarten Stephanie M. , Li Zilin , Polfus Linda M. , Salimi Shabnam , Bis Joshua C. , Pankratz Nathan , Yanek Lisa R. , Durda Peter , Tracy Russell P. , Rich Stephen S. , Rotter Jerome I. , Mitchell Braxton D. , Lewis Joshua P. , Psaty Bruce M. , Pratte Katherine A. , Silverman Edwin K. , Kaplan Robert C. , Avery Christy , North Kari , Mathias Rasika A. , Faraday Nauder , Lin Honghuang , Wang Biqi , Carson April P. , Norwood Arnita F. , Gibbs Richard A. , Kooperberg Charles , Lundin Jessica , Peters Ulrike , Dupuis Josée , Hou Lifang , Fornage Myriam , Benjamin Emelia J. , Reiner Alexander P. , Bowler Russell P. , Lin Xihong , Auer Paul L. , Raffield Laura M. ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,   TOPMed Inflammation Working Group
Published: September 2023

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38,465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program. We identified 22 distinct single-variant associations across 6 traits – E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin – that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.
Protein generation with evolutionary diffusion: sequence is all you need
Authors: Alamdari Sarah , Thakkar Nitya , van den Berg Rianne , Tenenholtz Neil , Strome Robert , Moses Alan M. , Lu Alex X. , Fusi Nicolò , Amini Ava P. , Yang Kevin K.
Published: September 2023

Deep generative models are increasingly powerful tools for thein silicodesign of novel proteins. Recently, a family of generative models called diffusion models has demonstrated the ability to generate biologically plausible proteins that are dissimilar to any actual proteins seen in nature, enabling unprecedented capability and control inde novoprotein design. However, current state-of-the-art diffusion models generate protein structures, which limits the scope of their training data and restricts generations to a small and biased subset of protein design space. Here, we introduce a general-purpose diffusion framework, EvoDiff, that combines evolutionary-scale data with the distinct conditioning capabilities of diffusion models for controllable protein generation in sequence space. EvoDiff generates high-fidelity, diverse, and structurally-plausible proteins that cover natural sequence and functional space. We show experimentally that EvoDiff generations express, fold, and exhibit expected secondary structure elements. Critically, EvoDiff can generate proteins inaccessible to structure-based models, such as those with disordered regions, while maintaining the ability to design scaffolds for functional structural motifs. We validate the universality of our sequence-based formulation by experimentally characterizing intrinsically-disordered mitochondrial targeting signals, metal-binding proteins, and protein binders designed using EvoDiff. We envision that EvoDiff will expand capabilities in protein engineering beyond the structure-function paradigm toward programmable, sequence-first design.
The Effect of Arm Restriction on Dynamic Stability and Upper Body Responses to Lateral Loss of Balance During Walking: An Observational Study
Authors: Rosenblum Uri , Lavi Adi , Fischer Arielle , Parmet Yisrael , Haim Amir , Handelzalts Shirley
Published: September 2023

When losing balance, upper-body movements serve as mechanical aids to regain stability. However, it remains unclear how these movements contribute to dynamic stability during recovery from a lateral loss of balance while walking with arm restriction. We aimed to 1) quantify the effect of arm restriction on gait stability and upper-body velocities, and 2) characterize upper-body kinematic strategies in response to lateral surface translations under different arm restriction conditions. Healthy adults were exposed to lateral surface translations while walking on a computerized treadmill under three conditions: ‘free arms’, ‘1-arm restricted’ and, ‘2-arms restricted’. Dynamic stability and upper-body velocities for the first step after perturbation onset were extracted. We found decreased dynamic stability in the sagittal plane and increased trunk velocity in the ‘2-arm restricted’ condition compared to the ‘free arms’ condition. Head and trunk movements in the mediolateral plane were in opposite directions in 44.31% of responses. Additionally, significant trunk velocities were observed in the opposite direction to the perturbation-induced loss of balance. Our results support the contribution of increased upper-body velocities to balance responses following arm-restricted walking perturbations and suggest that the ‘2-arm restricted’ condition may be utilized as a perturbation-based balance training, focusing on head and trunk responses.
Honey bees perform fine-scale detailing that continuously reduces comb area after nest expansion
Authors: Bailey Claire S. , Marting Peter R. , Smith Michael L.
Published: September 2023

Honey bees are renowned architects. The workers use expensive wax secretions to build their nests, which reach a mature, seemingly steady state, relatively quickly. After nest expansion is complete, workers do not tear down combs completely and begin anew, but there is the possibility they may make subtle changes like adding, removing, and repositioning existing wax. Previous work has focused on nest initiation and nest expansion, but here we focus on mature nests that have reached a steady-state. To investigate subtle changes to comb shape over time, we tracked six colonies from nest initiation through maturity (211 days), photographing their combs every 1-2 weeks. By aligning comb images over time, we show that workers continuously remove wax from the comb edges, thereby reducing total nest area over time. All six colonies trimmed comb edges, and 98.3% of combs were reduced (n = 59). Comb reduction began once workers stopped expanding their nests and continued throughout the experiment. The extent to which a comb was reduced did not correlate with its position within the nest, comb perimeter, or comb area. It is possible that workers use this removed wax as a reserve wax source, though this remains untested. These results show that the superorganism nest is not static; workers are constantly interacting with their nest, and altering it, even after nest expansion is complete.
Uncoupling the TFIIH Core and Kinase Modules Leads To Misregulated RNA Polymerase II CTD Serine 5 Phosphorylation
Authors: Giordano Gabriela , Buratowski Robin , Jeronimo Célia , Poitras Christian , Robert François , Buratowski Stephen
Published: September 2023

TFIIH is an essential transcription initiation factor for RNA polymerase II (RNApII). This multi-subunit complex comprises two modules that are physically linked by the subunit Tfb3 (MAT1 in metazoans). The TFIIH Core Module, with two DNA-dependent ATPases and several additional subunits, promotes DNA unwinding. The TFIIH Kinase Module phosphorylates Serine 5 of the C-terminal domain (CTD) of RNApII subunit Rpb1, a modification that coordinates exchange of initiation and early elongation factors. While it is not obvious why these two disparate activities are bundled into one factor, the connection may provide temporal coordination during early initiation. Here we show that Tfb3 can be split into two parts to uncouple the TFIIH modules. The resulting cells grow slower than normal, but are viable. Chromatin immunoprecipitation of the split TFIIH shows that the Core Module, but not the Kinase, is properly recruited to promoters. Instead of the normal promoter-proximal peak, high CTD Serine 5 phosphorylation is seen throughout transcribed regions. Therefore, coupling the TFIIH modules is necessary to localize and limit CTD kinase activity to early stages of transcription. These results are consistent with the idea that the two TFIIH modules began as independent functional entities that became connected by Tfb3 during early eukaryotic evolution.

Significance Statement

The RNA polymerase II initiation factor TFIIH provides two activities needed for efficient transcription: promoter unwinding and phosphorylation of polymerase subunit Rpb1 on its C-terminal domain (CTD). This study shows these two functions can be physically uncoupled. Unexpectedly, when the CTD kinase is no longer recruited to the promoter, the CTD phosphorylation on Serine 5 is not lost, but instead occurs throughout transcription. These results suggest that fusion of the two TFIIH activities evolved to better target CTD Serine 5 phosphorylation to early elongation.
The Effect of Transcranial Direct Current and Magnetic Stimulation on Fear Extinction and Return of Fear: A meta-analysis and Systematic Review
Authors: Lei Grace L.T. , Lai Cora S.W. , Lee Tatia M.C. , Lam Charlene L.M.
Published: September 2023

Anxiety and fear-related disorders are among the most prevalent mental illnesses. Non-invasive brain stimulation methods such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) have been employed to modulate anxiety and fear-related symptoms, but their therapeutic effects remain inconclusive. Pavlovian conditioning and extinction are experimental analogues of exposure therapy that investigate the neural mechanisms of fear extinction and return of fear. We conducted a meta-analysis and qualitative review on the effects of tDCS and TMS on fear extinction and return of fear in non-primate animals and humans. Results show that both anodal and cathodal tDCS over the prefrontal cortex inhibit short-term contextual and cued fear retrieval in animal models. In human studies, anodal tDCS over the medial/ventromedial prefrontal cortex enhances fear extinction, whereas TMS over the dorsolateral/ventromedial prefrontal cortex inhibits return of fear. Our findings suggest the optimal non-invasive brain stimulation protocols for threat extinction in humans.
ATP burst is the dominant driver of antibiotic lethality inMycobacterium smegmatis
Authors: Lodhiya Tejan , Palande Aseem , Veeram Anjali , Larrouy-Maumus Gerald , Beste Dany J V , Mukherjee Raju
Published: September 2023

Abstract

Antibiotic-tolerant bacteria, due to their unique physiology, are refractory to antimicrobial killing and pose challenges for infection control. Incomplete knowledge of how bactericidal antibiotics work, limits our understanding of partial resistance due to phenotypic tolerance in mycobacteria, a driver for developing genetic resistance. Using proteomics,13C isotopomer analysis, genetic and biochemical assays, we investigated the physiological response ofM. smegmatischallenged with aminoglycoside and fluoroquinolone antibiotics. Two distinct classes of antibiotics elicited remarkably similar responses and increased flux through the TCA cycle, causing enhanced respiration, ROS generation, and ATP burst. We observed that excessive ATP levels and not ROS, dominantly contributes to cidality, which may in part be, conferred by sequestration of divalent metal ions by ATP. Consequently,13C isotope tracing indicated TCA cycle flux deviation from its oxidative arm as a bacterial adaptive mechanism, which also included activated intrinsic resistance and a higher propensity to develop antibiotic resistance. Our study provides a new understanding of the intricate mechanisms of antibiotic-induced cell death and expands the current paradigm for antibiotic action.
Charting Aging Trajectories of Knee Cartilage Thickness for Early Osteoarthritis Risk Prediction: An MRI Study from the Osteoarthritis Initiative Cohort
Authors: Li Tengfei , Luo Tianyou , Chen Boqi , Huang Chao , Shen Zhengyang , Xu Zhenlin , Nissman Daniel , Golightly Yvonne M. , Nelson Amanda E. , Niethammer Marc , Zhu Hongtu
Published: September 2023

Knee osteoarthritis (OA), a prevalent joint disease in the U.S., poses challenges in terms of predicting of its early progression. Although high-resolution knee magnetic resonance imaging (MRI) facilitates more precise OA diagnosis, the heterogeneous and multifactorial aspects of OA pathology remain significant obstacles for prognosis. MRI-based scoring systems, while standardizing OA assessment, are both time-consuming and labor-intensive. Current AI technologies facilitate knee OA risk scoring and progression prediction, but these often focus on the symptomatic phase of OA, bypassing initial-stage OA prediction. Moreover, their reliance on complex algorithms can hinder clinical interpretation. To this end, we make this effort to construct a computationally efficient, easily-interpretable, and state-of-the-art approach aiding in the radiographic OA (rOA) auto-classification and prediction of the incidence and progression, by contrasting an individual’s cartilage thickness with a similar demographic in the rOA-free cohort. To better visualize, we have developed the toolset for both prediction and local visualization. A movie demonstrating different subtypes of dynamic changes in local centile scores during rOA progression is available athttps://tli3.github.io/KneeOA/. Specifically, we constructed age-BMI-dependent reference charts for knee OA cartilage thickness, based on MRI scans from 957 radiographic OA (rOA)-free individuals from the Osteoarthritis Initiative cohort. Then we extracted local and global centiles by contrasting an individual’s cartilage thickness to the rOA-free cohort with a similar age and BMI. Using traditional boosting approaches with our centile-based features, we obtain rOA classification of KLG ≤ 1 versus KLG = 2 (AUC =0.95, F1 =0.89), KLG ≤ 1 versus KLG ≥ 2 (AUC =0.90, F1 =0.82) and prediction of KLG2 progression (AUC =0.98, F1 =0.94), rOA incidence (KLG increasing from <2to ≥2; AUC =0.81, F1 =0.69) and rOA initial transition (KLG from 0 to 1; AUC =0.64, F1 =0.65) within a future 48-month period. Such performance in classifying KLG ≥ 2 matches that of deep learning methods in recent literature. Furthermore, its clinical interpretation suggests that cartilage changes, such as thickening in lateral femoral and anterior femoral regions and thinning in lateral tibial regions, may serve as indicators for prediction of rOA incidence and early progression. Meanwhile, cartilage thickening in the posterior medial and posterior lateral femoral regions, coupled with a reduction in the central medial femoral region, may signify initial phases of rOA transition.
Excess risk of Covid-19 infection and mental distress in healthcare workers during successive pandemic waves. Analysis of matched cohorts of healthcare workers and community referents in Alberta, Canada
Authors: Galarneau Jean-Michel , Labrèche France , Durand-Moreau Quentin , Ruzycki Shannon , Adisesh Anil , Burstyn Igor , Zadunayski Tanis , Cherry Nicola
Published: September 2023

Objectives

To investigate changes in risk of infection and mental distress in healthcare workers (HCWs) relative to the community as the Covid-19 pandemic progressed.

Methods

HCWs in Alberta, Canada, recruited to an interprovincial cohort, were asked consent to link to Alberta’s administrative health database (AHDB) and to information on Covid-19 immunization and polymerase chain reaction (PCR) testing. Those consenting were matched to records of up to 5 community referents (CRs). Physician diagnoses of Covid-19 were identified in the AHDB from the start of the pandemic to 31 March 2022. Physician consultations for mental health (MH) conditions (anxiety, stress/adjustment reaction, depressive) were identified from 1 April 2017 to 31 March 2022. Relative risk for HCWs was estimated for each condition, overall and for successive infection waves.

Results

80% (3050/3812) of HCWs consented to be linked to the AHDB: 97% (2959/3050) were matched to 14546 CRs. HCWs were at greater risk of Covid-19 overall, with first infection defined either from PCR tests or physician records They were also at increased risk for each of the three MH diagnoses. In analyses adjusted for confounding, risk of Covid-19 infection was higher than CRs early in the pandemic and during the fifth (Omicron) wave. The excess risk of stress/adjustment reactions and depressive conditions increased with successive waves during the epidemic, peaking in the 4thwave.

Conclusion

Administrative health data, although not a complete reflection of infection or MH, contributed to an understanding of changing risk over time, with excess risk continuing late in the pandemic
Transcriptional Signatures of Hippocampal Tau Pathology in Primary Age-Related Tauopathy and Alzheimer’s Disease
Authors: Stein-O’Brien Genevieve L , Palaganas Ryan , Meyer Ernest M. , Redding-Ochoa Javier , Pletnikova Olga , Guo Haidan , Bell William R , Troncoso Juan C , Huganir Richard L , Morris Meaghan
Published: September 2023

Background

Tau pathology is common in age-related neurodegenerative diseases. Tau pathology in primary age-related tauopathy (PART) and in Alzheimer’s disease (AD) has a similar biochemical structure and anatomic distribution, which is distinct from tau pathology in other diseases. However, the molecular changes associated with intraneuronal tau pathology in PART and AD, and whether these changes are similar in the two diseases, is largely unexplored.

Methods

Using GeoMx spatial transcriptomics, mRNA was quantified in CA1 pyramidal neurons with tau pathology and adjacent neurons without tau pathology in 6 cases of PART and 6 cases of AD, and compared to 4 control cases without pathology. Transcriptional changes were analyzed for differential gene expression and for coordinated patterns of gene expression associated with both disease state and intraneuronal tau pathology.

Results

Synaptic gene changes and two novel gene expression signatures associated with intraneuronal tau were identified in PART and AD. Overall, gene expression changes associated with intraneuronal tau pathology were similar in PART and AD. Synaptic gene expression was decreased overall in neurons in AD and PART compared to control cases. However, this decrease was largely driven by neurons lacking tau pathology. Synaptic gene expression was increased in tau-positive neurons compared to tau-negative neurons in disease. Two novel gene expression signatures associated with intraneuronal tau were identified by examining coordinated patterns of gene expression. Genes in the up-regulated expression pattern were enriched in calcium regulation and synaptic function pathways, specifically in synaptic exocytosis. These synaptic gene changes and intraneuronal tau expression signatures were confirmed in a published transcriptional dataset of cortical neurons with tau pathology in AD.

Conclusions

PART and AD show similar transcriptional changes associated with intraneuronal tau pathology in CA1 pyramidal neurons, raising the possibility of a mechanistic relationship between the tau pathology in the two diseases. Intraneuronal tau pathology was also associated with increased expression of genes associated with synaptic function and calcium regulation compared to tau-negative disease neurons. The findings highlight the power of molecular analysis stratified by pathology in neurodegenerative disease and provide novel insight into common molecular pathways associated with intraneuronal tau in PART and AD.

Graphical Abstract

Created withBioRender.com(License GLSO).
Long- versus short-duration systemic corticosteroid regimens for acute exacerbations of COPD: A systematic review and meta-analysis of randomized trials and cohort studies
Authors: Zhao Zhen , Lou Owen , Wang Yiyang , Yin Raymond , Gong Carrie , Deng Florence , Wu Ethan C , Xie Jing Yi , Wu Jerry , Ma Avery , Guo Yongzhi , Xiong Wei Ting
Published: September 2023

While systemic corticosteroids quicken patient recovery during acute exacerbations of COPD, they also have many adverse effects. The optimal duration of corticosteroid administration remains uncertain. We performed a systematic review and meta-analysis to compare patient outcomes between short-(≤7 day) and long- (>7 day) corticosteroid regimens in adults with acute exacerbations of COPD.

MEDLINE, EMBASE, CENTRAL, and hand searches were used to identify eight eligible RCTs and three retrospective cohort studies. Risk of bias was assessed using the Cochrane RoB 2.0 tool and ROBINS-I. Data were summarized as odds ratios (ORs) or mean differences (MDs) whenever possible and qualitatively described otherwise.

A total of 11532 participants were included, with 1296 eligible for meta-analyses. Heterogeneity was present in the methodology and settings of the studies. The OR for mortality was 0.76 (95% CI=0.40–1.44, n=1055). The MD for hospital length-of-stay was -0.91 days (95% CI=-1.81–-0.02 days, n=421). The OR for re-exacerbations was 1.31 (95% CI=0.90–1.90, n=552). The OR for hyperglycemia was 0.90 (95% CI=0.60–1.33, n=423). The OR for infection incidence was 0.96 (95% CI=0.59–1.156, n=389). The MD for one-second forced expiratory volume change was -18.40 mL (95% CI=-111.80–75.01 mL, n=161).

The RCTs generally had low or unclear risks of bias, while the cohort studies had serious or moderate risks of bias. Our meta-analyses were affected by imprecision due to insufficient data. Some heterogeneity was present in the results, suggesting population, setting, and treatment details are potential prognostic factors. Our evidence suggests that short-duration treatments are not worse than long-duration treatments in moderate/severe exacerbations and may lead to considerably better outcomes in milder exacerbations. This supports the current GOLD guidelines for corticosteroid administration.

No funding was given for this review. Our protocol is registered in PROSPERO: CRD42023374410.
A novelkitmutant rat enables hematopoietic stem cell engraftment without irradiation
Authors: Iida Ryuya , Ishida Saeko , Wang Jinxi , Hattori Kosuke , Yoshimi Kazuto , Yamazaki Satoshi , Mashimo Tomoji
Published: September 2023

Hematopoietic stem cell (HSC) transplantation is extensively studied in mouse models, but their limited scale presents challenges for effective engraftment and comprehensive evaluations. Rats, due to their larger size and anatomical similarity to humans, offer a promising alternative. In this study, we establish a rat model with theKitV834Mmutation, mirroringKitW41mice often used in KIT signaling and HSC research.KitV834Mrats are viable and fertile, displaying anemia and mast cell depletion similar toKitW41mice. The mutation affects myeloid cell proliferation and differentiation, as seen in the colony-forming unit granulocyte-macrophage assay. Importantly,KitV834Mrats support donor rat-HSC engraftment without irradiation. Competitive transplantation assays reveal reduced reconstruction capacity inKitV834MHSCs. Leveraging the larger scale of this rat model enhances our understanding of HSC biology and transplantation dynamics, potentially advancing our knowledge in this field.
Cep290 is cooperatively maintained at basal body by Cep131-Cep162 and Cby-Fam92 modules
Authors: Wu Zhimao , Chen Huicheng , Zhang Yingying , Wang Yaru , Wang Qiaoling , Augière Céline , Hou Yanan , Fu Yuejun , Peng Ying , Durand Bénédicte , Wei Qing
Published: September 2023

Cilia play critical roles in cell signal transduction and organ development. Defects in cilia function result in a variety of genetic disorders. Cep290 is an evolutionarily conserved ciliopathy protein that bridges the ciliary membrane and axoneme at the basal body and plays critical roles in the initiation of ciliogenesis and TZ assembly. How Cep290 is maintained at basal body and whether axonemal and ciliary membrane localized cues converge to determine the localization of Cep290 remain unknown. Here, we report that the Cep131-Cep162 module near the axoneme and the Cby-Fam92 module close to the membrane synergistically control the basal body localization of Cep290 and the subsequent initiation of ciliogenesis. Concurrent deletion of any protein of the Cep131-Cep162 module and of the Cby-Fam92 module leads to a complete loss of Cep290 from basal body and blocks ciliogenesis at its initiation stage. Our results reveal that the first step of ciliogenesis strictly depend on cooperative and retroactive interactions between Cep131-Cep162, Cby-Fam92 and Cep290, which may contribute to the complex pathogenesis of Cep290-related ciliopathies.
m6a methylation orchestrates IMP1 regulation of microtubules during human neuronal differentiation
Authors: Klein Pierre , Harley Jasmine , Crook Harry , Serna Sofia Esteban , Howe Marija Petrić , Roumeliotis Theodoros I. , Choudhary Jyoti S. , Chakrabarti Anob M , Luisier Raphaëlle , Patani Rickie , Ramos Andres
Published: September 2023

Neuronal differentiation requires building a complex intracellular architecture, and therefore the coordinated regulation of defined sets of genes. RNA-binding proteins (RBPs) play a key role in this regulation. However, while their action on individual mRNAs has been explored in depth, the mechanisms used to coordinate expression of the gene programs shaping neuronal morphology are poorly understood. To address this, we analysed how the paradigmatic RBP IMP1 (IGF2BP1), an essential developmental factor, selects and regulates its RNA targets during the differentiation of human neurons. We performed a combination of system-wide and molecular analyses, revealing that IMP1 developmentally transitions to and directly regulates the expression of mRNAs encoding essential regulators of the microtubule network, a key component of neuronal morphology. Furthermore, we showed that m6A methylation drives the selection of specific IMP1 mRNA targets and their protein expression during the developmental transition from neural precursors to neurons, providing a molecular principle for the onset of target selectivity.
Hyperpolarization-Activated Currents Drive Neuronal Activation Sequences in Sleep
Authors: Mehrotra Dhruv , Levenstein Daniel , Duszkiewicz Adrian J , Carrasco Sofia Skromne , Booker Sam A , Kwiatkowska Angelika , Peyrache Adrien
Published: September 2023

Sequential neuronal patterns are believed to support information processing in the cortex, yet their origin is still a matter of debate. We report that neuronal activity in the mouse head-direction cortex (HDC, i.e., the post-subiculum) was sequentially activated along the dorso-ventral axis during sleep at the transition from hyperpolarized “DOWN” to activated “UP” states, while representing a stable direction. Computational modelling suggested that these dynamics could be attributed to a spatial gradient of hyperpolarization-activated current (Ih), which we confirmed inex vivoslice experiments and corroborated in other cortical structures. These findings open up the possibility that varying amounts of Ihacross cortical neurons could result in sequential neuronal patterns, and that travelling activity upstream of the entorhinal-hippocampal circuit organises large-scale neuronal activity supporting learning and memory during sleep.

Highlights

Neuronal Activation Sequence in HDC: neuronal activity was sequentially reinstated along the dorsoventral axis of the HDC at UP state but not DOWN state onset.

Role of Ihin Sequence Generation: Incorporating the hyperpolarization-activated current (Ih) into computational models, we identified its pivotal role in UP/DOWN dynamics and neuronal activity sequences.

Ex VivoVerification: slice physiology revealed a dorsoventral gradient of Ih in the HDC.

Implications Beyond HDC: the gradient of Ihcould account for the sequential organization of neuronal activity across various cortical areas.
Characteristics of spontaneous anterior-posterior oscillation-frequency convergences in the alpha band
Authors: Suzuki Satoru , Grabowecky Marcia , Menceloglu Melisa
Published: September 2023

Alpha oscillation frequencies vary along the anterior-posterior axis, but they also dynamically converge. We investigated spontaneous anterior-posterior oscillation-frequency convergences while participants rested with their eyes open or closed, by tracking their oscillatory EEG activity in an extended alpha range (5-15 Hz) with appropriate temporal (∽370 ms) and spectral (∽1 Hz) resolutions. Oscillation-frequency convergences were prominent in the alpha band (8-12 Hz) and our analyses revealed three primary characteristics. First, the probability of an additional site joining a frequency convergence increased as more sites frequency-converged, suggesting that synergistic interactions drive anterior-posterior frequency convergences. Second, the oscillatory power at participating sites increased as more sites frequency-converged, suggesting that the synergistic interactions are mediated by regional synchronizations, being boosted by inter-regional frequency matching, facilitating the entrainment of additional regions. Third, frequency convergences generated two opposing phase gradients, posterior-behind and posterior-ahead, potentially mediating directional information flows to and from posterior regions. These gradients became steeper as more sites frequency-converged (while maintaining relatively constant levels of phase consistency), suggesting that frequency convergences increase the directionality of anterior-posterior information flows. Interestingly, when participants closed their eyes, the opposing phase gradients spatially organized, forming posterior-ahead gradients along the midline and posterior-behind gradients within each hemisphere, suggesting that closing eyes streamlines the opposing information flows. Taken together, these results suggest that synergistic interactions drive spontaneous anterior-posterior oscillation-frequency convergences in the alpha band, which may contribute to directional flows of information to and from posterior regions.
A robust measure of metacognitive sensitivity and confidence criteria
Authors: Arnold Derek H. , Clendinen Mitchell , Johnston Alan , Lee Alan L.F. , Yarrow Kielan
Published: September 2023

Humans experience feelings of confidence in their decisions. In perception, these feelings are typically accurate – we tend to feel more confident about correct decisions. The degree of insight people have into the accuracy of their decisions is known as metacognitive sensitivity. Currently popular methods of estimating metacognitive sensitivity are subject to interpretive ambiguities because they assume that humans experience normally-shaped distributions of different experiences when they are repeatedly exposed to a single input. If, however, people have skewed distributions of experiences, or distributions with excess kurtosis (i.e. a distribution containing greater numbers of extreme experiences than is predicted by a normal distribution), calculations can erroneously underestimate metacognitive sensitivity. Here, we describe a means of estimating metacognitive sensitivity that is more robust against violations of the normality assumption. This improved method relies on estimating the precision with which people transition between making categorical decisions with relatively low to high confidence, and on comparing this with the precision with which they transition between making different types of perceptual category decision. The new method can easily be added to standard behavioral experiments. We provide free Matlab code to help researchers implement these analyses and procedures in their own experiments.

Public Significance Statement

Signal-detection theory is one of the most popular frameworks for analysing data from experiments of human behaviour – including investigations of confidence. The authors demonstrate that if a key assumption of this framework is inadvertently violated, analyses of confidence can lead to unwarranted conclusions. They develop a new and more robust measure of confidence.
Neural correlates of model-based behavior in internet gaming disorder and alcohol use disorder
Authors: Kwon Mina , Choi Hang-Nyoung , Park Harhim , Ahn Woo-Young , Jung Young-Chul
Published: September 2023

Background

An imbalance between model-based and model-free decision-making systems is a common feature in addictive disorders. However, little is known about whether similar decision-making deficits appear in internet gaming disorder (IGD). This study compared neurocognitive features associated with model-based and model-free systems in IGD and alcohol use disorder (AUD).

Method

Participants diagnosed with IGD (n=22) and AUD (n=22), and healthy controls (n=30) performed the two-stage task inside the functional magnetic resonance imaging (fMRI) scanner. We used computational modeling and hierarchical Bayesian analysis to provide a mechanistic account of their choice behavior. Then, we performed a model-based fMRI analysis and functional connectivity analysis to identify neural correlates of the decision-making processes in each group.

Results

The computational modeling results showed similar levels of model-based behavior in the IGD and AUD groups. However, we observed distinct neural correlates of the model-based reward prediction error (RPE) between the two groups. The IGD group exhibited insula-specific activation associated with model-based RPE, while the AUD group showed prefrontal activation, particularly in the orbitofrontal cortex and superior frontal gyrus.

Furthermore, individuals with IGD demonstrated hyper-connectivity between the insula and brain regions in the salience network in the context of model-based RPE.

Discussion and Conclusions

The findings suggest potential differences in the neurobiological mechanisms underlying model-based behavior in IGD and AUD, albeit shared cognitive features observed in computational modeling analysis. As the first neuroimaging study to compare IGD and AUD in terms of the model-based system, this study provides novel insights into distinct decision-making processes in IGD.
Genomic locus of lncRNA-Gm26793forms an inter-chromosomal molecular lock withCubnto ensure proper stem cell differentiation and mouse embryogenesis
Authors: Liu Zhiwen , Yang Xianfa , Chen Jiehui , Ma Yongjian , Wan Xing , Fu Yonggao , Chen Yingying , Wen Mingzhu , Qian Yun , Zhang Yong , Zhu Dahai , Li Jinsong , Jing Naihe
Published: September 2023

Inter-chromosomal interactions play a crucial role in 3D genome organization, yet the organizational principles and functional significances remain elusive. In general, long non-coding RNA (lncRNA) loci and transcripts are frequently associated with transcriptional programs modulated by long-range chromatin interactions. Here, we identified a novel lncRNA namedGm26793, which is abundantly distributed in the primitive streak and mesodermal cells of E7.5 mouse gastrula. Through genetic ablation ofGm26793, we observed a preferential responsiveness to primitive endoderm lineage during stem cell differentiation, as well as enhanced occurrence of transient and degenerative state cells in early mouse embryos when the cell fate segregates between epiblast and primitive endoderm. Mechanistically, we revealed the genomic locus ofGm26793, rather than the lncRNA transcript or adjacent gene governs the cell fate preference towards primitive endoderm. Concretely,Gm26793locus (Chr 7) forms an inter-chromosomal molecular lock withCubn(Chr 2), restraining the expression ofCubnand maintaining a natural epigenetic landscape, thus ensuring the proper lineage specificationin vitroandin vivo. In order to reinforce this lock, CTCF and cohesin complex serves as a ring to fasten the inter-chromosomal contact. Overall, our study provides a clear paradigm that inter-chromosomal interaction collaborates with architectural factors to stabilize nuclear conformation and guarantee faithful gene expression during stem cell differentiation and mammalian embryogenesis.
Electrochemically controlled blinking of fluorophores to enable quantitative stochastic optical reconstruction microscopy (STORM) imaging
Authors: Yang Ying , Ma Yuanqing , Tilley Richard , Gaus Katharina , Gooding J. Justin
Published: September 2023

Stochastic optical reconstruction microscopy (STORM) allows widefield imaging with single molecule resolution through calculating the coordinates of individual fluorophores from the separation of the fluorophore emission in both time and space. Such separation is achieved by photoswitching the fluorophores between a long lived OFF state and an emissive ON state. Despite STORM having revolutionized cellular imaging it remains challenging for quantitative imaging of single molecules due to a number of limitations, such as photobleaching caused under counting, overlapping emitters related fitting error, and repetitive but random blinking induced over counting. To overcome these limitations, we develop an electrochemical approach to switch the fluorophores between ON and OFF states for STORM (EC-STORM). The approach provides greater control over the fluorophore recovery yield, emitter density, and random blinking than photochemically switching. The result is EC-STORM has superior imaging capability than conventional photochemical STORM and can perform molecular counting; a significant advance.
Male-specific vasotocin expression in the medaka tuberal hypothalamus: androgen dependence and probable role in aggression
Authors: Kawabata-Sakata Yukika , Kanda Shinji , Okubo Kataaki
Published: September 2023

Terrestrial vertebrates have a population of androgen-dependent vasotocin (VT)-expressing neurons in the extended amygdala that are more abundant in males and mediate male-typical social behaviors, including aggression. Teleosts lack these neurons but instead have novel male-specific VT-expressing neurons in the tuberal hypothalamus. Here we found in medaka thatvtexpression in these neurons is dependent on post-pubertal gonadal androgens and that androgens can act on these neurons to directly stimulatevttranscription via the androgen receptor subtype Ara. Furthermore, administration of exogenous VT induced aggression in females and alterations in the androgen milieu led to correlated changes in the levels of tuberal hypothalamicvtexpression and aggression in both sexes. However, genetic ablation ofvtfailed to prevent androgen-induced aggression in females. Collectively, our results demonstrate a marked androgen dependence of male-specificvtexpression in the teleost tuberal hypothalamus, although its relevance to male-typical aggression needs to be further validated.
A long journey to oyster stem cell markers.CgSox2 andCgPOU2 synergic DNA binding and NODE proteins
Authors: Delsert Claude D.
Published: September 2023

Summary statement

Oyster Sox2 and POU bind in synergy to human Sox-Oct DNA motif, which suggests a role in stem cell maintenance. Sole among the oyster NODE proteins to alter chromatin SalL assembles in large hollow structures that exclude chromatin.

Precursor or stem cells have been identified in mollusk, but determination of differentiation stages is still hampered by lack of markers, notably Oct4, that does not exist among invertebrates. To address this thorny question, oyster Nanog Oct4 DEacetylase proteins were studied, particularly POU proteins, a family that includes vertebrate Oct4.

First, we showed that essential residues of 2 major vertebrate stem cell proteins, Sox2 and Oct4, are conserved through most metazoans which led to experimentally showin vitrothat recombinant Sox2 protein specifically binds to WT, the mammalian Sox2-Oct4 consensus DNA motif. Furthermore, oyster Sox2 and POU2-3 synergistically bound to WT thus mimicking Sox2 and Oct4 synergy. Altogether, these data suggest that invertebrate POU2 or 3 are Oct4 orthologs. Expression in mammalian cells showed that oyster NODE proteins do not significantly alter chromatin structure except SalL, the homolog of SalL4. Confocal images revealed barrel-shaped hollow structures, orthogonal to cell plane and constituted of aggregates. These bodies were able to fuse or to disassemble/reassemble in fewer but much bigger hollow structures that excluded chromatin.
Auditory corticofugal circuits drive vocalization-guided maternal behavior
Authors: LeMessurier Amy M. , Agha Ayat A. , Froemke Robert C.
Published: September 2023

Perception of vocalizations is crucial for social behavior. A conserved example of this is mothers responding to distress calls from infants. In mice, experienced mothers (dams) find and retrieve isolated pups into the nest when pups emit ultrasonic vocalizations (USVs). Virgin females generally don’t retrieve pups until they gain experience, for example by co-housing with a dam and litter. The onset of retrieval behavior is correlated with heightened sensitivity to USVs in left auditory cortex (AC). This plasticity may support learning via projections from cortex to early structures in the auditory pathway. To test whether projections from left AC are required for retrieval, we chemogenetically silenced activity in layer 5 during retrieval. In expert retrievers, silencing only neurons projecting to inferior colliculus (corticocollicular) led to impairment in retrieval. However, silencing neurons projecting to striatum had no effect. We used optically-tagged in vivo whole-cell recordings and 2-photon Ca2+imaging in awake mice to compare encoding of USVs in corticostriatal and corticollicular neurons. Corticocollicular neurons in expert retrievers exhibited sustained increases in activity during USV playback compared to presentation of pure tones, while activity was equivalent during USV and pure tone presentation in corticostriatal neurons. The sustained activity we observed in corticollicular neurons may reflect increased excitability in a dedicated network of recurrently-linked cortical and subcortical areas. We tracked activity in corticocollicular and corticostriatal neurons over several days before and during co-housing as retrieval performance improved. This revealed robust population responses to USVs on each day in both groups. In both groups, delayed responses to USVs were larger in magnitude on days in which mice had reached expert performance, which may reflect network-level plasticity upregulating activity in recurrent auditory circuits to support perception of USVs.
Uncovering a mammalian neural-specific poly(A) binding protein with unique properties
Authors: Sharma Sahil , Kajjo Sam , Harra Zineb , Hasaj Benedeta , Delisle Victoria , Ray Debashish , Gutierrez Rodrigo L. , Carrier Isabelle , Kleinman Claudia , Morris Quaid , Hughes Timothy R. , McInnes Roderick , Fabian Marc R.
Published: September 2023

The mRNA 3′ poly(A) tail plays a critical role in regulating both mRNA translation and turnover. It is bound by the cytoplasmic poly(A) binding protein (PABPC), an evolutionarily conserved protein that can interact with translation factors and mRNA decay machineries to regulate gene expression. Mammalian PABPC1, the prototypical PABPC, is expressed in most tissues and interacts with eukaryotic translation initiation factor 4G (eIF4G) to stimulate translation in specific contexts. In this study, we uncovered a new mammalian PABPC, which we named neural PABP (neuPABP), as it is predominantly expressed in the brain. neuPABP maintains a unique architecture as compared with other PABPCs, containing only two RNA recognition motifs (RRMs) and maintaining a unique N-terminal domain of unknown function. neuPABP expression is activated in neurons as they mature during synaptogenesis, where neuPABP localizes to the soma and postsynaptic densities. neuPABP interacts with the noncoding RNA BC1, as well as mRNAs coding for ribosomal and mitochondrial proteins. However, in contrast to PABPC1, neuPABP does not associate with actively translating mRNAs in the brain. In keeping with this, we show that neuPABP has evolved such that it does not bind eIF4G and as a result fails to support protein synthesis in vitro. Taken together, these results indicate that mammals have expanded their PABPC repertoire in the brain and propose that neuPABP may support the translational repression of select mRNAs.
3D-printed sheet jet for stable megahertz liquid sample delivery at X-ray free-electron lasers
Authors: Konold Patrick E. , You Tong , Bielecki Johan , Valerio Joana , Kloos Marco , Westphal Daniel , Bellisario Alfredo , Varma Yenupuri Tej , Wollter August , Koliyadu Jayanath C. P. , Koua Faisal H.M. , Letrun Romain , Round Adam , Sato Tokushi , Mészáros Petra , Monrroy Leonardo , Mutisya Jennifer , Bódizs Szabolcs , Larkiala Taru , Nimmrich Amke , Alvarez Roberto , Adams Patrick , Bean Richard , Ekeberg Tomas , Kirian Richard A. , Martin Andrew V. , Westenhoff Sebastian , Maia Filipe R. N. C.
Published: September 2023

X-ray free-electron lasers (XFELs) can probe chemical and biological reactions as they unfold with unprecedented spatial and temporal resolution. A principal challenge in this pursuit involves the delivery of samples to the X-ray interaction point in such a way that produces data of the highest possible quality and with maximal efficiency. This is hampered by intrinsic constraints posed by the light source and operation within a beamline environment. For liquid samples, the solution typically involves some form of high-speed liquid jet, capable of keeping up with the rate of X-ray pulses. However, conventional jets are not ideal because of radiation-induced explosions of the jet, as well as their cylindrical geometry combined with the X-ray pointing instability of many beamlines which causes the interaction volume to differ for every pulse. This complicates data analysis and contributes to measurement errors. An alternative geometry is a liquid sheet jet which, with its constant thickness over large areas, eliminates the problems related to X-ray pointing. Since liquid sheets can be made very thin, the radiation-induced explosion is reduced, boosting their stability. These are especially attractive for experiments which benefit from small interaction volumes such as fluctuation X-ray scattering and several types of spectroscopy. Although their use has increased for soft X-ray applications in recent years, there has not yet been wide-scale adoption at XFELs. Here, gas-accelerated liquid sheet jet sample injection is demonstrated at the European XFEL SPB/SFX nano focus beamline. Its performance relative to a conventional liquid jet is evaluated and superior performance across several key factors has been found. This includes a thickness profile ranging from hundreds of nanometres to 60 nm, a fourfold increase in background stability and favorable radiation-induced explosion dynamics at high repetition rates up to 1.13 MHz. Its minute thickness also suggests that ultrafast single-particle solution scattering is a possibility.