bluuebunny/crossref_metadata_2025 huggingface dataset:
Early tetrapod diversification under neutral theory
Authors: Dunne Emma M. , Thompson Samuel E. D. , Butler Richard J. , Rosindell James , Close Roger A.
Published: February 2022

Estimates of deep-time biodiversity typically rely on statistical methods to mitigate the impacts of sampling biases in the fossil record. However, these methods are limited by the spatial and temporal scale of the underlying data. Here we use a spatially explicit mechanistic model, based on neutral theory, to test hypotheses of early tetrapod diversity change during the late Carboniferous and early Permian, critical intervals for the diversification of vertebrate life on land. Our neutral simulations suggest, in contrast to previous studies, that increases in early tetrapod diversity were not driven by local endemism following the ‘Carboniferous Rainforest Collapse’. We show that apparent changes in face-value diversity can instead be explained by variation in sampling intensity through time. Our results further demonstrate the importance of accounting for sampling biases in analyses of the fossil record and demonstrate the vast potential of mechanistic models, including neutral models, for testing hypotheses in palaeobiology.
Integrating region- and network-level contributions to episodic recollection using multilevel structural equation modeling
Authors: Kurkela Kyle A. , Cooper Rose A. , Ryu Ehri , Ritchey Maureen
Published: February 2022

The brain is composed of networks of interacting brain regions that support higher order cognition. For instance, a posterior medial (PM) network appears to support recollection and other forms of episodic construction. Past research has focused largely on the roles of individual brain regions in recollection or on their mutual engagement as part of an integrated network. Yet the relationship between these region- and network-level contributions remains poorly understood. Here we applied multilevel structural equation modeling (SEM) to examine the functional organization of the PM network and its relationship to episodic memory outcomes. We evaluated two aspects of functional heterogeneity in the PM network: first, the organization of individual regions into subnetworks, and second, the presence of regionally-specific contributions while accounting for network-level effects. The results suggest that the PM network is composed of ventral and dorsal subnetworks, with the ventral subnetwork making a unique contribution to recollection, and that memory-related activity in individual regions is well accounted for by these network-level effects. These findings highlight the importance of considering both region and network levels of analysis when studying brain-behavior relationships.
Not all noise-reduction methods for fMRI preprocessing are created equal
Authors: Hoeppli M.E. , Garenfeld M.A. , Mortensen C.K. , Nahman-Averbuch H. , King C.D. , Coghill R.C.
Published: February 2022

Preprocessing fMRI data requires striking a fine balance between conserving signals of interest and removing noise. Typical steps of preprocessing include motion correction, slice timing correction, spatial smoothing, and high-pass filtering. However, these standard steps do not remove many sources of noise. Thus, noise-reduction techniques such as CompCor and FIX have been developed to further improve the ability to draw meaningful conclusions from the data. The ability of these techniques to minimize noise while conserving signals of interest has been tested almost exclusively in resting-state fMRI datasets and, only rarely, in task-related fMRI datasets. Application of noise-reduction techniques to task-related fMRI is particularly important given that such procedures have been shown to reduce false positive rates. However, little remains known about the impact of different noise reduction techniques on the retention of signal, particularly during tasks that may be associated with systemic physiological changes. In this paper, we compared two noise-reduction techniques, i.e. FIX and CompCor, in an fMRI dataset including noxious heat stimulation and non-noxious auditory stimulation.

Results show that preprocessing including FIX noise-reduction technique conserves significantly more signal than a preprocessing protocol including CompCor noise-reduction technique in both noxious heat and non-noxious auditory stimulations, while removing only slightly less noise. These results suggest that FIX might be the most appropriate technique to achieve the balance between conserving signals of interest and removing noise.
An explainable unsupervised framework for alignment-free protein classification using sequence embeddings
Authors: Yeung Wayland , Zhou Zhongliang , Mathew Liju , Gravel Nathan , Taujale Rahil , Venkat Aarya , Lanzilotta William , Li Sheng , Kannan Natarajan
Published: February 2022

Protein classification is a cornerstone of biology that relies heavily on alignment-based comparison of primary sequences. However, the systematic classification of large protein superfamilies is impeded by unique challenges in aligning divergent sequence datasets. We developed an alignment-free approach for sequence analysis and classification using embedding vectors generated from pre-trained protein language models that capture underlying protein structural-functional properties from unsupervised training on millions of biologically-observed sequences. We constructed embedding-based trees (with branch support) which depict hierarchical clustering of protein sequences and infer fast/slow evolving sites through interpretable sequence projections. Applied towards diverse protein superfamilies, embedding tree infers Casein Kinase 1 (CK1) as the basal protein kinase clade, identifies convergent functional motifs shared between divergent phosphatase folds, and infers evolutionary relationships between diverse radical S-Adenosyl-L-Methionine (SAM) enzyme families. Overall results indicate that embedding trees effectively capture global data structures, functioning as a general unsupervised approach for visualizing high-dimensional manifolds.
Alterations to parvalbumin-expressing interneuron function and associated network oscillations in the hippocampal – medial prefrontal cortex circuit during natural sleep in AppNL-G-Fmice
Authors: Brady Erica S , Griffiths Jessica , Andrianova Lilya , Saito Takashi , Saido Takaomi C , Randall Andrew D , Tamagnini Francesco , Witton Jonathan , Craig Michael T
Published: February 2022

In the early stages of Alzheimer’s disease (AD), the accumulation of the peptide amyloid-β (Aβ) damages synapses and disrupts neuronal activity and leads to disruption of neuronal oscillations associated with cognition. This is thought to be largely due to impairments in CNS synaptic inhibition, particularly via parvalbumin (PV)-expressing interneurons that essential for generating several key oscillations. Research in this field has largely been conducted in mouse models that over-express humanised, mutated forms of AD-associated genes that produce exaggerated pathology. This has prompted the development and use of knock-in mouse lines that express these genes at an endogenous level, such as the AppNL-G-F/NL-G-Fmouse model used in the present study. These mice appear to model the early stages of Aβ-induced network impairments, yet an in-depth characterisation of these impairments in currently lacking. Therefore, using 16 month-old AppNL-G-F/NL-G-Fmice, we analysed neuronal oscillations found in the hippocampal – medial prefrontal cortex (mPFC) during awake behaviour, rapid eye movement (REM) and non-REM (NREM) sleep to assess the extent of network dysfunction. No alterations to gamma oscillations were found to occur in the hippocampus or mPFC during either awake behaviour, REM or NREM sleep. However, during NREM sleep an increase in the amplitude of mPFC spindles and decrease in the power of hippocampal SWRs was identified. The former was associated with a decrease in the density of mPFC PV-expressing interneurons and the latter was accompanied by an increase in the synchronisation of PV-expressing interneuron activity, as measured using two-photon Ca2+imaging. Furthermore, although changes were detected in local network function of mPFC and hippocampus, long-range communication between these regions appeared intact. Altogether, our results suggest that these NREM sleep-specific impairments represent the early stages of circuit breakdown in response to amyloidopathy.
Loss of SUMO-specific protease 2 causes isolated glucocorticoid deficiency by blocking adrenal cortex zonal transdifferentiation
Authors: Dufour Damien , Dumontet Typhanie , Sahut-Barnola Isabelle , Onzon Meline , Pussard Eric , Wilmouth James , Olabe Julie , Lucas Cecily , Levasseur Adrien , Soubeyrand-Damon Christelle , Pointud Jean-Christophe , Roucher-Boulez Florence , Tauveron Igor , Bossis Guillaume , Yeh Edward T. , Breault David T. , Val Pierre , Lefrançois-Martinez Anne-Marie , Martinez Antoine
Published: February 2022

SUMOylation is a dynamic posttranslational modification, that provides fine-tuning of protein function involved in the cellular response to stress, differentiation, and tissue development. In the adrenal cortex, an emblematic endocrine organ that mediates adaptation to physiological demands, the SUMOylation gradient is inversely correlated with the gradient of cellular differentiation raising important questions about its role in functional zonation and the response to stress. Considering that SUMO-specific protease 2 (SENP2), a deSUMOylating enzyme, is upregulated by ACTH/PKA signalling within the zona Fasciculata (zF), we generated mice with adrenal-specific Senp2 loss to address these questions. Disruption of SENP2 activity in steroidogenic cells leads to specific hypoplasia of the zF, a blunted reponses to ACTH and isolated glucocorticoid deficiency. Mechanistically, overSUMOylation resulting from SENP2 loss shifts the balance between ACTH/PKA and WNT/β-catenin signalling leading to repression of PKA activity and ectopic activation of β-catenin. At the cellular level, this blocks transdifferentiation of β-catenin-positive zona Glomerulosa cells into zF cells and sensitises them to premature apoptosis. Our findings indicate that the SUMO pathway is critical for adrenal homeostasis and stress responsiveness.
PDR6-mediated camalexin efflux and disease resistance are regulated through direct phosphorylation by the kinases OXI1 and AGC2-2
Authors: Miao Guopeng , Han Juan , Liu Chang-xin , Liu Jian , Wang Cheng-run , Wang Shun-chang
Published: February 2022

Plant immune signaling largely relies on post-translational modifications to establish a rapid and appropriate defense response to different pathogen types and infection pressure. Specific pleiotropic drug resistance (PDR) transporters can transport secondary metabolites to contribute to pathogen invasion resistance. However, the establishment of the post-translational regulation of PDR transporters that efflux secondary metabolites is unclear. In this study, by detecting the camalexin contents on the leaf surfaces of mutants and overexpression lines, two AGC kinases, namely, OXI1 and its closest homologue AGC2-2, were found to be related to extracellular camalexin secretion. The overexpression of OXI1 or AGC2-2 resulted in an increase in camalexin contents on the leaf surface and a decrease in camalexin contents in the leaf interior. These effects increased the resistance of the transgenic lines to surface-inoculated Pseudomonas syringae and Botrytis cinerea. Through in vitro kinase assay and in vivo phosphorylation level detection, we confirmed that the two kinases were related to the phosphorylation modification of PDR6. Pull-down assays, bimolecular fluorescence complementation, and rapamycin-dependent delocalization assays indicated the existence of direct protein–protein interaction between the two kinases and PDR6. By using LC–MS/MS, we also identified the PDR6 phosphorylation sites that were modified by the two kinases in vitro. Through the expression of the dephosphorylated variants of PDR6 in the mutant background, the action site S31 of OXI1 and the action sites S33 and S827 of AGC2-2 were found to have positive effects on the efflux activity of PDR6. In addition, T832, the action site of OXI1, may contribute to the stability of PDR6 on the plasma membrane.
The Requirement of Ubiquitin C-Terminal Hydrolase L1 (UCHL1) in Mouse Ovarian Development and Fertility
Authors: Woodman Morgan F. , Ozcan Meghan C.H. , Gura Megan A. , De La Cruz Payton , Gadson Alexis K. , Grive Kathryn J.
Published: February 2022

Ubiquitin C-Terminal Hydrolase L1 (UCHL1) is a de-ubiquitinating enzyme enriched in neuronal and gonadal tissues known to regulate the cellular stores of mono-ubiquitin and protein turnover. While its function in maintaining proper motor neuron function is well-established, investigation into its role in the health and function of reproductive processes is only just beginning to be studied. Single-cell-sequencing analysis of all ovarian cells from the murine perinatal period revealed that Uchl1 is very highly expressed in the developing oocyte population, an observation which was corroborated by high levels of oocyte-enriched UCHL1 protein expression in oocytes of all stages throughout the mouse reproductive lifespan. To better understand the role UCHL1 may be playing in oocytes, we utilized a UCHL1-deficient mouse line, finding reduced number of litters, reduced litter sizes, altered folliculogenesis, morphologically abnormal oocytes, disrupted estrous cyclicity and apparent endocrine dysfunction in these animals compared to their wild-type and heterozygous littermates. These data reveal a novel role of UCHL1 in female fertility as well as overall ovarian function, and suggest a potentially essential role for the ubiquitin proteasome pathway in mediating reproductive health.

Summary sentence

Ubiquitin C-Terminal Hydrolase L1 (UCHL1) is required for proper ovarian folliculogenesis, estrous cyclicity, and fertility in the female mouse.
Fused in sarcoma undergoes cold denaturation: Implications on phase separation
Authors: Félix Sara S. , Laurents Douglas V. , Oroz Javier , Cabrita Eurico J.
Published: February 2022

The mediation of fused in sarcoma (FUS) protein liquid-liquid phase separation (LLPS) is generally attributed to the low-complexity and disordered domains, while the role of its folded domains remains unknown. In this work we questioned the role of the folded domains on the full-length (FL) FUS LLPS and studied the influence of several metabolites, ions and overall conditions on the LLPS process using turbidity assays, differential interference contrast microscopy and nuclear magnetic resonance spectroscopy. We demonstrate that FL FUS LLPS is highly responsive to the surrounding conditions, and that overall intrinsic disorder is crucial for LLPS. To promote such disorder, we reveal that the FUS RNA-recognition domain (RRM) and the zinc-finger motif (ZnF) undergo cold denaturation above 0ºC, at a temperature that is determined by the conformational stability of the ZnF domain. We hypothesize that, in cold shock conditions, cold denaturation might provide a pathway that exposes additional residues to promote FUS self-assembly. Such findings mark the first evidence that FUS globular domains may have an active role in stress granule formation in cold stress.
A parvocellular-magnocellular functional gradient in human visual cortex
Authors: Ibarbia-Garate Maddi , Paz-Alonso Pedro M.
Published: February 2022

The magnocellular and parvocellular systems are major visual recognition pathways, with distinct histological and physiological properties. Despite their critical role, there is limited evidence on the specific contributions these visual pathways make to visual recognition in general and to word reading in particular. Using a multimodal functional MRI approach and individual-subject analyses, here we investigate the involvement of visual cortex regions in the recognition of magnocellular- and parvocellular-biased words and images. Our results reveal a functional gradient in the activation profile of both left and right visual cortex: posterior regions are more strongly recruited for processing parvocellular-biased, while anterior regions are more involved in processing magnocellular-biased stimuli. Furthermore, functional connectivity analyses show clustering in the strength of functional coupling among visual cortex regions as a function of the distance between regions, with greater coupling within and less coupling across posterior and anterior regions. Finally, we found minimal differences in lateralization for word and image recognition in these visual cortical regions. These results were replicated in a retest session with a subset of participants. Our findings underscore a functional division of labor in the visual cortex as a function determined by a parvocellular or magnocellular bias in properties of the stimuli and further reveal that in this context the visual cortex is not particularly biased towards words or images.
Membrane binding of pore-forming γ-hemolysin components studied at different lipid compositions
Authors: Tarenzi Thomas , Lattanzi Gianluca , Potestio Raffaello
Published: February 2022

Methicillin-resistant Staphylococcus aureus is is among those pathogens currently posing the highest threat to public health. Its host immune evasion strategy is mediated by pore-forming toxins (PFTs), among which the bicomponent γ-hemolysin is one of the most common. The complexity of the porogenesis mechanism by γ-hemolysin poses difficulties in the development of antivirulence therapies targeting PFTs from S. aureus, and sparse and apparently contrasting experimental data have been produced. Here, through a large set of molecular dynamics simulations at different levels of resolution, we investigate the first step of pore formation, and in particular the effect of membrane composition on the ability of γ-hemolysin components, LukF and Hlg2, to steadily adhere to the lipid bilayer in the absence of proteinaceous receptors. Our simulations are in agreement with experimental data of γ-hemolysin pore formation on model membranes, which are here explained on the basis of the bilayer properties. Our computational investigation suggests a possible rationale to explain experimental data on phospholipid binding to the LukF component, and to hypothesise a mechanism by which, on purely lipidic bilayers, the stable anchoring of LukF to the cell surface facilitates Hlg2 binding, through the exposure of its N-terminal region. We expect that further insights on the mechanism of transition between soluble and membrane bound-forms and on the role played by the lipid molecules will contribute to the design of antivirulence agents with enhanced efficacy against methicillin-resistant S. aureus infections.

Graphical Abstract

Highlights

The presence of cholesterol and unsaturated phospholipid tails facilitates the binding of γ-hemolysin components, LukF and Hlg2, on model membranes.

Coarse-grained simulations show that the two components have different absorption capabilities, with LukF undergoing the most stable binding.

The spontaneous docking of LukF on the membrane is mediated by two distant phosphatidylcholine binding sites.
Behavioral decomposition reveals rich encoding structure employed across neocortex
Authors: Mimica Bartul , Tombaz Tuçe , Battistin Claudia , Fuglstad Jingyi Guo , Dunn Benjamin A. , Whitlock Jonathan R.
Published: February 2022

Abstract

The Cortical population code is pervaded by activity patterns evoked by movement, but how such signals relate to the natural actions of unrestrained animals remains largely unknown, particularly in sensory areas. To address this we compared high-density neural recordings across four cortical regions (visual, auditory, somatosensory, motor) in relation to sensory modulation, posture, movement, and ethograms of freely foraging rats. Momentary actions, such as rearing or turning, were represented ubiquitously and could be decoded from all sampled structures. However, more elementary and continuous features, such as pose and movement, followed region-specific organization, with neurons in visual and auditory cortices preferentially encoding mutually distinct head-orienting features in world-referenced coordinates, and somatosensory and motor cortices principally encoding the trunk and head in egocentric coordinates. The tuning properties of synaptically coupled cells also exhibited connection patterns suggestive of different uses of behavioral information within and between regions. Together, our results speak for detailed, multi-level encoding of animal behavior subserving its dynamic employment in local cortical computations.
Abundance and expression ofhgcABgenes and mercury availability jointly explain methylmercury formation in stratified brackish waters
Authors: Capo Eric , Feng Caiyan , Bravo Andrea G. , Bertilsson Stefan , Soerensen Anne L. , Pinhassi Jarone , Buck Moritz , Karlsson Camilla , Hawkes Jeffrey , Björn Erik
Published: February 2022

Neurotoxic methylmercury (MeHg) is formed by microbial methylation of inorganic divalent Hg (HgII) and constitutes severe environmental and human health risks. The methylation is enabled byhgcAandhgcBgenes, but it is not known if the associated molecular-level processes are rate-limiting or enable accurate prediction of MeHg formation in nature. In this study, we investigated the relationships betweenhgcAgenes and MeHg across redox stratified water columns in the brackish Baltic Sea. We found that the abundance ofhgcAgenes and transcripts combined with the concentration of dissolved HgII-sulfide species were strong predictors of both HgIImethylation rate and MeHg concentration, implying their roles as principal joint drivers of MeHg formation in these systems. In establishing relationships betweenhgcAgenes and MeHg, we advance the fundamental understanding of mechanistic principles governing MeHg formation in nature and enable refined predictions of MeHg levels in coastal seas in response to the accelerating spread of oxygen deficient zones.
Network States Classification based on Local Field Potential Recordings in the Awake Mouse Neocortex
Authors: Zerlaut Yann , Zucca Stefano , Fellin Tommaso , Panzeri Stefano
Published: February 2022

Recent studies using intracellular recordings in awake behaving mice revealed that cortical network states, defined based on membrane potential features, modulate sensory responses and perceptual outcomes. Single cell intracellular recordings are difficult to achieve and have low yield compared to extracellular recordings of population signals, such as local field potentials (LFPs). However, it is currently unclear how to identify these behaviorally-relevant network states from the LFP. We used simultaneous LFP and intracellular recordings in the somatosensory cortex of awake mice to design and calibrate a model-based analysis method, the Network State Index (NSI), that enables network state classification from the LFP. We used the NSI to analyze the relationship between single-cell (intracellular) and population (LFP) signals over different network states of wakefulness. We found that graded levels of population signal faithfully predicted the levels of single cell depolarization in non-rhythmic regimes whereas, in delta ([2-4 Hz]) oscillatory regimes, the graded levels of rhythmicity in the LFP mapped into a stereotypical oscillatory pattern of membrane potential. Finally, we showed that the variability of network states, beyond the occurrence of slow oscillatory activity, critically shaped the average correlations between single cell and population signals. NSI-based characterization provides a ready-to-use tool to understand from LFP recordings how the modulation of local network dynamics shapes the flexibility of sensory processing during behavior.

Significance statement

Sensation during behaviour is strongly modulated by the animal’s internal state. Such context-dependent modulation of sensory processing is believed to largely stem from top-down control of network states in sensory cortices, with different network states being associated with distinct computational properties of the circuit. So far, a detailed characterization of network states in the awake cortex has mostly been achieved through single-cell intracellular recordings, which however cannot be easily recorded. Here, we developed a new method to classify network states from the easily accessible extracellular LFP recordings of population activity. Given the widespread use of LFPs, our work provides a critical methodology to greatly expand our understanding of the mechanisms underlying state-dependent computations in neocortex.
Express detection and discrimination of visual objects by primate superior colliculus neurons
Authors: Bogadhi Amarender R. , Hafed Ziad M.
Published: February 2022

Primate superior colliculus (SC) neurons exhibit rich visual feature tuning properties and are implicated in a subcortical network hypothesized to mediate fast threat and/or conspecific detection. However, the mechanisms through which generalized object detection may be mediated by SC neurons remain unclear. Here we explored whether, and how quickly, SC neurons detect and discriminate real-life object stimuli. We presented experimentally-controlled gray-scale images of seven different object categories within the response fields (RF’s) of SC neurons, and we also presented a variety of luminance- and spectral-matched image controls. We found that all of our functionally-identified SC neuron types preferentially detected real-life objects even in their very first stimulus-evoked visual bursts (starting within approximately 50 ms from image onset). Intriguingly, even visually-responsive motor-related neurons exhibited such robust early object detection, and they also preferentially discriminated between object categories in their initial visual bursts. We further identified spatial frequency information in visual images as a critical source for early object detection and discrimination by SC neurons. Our results demonstrate rapid and robust SC processing of visual objects, and they underline how the visual processing capabilities of the primate SC support perception and action.
Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth
Authors: Gustafsson Johan , Roshanzamir Fariba , Hagnestål Anders , Patel Sagar M. , Daudu Oseeyi I. , Becker Donald F. , Robinson Jonathan L. , Nielsen Jens
Published: February 2022

The tumor microenvironment is comprised of a complex mixture of different cell types interacting under conditions of nutrient deprivation, but the metabolism therein is not fully understood due to difficulties in measuring metabolic fluxes and exchange of metabolites between different cell typesin vivo. Genome-scale metabolic modeling enables estimation of such exchange fluxes as well as an opportunity to gain insight into the metabolic behavior of individual cell types. Here, we estimated the availability of nutrients and oxygen within the tumor microenvironment using concentration measurements from blood together with a metabolite diffusion model. In addition, we developed an approach to efficiently apply enzyme usage constraints in a comprehensive metabolic model of human cells. The combined modeling reproduced severe hypoxic conditions and the Warburg effect, and we found that limitations in enzymatic capacity contribute to cancer cells’ preferential use of glutamine as a substrate to the citric acid cycle. Furthermore, we investigated the common hypothesis that some stromal cells are exploited by cancer cells to produce metabolites useful for the cancer cells. We identified over 200 potential metabolites that could support collaboration between cancer cells and cancer associated fibroblasts, but when limiting to metabolites previously identified to participate in such collaboration, no growth advantage was observed. Our work highlights the importance of enzymatic capacity limitations for cell behaviors and exemplifies the utility of enzyme constrained models for accurate prediction of metabolism in cells and tumor microenvironments.
Principled clustering of functional signals reveals gradients in processing both within the anterior hippocampus and across its long axis
Authors: Thorp John N. , Gasser Camille , Blessing Esther , Davachi Lila
Published: February 2022

A particularly elusive puzzle concerning the hippocampus is how the structural differences along its long, anteroposterior axis might beget meaningful functional differences, particularly in terms of the granularity of information processing. One measure posits to quantify this granularity by calculating the average statistical independence of the BOLD signal across neighboring voxels, or inter-voxel similarity (IVS), and has shown the anterior hippocampus to process coarser-grained information than that in the posterior hippocampus. This model of the hippocampus, however, conflicts with a number of task-oriented findings, many of which have varied in their fMRI acquisition parameters and hippocampal parcellation methods. In order to reconcile these findings, we measured IVS across two separate resting-state fMRI acquisitions and compared the results across many of the most widely used parcellation methods in a large young-adult sample (Acquisition 1, N = 253; Acquisition 2, N = 183). Finding conflicting results across acquisitions and parcellations, we reasoned that a principled, data-driven approach to hippocampal parcellation is necessary. To this end, we implemented a group masked independent components analysis (mICA) to identify functional subunits of the hippocampus, most notably separating the anterior hippocampus into separate anterior-medial, anterior-lateral, and posteroanterior-lateral components. Measuring IVS across these components revealed a decrease in IVS along the medial-lateral axis of the anterior hippocampus but an increase from anterior to posterior. We conclude that representational granularity may not change linearly or unidirectionally across the hippocampus, and that moving the study of the hippocampus towards reproducibility requires grounding it in a functionally informed approach.

Significance Statement

Processing information along hierarchical scales of granularity is critical for many of the feats of cognition considered most human. Recently, the changes in structure, cortical connectivity, and apparent functional properties across parcels of the hippocampal long axis have been hypothesized to underlie this hierarchical gradient in information processing. We show here, however, that the choice of parcellation method itself drastically affects the perceived granularity across the hippocampus, and that a principled, functionally informed approach to parcellation reveals gradients both within the anterior hippocampus and in non-linear form across the long axis. These results point to the issue of parcellation as a critical one in the study of the hippocampus and reorient interpretation of existing results.
Unbiased stereological estimates of dopaminergic and GABAergic neurons in the A10, A9, and A8 subregions in the young male Macaque
Authors: Kelly Emily A. , Contreras Jancy , Duan Annie , Vassell Rochelle , Fudge Julie L.
Published: February 2022

The ventral midbrain is the primary source of dopamine- (DA) expressing neurons in most species. GABA-ergic and glutamatergic cell populations are intermixed among DA-expressing cells and purported to regulate both local and long-range dopamine neuron activity. Most work has been conducted in rodent models, however due to evolutionary expansion of the ventral midbrain in primates, the increased size and complexity of DA subpopulations warrants further investigation. Here, we quantified the number of DA neurons, and their GABA-ergic complement in classic DA cell groups A10 (midline ventral tegmental area nuclei [VTA] and parabrachial pigmented nucleus [PBP]), A9 (substantia nigra, pars compacta [SNc]) and A8 (retrorubral field [RRF]) in the macaque. Because the PBP is a disproportionately expanded feature of the A10 group, and has unique connectional features in monkeys, we analyzed A10 data by dividing it into ‘classic’ midline nuclei and the PBP. Unbiased stereology revealed total putative DA neuron counts to be 210,238 +/− 17,127 (A10 = 110,319 +/− 9,649, A9= 87,399 +/−7,751 and A8=12,520 +/− 827). Putative GABAergic neurons were fewer overall, and evenly dispersed across the DA subpopulations (GAD67= 71,215 +/− 5,663; A10=16,836 +/− 2,743; A9=24,855 +/− 3,144 and A8=12,633 +/− 3,557). Calculating the GAD67/TH ratio for each subregion revealed differential balances of these two cell types across the DA subregions. The A8 subregion had the highest complement of GAD67-positive neurons compared to TH-positive neurons (1:1), suggesting a potentially high capacity for GABAergic inhibition of DA output in this region.

HIGHLIGHTS

The A10 subregion expands laterally and caudally in nonhuman primates

The A10, A9, and A8 comprise 52%, 42% and 6% of DA neurons, respectively

GABAergic neurons are more evenly dispersed across subregions

The A8 subpopulation has the highest ratio of GABA: DA neurons
Mutagenesis at non-B DNA motifs in the human genome: a course correction
Authors: McGinty RJ , Sunyaev SR
Published: February 2022

Non-B DNA structures formed by repetitive sequence motifs are known instigators of mutagenesis in experimental systems. Analyzing this phenomenon computationally in the human genome requires careful disentangling of intrinsic confounding factors, including overlapping and interrupted motifs, and recurrent sequencing errors. Accounting for these factors eliminates all signals of repeat-induced mutagenesis that extend beyond the motif boundary, and eliminates or dramatically shrinks the magnitude of mutagenesis within some motifs, contradicting previous reports. Mutagenesis not attributable to artifacts revealed several biological mechanisms. Polymerase slippage generates frequent indels within every variety of short tandem repeat motif, implicating slipped-strand structures. Interruption-correcting SNVs within STRs distinctly implicate error-prone Polκ. Secondary-structure formation promotes SNVs within palindromic repeats, as well as duplications within direct repeats. G-quadruplex motifs cause recurrent sequencing errors, while mutagenesis at Z-DNAs is conspicuously absent.
The cortical N1 response to balance perturbation is associated with balance and cognitive function in different ways between older adults with and without Parkinson’s disease
Authors: Payne Aiden M. , McKay J. Lucas , Ting Lena H.
Published: February 2022

Mechanisms underlying associations between balance and cognitive impairments in older adults with and without Parkinson’s disease are poorly understood. Balance disturbances evoke a cortical N1 response that is associated with both balance and cognitive abilities in unimpaired populations. We hypothesized that the N1 response reflects neural mechanisms that are shared between balance and cognitive function, and would therefore be associated with both balance and cognitive impairments in Parkinson’s disease. Although N1 responses did not differ at the group level, they showed different associations with balance and cognitive function in the Parkinson’s disease vs. control groups. In the control group, higher N1 amplitudes were correlated with lower cognitive set shifting ability and lower balance confidence. However, in Parkinson’s disease, narrower N1 widths (i.e., shorter durations) were associated with greater parkinsonian motor symptom severity, lower balance ability and confidence, lower mobility, and lower overall cognitive function. Despite different relationships across populations, the present results suggest the N1 response reflects neural processes related to both balance and cognitive function. A better understanding of neural mechanisms linking balance and cognitive function could provide insight into associations between balance and cognitive decline in aging populations.
RCFGL: Rapid Condition adaptive Fused Graphical Lasso and application to modeling brain region co-expression networks
Authors: Seal Souvik , Li Qunhua , Basner Elle Butler , Saba Laura M. , Kechris Katerina
Published: February 2022

Inferring gene co-expression networks is a useful process for understanding gene regulation and pathway activity. The networks are usually undirected graphs where genes are represented as nodes and an edge represents a significant co-expression relationship. When gene-expression data from multiple conditions (e.g., treatments, tissues, strains) are available, joint estimation of networks harnessing shared information across them can significantly increase the power of analysis. In addition, examining condition-specific patterns of co-expression can provide insights into the underlying cellular processes activated in a particular condition. Condition adaptive fused graphical lasso (CFGL) is an existing method that incorporates condition specificity in a fused graphical lasso (FGL) model for estimating multiple co-expression networks. However, the current implementation of CFGL is prohibitively slow even for a moderate number of genes and can only be used for a maximum of three conditions. In this paper, we propose a fast alternative of CFGL known as rapid condition adaptive fused graphical lasso (RCFGL). In RCFGL, we incorporate the condition specificity into another popular model for joint network estimation, known as fused multiple graphical lasso (FMGL). We use a more efficient algorithm in the iterative steps compared to CFGL, enabling faster computation and making it easily generalizable for more than three conditions. We also present a novel screening rule to determine if the full network estimation problem can be broken down into estimation of smaller disjoint sub-networks, thereby reducing the complexity further. We demonstrate the computational advantage and superior performance of our method compared to two non-condition adaptive methods, FGL and FMGL, and one condition adaptive method, CFGL in several simulation scenarios. We use RCFGL to jointly estimate the gene co-expression networks of different brain regions (conditions) using a cohort of heterogeneous stock rats. We also provide an accommodatingCandPythonbased package that implements RCFGL.

Author summary

Inferring gene co-expression networks can be useful for understanding pathway activity and gene regulation. While jointly estimating co-expression networks of multiple conditions, taking into account condition specificity such as information about an edge being present only in a specific condition, substantially increases the power. In this paper, a computationally rapid condition adaptive method for jointly estimating gene co-expression networks of multiple conditions is proposed. The novelty of the method is demonstrated through a broad range of simulation studies and a real data analysis with multiple brain regions from a genetically diverse cohort of rats.
Keap1 moderates the transcription of virus induced genes through G9a-GLP and NFкB p50 recruitment, and H3K9me2 deposition
Authors: Burns Veronica Elizabeth , Kerppola Tom Klaus
Published: February 2022

Cells must moderate transcription that is induced by virus infection to mitigate deleterious consequences of inflammation. We investigated the mechanisms whereby Keap1 moderates the transcription of genes that are induced by Sendai virus infection in mouse embryo fibroblasts (MEFs). Virus infection induced Keap1 to bindIfnb1, TnfandIl6, and reduced Keap1 binding atCdkn1aandCcng1. Keap1 was required for G9a and GLP to bind and to deposit H3K9me2 at these genes upon virus infection. Keap1 moderated the transcription of genes that were induced by virus infection in concert with G9a, GLP, and NFкB p50 recruitment. G9a-GLP lysine methyltransferase activity was required for Keap1 to moderate the transcription of virus induced genes. G9a-GLP inhibitors enhanced the transcription of virus induced genes, and they augmented Keap1 and NFкB p50 recruitment, in parallel with the inhibition of H3K9me2 deposition. The interdependent effects of Keap1 and G9a-GLP on transcription and on the recruitment of each other constitute a feedback circuit that moderates the transcription of virus induced genes. G9a-GLP inhibitors augmented Keap1 binding to different genes in virus infected and in uninfected MEFs, whereas they inhibited H3K9me2 deposition that was induced by virus infection selectively. G9a-GLP inhibitors stabilized Keap1 retention in permeabilized MEFs and augmented Keap1 binding to specific genes in parallel. Keap1 was required for NFкB p50 recruitment, and for the augmentation of NFкB binding by G9a-GLP inhibitors. Keap1 and the electrophile tBHQ attenuated virus induced gene transcription through independent mechanisms, and they regulated the recruitment of different NFкB subunits.

Importance

Excess and maladaptive immune responses to virus infections are a major contributing factor to the morbidity and mortality of COVID-19 and other diseases. Conversely, inadequate immune responses to vaccines and pathogens by individuals with suppressed immune function expose them to infections. Currently available drugs that enable therapeutic management of immune responses have low specificity and can blunt beneficial immune functions. The molecular mechanisms that moderate the transcription of genes that are induced by virus infection are incompletely understood. Characterization of the mechanisms whereby Keap1, G9a-GLP and NFкB p50 moderate virus induced gene transcription in mouse embryo fibroblasts represents the first step toward the identification of new targets for therapeutic agents that can modulate immune responsiveness.
Pectobacterium colocasium sp. nov. isolated from taro (Colocasia esculenta)
Authors: Klair Diksha , Arizala Dario , Dobhal Shefali , Boluk Gamze , Alvarez Anne M. , Arif Mohammad
Published: February 2022

Pectobacterium, agenus comprising gram-negative, pectinolytic phytopathogens, is responsible for economic losses in a wide host range of plants. In this study, the bacterial strains PL152T and PL155 were isolated from taro corms in Hawai’i in 2018, and characterized using genomic and biochemical assays. The Next Generation Sequencing technologies, Oxford Nanopore MinION and Illumina NovaSeq, were used for whole genome sequencing of the PL152T strain. Short and long reads were assembled using the Unicycler tool accessible at the bioinformatic resource center, and PATRIC (PathoSystems Resource Integration Center) was used to generate a more accurate and reliable “hybrid” assembly. The 16S rRNA analysis of PL152T with type strains of other known Pectobacterium species showed a close relationship with P. fontis. Multi-locus sequence analysis using nine housekeeping genes (dnaA, gapA, gyrB, recA, dnaN, rpoS, mdh, rpoA and dnaK) differentiated strain PL152T from other species of Pectobacterium and formed a unique and well-defined clade. The concurrent results of average nucleotide identity (ANI) and digital DNA-DNA hybridization, with calculated values lower than 95 and 70%, respectively, supported the delineation of a novel bacterial species. Here, we proposed Pectobacterium colocasium, strain PL152T (=ICMP 24362T; LMG 32536 T) and PL155 as a novel species in the genus Pectobacterium.

1.5

Repositories

CP091064; MZ542535 - MZ542540; OM457660
Evidence for RNA or protein transport from somatic tissues to the male reproductive tract in mouse
Authors: Rinaldi Vera , Messemer Kathleen , Desevin Kathleen , Sun Fengyun , Berry Bethany C. , Kukreja Shweta , Tapper Andrew R. , Wagers Amy J. , Rando Oliver J.
Published: February 2022

The development of tools to manipulate the mouse genome, including knockout and transgenic technology, revolutionized our ability to explore gene function in mammals. Moreover, for genes that are expressed in multiple tissues or at multiple stages of development, the use of tissue-specific expression of the Cre recombinase allows gene function to be perturbed in specific cell types and/or at specific times. However, it is well known that putative tissue-specific promoters often drive unanticipated “off target” expression. In our efforts to explore the biology of the male reproductive tract, we unexpectedly found that expression of Cre in the central nervous system resulted in recombination in the epididymis, a tissue where sperm mature for ~1-2 weeks following the completion of testicular development. Remarkably, we not only observed reporter expression in the epididymis when Cre expression was driven from neuron-specific transgenes, but also when Cre expression in the brain was induced from an AAV vector carrying a Cre expression construct. A surprisingly wide range of Cre drivers – including six different neuronal promoters as well as the adipose-specific AdipoQ Cre promoter – exhibited off target recombination in the epididymis, with a subset of drivers also exhibiting unexpected activity in other tissues such as the reproductive accessory glands. Finally, using a combination of parabiosis and serum transfer experiments, we find evidence supporting the hypothesis that Cre may be trafficked from its cell of origin to the epididymis through the circulatory system. Together, our findings should motivate extreme caution when interpreting conditional alleles, and suggest the exciting possibility of inter-tissue RNA or protein trafficking in modulation of reproductive biology.
Investigating carbohydrate-rich feed supplements and the feeding preferences of European starlings (Sturnus vulgaris)
Authors: Brown Dylan J.
Published: February 2022

In the current ecological and ornithological environment in the continental United States, the European starling (Sturnus vulgaris) is one of the most common exotic bird species. After being introduced on the East Coast of the United States, the species spread rapidly across regions and ecosystems, significantly affecting the greater ecology of the nation and often disturbing local species populations. To better understand the behavior and preferences of this species, a study was devised to test the field responses of a population of European starlings in Lyon County, Kansas over a total period of 144 hours (during 48 individual observation periods) to assess and yield knowledge pertaining to their behavior and feeding patterns within a suburban environment. For this experiment, four feed alternatives (i.e., one control and three experimental) were prepared to test the impact of the utilization of carbohydrate-rich feed supplements on the degree to which the starlings would frequent a feeding location. The different feed offered to the local starlings would consist of either 300g of conventional bird feed, 200g of conventional bird feed and 100g of the supplement, 100g of conventional bird feed and 200g of the supplement, or 300g of the supplement, with the conventional bird seed acting as the control. The data suggest that the differences observed with relation to the feed alternatives were negligible, as demonstrated by the starlings’ preference for the different supplement concentrations (according to their feeding frequency for the four alternatives).