bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling of mitochondrial genetic polymorphisms reveals induction of heteroplasmy by pleiotropic disease locus MT:10398A>G
Authors: Smullen Molly , Olson Meagan N , Murray Liam F , Suresh Madhusoodhanan , Yan Guang , Dawes Pepper , Barton Nathaniel J , Mason Jivanna N , Zhang Yucheng , Fernandez-Fontaine Aria A , Church George M , Mastroeni Diego , Wang Qi , Lim Elaine T , Chan Yingleong , Readhead Benjamin
Published: June 2023

Mitochondrial (MT) dysfunction has been associated with several neurodegenerative diseases including Alzheimer’s disease (AD). While MT-copy number differences have been implicated in AD, the effect of MT heteroplasmy on AD has not been well characterized. Here, we analyzed over 1,800 whole genome sequencing data from four AD cohorts in seven different tissue types to determine the extent of MT heteroplasmy present. While MT-heteroplasmy was present throughout the entire MT genome for blood samples, we detected MT-heteroplasmy only within the MT control region for brain samples. We observed that an MT variant 10398A>G (rs2853826) was significantly associated with overall MT-heteroplasmy in brain tissue while also being linked with the largest number of distinct disease phenotypes of all annotated MT variants inMitoMap. Using gene-expression data from our brain samples, our modeling discovered several gene networks involved in mitochondrial respiratory chain and Complex I function associated with 10398A>G. The variant was also found to be an expression quantitative trait loci (eQTL) for the gene MT-ND3. We further characterized the effect of 10398A>G by phenotyping a population of lymphoblastoid cell-lines (LCLs) with and without the variant allele. Examination of RNA sequence data from these LCLs reveal that 10398A>G was an eQTL for MT-ND4. We also observed in LCLs that 10398A>G was significantly associated with overall MT-heteroplasmy within the MT control region, confirming the initial findings observed in post-mortem brain tissue. These results provide novel evidence linking MT SNPs with MT heteroplasmy and open novel avenues for the investigation of pathomechanisms that are driven by this pleiotropic disease associated loci.
Impaired parvalbumin interneurons in the retrosplenial cortex as the cause of sex-dependent vulnerability in Alzheimer’s disease
Authors: Terstege Dylan J. , Ren Yi , Ahn Bo Young , Seo Heewon ,   Alzheimer’s Disease Neuroimaging Initiative, Galea Liisa A. M. , Sargin Derya , Epp Jonathan R.
Published: June 2023

Alzheimer’s disease is a debilitating neurodegenerative disorder with no cure and few treatment options. In early stages of Alzheimer’s disease, impaired metabolism, and functional connectivity of the retrosplenial cortex strongly predict future cognitive impairments. Therefore, understanding Alzheimer’s disease-related deficits in the retrosplenial cortex is critical for understanding the origins of cognitive impairment and identifying early treatment targets. Using the 5xFAD mouse model, we discovered early, sex-dependent alterations in parvalbumin-interneuron transcriptomic profiles. This corresponded with impaired parvalbumin-interneuron activity, which was sufficient to induce cognitive impairments and dysregulate retrosplenial functional connectivity. In fMRI scans from patients with mild cognitive impairment and Alzheimer’s disease, we observed a similar sex-dependent dysregulation of retrosplenial cortex functional connectivity and, in post-mortem tissue from subjects with Alzheimer’s disease, a loss of parvalbumin interneurons. Reversal of cognitive deficits by stimulation of parvalbumin interneurons in the retrosplenial cortex suggests that this may serve as a promising novel therapeutic strategy.

One Sentence Summary

Altered function, connectivity, and survival of parvalbumin expressing neurons in the retrosplenial cortex in Alzheimer’s Disease.
Methods to Utilize Pulse Wave Velocity to Measure Alterations in Cerebral and Cardiovascular Parameters
Authors: Marshall Andrea G. , Neikirk Kit , Shao Bryanna , Crabtree Amber , Vue Zer , Beasley Heather K. , Garza-Lopez Edgar , Scudese Estevão , Wanjalla Celestine N. , Kirabo Annet , Albritton Claude F , Jamison Sydney , Demirci Mert , Murray Sandra A. , Cooper Anthonya T. , Taffet George E , Hinton Antentor O. , Reddy Anilkumar K.
Published: June 2023

Alzheimer’s Disease (AD) is a global health issue, affecting over 6 million in the United States, with that number expected to increase as the aging population grows. As a neurodegenerative disorder that affects memory and cognitive functions, it is well established that AD is associated with cardiovascular risk factors beyond only cerebral decline. However, the study of cerebrovascular techniques for AD is still evolving. Here, we provide reproducible methods to measure impedance-based pulse wave velocity (PWV), a marker of arterial stiffness, in the systemic vascular (aortic PWV) and in the cerebral vascular (cerebral PWV) systems. Using aortic impedance and this relatively novel technique of cerebral impedance to comprehensively describe the systemic vascular and the cerebral vascular systems, we examined the sex-dependent differences in 5x transgenic mice (5XFAD) with AD under normal and high-fat diet, and in wild-type mice under a normal diet. Additionally, we validated our method for measuring cerebrovascular impedance in a model of induced stress in 5XFAD. Together, our results show that sex and diet differences in wildtype and 5XFAD mice account for very minimal differences in cerebral impedance. Interestingly, 5XFAD, and not wildtype, male mice on a chow diet show higher cerebral impedance, suggesting pathological differences. Opposingly, when we subjected 5XFAD mice to stress, we found that females showed elevated cerebral impedance. Using this validated method of measuring impedance-based aortic and cerebral PWV, future research may explore the effects of modifying factors including age, chronic diet, and acute stress, which may mediate cardiovascular risk in AD.

New and Noteworthy

Here, we presented a new technique which is an application of the concept of aortic impedance to determining cerebral impedance. While aortic PWV is typically utilized to study aortic stiffness, we also developed a technique of cerebral PWV to study cerebral vascular stiffness. This method may be useful in improving the rigor of studies that seek to have a dual focus on cardiovascular and cerebral function.
Speech recognition from MEG data using covariance filters
Authors: Verkhlyutov Vitaly , Vvedensky Victor , Gurtovoy Konstantin , Burlakov Evgenii , Martynova Olga
Published: June 2023

Speech recognition from EEG and MEG data is the first step in the development of BCI and AI systems for further use in the decoding of inner speech. Great achievements in this direction have been made with the use of ECoG and stereo-EEG. At the same time, there are few works on this topic on the analysis of data obtained by nonin-vasive methods of brain activity registration. Our approach is based on the evaluation of connections in the sensor space with the extraction of the MEG connectivity pattern specific to a given segment of speech. We tested our method on 7 subjects. In all cases, our processing pipeline was sufficiently reliable and worked either without recognition errors or with few errors. After ”training” the algorithm is able to recognize a fragment of spoken speech in a single presentation. For recognition, we used MEG recording segments of 50-1200 ms from the beginning of the word. A segment of at least 600 ms was required for high-quality recognition. Intervals longer than 1200 ms degraded the quality of recognition. Band-pass filtering of MEG showed that the quality of recognition is higher when using the gamma frequency range compared to the low-frequency range of the analyzed signal.
Solitary Silence and Social Sounds: Music influences mental imagery, inducing thoughts of social interactions
Authors: Herff Steffen A. , Cecchetti Gabriele , Ericson Petter , Cano Estefania
Published: June 2023

The COVID-19 pandemic was accompanied by a marked increase in the use of music listening for self-regulation1. During these challenging times, listeners reported they used music ‘to keep them company’2; indicating that they may have turned to music for social solace3. However, whether this is simply a figure of speech or an empirically observable effect on social thought was previously unclear.

In three experiments, six hundred participants were presented with silence or task-irrelevant music in Italian, Spanish, or Swedish while performing a directed mental-imagery task in which they imagined a journey towards a topographical landmark4. To control for a possible effect of vocals on imagined content, the music was presented with or without vocals to the participants, of which half were native speakers and the other half non-speakers of the respective languages.

Music, compared to silence, led to more vivid imagination and changes in imagined content. Specifically, social interaction emerged as a clear thematic cluster in participants’ descriptions of their imagined content through Latent Dirichlet Allocation. Moreover, Bayesian Mixed effects models revealed that music significantly increased imagined social content compared to silence conditions. This effect remained robust irrespective of vocals or language comprehension. Using stable diffusion, we generated visualisations of participants’ imagined content. In a fourth experiment, a new group of participants was able to use these visualisations to differentiate between content imagined during music listening and that of the silence condition, but only when listening to the associated music. Results converge to show that music, indeed, can be good company.
Closed-loop optogenetic perturbation of macaque oculomotor cerebellum: evidence for an internal saccade model
Authors: Soetedjo Robijanto , Horwitz Gregory D.
Published: June 2023

Internal models are essential for the production of accurate movements. The accuracy of saccadic eye movements is thought to be mediated by an internal model of oculomotor mechanics encoded in the cerebellum. The cerebellum may also be part of a feedback loop that predicts the displacement of the eyes and compares it to the desired displacement in real time to ensure that saccades land on target. To investigate the role of the cerebellum in these two aspects of saccade production, we delivered saccade-triggered light pulses to channelrhodopsin-2-expressing Purkinje cells in the oculomotor vermis (OMV) of two macaque monkeys. Light pulses delivered during the acceleration phase of ipsiversive saccades slowed the deceleration phase. The long latency of these effects and their scaling with light pulse duration are consistent with an integration of neural signals at or downstream of the stimulation site. In contrast, light pulses delivered during contraversive saccades reduced saccade velocity at short latency and were followed by a compensatory reacceleration which caused gaze to land near or on the target. We conclude that the contribution of the OMV to saccade production depends on saccade direction; the ipsilateral OMV is part of a forward model that predicts eye displacement, whereas the contralateral OMV is part of an inverse model that creates the force required to move the eyes with optimal peak velocity for the intended displacement.

Significance Statement

Theory and experiment suggest that saccade production involves an internal model of oculomotor mechanics that resides inside the cerebellum. How cerebellar neurons implement this model is poorly understood. To illuminate this issue, we stimulated Purkinje cells in the oculomotor vermis (OMV) optogenetically during saccades and examined the resultant movement deviations. Stimulation of the contralateral OMV affected saccade dynamics at short latency, suggesting that the contralateral OMV is part of the feedforward pathway that produces the saccade motor command. In contrast, perturbation of the ipsilateral OMV affected saccade dynamics at longer latency, prolonging the saccade deceleration phase and leading to hypermetria. These effects are consistent with perturbation of the eye displacement integrator in the feedback loop of the saccade generator.
The speed and phase of locomotion dictate saccade probability and simultaneous low-frequency power spectra
Authors: Barnes Lydia , Davidson Matthew J , Alais David
Published: June 2023

Everyday we make thousands of saccades and take thousands of steps as we explore our environment. Despite their common co-occurrence in a typical active state, we know little about the coordination between eye-movements and walking behaviour and related changes in cortical activity. Technical limitations have been a major impediment which we overcome here by leveraging the advantages of an immersive wireless virtual reality (VR) environment with three-dimensional position tracking, together with simultaneous recording of eye-movements and mobile electroencephalography (EEG). Using this approach with participants engaged in unencumbered walking along a clear, level path, we find that the likelihood of eye-movements at both slow and natural walking speeds entrains to the rhythm of footfall, peaking shortly after the heel-strike of each step. Simultaneous EEG recordings reveal a concomitant modulation entrained to heel-strike, with increases and decreases in oscillatory power for a broad range of frequencies. The peak of these effects occurred in the theta and alpha range for both walking speeds. Together, our data show that the step-rate of locomotion influences other behaviours such as eye movements and produces related modulations of simultaneous EEG following the same rhythmic pattern. These results reveal gait as an important factor to be considered when interpreting saccadic and time-frequency EEG data in active observers.
Identification of Cerebrospinal Fluid Proteomic Signatures Associated with Intramedullary Surgery Outcome
Authors: Di Weihao , Gu Wentao , Peng Xike , Shou Jiajun , Zhang Yi , Ge Shufei , Zhao Jian , Gu Shixin ,   the Neurospine Group
Published: June 2023

Abstracts

Importance

Neurological function recovery after intramedullary microsurgery is susceptible to various factors. Investigating alterations in cerebrospinal fluid (CSF) protein profiles associated with spinal function recovery could provide valuable insights into prognosis and the development of postoperative therapeutic approaches.

Objective

The aim of this research was to identify CSF protein sets linked to recovery outcomes of intramedullary microsurgery.

Design

This research is an observational cohort investigation that collected data from August 2020 to March 2023.

Setting

The Neurospine group conducted this single-centered cohort research (http://www.chictr.org.cn, registration ID: ChiCTR2300072704). Participants were followed up for 6 months or more. CSF samples were collected pre-and postoperatively. Perioperative treatments, neurological deficits, and rehabilitation therapies were recorded.

Participants

The Neurospine group screened adult patients with intramedullary lesions scheduled for surgical intervention. The exclusion criteria included prior spinal surgery, neurological disorders, surgical complications, or relevant medications.

Exposures

The patients underwent standard intramedullary microsurgical procedures, received medications, and underwent assessments. The CSF protein profiles were examined using tandem mass spectrometry.

Main outcomes and measures

The evaluation of spinal function recovery involved various assessments and correlation analysis was performed. In addition, CSF protein features were identified and their clinical associations were assessed using least absolute shrinkage and selection operator (LASSO) regression modeling.

Results

Of the 43 patients who completed follow-up assessments, 23 were women and 20 were men, with a mean age of 42.8±11.8 years. Histological diagnoses confirmed invasive lesions in 20 patients. Twenty-three patients demonstrated stable or improved spinal function, while 20 patients experienced deterioration during the 3rd and 6th month follow-ups. As indicated by the changes in EMS scales (P= 0.02) and JOA scores (P= 0.03), functional prognosis was associated with pathological characteristics. We developed four models using the CSF proteomics datasets of noninvasive and invasive patients. These LASSO regression models exhibited high accuracy in predicting the recovery rates of the corresponding groups (P> 0.99).

Conclusions and relevance

This research demonstrates that lesion sizes and pathological characteristics are significant factors influencing spinal function recovery. The LASSO regression models developed using identified CSF protein variables for invasive and noninvasive patients, respectively, offer novel methods for the prediction of prognosis and the development of therapeutic approaches.
Lifestyles, left atrial structure and function, and cognitive decline in adults with the metabolic syndrome
Authors: Gonzalez Casanova Ines , Alonso-Gómez Ángel M. , Romaguera Dora , Toledo Estefanía , Li Linzi , Fortuny Elena , López Luis , Ramallal Raúl , Salas-Salvadó Jordi , Tojal-Sierra Lucas , Castañer Olga , Alonso Alvaro
Published: June 2023

Evidence supports associations of lifestyle–including diet and physical activity—and weight with cognitive functioning, but the pathways responsible for these associations have not been fully elucidated. Because healthier lifestyles have been associated with better left atrial structure and function, which in turn is associated with better cognitive functioning, we tested the hypothesis that left atrial structure and function is a potential mediator of the association between lifestyles and cognition. We included 476 participants with overweight or obesity and metabolic syndrome from three centers in Spain who underwent lifestyle assessment and transthoracic echocardiography at baseline and had repeated measurements of the Trail Making A test, a measure of executive function, at baseline and at the two-year follow-up. We conducted mediation analyses to test if measures of left atrial structure and function mediated associations between adherence to the Mediterranean diet scores, physical activity, or weight at baseline, and two-year change in Trail Making A scores. The analysis did not find an effect between these factors and Trail Making A scores, and no indirect effects mediated through the echocardiographic measurements. The modest sample size in this analysis is a limitation, and larger studies should be conducted to determine potential cardiovascular factors mediating the association between lifestyle and cognition.
Present: flexible neuroscience- and technology-driven frameworks for the study of classroom engagement
Authors: Shatto Conor Lee , Thorp John , Friedman Josh Sterling , Rosario Isabella , Gu Zhuowei , Shi Junsheng , Zhuo Megan , Brown Adam , He Xiaofu , Spagna Alfredo
Published: June 2023

Classroom engagement’s impact on academic success is crucial. However, the contributions of affective, cognitive, and behavioral components of engagement remain uncertain. We conducted two studies using non-invasive, research-based approaches to clarify these contributions. Study 1 employed portable EEG headsets to measure cognitive engagement, in-class quizzes assessed content retention, and post-class subjective questionnaires indexed affective engagement by measuring feelings of learning and engagement. Content retention predicted subjective measures, while the EEG theta/beta ratio was negatively related to content retention but positively related to subjective measures. Study 2 featured embedded measures of content retention, confidence, engagement, background knowledge, and indexed behavioral engagement looking at nonverbal behavior quantified via video camera recordings. Confidence and engagement were significantly correlated with each other and with particular facial muscle, gaze direction, and head pose movements. We discuss how these approaches enable real-time studies of classroom engagement and can be integrated to develop neurofeedback interventions.
The Physical Effects of Learning
Authors: Stern Menachem , Liu Andrea J. , Balasubramanian Vijay
Published: June 2023

Interacting many-body physical systems ranging from neural networks in the brain to folding proteins to self-modifying electrical circuits can learn to perform specific tasks. This learning, both in nature and in engineered systems, can occur through evolutionary selection or through dynamical rules that drive active learning from experience. Here, we show that learning leaves architectural imprints on the Hessian of a physical system. Compared to a generic organization of the system components, (a) the effective physical dimension of the response to inputs (the participation ratio of low-eigenvalue modes) decreases, (b) the response of physical degrees of freedom to random perturbations (or system “susceptibility”) increases, and (c) the low-eigenvalue eigenvectors of the Hessian align with the task. Overall, these effects suggest a method for discovering the task that a physical network may have been trained for.
The first European woolly rhinoceros mitogenomes retrieved from within cave hyena coprolites suggest long-lasting phylogeographic differentiation
Authors: Seeber PA , Palmer Z , Schmidt A , Chagas A , Kitagawa K , Marinova-Wolff E , Tafelmaier Y , Epp LS
Published: June 2023

The woolly rhinoceros (Coelodonta antiquitatis) is an iconic species of the Eurasian Pleistocene megafauna, which was abundant in Eurasia in the Pleistocene until its demise beginning approximately 10,000 years ago. Despite the early recovery of several specimens from well-known European archaeological sites, including its type specimen (Blumenbach 1799), no genomes of European populations were available so far, and all available genomic data originated exclusively from the Siberian population1. Using coprolites of cave hyenas (Crocuta crocuta spelea) recovered from Middle Palaeolithic layers of two caves in Germany (Bockstein-Loch and Hohlenstein-Stadel), we isolated and enriched predator and prey DNA to assemble the first European woolly rhinoceros mitogenomes, in addition to cave hyena mitogenomes. These mitogenomes of European woolly rhinoceros are genetically distinct from the Siberian woolly rhinoceros, and analyses of the more complete mitogenome suggests a split of the populations potentially coinciding with the earliest fossil records of wooly rhinoceros in Europe.
An adversarial collaboration to critically evaluate theories of consciousness
Authors:   Cogitate Consortium, Ferrante Oscar , Gorska-Klimowska Urszula , Henin Simon , Hirschhorn Rony , Khalaf Aya , Lepauvre Alex , Liu Ling , Richter David , Vidal Yamil , Bonacchi Niccolò , Brown Tanya , Sripad Praveen , Armendariz Marcelo , Bendtz Katarina , Ghafari Tara , Hetenyi Dorottya , Jeschke Jay , Kozma Csaba , Mazumder David R. , Montenegro Stephanie , Seedat Alia , Sharafeldin Abdelrahman , Yang Shujun , Baillet Sylvain , Chalmers David J. , Cichy Radoslaw M. , Fallon Francis , Panagiotaropoulos Theofanis I. , Blumenfeld Hal , de Lange Floris P , Devore Sasha , Jensen Ole , Kreiman Gabriel , Luo Huan , Boly Melanie , Dehaene Stanislas , Koch Christof , Tononi Giulio , Pitts Michael , Mudrik Liad , Melloni Lucia
Published: June 2023

Different theories explain how subjective experience arises from brain activity1,2. These theories have independently accrued evidence, yet, confirmation bias and dependence on design choices hamper progress in the field3. Here, we present an open science adversarial collaboration which directly juxtaposes Integrated Information Theory (IIT)4,5and Global Neuronal Workspace Theory (GNWT)6–10, employing a theory-neutral consortium approach11,12. We investigate neural correlates of the content and duration of visual experience. The theory proponents and the consortium developed and preregistered the experimental design, divergent predictions, expected outcomes, and their interpretation12. 256 human subjects viewed suprathreshold stimuli for variable durations while neural activity was measured with functional magnetic resonance imaging, magnetoencephalography, and electrocorticography. We find information about conscious content in visual, ventro-temporal and inferior frontal cortex, with sustained responses in occipital and lateral temporal cortex reflecting stimulus duration, and content-specific synchronization between frontal and early visual areas. These results confirm some predictions of IIT and GNWT, while substantially challenging both theories: for IIT, a lack of sustained synchronization within posterior cortex contradicts the claim that network connectivity specifies consciousness. GNWT is challenged by the general lack of ignition at stimulus offset and limited representation of certain conscious dimensions in prefrontal cortex. Beyond challenging the theories themselves, we present an alternative approach to advance cognitive neuroscience through a principled, theory-driven, collaborative effort. We highlight the challenges to change people’s mind13and the need for a quantitative framework integrating evidence for systematic theory testing and building.
Oxysterol-liver X receptor signaling mediates CYFIP1 regulation of cortical neurogenesis
Authors: De La Fuente Daniel Cabezas , Tamburini Claudia , Stonelake Emily , Griffiths William J , Hall Jeremy , Owen Michael J. , Linden David E. J. , Pocklington Andrew , Wang Yuqin , Li Meng
Published: June 2023

Dysregulation in neural progenitor proliferation and neuronal differentiation has been increasingly recognised as a common pathology in neural cells harboring genetic risks to neuropsychiatric and neurodevelopmental disorders, yet the underlying molecular mechanisms remains largely unknown. Deletions and duplications of the 15q11.2 region containing the CYFIP1 gene have been associated with autism and schizophrenia. Using patient-derived iPSCs carrying 15q11.2 deletion and genetically manipulated hESCs with CYFIP1 gain- and loss-of-function (GoF and LoF), we show that 15q11.2 deletion and CYFIP1-LoF leads to premature neuronal differentiation while CYFIP1-GoF favours neural progenitor maintenance. We identified cholesterol biosynthesis and metabolism as a biological process disturbed by CYFIP1 dosage change, leading to altered neuro-oxysterol profiles. 24S,25-epoxycholesterol, which was decreased in CYFIP1-GoF and increased in CYFIP1-LoF and 15q11.2del neural cells, can mimic the 15q11.2del and CYFIP1-LoF phenotype by promoting cortical neuronal differentiation and restore the impaired neuronal differentiation of CYFIP1-GoF neural progenitors. Moreover, the neurogenic activity of 24S,25-epoxycholesterol is lost following genetic deletion of the brain expressed isoform of the liver X receptor LXRb while compound deletion of LXRb in CYFIP1-/- background rescued their premature neurogenesis. This work delineates LXR mediated oxysterol regulation of neurogenesis as a novel pathological mechanism in neural cells carrying 15q11.2CNV and provides a potential target for therapeutic strategies for genetic disorders associated with this risk locus.
Acquired Cross-resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification ofMYCparalogs
Authors: Choudhuri Shreoshi Pal , Girard Luc , Lim Jun Yi Stanley , Wise Jillian F. , Freitas Braeden , Yang Di , Wong Edmond , Hamilton Seth , Chien Victor D. , Gilbreath Collin , Zhong Jun , Phat Sarah , Myers David T. , Christensen Camilla L. , Stanzione Marcello , Wong Kwok-Kin , Farago Anna F. , Meador Catherine B. , Dyson Nicholas J. , Lawrence Michael S. , Wu Sihan , Drapkin Benjamin J.
Published: June 2023

Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here we present a pre-clinical system that recapitulates acquired cross-resistance in SCLC, developed from 51 patient-derived xenografts (PDXs). Each model was tested forin vivosensitivity to three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These functional profiles captured hallmark clinical features, such as the emergence of treatment-refractory disease after early relapse. Serially derived PDX models from the same patient revealed that cross-resistance was acquired through aMYCamplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that this was not unique to one patient, asMYCparalog amplifications on ecDNAs were recurrent among cross-resistant models derived from patients after relapse. We conclude that ecDNAs withMYCparalogs are recurrent drivers of cross-resistance in SCLC.

SIGNIFICANCE

SCLC is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. We use a population of PDX models to discover that amplifications ofMYCparalogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC.
A multi-layered integrative analysis reveals a cholesterol metabolic program in outer radial glia with implications for human brain evolution
Authors: Moriano Juan , Leonardi Oliviero , Vitriolo Alessandro , Testa Giuseppe , Boeckx Cedric
Published: June 2023

The definition of molecular and cellular mechanisms contributing to evolutionary divergences in brain ontogenetic trajectories is essential to formulate hypotheses about the emergence of our species. Yet the functional dissection of evolutionary modifications derived in theHomo sapienslineage at an appropriate level of granularity remains particularly challenging. Capitalizing on recent single-cell sequencing efforts that have massively profiled neural stem cells from the developing human cortex, we develop an integrative computational framework in which we perform (i) trajectory inference and gene regulatory network reconstruction, (ii) (pseudo)time-informed non-negative matrix factorization for learning the dynamics of gene expression programs, and (iii) paleogenomic analysis for a higher-resolution mapping of the regulatory landscape where our species acquired derived mutations in comparison to our closest relatives. We provide evidence for cell type-specific activation and regulation of gene expression programs during indirect neurogenesis. In particular, our analysis uncovers a zinc-finger transcription factor, KLF6, as a key regulator of a cholesterol metabolic program specifically in outer radial glia. Our strategy allows us to further probe whether the (semi)discrete gene expression programs identified have been under selective pressures in our species lineage. A cartography of the regulatory landscape impacted byHomo sapiens-derived transcription factor binding site disruptions reveals signals of selection clustering around regulatory regions associated withGLI3, a well-known regulator of the radial glial cell cycle. As a whole, our study contributes to the evidence of significant changes impacting metabolic pathways in recent human brain evolution.
Waste not, want not: Revisiting the analysis that called into question the practice of rarefaction
Authors: Schloss Patrick D.
Published: June 2023

In 2014, McMurdie and Holmes published the provocatively titled, “Waste not, want not: why rarefying microbiome data is inadmissible”. The claims of their study have significantly altered how microbiome researchers control for the unavoidable uneven sequencing depths that are inherent in modern 16S rRNA gene sequencing. Confusion over the distinction between the definitions of rarefying and rarefaction continues to cloud the interpretation of their results. More importantly, the authors made a variety of choices in designing and analyzing their simulations that were potentially problematic. I identified 11 factors that could have compromised the results of the original study. I reproduced the original simulation results and assessed the impact of those 11 factors on the underlying conclusion that rarefying data is inadmissible. Throughout, the design of the original study made choices that caused rarefying and rarefaction to appear to perform worse than they truly did. Most important were the approaches used to assess ecological distances, the removal of samples with low sequencing depth, and not accounting for conditions where sequencing effort is confounded with treatment group. Although the original study criticized rarefying for the arbitrary removal of valid data, repeatedly rarefying data many times (i.e., rarefaction) incorporates all the data. In contrast, it is the removal of rare taxa that would appear to remove valid data. Overall, I show that rarefaction is the most robust approach to control for uneven sequencing effort when considered across a variety of alpha and beta diversity metrics.

Importance

Over the past 10 years, the best method for normalizing the sequencing depth of samples characterized by 16S rRNA gene sequencing has been contentious. An often cited paper by McMurdie and Holmes forcefully argued that rarefying the number of sequence counts was “inadmissible” and should not be employed. However, I identified a number of problems with the design of their simulations and analysis that could compromise their results. In fact, when I reproduced and expanded upon their analysis, it was clear that rarefaction was actually the most robust approach for controlling for uneven sequencing effort across samples. Rarefaction limits the rate of falsely detecting and rejecting differences between treatment groups. Far from being “inadmissible”, rarefaction is a valuable tool for analyzing microbiome sequence data.
Size dependent diffusion and dispersion of particles in mucin
Authors: Kumar Parveen , Tamayo Joshua , Shiu Ruei-Feng , Chin Wei-Chun , Gopinath Arvind
Published: June 2023

Mucus, composed significantly of glycosylated mucins, is a soft rheologically complex vis-coelastic material lining respiratory, reproductive, and gastrointestinal tracts in mammals. Mucus may present as a gel or as a fluid, and serves as a barrier to the transport of microbes including, harmful particles, and inhaled atmospheric pollutants. Studies on mucin gels have provided insight into swelling kinetics, and the diffusion and permeability of molecular constituents such as water. The transport and dispersion of micron and sub-micron tracer particles in mucin gels and solutions differs from the motion of molecular water since the much larger tracers may interact with microstructure and larger features of the mucin network. Here, using brightfield and florescence microscopy, high speed particle-tracking, and passive microrheology, we study the thermally driven stochastic movement of 0.5 − 5.0µm tracer particles in 10% mucin solutions at neutral pH, and in 10% mucin mixed with unmodified limestone rock dust, modified limestone, and crystalline silica. Particle trajectories, mean square displacements, and the displacement probability distributions, are used to assess tracer diffusion and transport. Complex moduli are concomitantly extracted using microrheology techniques. We find that under the conditions analyzed in our experiments the mucin solution present as a highly viscous, weakly viscoelastic fluid rather than as a viscoelastic gel. For small to moderately sized tracers with diameter than 2µm, effective diffusion coefficients follow predictions of classical Stokes-Einstein relationship. Diffusivity in rock-dust laden mucin is surprisingly larger than in bare mucin. Probability distributions of squared particle displacements indicate that heterogeneity, transient trapping, and electrostatic interactions impact tracer transport, especially for larger tracers. Our results prompt further exploration of physiochemical and rheological mechanisms mediating particle transport in soft, viscoelastic biopolymer networks and materials.
Not alpha power: prestimulus beta power predicts the magnitude of individual temporal order bias for audiovisual stimuli
Authors: Jiang Zeliang , wang Lu , An Xingwei , Liu Shuang , Yin Erwei , Yan Ye , Ming Dong
Published: June 2023

Individuals exhibit significant variations in audiovisual temporal order perception. Previous studies have investigated the neural mechanisms underlying these individual differences by analyzing ongoing neural oscillations using stimuli specific to each participant. This study explored whether these effects could extend to different paradigms with the same stimuli across subjects in each paradigm. The two human participants groups performed a temporal order judgment (TOJ) task in two experimental paradigms while recording EEG. One is the beep-flash paradigm, while the other is the stream-bounce paradigm. We focused on the correlation between individual temporal order bias (i.e., point of subjective simultaneity (PSS)) and spontaneous neural oscillations. In addition, we also explored whether the frontal cortex could modulate the correlation through a simple mediation model. We found that the beta band power in the auditory cortex could negatively predict the individual’s PSS in the beep-flash paradigm. Similarly, the same effects were observed in the visual cortex during the stream-bounce paradigm. Furthermore, the frontal cortex could influence the power in the sensory cortex and further shape the individual’s PSS. These results suggested that the individual’s PSS was modulated by auditory or visual cortical excitability depending on the experimental stimuli. The frontal cortex could shape the relation between sensory cortical excitability and the individual’s PSS in a top-down manner. In conclusion, our findings indicated that the prefrontal cortex could effectively regulate an individual’s temporal order bias, providing insights into audiovisual temporal order perception mechanisms and potential interventions for modulating temporal perception.
Maternal choline supplementation lessens the behavioral dysfunction produced by developmental manganese exposure in a rodent model of ADHD
Authors: Howard Shanna L. , Beaudin Stephane A. , Strupp Barbara J. , Smith Donald R.
Published: June 2023

Studies in children have reported associations between elevated manganese (Mn) exposure and ADHD-related symptoms of inattention, impulsivity/hyperactivity, and psychomotor impairment. Maternal choline supplementation (MCS) during pregnancy/lactation may hold promise as a protective strategy because it has been shown to lessen cognitive dysfunction caused by numerous early insults. Our objectives were to determine whether (1) developmental Mn exposure alters behavioral reactivity/emotion regulation, in addition to impairing learning, attention, impulse control, and sensorimotor function, and (2) MCS protects against these Mn-induced impairments. Pregnant Long-Evans rats were given standard diet, or a diet supplemented with additional choline throughout gestation and lactation (G3 - PND 21). Male offspring were exposed orally to 0 or 50 mg Mn/kg/day over PND 1–21. In adulthood, animals were tested in a series of learning, attention, impulse control, and sensorimotor tasks. Mn exposure caused lasting dysfunction in attention, reactivity to errors and reward omission, learning, and sensorimotor function, recapitulating the constellation of symptoms seen in ADHD children. MCS lessened Mn-induced attentional dysfunction and partially normalized reactivity to committing an error or not receiving an expected reward but provided no protection against Mn-induced learning or sensorimotor dysfunction. In the absence of Mn exposure, MCS produces lasting offspring benefits in learning, attention, and reactivity to errors. To conclude, developmental Mn exposure produces a constellation of deficits consistent with ADHD symptomology, and MCS offered some protection against the adverse Mn effects, adding to the evidence that maternal choline supplementation is neuroprotective for offspring and improves offspring cognitive functioning.

Highlights

Developmental Mn exposure causes lasting dysfunction consistent with ADHD symptomology.

Maternal choline supplementation (MCS) protects against Mn-induced deficits in attention and behavioral reactivity.

MCS in control animals produces lasting benefits to offspring in learning, attention, and error reactivity.

These data support efforts to increase choline intake during pregnancy, particularly for individuals at risk of neurotoxicant exposure.
Luminal transport through intact endoplasmic reticulum limits the magnitude of localized Ca2+signals
Authors: Crapart Cécile C. , Scott Zubenelgenubi C. , Konno Tasuku , Sharma Aman , Parutto Pierre , Bailey David M. D. , Westrate Laura M. , Avezov Edward , Koslover Elena F.
Published: June 2023

The endoplasmic reticulum (ER) forms an interconnected network of tubules stretching throughout the cell. Understanding how ER functionality relies on its structural organization is crucial for elucidating cellular vulnerability to ER perturbations, which have been implicated in several neuronal pathologies. One of the key functions of the ER is enabling Ca2+signalling by storing large quantities of this ion and releasing it into the cytoplasm in a spatiotemporally controlled manner. Through a combination of physical modeling and livecell imaging, we demonstrate that alterations in ER shape significantly impact its ability to support efficient local Ca2+releases, due to hindered transport of luminal content within the ER. Our model reveals that rapid Ca2+release necessitates mobile luminal buffer proteins with moderate binding strength, moving through a well-connected network of ER tubules. These findings provide insight into the functional advantages of normal ER architecture, emphasizing its importance as a kinetically efficient intracellular Ca2+delivery system.

Significance Statement

The peripheral endoplasmic reticulum forms a continuous network of tubules extending through the entire cell. One of the key functional roles of the ER is the release of Ca2+ions into the cytosol to support a broad diversity of intracellular signaling processes. Such release events are enabled by the high Ca2+storage capacity of the ER. This work demonstrates that mobile Ca2+binding buffer proteins and a well-connected lattice-like architecture of the ER network are optimal to supply local Ca2+signals and that changes in ER structure can modulate Ca2+release. By linking transport kinetics to Ca2+release, we demonstrate a key functional role for the interconnected network architecture of the ER.
Synapsin E-domain is essential for α-synuclein function
Authors: Stavsky Alexandra , Parra-Rivas Leonardo A. , Tal Shani , Riba Jen , Madhivanan Kayalvizhi , Roy Subhojit , Gitler Daniel
Published: June 2023

The cytosolic proteins synucleins and synapsins are thought to play cooperative roles in regulating synaptic vesicle (SV) recycling, but mechanistic insight is lacking. Here we identify the synapsin E-domain as an essential functional binding-partner of α-synuclein (α-syn). Synapsin E-domain allows α-syn functionality, binds to α-syn, and is necessary and sufficient for enabling effects of α-syn at the synapse. Together with previous studies implicating the E-domain in clustering SVs, our experiments advocate a cooperative role for these two proteins in maintaining physiologic SV clusters.
Locomotor effects of a fibrosis-based immune response in stickleback fish
Authors: Matthews David G. , Maciejewski Meghan F. , Wong Greta A. , Lauder George V. , Bolnick Daniel I.
Published: June 2023

The vertebrate immune system provides an impressively effective defense against parasites and pathogens. However, these benefits must be balanced against a range of costly side-effects including energy loss and risks of auto-immunity. These costs might include biomechanical impairment of movement, but little is known about the intersection between immunity and biomechanics. Here, we show that a fibrosis immune response in threespine stickleback (Gasterosteus aculeatus) has collateral effects on their locomotion. When freshwater stickleback are infected with the tapeworm parasite Schistocephalus solidus, they face an array of fitness consequences ranging from impaired body condition and fertility to an increased risk of mortality. To fight the infection, some stickleback will initiate a fibrosis immune response in which they produce excess collagenous tissue in their coelom. Although fibrosis is effective at reducing infection, some populations of stickleback actively suppress this immune response, possibly because the costs of fibrosis outweigh the benefits. Here we quantify the locomotor effects of the fibrosis immune response in the absence of parasites to investigate whether there are collateral costs of fibrosis that could help explain why some fish forego this effective defense. To do this, we induce fibrosis in stickleback and then test their C-start escape performance. Additionally, we measure the severity of fibrosis, body stiffness, and body curvature during the escape response. We were able to estimate performance costs of fibrosis by including these variables as intermediates in a structural equation model. This model reveals that among control fish without fibrosis, there is a performance cost associated with increased body stiffness. However, fish with fibrosis did not experience this cost but rather displayed increased performance with higher fibrosis severity. This result demonstrates that the adaptive landscape of immune responses can be complex with the potential for wide reaching and unexpected fitness consequences.
Hypoxia induced oxidative stress and endoplasmic reticulum stress promoted myocardial cell fibrosis
Authors: Jiang Zhan , Chun Zhang , Guang Xu
Published: June 2023

Myocardial cells, fibroblasts and vascular cells in the heart are connected by a complex matrix mainly composed of fibrillar collagen, which helps to protect the integrity and compliance of the heart structure. Previous studies have shown that hypoxia can induce myocardial hypoxia, but the mechanism is still unclear. In this study, we found that hypoxia promotes TGF beta induced collagen deposition and myocardial fibrosis by inducing Endoplasmic reticulum stress and oxidative stress in cardiomyocytes. Moreover, we also found that antioxidant drugs can effectively alleviate hypoxia induced myocardial fibrosis. Therefore, our study provides an experimental basis for the treatment of myocardial fibrosis.