bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimizing magnetometers arrays and analysis pipelines for multivariate pattern analysis
Authors: Bezsudnova Yulia , Quinn Andrew J. , Jensen Ole
Published: September 2023

Background

Multivariate pattern analysis (MVPA) has proven an excellent tool in cognitive neuroscience used M/EEG, and MRI. It also holds a strong promise when applied to optically-pumped magnetometer-based magnetoencephalography.

New method

To optimize OPM-MEG systems for MVPA experiments this study examines data from a conventional MEG magnetometer array, focusing on appropriate noise reduction techniques for magnetometers. We also determined the least required number of sensors needed for robust MVPA for image categorization experiments.

Results

We found that the use of signal space separation (SSS) significantly lowered the classification accuracy considering a sub-array of 102 magnetometers or a sub-array of 204 gradiometers. We also found that classification accuracy did not improve when going beyond 30 sensors irrespective of whether SSS has been applied.

Comparison with existing methods

The power spectra of data filtered with SSS has a substantially higher noise floor that data cleaned with SSP or HFC. Consequently, the MVPA decoding results obtained from the SSS-filtered data are significantly lower compared to all other methods employed.

Conclusions

When designing an MEG system based on SQUID magnetometers optimized for multivariate analysis for image categorization experiments, about 30 magnetometers are sufficient. We advise against applying SSS filters to data from MEG and OPM systems prior to performing MVPA as this method, albeit reducing low-frequency external noise contributions, also introduces an increase in broadband noise. We recommend employing noise reduction techniques that either decrease or maintain the noise floor of the data like signal-space projection, homogeneous field correction and gradient noise reduction.

Highlights

A sensor array of about 30 sensors is sufficient for multivariate pattern analysis using conventional MEG magnetometers for image classification.

Using signal space separation filter on magnetometer data prior to multivariate pattern analysis might reduce classification accuracy due to an increase in white noise in the data contributed by the algorithm.

When performing multivariate data analysis, other noise reduction approaches that diminish the contribution of external noise sources and reduce the variance of the data are advisable such as synthetic gradiometers, signal space projection or homogeneous field correction.
Unraveling the role ofXistin X chromosome inactivation: insights from rabbit model and deletion analysis of exons and repeat A
Authors: Liang Mingming , Zhang Lichao , Lai Liangxue , Li Zhanjun
Published: September 2023

X chromosome inactivation (XCI) is a dosage compensation process that aims to equalize the expression of X-linked genes between males and females. Initiation of XCI relies onXist, which is continuously expressed in somatic cells during XCI maintenance. HowXistimpacts XCI maintenance remains unclear, and its functional motifs remain unclear. In this study, we conducted a comprehensive analysis of theXist. The results demonstrate that rabbits serve as an ideal non-primate animal model for investigating the functions ofXistin vivo. And homozygous knockout of exon 1, exon 6 and repeat A in females resulted in embryonic lethality. However, XΔReAX females withXistexpression from the intact X chromosome, did not display any abnormalities. Interestingly, there were no significant differences between females with homozygous knockout of exons 2-5 and wild-type rabbits. This suggests that exons 2, 3, 4, and 5 ofXistare less important for XCI. These insights provide valuable knowledge about the functional mechanism ofXist.
Neural shape mediation analysis
Authors: Brochard Jules , Combrisson Etienne , Chatard Benoit , Lachaux Jean-Philippe , Brovelli Andrea , Daunizeau Jean
Published: September 2023

Neural signal shapes convey significant information about their generating processes. In this study, we introduce a data-driven methodology to identify sensory and behaviourally-relevant traces within neural responses. We present a phenomenological model that characterises temporal variations in intracranial EEG using eight interpretable parameters: peak time, peak intensity, initial and final baselines, accumulation and depletion period, and their respective concavities. This model effectively captures subtle signal variations, especially in sensory decision-making tasks. By decomposing the signals in this manner, we then conduct a comprehensive brain mediation analysis on iEEG data’s shape, pinpointing regions that mediate behavioural processes. Importantly, we can determine which signal dynamics specifically reflect underlying behavioural processes, enhancing the depth of analysis and critique of their role in behaviour. Preliminary applications on a cohort of epileptic patients reveal that our model explains over a third of the signal variance at the trial level across all brain regions. We identified four key regions—encompassing sensory, associative, frontal, and premotor areas—that mediate the impact of task difficulty on reaction time. Notably, in these regions, it was the depletion period, rather than signal amplitude, that correlated with behavioural speed. This study highlights the potential of our approach in providing detailed insights into the neural mechanisms linking stimuli to behaviour.
A reference genome and its epigenetic landscape of potentialOrychophragmus violaceus, an industrial crop species
Authors: Jia Changfu , Hou Yukang , Lai Qiang , Zhang Yuling , Wang Rui , Liu Jianquan , Wang Jing
Published: September 2023

Orychophragmus violaceus, also called ‘er-yue-lan’ in China, is an annual plant of the family of Brassicaceae. The seed oil ofO. violaceuscontained two specific di-hydroxy fatty acids which were produced by functional divergence between twoFAD2WGD copies determine its industrial property. Here, we assembled a high-quality chromosome-level genome ofO. violaceusvia based on PacBio CLR technology and its cis-regulatory landscape of five mature tissues, including root, leaf, flower, seed and stem, based on ATAC-seq technology. 1.2 Gb draft genomic sequences were anchored to 12 pseudo-chromosomes and 49904 protein-coding genes were annotated on these chromosomes. To fully understand the epigenetic landscape ofO. violaceus, we further performed WGBS-seq for leaf, flower and silique tissues. In total, our multi-omics data provide opportunity to find out the differences between two WGD copies and also a valuable resource for downstream breeding effort of this potential industrial species.
Systematic identification of inter-chromosomal interaction networks supports the existence of RNA factories
Authors: Hristov Borislav Hrisimirov , Noble William Stafford , Bertero Alessandro
Published: September 2023

Most studies of genome organization have focused on intra-chromosomal (cis) contacts because they harbor key features such as DNA loops and topologically associating domains. Inter-chromosomal (trans) contacts have received much less attention, and tools for interrogating potential biologically relevanttransstructures are lacking. Here, we develop a computational framework to identify sets of loci that jointly interact intransfrom Hi-C data. This method, trans-C, initiates probabilistic random walks with restarts from a set of seed loci to traverse an input Hi-C contact network, thereby identifying sets oftrans-contacting loci. We validate trans-C in three increasingly complex models of establishedtranscontacts: thePlasmodium falciparum vargenes, the mouse olfactory receptor “Greek islands”, and the human RBM20 cardiac splicing factory. We then apply trans-C to systematically test the hypothesis that genes co-regulated by the sametrans-acting element (i.e., a transcription or splicing factor) co-localize in three dimensions to form “RNA factories” that maximize the efficiency and accuracy of RNA biogenesis. We find that many loci with multiple binding sites of the same transcription factor interact with one another intrans, especially those bound by transcription factors with intrinsically disordered domains. Similarly, clustered binding of a subset of RNA binding proteins correlates withtransinteraction of the encoding loci. These findings support the existence oftransinteracting chromatin domains (TIDs) driven by RNA biogenesis. Trans-C provides an efficient computational framework for studying these and other types oftransinteractions, empowering studies of a poorly understood aspect of genome architecture.
Bypassing spike sorting: Density-based decoding using spike localization from dense multielectrode probes
Authors: Zhang Yizi , He Tianxiao , Boussard Julien , Windolf Charlie , Winter Olivier , Trautmann Eric , Roth Noam , Barrell Hailey , Churchland Mark , Steinmetz Nicholas A. ,   The International Brain Laboratory, Varol Erdem , Hurwitz Cole , Paninski Liam
Published: September 2023

Neural decoding and its applications to brain computer interfaces (BCI) are essential for understanding the association between neural activity and behavior. A prerequisite for many decoding approaches isspike sorting, the assignment of action potentials (spikes) to individual neurons. Current spike sorting algorithms, however, can be inaccurate and do not properly model uncertainty of spike assignments, therefore discarding information that could potentially improve decoding performance. Recent advances in high-density probes (e.g., Neuropixels) and computational methods now allow for extracting a rich set of spike features from unsorted data; these features can in turn be used to directly decode behavioral correlates. To this end, we propose a spike sorting-free decoding method that directly models the distribution of extracted spike features using a mixture of Gaussians (MoG) encoding the uncertainty of spike assignments, without aiming to solve the spike clustering problem explicitly. We allow the mixing proportion of the MoG to change over time in response to the behavior and develop variational inference methods to fit the resulting model and to perform decoding. We benchmark our method with an extensive suite of recordings from different animals and probe geometries, demonstrating that our proposed decoder can consistently outperform current methods based on thresholding (i.e. multi-unit activity) and spike sorting. Open source code is available athttps://github.com/yzhang511/density_decoding.
Sex differences in offspring risk and resilience following 11β-hydroxylase antagonism in a rodent model of maternal immune activation
Authors: Martz Julia , Shelton Micah A. , Geist Laurel , Seney Marianne L. , Kentner Amanda C.
Published: September 2023

Maternal immune activation (MIA) puts offspring at greater risk for neurodevelopmental disorders associated with impaired social behavior. While it is known that immune signaling through maternal, placental, and fetal compartments contributes to these phenotypical changes, it is unknown to what extent the stress response to illness is involved and how it can be harnessed for potential interventions. To this end, on gestational day 15, pregnant rat dams were administered the bacterial mimetic lipopolysaccharide (LPS; to induce MIA) alongside metyrapone, a clinically available 11β-hydroxylase inhibitor used to treat hypercortisolism in pregnant and neonatal populations. Maternal, placental, and fetal CNS levels of corticosterone and placental 11βHSD enzymes type 1 and 2 were measured 3-hrs post treatment. Offspring social behaviors were evaluated across critical phases of development. MIA was associated with increased maternal, placental, and fetal CNS corticosterone concentrations that were diminished with metyrapone exposure. Metyrapone protected against reductions in placental 11βHSD2 in males only, suggesting that less corticosterone was inactivated in female placentas. Behaviorally, metyrapone-exposure attenuated MIA-induced social disruptions in juvenile, adolescent, and adult males, while females were unaffected or performed worse. Metyrapone-exposure reversed MIA-induced transcriptional changes in monoamine-, glutamate-, and GABA-related genes in the ventral hippocampus of adult males, but not females. Taken together, these findings illustrate that MIA-induced HPA responses act alongside the immune system to produce behavioral deficits. As a clinically available drug, the sex-specific benefits and constraints of metyrapone should be investigated further as a potential means of reducing neurodevelopmental risks due to gestational MIA.
AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML
Authors: Sayitoglu Ece Canan , Luca Bogdan A. , Boss Allison P. , Thomas Benjamin Craig , Freeborn Robert Arthur , Uyeda Molly J. , Chen Pauline P. , Nakauchi Yusuke , Waichler Colin , Lacayo Norman , Bacchetta Rosa , Majeti Ravindra , Gentles Andrew J. , Cepika Alma-Martina , Roncarolo Maria Grazia
Published: September 2023

T cells are important for the control of acute myeloid leukemia (AML), a common and often deadly malignancy. We observed that some AML patient samples are resistant to killing by human engineered cytotoxic CD4+T cells. Single-cell RNA-seq of primary AML samples and CD4+T cells before and after their interaction uncovered transcriptional programs that correlate with AML sensitivity or resistance to CD4+T cell killing. Resistance-associated AML programs were enriched in AML patients with poor survival, and killing-resistant AML cells did not engage T cellsin vitro. Killing-sensitive AML potently activated T cells before being killed, and upregulatedICAM1, a key component of the immune synapse with T cells. Without ICAM1, killing-sensitive AML became resistant to killing to primaryex vivo-isolated CD8+T cellsin vitro, and engineered CD4+T cellsin vitroandin vivo. Thus, ICAM1 on AML acts as an immune trigger, allowing T cell killing, and could affect AML patient survivalin vivo.

SIGNIFICANCE

AML is a common leukemia with sub-optimal outcomes. We show that AML transcriptional programs correlate with susceptibility to T cell killing. Killing resistance-associated AML programs are enriched in patients with poor survival. Killing-sensitive, but not resistant AML activate T cells and upregulateICAM1that binds to LFA-1 on T cells, allowing immune synapse formation which is critical for AML elimination.

GRAPHICAL ABSTRACT
Continuous motor skills as flexible control policies: a video game study
Authors: Huberdeau David M. , Haith Adrian M. , Krakauer John W.
Published: September 2023

Many motor skills consist of continuous sequential actions, such as a tennis serve. It is currently unclear how these surprisingly understudied behaviors are learned, with the leading hypothesis being that sequences of single actions become “chunked” into larger single executable units. Under this hypothesis, continuous sequential actions should become more task-specific and less generalizable with practice. To test this, we developed a video game that requires participants to hold a tablet with both hands and steer a virtual car (the “ant car”) along a curving track. We tested participants’ ability to generalize their skill to a probe track that required a different sequence of turns. Across days of practice, task success increased, and movement variability decreased. On the probe track, movement quality at the level of kinematics fully generalized but performance at the level of task success showed a consistent decrement. To address this apparent paradox, we empirically derived the control policy participants used at their maximal skill level on the training track. Notably, this policy was fully transferred to the probe track, but there were more instances of momentary deviations from it (lapses), which explains the worse performance despite equivalent skill. We conclude that continuous motor skills are acquired through learning of a flexible control policy that maps states onto actions and not through chunking or automatizing of a specific sequence of actions.
Automated customization of large-scale spiking network models to neuronal population activity
Authors: Wu Shenghao , Huang Chengcheng , Snyder Adam , Smith Matthew , Doiron Brent , Yu Byron
Published: September 2023

Understanding brain function is facilitated by constructing computational models that accurately reproduce aspects of brain activity. Networks of spiking neurons capture the underlying biophysics of neuronal circuits, yet the dependence of their activity on model parameters is notoriously complex. As a result, heuristic methods have been used to configure spiking network models, which can lead to an inability to discover activity regimes complex enough to match large-scale neuronal recordings. Here we propose an automatic procedure, Spiking Network Optimization using Population Statistics (SNOPS), to customize spiking network models that reproduce the population-wide covariability of large-scale neuronal recordings. We first confirmed that SNOPS accurately recovers simulated neural activity statistics. Then, we applied SNOPS to recordings in macaque visual and prefrontal cortices and discovered previously unknown limitations of spiking network models. Taken together, SNOPS can guide the development of network models and thereby enable deeper insight into how networks of neurons give rise to brain function.
Multiscale effective connectivity analysis of brain activity using neural ordinary differential equations
Authors: Chang Yin-Jui , Chen Yuan-I , Stealey Hannah M. , Zhao Yi , Lu Hung-Yun , Contreras-Hernandez Enrique , Baker Megan N. , Yeh Hsin-Chih , Santacruz Samantha R.
Published: September 2023

Neural mechanisms and underlying directionality of signaling among brain regions depend on neural dynamics spanning multiple spatiotemporal scales of population activity. Despite recent advances in multimodal measurements of brain activity, there is no broadly accepted multiscale dynamical models for the collective activity represented in neural signals. Here we introduce a neurobiological-driven deep learning model, termedmultiscale neuraldynamicsneuralordinarydifferentialequation (msDyNODE), to describe multiscale brain communications governing cognition and behavior. We demonstrate that msDyNODE successfully captures multiscale activity using both simulations and electrophysiological experiments. The msDyNODE-derived causal interactions between recording locations and scales not only aligned well with the abstraction of the hierarchical neuroanatomy of the mammalian central nervous system but also exhibited behavioral dependences. This work offers a new approach for mechanistic multiscale studies of neural processes.

Author Summary

Multi-modal measurements have become an emerging trend in recent years due to the capability of studying brain dynamics at disparate scales. However, an integrative framework to systematically capture the multi-scale nonlinear dynamics in brain networks is lacking. A major challenge for creating a cohesive model is a mismatch in the timescale and subsequent sampling rate of the dynamics for disparate modalities. In this work, we introduce a deep learning-based approach to characterize brain communications between regions and scales. By modeling the continuous dynamics of hidden states using the neural network-based ordinary differential equations, the requirement of downsampling the faster sampling signals is discarded, thus preventing from losing dynamics information. Another advantageous feature of the proposed method is flexibility. An adaptable framework to bridge the gap between scales is necessary. Depending on the neural recording modalities utilized in the experiment, any suitable pair of well-established models can be plugged into the proposed multi-scale modeling framework. Thus, this method can provide insight into the brain computations of multi-scale brain activity.
The social determinants associated with decreased rate of breast cancer screening, delayed presentation, and advanced stage diagnosis of breast cancer: A systematic review
Authors: Fekry Madonna A. , Yang Justin C.
Published: September 2023

Background

There are many barriers that hinder breast cancer (BC) early detection such as social, demographic, and economic factors. We examined the barriers to early detection.

Methods

PubMed, Scopus, and Web of Science databases were chosen to conduct a comprehensive literature search. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) was used to select the relevant studies on decreased rate of BC screening, delayed presentation of BC, and advanced stage diagnosis of BC.

Results

The literature demonstrates that several determinants had a significant impact on the delay in seeking medical help, rate of performing breast cancer screening (BCS), and stage at diagnosis of BC. Younger age, rural residence, being non-white, being single, low socioeconomic status, absence of medical insurance, having no paid job, low educational level, positive family history of BC, and having TNBC or HER2E BC subtypes were significantly associated with presenting at advanced stages, decreased rate of BCS, and delayed presentation. Meanwhile, the associations between BC and BMI, parity, religion, and menopausal status were underexamined in the literature.

Conclusion

Promoting early detection of BC should be taking the sociodemographic disparities into consideration. To address these disparities, raising public awareness, implementing universal health coverage (UHC), and increasing government expenditure on health and education are needed, especially among vulnerable societies.
Genetic synergy inAcinetobacter baumanniiundecaprenyl biosynthesis and maintenance of lipid asymmetry impacts outer membrane and antimicrobial resistance
Authors: Noel Hannah R. , Keerthi Sowmya , Ren Xiaomei , Winkelman Jonathan D. , Troutman Jerry M. , Palmer Lauren D.
Published: September 2023

Acinetobacter baumanniiis a Gram-negative healthcare-associated pathogen that poses a major health concern due to increasing multidrug resistance. The Gram-negative cell envelope is a key barrier to antimicrobial entry and includes an inner and outer membrane. The outer membrane has an asymmetric composition that is important for structural integrity and barrier to the environment. Therefore, Gram-negative bacteria have mechanisms to uphold this asymmetry such as the maintenance of lipid asymmetry system (Mla), which removes glycerophospholipids from the outer leaflet of the outer membrane and transports them to the inner membrane. Loss of this system inA. baumanniiresults in attenuated virulence and increased susceptibility to membrane stressors and some antibiotics. We recently reported two strain variants of theA. baumanniitype strain ATCC 17978, 17978VU and 17978UN. We show here that ΔmlaFmutants in the two strains display different phenotypes for membrane stress resistance, antibiotic resistance, and pathogenicity in a murine pneumonia model. We used comparative genetics to identify interactions between ATCC 17978 strain alleles andmlaFto uncover the cause behind the phenotypic differences. Although allele differences inobgEwere previously reported to synergize with ΔmlaFto affect growth and stringent response, we show thatobgEalleles do not affect membrane stress resistance. Instead, a single nucleotide polymorphism (SNP) in the essential gene encoding undecaprenyl pyrophosphate (Und-PP) synthase,uppS, synergizes with ΔmlaFto increase susceptibility to membrane stress and antibiotics, and reduce persistence in a mouse lung infection. Und-P is a lipid glycan carrier known to be required for biosynthesis ofA. baumanniicapsule, cell wall, and glycoproteins. Our data suggest that in the absence of the Mla system, the cellular level of Und-P is critical for envelope integrity, antibiotic resistance, and lipooligosaccharide abundance. These findings uncover synergy between Und-P and the Mla system in maintaining theA. baumanniiouter membrane and stress resistance.
Natural selection drives emergent genetic homogeneity in a century-scale experiment with barley
Authors: Landis Jacob B , Guercio Angelica M , Brown Keely E , Fiscus Christopher J , Morrell Peter L , Koenig Daniel
Published: September 2023

Direct observation is central to our understanding of the process of adaptation, but evolution is rarely documented in a large, multicellular organism for more than a few generations. Here, we observe genetic and phenotypic evolution across a century-scale competition experiment, barley composite cross II (CCII). CCII was founded in 1929 with tens of thousands of unique genotypes and has been adapted to local conditions in Davis, CA, USA for 58 generations. We find that natural selection has massively reduced genetic diversity leading to a single clonal lineage constituting most of the population by generation F50. Selection favored alleles originating from similar climates to that of Davis, and targeted genes regulating reproductive development, including some of the most well-characterized barley diversification loci,Vrs1,HvCEN, andPpd-H1. We chronicle the dynamic evolution of reproductive timing in the population and uncover how parallel molecular pathways are targeted by stabilizing selection to optimize this trait. Our findings point to selection as the predominant force shaping genomic variation in one of the world’s oldest ongoing biological experiments.

One-Sentence Summary

Wholesale genetic restructuring of an experimental population is a consequence of rapid environmental adaptation.
Mitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease
Authors: Flønes Irene H , Toker Lilah , Sandnes Dagny Ann , Castelli Martina , Mostafavi Sepideh , Lura Njål , Shadad Omnia , Fernandez-Vizarra Erika , Painous Cèlia , Pérez-Soriano Alexandra , Compta Yaroslau , Molina-Porcel Laura , Alves Guido , Tysnes Ole-Bjørn , Dölle Christian , Nido Gonzalo S , Tzoulis Charalampos
Published: September 2023

Idiopathic Parkinson’s disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies.
Cryo-EM structure of Alzheimer’s disease tau filaments with PET ligand MK-6240
Authors: Kunach Peter , Vaquer-Alicea Jaime , Smith Matthew S. , Hopewell Robert , Monistrol Jim , Moquin Luc , Therriault Joseph , Tissot Cecile , Rahmouni Nesrine , Massarweh Gassan , Soucy Jean-Paul , Guiot Marie-Christine , Shoichet Brian K. , Rosa-Neto Pedro , Diamond Marc I. , Shahmoradian Sarah H.
Published: September 2023

Positron Emission Tomography (PET) ligands have advanced Alzheimer’s disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identified AD brain tissue with elevated tau burden, purified filaments, and determined the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine K353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids.
A history of avoidance does not impact extinction learning in male rats
Authors: López-Moraga Alba , Luyten Laura , Beckers Tom
Published: September 2023

Pervasive avoidance is one of the central symptoms of all anxiety-related disorders. In treatment, avoidance behaviors are typically discouraged because they are assumed to maintain anxiety. Yet, it is not clear that engaging in avoidance is always detrimental. In this study, we used a platform-mediated avoidance task to investigate the influence of avoidance history on extinction learning in male rats. Our results show that having the opportunity to avoid during fear acquisition training has no marked effect on the extinction of auditory cued fear in a platform-mediated avoidance procedure that constitutes a realistic approach/avoidance conflict in male rats, regardless of whether avoidance was possible during extinction or not. This suggests that imposing a realistic cost on avoidance behavior prevents the adverse effects that avoidance has been claimed to have on extinction, but even then, avoidance does not appear to have clear positive effects on extinction learning nor on retention either.
When the whole is only the parts: non-holistic object parts predominate face-cell responses to illusory faces
Authors: Sharma Saloni , Vinken Kasper , Livingstone Margaret S.
Published: September 2023

Humans are inclined to perceive faces in everyday objects with a face-like configuration. This illusion, known as face pareidolia, is often attributed to a specialized network of ‘face cells’ in primates. We found that face cells in macaque inferotemporal cortex responded selectively to pareidolia images, but this selectivity did not require a holistic, face-like configuration, nor did it encode human faceness ratings. Instead, it was driven mostly by isolated object parts that are perceived as eyes only within a face-like context. These object parts lack usual characteristics of primate eyes, pointing to the role of lower-level features. Our results suggest that face-cell responses are dominated by local, generic features, unlike primate visual perception, which requires holistic information. These findings caution against interpreting neural activity through the lens of human perception. Doing so could impose human perceptual biases, like seeing faces where none exist, onto our understanding of neural activity.
Neural stem cells protect blood-brain barrier integrity via the p38, JNK, and ERK1/2 pathways following intracerebral hemorrhage in rats
Authors: Sun Jing , Yang Xiuli , Carmichael Austin , Kim Tae Jung , Kim Young-Ju , Wei Zhiliang , Han Ling , Stanciu Nicolas , Ko Sang-Bae , Nan Guangxian , Yoon Byung-Woo
Published: September 2023

Neural stem cells (NSCs) have displayed great potential in ameliorating brain damage following intracerebral hemorrhage (ICH) via proliferation, differentiation, and immunomodulation. However, it remains unclear whether NSCs can improve microvascular function, e.g., blood-brain barrier (BBB) integrity, after ICH. In this study, we investigate the potential therapeutic benefit of NSCs on BBB integrity as well as the underlying mechanism. Adult male Sprague-Dawley rats were randomly divided into sham, ICH+PBS, and ICH+NSCs groups for comparisons. ICH was induced by intrastriatal injection of bacterial collagenase. An aliquot of NSCs or PBS was injected via the tail vein 2 h after ICH induction. The following multiparametric measurements were compared: brain edema, hematoma volume, behavior, BBB permeability, and mitogen-activated protein kinase (MAPK) signaling pathway activity. We found that NSCs treatment attenuates BBB permeability, reduces brain edema, and promotes brain function recovery after ICH by inhibiting ERK1/2, p38, and JNK signaling pathway activation. These findings provide novel insight for future therapies aiming to prevent BBB dysfunction and improve functional recovery in ICH patients.
Neuroimaging and plasma marker evidence for white matter macrostructure loss in Parkinson’s disease
Authors: Zarkali Angeliki , Hannaway Naomi , McColgan Peter , Heslegrave Amanda J , Veleva Elena , Laban Rhiannon , Zetterberg Henrik , Lees Andrew J , Fox Nick C. , Weil Rimona S
Published: September 2023

Parkinson’s disease (PD) is the second commonest neurodegenerative disorder and over half of patients progress to postural instability, dementia or death within 10 years of diagnosis.

However, onset and rate of progression to poor outcomes is highly variable, underpinned by heterogeneity in the underlying pathological process. Improved biomarkers of poor outcomes would be helpful for targeted treatment, but most studies to-date have been limited to a single modality or the assessment of patients with established cognitive impairment. Here, we use multimodal neuroimaging and plasma biomarkers in 98 patients with PD and 28 age-matched controls followed-up over 3 years, including: gray matter (cortical thickness), white matter (macrostructure: fibre-cross section and microstructure: fibre density) at whole-brain and tract level, structural and functional connectivity and plasma levels of neurofilament light chain (NFL) and phosphorylated tau (p-tau) 181. We show extensive reductions in fibre cross-section and structural connectivity in PD with poor outcomes, with preserved gray matter and functional connectivity. NFL, but not p-tau181 levels was increased in PD with poor outcomes and correlated with white matter loss. These findings suggest that imaging sensitive to white matter macrostructure and plasma NFL may be useful biomarkers of poor outcomes in PD. As new targeted treatments are emerging, these biomarkers show important potential to aid patient selection for treatments and improve stratification to clinical trials.
Inhibition of mammalian mtDNA transcription paradoxically activates liver fatty acid oxidation to reverse diet-induced hepatosteatosis and obesity
Authors: Jiang Shan , Yuan Taolin , Kremer Laura S , Rosenberger Florian A , Hansen Fynn M , Borg Melissa , Rubalcava-Gracia Diana , Mennuni Mara , Filograna Roberta , Alsina David , Misic Jelena , Koolmeister Camilla , Ren Lipeng , Andersson Olov , Unger Anke , Bergbrede Tim , Lucrezia Raffaella Di , Wibom Rolf , Zierath Juleen R , Krook Anna , Giavalisco Patrick , Mann Matthias , Larsson Nils-Göran
Published: September 2023

The oxidative phosphorylation (OXPHOS) system in mammalian mitochondria plays a key role in harvesting energy from ingested nutrients1, 2. Mitochondrial metabolism is very dynamic and can be reprogrammed to support both catabolic and anabolic reactions, depending on physiological demands or disease states3, 4. Rewiring of mitochondrial metabolism is intricately linked to metabolic diseases5, 6and is also necessary to promote tumour growth7–11. Here, we demonstrate thatper oraltreatment with an inhibitor of mitochondrial transcription (IMT)11shifts whole animal metabolism towards fatty acid oxidation, which, in turn, leads to rapid normalization of body weight, reversal of hepatosteatosis and restoration of glucose tolerance in mice on high-fat diet. Paradoxically, the IMT treatment causes a severe reduction of OXPHOS capacity concomitant with a marked upregulation of fatty acid oxidation in the liver, as determined by proteomics and non-targeted metabolomics analyses. The IMT treatment leads to a marked reduction of complex I, the main dehydrogenase that feeds electrons into the ubiquinone (Q) pool, whereas the levels of electron transfer flavoprotein dehydrogenase (ETF-DH) and other dehydrogenases connected to the Q pool are increased. This rewiring of metabolism caused by reduced mtDNA expression in the liver provides a novel principle for drug treatment of obesity and obesity-related pathology.
Genomic insights intoLactobacillaceae: Analyzing the “Alleleome” of core pangenomes for enhanced understanding of strain diversity and revealing Phylogroup-specific unique variants
Authors: Harke Archana S. , Josephs-Spauling Jonathan , Mohite Omkar S. , Chauhan Siddharth M. , Ardalani Omid , Palsson Bernhard , Phaneuf Patrick V.
Published: September 2023

TheLactobacillaceaefamily’s significance in food and health, combined with available strain-specific genomes, enables genome assessment through pangenome analysis. The ‘Alleleome’ of the core pangenomes ofthe Lactobacillaceaefamily, which identifies natural sequence variations, was reconstructed from the amino acid and nucleotide sequences of the core genes across 2,447 strains of 26 species. It comprised 3.71 million amino acid variants in 29,448 core genes across the family. The alleleome analysis of theLactobacillaceaefamily revealed key findings: 1) In the core pangenome, amino acid substitutions prevailed over rare insertions and deletions, 2) Purifying negative selection primarily influenced core gene variations in the family, with diversifying selection noted inL. helveticus.L. plantarum’s core alleleome was investigated due to its industrial importance. InL. plantarum, the defining characteristics of its core alleleome included: 1) It is highly conserved; 2) Among 235 isolation sources, the primary categories displaying variant prevalence were fermented food, feces, and unidentified sources; 3) It is predominantly characterized by ‘conservative’ and ‘moderately conservative’ mutations; and 4) Phylogroup-specific core variant gene analysis identified unique variants (DltX, FabZ1, Pts23B, CspP) in phylogroups ‘I’ and ‘B’ which could be used as identifier or validation markers of strain or phylogroup.
Dynamic mRNA stability changes buffer transcriptional activation during neuronal differentiation and are regulated by RNA binding proteins
Authors: Zhou Yuan , Rashad Sherif , Tominaga Teiji , Niizuma Kuniyasu
Published: September 2023

The steady state levels of mRNA are outcomes of a finely tuned interplay between RNA transcription and decay. Therefore, the modulation of RNA stability is generally assumed to influence RNA abundance in a positive direction. However, the correlation between mRNA transcription, translation and stability remains elusive. Here, we employed a newly developed simplified mRNA stability profiling technique to explore the role of mRNA stability in SH-SY5Y neuronal differentiation model. Transcriptome-wide mRNA stability analysis revealed neural-specific RNA stability kinetics, including stabilization of transcripts encoding regulators of neuronal morphogenesis and function and destabilization of mitochondrial electron transport and redox homeostasis. When we further examined the relationship between transcription, translation and mRNA stability, a bidirectional regulation of RNA stability was revealed, wherein mRNA stability could either exert the buffering effect on gene products or change in a same direction as transcription. Motif analysis unveiled SAMD4A as a major regulator of the dynamic changes in mRNA stability observed during differentiation. Knockdown of SAMD4A impaired neuronal differentiation and influenced the response to oxidative stress. Mechanistically, SAMD4A was found to alter the stability of several mRNAs to which it binds. Meanwhile, a dimorphic pattern of the correlation between gene expression and SAMD4A-regulated mRNA stability was observed, suggesting dynamic regulation mRNA stability during the neuronal differentiation guided by SAMD4A. The novel insights into the interplay between mRNA stability and cellular behaviors provide a foundation for understanding neurodevelopmental processes and neurodegenerative disorders and highlights dynamic mRNA stability as an important layer of gene expression regulation.
Unravelling the complexity of silk sericins:P150/sericin 6is a new silk gene inBombyx mori
Authors: Wu Bulah Chia-hsiang , Zabelina Valeriya , Zurovcova Martina , Žurovec Michal
Published: September 2023

Sericins are a small family of highly divergent proteins that serve as adhesives and coatings for silk fibers and are produced in the middle part of the silk gland. So far, five genes encoding sericin proteins have been found inBombyx mori. Sericins 1 and 3 are responsible for silk adhesion in the cocoon, while sericins 2, 4, and 5 are present in non-cocoon spun silk of younger larvae (including the early last instar). We found a new gene, which we namedP150/sericin 6, which appears to be an ortholog of the sericin-like protein previously found inGalleria mellonella. TheB. morisequence of theP150/sericin 6ORF was previously incorrectly predicted and assigned to two smaller, uncharacterized genes. We present a newP150/sericin 6gene model and show that it encodes a large protein of 467 kDa. It is characterized by repeats with a high proportion of threonine residues and a short conserved region with a cysteine knot motif (CXCXCX) at the C-terminus. Expression analysis has shown thatB. mori P150/ser6has low transcriptional level in contrast to itsG. mellonellahomolog. We also discuss the synteny of homologous genes on corresponding chromosomes between moth species and possible phylogenetic relationships betweenP150/ser6and cysteine knot mucins. Our results improve our understanding of the evolutionary relationships between adhesion proteins in different lepidopteran species.
Uncoupling of synaptic loss from amyloid burden by an Alzheimer’s disease protective variant of PLCγ2
Authors: Bevan Ryan J. , Maguire Emily , Phillips Thomas , Simonazzi Elena , Vassileva Marieta , Williams Julie , Taylor Philip R.
Published: September 2023

A rare coding missense variant (rs72824905; P522R) inPLCG2decreases the risk of late-onset Alzheimer’s disease, but how this protective effect is mediated is unclear. Here we demonstrate a mechanism for this protection, the R522 variant of PLCγ2 alters microglial activity leading to a marked preservation of synaptic integrity and reduced peri-plaque microglial engulfment of synapses independently of amyloid burden. Our data advocate for a direct central role of PLCγ2 in mediating synaptic loss as part of the pathological process of Alzheimer’s disease (AD), prioritising it as a therapeutic target and modulator of disease.
TheHelicobacter pyloriMethylome is Acid-Responsive due to Regulation by the Two-Component System ArsRS and the Type I DNA Methyltransferase HsdM1 (HP0463)
Authors: Zimmerman Elise H. , Ramsey Erin L. , Hunter Katherine E. , Villadelgado Sarah M. , Phillips Celeste M. , Shipman Ryan T. , Forsyth Mark H.
Published: September 2023

In addition to its role in genome protection, DNA methylation can regulate gene expression. In this study, we characterized the impact of acidity, phase variation, and the ArsRS TCS on the expression of the Type I m6A DNA methyltransferase HsdM1 (HP0463) ofHelicobacter pylori26695 and their subsequent effects on the methylome. Transcription ofhsdM1 increases at least 4-fold in the absence of the sensory histidine kinase ArsS, the major acid-sensing protein ofH. pylori.hsdM1 exists in the phase-variable operonhsdR1-hsdM1. Phase-lockinghsdR1 (HP0464), the restriction endonuclease gene, has significant impacts on the transcription ofhsdM1. To determine the impacts of methyltransferase transcription patterns on the methylome, we conducted methylome sequencing on samples cultured at pH 7 or pH 5. We found differentially methylated motifs between these growth conditions, and that deletions ofarsSand/orhsdM1 interfere with the epigenetic acid response. Deletion ofarsSleads to altered activity of HsdM1 and multiple other methyltransferases under both pH conditions indicating that the ArsRS TCS, in addition to direct effects on regulon transcription during acid acclimation, may also indirectly impact gene expression via regulation of the methylome. We determined the target motif of HsdM1 (HP0463) to be the complementary bipartite sequence pair 5’-(HH)TCAm6AVN6TGY-3’ and 3’-AGTN6GAm6ACA-5’. The Type II m5C DNA methyltransferase M.HpyAVIII (HP1121) is regulated by ArsS and HsdM1. This complex regulation of DNA methyltransferases, and thus differential methylation patterns, may have implications for the decades-long persistent infection byH. pylori.

Importance

This study expands the possibilities for complex, epigenomic regulation inHelicobacter pylori. We demonstrate that theH. pylorimethylome is plastic and acid-sensitive via the two-component system ArsRS and the DNA methyltransferase HsdM1. The control of a methyltransferase by ArsRS may allow for a layered response to changing acidity. Likely, an early response whereby ArsR∼P affects regulon expression, including the methyltransferasehsdM1. Then, a somewhat later effect as the altered methylome, due to altered HsdM1 expression, subsequently alters the expression of other genes involved in acclimation. The intermediate methylation of certain motifs supports the hypothesis that methyltransferases play a regulatory role. Untangling this additional web of regulation could play a key role in understandingH. pyloricolonization and persistence.
Lys716 in the transmembrane domain of yeast mitofusin Fzo1 modulates anchoring and fusion
Authors: Versini Raphaëlle , Baaden Marc , Cavellini Laetitia , Cohen Mickaël M. , Taly Antoine , Fuchs Patrick F.J.
Published: September 2023

Outer mitochondrial membrane (OMM) fusion is an important process for the cell and organism survival, as its dysfunction is linked to neurodegenerative diseases and cancer. The OMM fusion is mediated by members of the dynamin-related protein (DRP) family, named mitofusins. The exact mechanism by which the mitofusins contribute to these diseases, as well as the exact molecular fusion mechanism mediated by mitofusin, remains elusive.

We have performed extensive multiscale molecular dynamics simulations using both coarse-grained and all-atom approaches to predict the dimerization of two transmembrane domain (TM) helices of the yeast mitofusin Fzo1. We identify specific residues, such as Lys716, that can modulate dimer stability. Comparison with a previous computational model reveals remarkable differences in helix crossing angles and interfacial contacts. Overall, however, the TM1-TM2 interface appears to be stable in the Martini and CHARMM force fields. Replica-exchange simulations further tune a detailed atomistic model, as confirmed by a remarkable agreement with an independent prediction of the Fzo1-Ugo1 complex by AlphaFold2. Functional implications, including a possible role of Lys716 that could affect membrane interactions during fusion, are suggested and consistent with experiments monitoring mitochondrial respiration of selected Fzo1 mutants.
Rewiring of the phosphoproteome executes two meiotic divisions
Authors: Koch Lori B. , Spanos Christos , Kelly Van , Ly Tony , Marston Adele L.
Published: September 2023

The cell cycle is ordered by a controlled network of kinases and phosphatases. To generate gametes via meiosis, two distinct and sequential chromosome segregation events occur without an intervening S phase. How canonical cell cycle controls are modified for meiosis is not well understood. Here, using highly synchronous budding yeast populations, we reveal how the global proteome and phosphoproteome changes during the meiotic divisions. While protein abundance changes are limited to key cell cycle regulators, dynamic phosphorylation changes are pervasive. Our data indicate that two waves of cyclin-dependent kinase and Polo (Cdc5Polo) kinase activity drive successive meiotic divisions. These two distinct waves of phosphorylation are ensured by the meiosis-specific Spo13Meikinprotein, which rewires the phosphoproteome. Spo13Meikinbinds to Cdc5Poloto promote phosphorylation of a subset of substrates in meiosis I containing a newly identified motif, which we define as the Spo13Meikin-Cdc5Poloconsensus phosphorylation motif. Overall, our findings reveal that a master regulator of meiosis redirects the activity of a kinase to change the phosphorylation landscape and elicit a developmental cascade.