bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single TolC-AcrA complex formation monitored by time dependent single-channel electrophysiology
Authors: Bodrenko Igor V. , Zewdie Tsedenia Alemu , Wang Jiajun , Paul Eshita , Witt Susanne , Winterhalter Mathias 
Published: June 2022

AbstractCharacterizing protein-protein interaction on a single molecular level is a challenge, experimentally as well as the interpretation of the data. For example, Gram-negative bacteria contain protein complexes spanning the outer and inner cell wall being able to efflux effectively cell toxic substances. Within the search for antibiotics with novel modes of action, inhibition of the efflux pump assembly is an interesting possible target. Recent seminal work revealed the high-resolution structure of the tripartic composition TolC-AcrA-AcrB. Here, we reconstitute a single TolC homotrimer into a planar lipid membrane and follow the assembly of AcrA using the modulation of the ion current through TolC during binding. In particular, the presence of AcrA increases the average ionic current through TolC and, moreover, reduces the ion-current fluctuations caused by flickering of TolC. Here, we demonstrate that statistical properties of ion-current fluctuations (the power spectral density) provide a complementary measure of the interaction of the TolC-AcrA complex with potential inhibitors. Both characteristics, the average current and the current noise, taken into consideration together, provide more robust information.
A single-cell atlas of the human brain in Alzheimer’s disease and its implications for personalized drug repositioning
Authors: Pei Guangsheng , Fernandes Brisa S , Wang Yin-Ying , Manuel Astrid M , Jia Peilin , Zhao Zhongming 
Published: June 2022

AbstractAlzheimer’s disease (AD) is a neurodegenerative disease with complex pathophysiology, and AD-dysregulated pathways are inconsistent across different brain regions and patients. Although single-cell RNA sequencing (scRNA-seq) has been performed in different regions of postmortem AD brains, the common and distinct molecular features among different regions remains largely unclear. This hinders the discovery of repurposable and personalized drugs for AD. We combined four scRNA-seq datasets and systematically investigated the common and distinct cellular responses, cell subpopulations, and transcription factors involved in AD. Moreover, we explored the transcriptional heterogeneity of different AD subtypes at the single-cell level. Finally, we conducted individual-based drug repurposing analysis to explore repurposable and personalized drugs. Six major brain cell types were detected after scRNA-seq batch-effect removal and noise cells filtering. Integration with genome-wide association studies (GWAS) summary statistics demonstrated that AD-susceptible genes were mainly enriched with differentially expressed genes (DEGs) in glial cells rather than neuronal cells. While most of DEGs were regulated in opposite directions among different cell types, cell-cell communication analysis revealed several common cellular interaction events involved in neurogenesis, as well as increased cell-cell adhesion. Our comprehensive drug repositioning analysis identified new candidates for AD treatment, including trichostatin, which was predicted to be broadly applicable to different identified AD subtypes, and vorinostat, which was specific for one subtype of AD. In summary, we delineated a cell-specific atlas of the AD transcriptome. Our work illustrated strong cellular heterogeneity in AD for defining AD subtypes. The cell-specific features are important for understanding AD etiology, progression, and drug discovery.
Single Molecule Imaging Simulations with Advanced Fluorophore Photophysics
Authors: Bourgeois Dominique 
Published: June 2022

AbstractAdvanced fluorescence imaging techniques such as single-molecule localization microscopy (SMLM) fundamentally rely on the photophysical behavior of the employed fluorophores. This behavior is generally complex and impacts data quality in a subtle manner. A simulation software named SMIS (Single-Molecule Imaging Simulator) is introduced that simulates a widefield microscope and incorporates fluorophores with their spectral and photophysical properties. With SMIS, data collection schemes combining 3D, multicolor, single-particle-tracking or quantitative SMLM can be implemented. The influence of advanced fluorophore characteristics, imaging conditions and environmental parameters can be evaluated, facilitating the design of real experiments and their proper interpretation.
PARG establishes a functional module with BRCA1-BARD1 that controls DNA repair pathway choice during gametogenesis
Authors: Trivedi Shalini , Blazicková Jitka , Silva Nicola 
Published: June 2022

ABSTRACTDuring meiosis, accurate chromosome segregation relies on the formation of programmed DNA double-strand breaks (DSBs). These are in turn repaired by homologous recombination (HR), generating physical attachments between the parental chromosomes called crossovers (COs). Fewer breaks yield recombinant outcomes, while CO-independent mechanisms are employed for repairing the majority of lesions. The balance between different repair pathways is crucial to ensure genome fidelity and to preserve its integrity. We show that Caenorhabditis elegans BRC-1/BRCA1-BRD-1/BARD1 and PARG-1/PARG form a complex in vivo, that is essential for accurate DNA repair in the germline. Contemporary depletion of BRC-1 and PARG-1 causes synthetic lethality due to reduced CO formation and impaired DSB repair, as evidenced by hindered RPA-1 removal and presence of aberrant chromatin bodies in diakinesis nuclei, whose formation depends on spo-11 function. These factors largely co-localize and undergo independent loading in developing oocytes, consistent with operating in different pathways. Abrogation of KU- or Theta-mediated end joining elicits opposite effects in brc-1; parg-1 doubles, highlighting differential involvement of DNA repair pathways and suggesting a profound impact in influencing DNA repair pathway choice by BRC-1-PARG-1. Importantly, lack of PARG-1 catalytic activity suppresses untimely accumulation of RAD-51 foci in brc-1 mutants but is only partially required to maintain fertility. Altogether, our data show that BRC-1/BRD-1-PARG-1 joined function is essential to keep genome integrity in meiotic cells by regulating multiple DNA repair pathways.
Hamilton’s rule, the evolution of behavior rules and the wizardry of control theory
Authors: Lehmann Laurent 
Published: June 2022

AbstractThis paper formalizes selection on a quantitative trait affecting the evolution of behavior (or development) rules through which individuals act and react with their surroundings. Combining Hamilton’s marginal rule for selection on scalar traits and concepts from optimal control theory, a necessary first-order condition for the evolutionary stability of the trait in a group-structured population is derived. The model, which is of intermediate level of complexity, fills a gap between the formalization of selection on evolving traits that are directly conceived as actions (no phenotypic plasticity) and selection on evolving traits that are conceived as strategies or function valued actions (complete phenotypic plasticity). By conceptualizing individuals as open deterministic dynamical systems expressing incomplete phenotypic plasticity, the model captures selection on a large class of phenotypic expression mechanisms, including developmental pathways and learning under life-history trade-offs. As an illustration of the results, a first-order condition for the evolutionary stability of behavior response rules from the social evolution literature is re-derived, strengthened, and generalized. All results of the paper also generalize directly to selection on multidimensional quantitative traits affecting behavior rule evolution, thereby covering neural and gene network evolution.
Early-Life Stress Impairs Perception and Neural Encoding of Rapid Signals in the Auditory Pathway
Authors: Ye Yi , Mattingly Michelle M. , Sunthimer Matthew J. , Gay Jennifer D. , Rosen Merri J. 
Published: June 2022

AbstractIn children, early ear infections are a risk factor for later speech perception deficits. This is likely because auditory deprivation during a developmental critical period (CP) induces long-lasting deficits in perception and ACx encoding of temporally-varying sounds. CPs also create susceptibility to early-life stress (ELS) in neural regions involved with cognition and anxiety. As CP mechanisms are shared by sensory cortices and higher neural regions, ACx and temporal encoding may also be susceptible to ELS. To examine the effects of ELS on temporal processing, we developed a model of ELS in the Mongolian gerbil, a well-established model for auditory processing. ELS induction impaired the behavioral detection of short gaps in sound, which are critical for speech perception. This was accompanied by reduced neural responses to gaps in ACx, the auditory periphery, and auditory brainstem. These ELS effects presumably degrade the fidelity of sensory representations available to higher regions, and could contribute to ELS-induced problems with cognition.
Distinct hippocampal and cortical contributions in the representation of hierarchies
Authors: Scholz Robert , Villringer Arno , Martins Mauricio J.D. 
Published: June 2022

SummaryHumans generate complex hierarchies across a variety of domains, including language and music, and this capacity is often associated with activity in inferior frontal gyrus (IFG). Non-human animals have also been shown to represent simple hierarchies in spatial navigation, and human neuroimaging work has implicated the hippocampus in the encoding of items-in-contexts representations, which constitute 2-level hierarchical dependencies. These fields of research use distinct paradigms, leading to disjoint models and precluding adequate cross-species comparisons. In this study, we developed a paradigm to bring together these two areas of research and show that anterior hippocampus and medial prefrontal cortex encode hierarchical context, mimicking findings from animal spatial navigation. Additionally, we replicated classic neurolinguistic findings of 1) left IFG and posterior temporal cortex in the representation of hierarchies and 2) the association between IFG and processing automaticity. We propose that mammals share an evolutionary ancient system for the generation of simple hierarchies which is complemented in humans by additional capacities.HighlightsHPC and mPFC activity is specifically modulated by hierarchical contextSyntax-related regions in the left hemisphere encode for hierarchy in generalIFGop activity is maintained in later trials for hierarchies but not sequencesThese findings mimic those from animal spatial navigation and neurolinguistics
Quantifying oligomer populations in real time during protein aggregation using single-molecule mass photometry
Authors: Paul Simanta Sarani , Lyons Aaron , Kirchner Russell , Woodside Michael T. 
Published: June 2022

ABSTRACTProtein aggregation is a hallmark of many neurodegenerative diseases. The early stages of the aggregation cascade are crucial because small oligomers are thought to be key neurotoxic species, but they are difficult to study because they feature heterogeneous mixtures of transient states. We show how the populations of different oligomers can be tracked as they evolve over time during aggregation by using single-molecule mass photometry to measure individually the masses of the oligomers present in solution. Applying the approach to tau protein, whose aggregates are linked to diseases including Alzheimer’s and frontotemporal dementia, we found that tau existed in an equilibrium between monomers, dimers, and trimers before aggregation was triggered. Once aggregation commenced, the monomer population dropped continuously, paired first with a rise in the population of the smallest oligomers and then a steep drop as the protein was incorporated into larger oligomers and fibrils. Fitting these populations to kinetic models allowed different models of aggregation to be tested, identifying the most likely mechanism and quantifying the microscopic rates for each step in the mechanism. This work demonstrates a powerful new approach for characterizing previously inaccessible regimes in protein aggregation and building quantitative mechanistic models.
Multi-omics alleviates the limitations of panel-sequencing for cancer drug response prediction
Authors: Baranovskii Artem , Gunduz Irem B. , Franke Vedran , Uyar Bora , Akalin Altuna 
Published: June 2022

AbstractComprehensive genomic profiling using cancer gene panels has been shown to improve treatment options for a variety of cancer types. However, genomic aberrations detected via such gene panels don’t necessarily serve as strong predictors of drug sensitivity. In this study, using pharmacogenomics datasets of cell lines, patient-derived xenografts, and ex-vivo treated fresh tumor specimens, we demonstrate that utilizing the transcriptome on top of gene panel features substantially improves drug response prediction performance in cancer.
Integrated Proteomics Identifies Neuritin (NRN1) as a Mediator of Cognitive Resilience to Alzheimer’s Disease
Authors: Hurst Cheyenne , Pugh Derian A. , Abreha Measho H. , Duong Duc M. , Dammer Eric B. , Bennett David A. , Herskowitz Jeremy H. , Seyfried Nicholas T. 
Published: June 2022

AbstractWe present an integrative proteomic strategy for the nomination and validation of proteins associated with cognitive resilience to Alzheimer’s disease (AD). Correlation network analysis across distinct stages of AD was used to prioritize protein modules linked to resilience. Neuritin (NRN1), a hub protein in a module associated with synaptic biology, was identified as a top candidate of resilience and selected for functional validation in cultured neurons. NRN1 provided dendritic spine resilience against amyloid-β (Aβ), and NRN1 blocked Aβ-induced neuronal hyperexcitability. The impact of exogenous NRN1 on the proteome of cultured neurons was assessed and integrated with the AD brain network. This revealed over-lapping synapse-related biology that linked NRN1-induced changes in cultured neurons with human pathways associated with AD resilience. Collectively, this highlights the utility of integrating the proteome from human brain and model systems to prioritize therapeutic targets that mediate resilience to AD.
CITED2 is a Conserved Regulator of the Uterine-Placental Interface
Authors: Kuna Marija , Dhakal Pramod , Iqbal Khursheed , Dominguez Esteban M. , Kent Lindsey N. , Muto Masanaga , Moreno-Irusta Ayelen , Kozai Keisuke , Varberg Kaela M. , Okae Hiroaki , Arima Takahiro , Sucov Henry M. , Soares Michael J. 
Published: June 2022

AbstractEstablishment of the hemochorial uterine-placental interface requires exodus of trophoblast cells from the placenta and their transformative actions on the uterus, which represent processes critical for a successful pregnancy, but are poorly understood. We examined the involvement of CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl terminal domain 2 (CITED2) in rat and human trophoblast cell development. The rat and human exhibit deep hemochorial placentation. CITED2 was distinctively expressed in the junctional zone and invasive trophoblast cells of the rat. HomozygousCited2gene deletion resulted in placental and fetal growth restriction. SmallCited2null placentas were characterized by disruptions in the junctional zone, delays in intrauterine trophoblast cell invasion, and compromised plasticity. In the human placentation site, CITED2 was uniquely expressed in the extravillous trophoblast (EVT) cell column and importantly contributed to development of the EVT cell lineage. We conclude that CITED2 is a conserved regulator of deep hemochorial placentation.Significance StatementThe process of establishing the uterine-placental interface is a poorly understood tissue re-engineering event that involves genetically foreign trophoblast cells breaching the immunologically secure uterus. When optimal, mother and fetus thrive, whereas failures represent the root cause of life-threatening diseases of pregnancy. CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl terminal domain 2 (CITED2) is a transcriptional co-regulator with a conspicuous presence in trophoblast cell lineages infiltrating the uterine parenchyma. CITED2 helps coordinate the differentiation of rat and human trophoblast cells into invasive/extravillous trophoblast cells capable of transforming the uterus. These actions ensure requisite placental development and adaptations to physiological stressors. CITED2 exemplifies a conserved regulator of transcriptional events essential for establishing the uterine-placental interface.
cAMP−EPAC−PKCε−RIM1α signaling regulates presynaptic long-term potentiation and motor learning
Authors: Wang Xin-Tai , Zhou Lin , Xu Fang-Xiao , Wang De-Juan , Cai Xin-Yu , Wang Yin , Ji Sheng-Jian , Schonewille Martijn , Zhu J. Julius , De Zeeuw Chris I. , Shen Ying 
Published: June 2022

AbstractThe cerebellum is involved in learning of fine motor skills, yet whether presynaptic plasticity contributes to such learning remains elusive. Here we report that the EPAC-PKCε module has a critical role in a presynaptic form of long-term potentiation in the cerebellum and motor behavior. Presynaptic cAMP−EPAC−PKCε signaling cascade induces a previously unidentified threonine phosphorylation of RIM1α, and thereby initiates the assembly of the Rab3A−RIM1α−Munc13-1 tripartite complex that facilitates docking and release of synaptic vesicles. Granule cell-specific blocking of EPAC−PKCε signaling abolishes presynaptic long-term potentiation at the parallel fiber to Purkinje cell synapses and impairs basic performance and learning of cerebellar motor behavior. These results unveil a functional relevance of presynaptic plasticity that is regulated through a novel signaling cascade, thereby enriching the spectrum of cerebellar learning mechanisms.
Glutamatergic neuron types in the amygdala of the urodele amphibian Pleurodeles waltl
Authors: Deryckere Astrid , Woych Jamie , Jaeger Eliza C. B. , Tosches Maria Antonietta 
Published: June 2022

AbstractThe amygdala is a complex brain structure in the vertebrate telencephalon, essential for regulating social behaviors, emotions and (social) cognition. In contrast to the vast majority of neuron types described in the many nuclei of the mammalian amygdala, little is known about the neuronal diversity in non-mammals, making reconstruction of its evolution particularly difficult. Here, we characterize glutamatergic neuron types in the amygdala of the salamander Pleurodeles waltl. Our single-cell RNA sequencing data indicate the existence of at least ten distinct types and subtypes of glutamatergic neurons in the salamander amygdala. In situ hybridization for marker genes indicates that these neuron types are located in three major subdivisions: the lateral amygdala, the medial amygdala, and a newly-defined area demarcated by high expression of the transcription factor Sim1. The gene expression profiles of these neuron types suggest similarities with specific neuron types in the sauropsid and mammalian amygdala, and in particular the evolutionary conservation of Sim1-expressing amygdalar neurons in tetrapods. Taken together, our results reveal a surprising diversity of glutamatergic neuron types in the amygdala of salamanders, despite the anatomical simplicity of their brain.
Source to sink partitioning is altered by the expression of the transcription factor AtHB5
Authors: Raminger L , Miguel VN , Zapata C. , Chan RL , Cabello JV 
Published: June 2022

AbstractCarbohydrates are transported from source to sink tissues. The efficiency of such transport determines plant growth and development. The process is finely regulated, and transcription factors are crucial in such modulation. AtHB5 is a homeodomain-leucine zipper I transcription factor, repressed during stem secondary growth. However, its function in this developmental event was unknown. Here, we investigated the expression pattern and role of AtHB5. AtHB5 localized in conductive tissues: roots, hypocotyls, stems, pedicels, and central leaf veins. Mutant plants exhibited wider and more lignified stems than controls, whereas overexpressors showed the opposite phenotype. Cross-sections of athb5 mutant stems showed enlarged vascular bundle, xylem, phloem, and petiole areas, whereas AtHB5 overexpressors exhibited callose deposits. Several genes involved in starch biosynthesis and degradation had altered transcript levels in athb5 mutants and AtHB5 overexpressors. Rosette and stem biomasses were enhanced in athb5 mutants, positively impacting seed yield and lipid content. Moreover, these effects were more evident in debranched plants. Finally, the transport to roots significantly slowed down in AtHB5 overexpressors.Altogether, the results indicated that AtHB5 is a negative modulator of sucrose transport from source to sink tissues, and its overexpression diminished plant biomass and seed yield.HighlightThe homeodomain-leucine zipper transcription factor AtHB5 is expressed in different tissues along the life cycle, repressing carbohydrate transport from source to sink and promoting callose and lignin deposition. AtHB5 mutants exhibit physiological differences with the wild-type, impacting seed yield and lipid content.
Sex-specific age-related changes in excitatory and inhibitory intra-cortical circuits in mouse primary auditory cortex
Authors: Xue Binghan , Kao Joseph P-Y , Kanold Patrick O. 
Published: June 2022

AbstractA common impairment in aging is age-related hearing loss (presbycusis), which manifests as impaired spectrotemporal processing. Aging is accompanied by alteration in normal inhibitory (GABA) neurotransmission and changes in excitatory (NMDA and AMPA) synapses in the auditory cortex (ACtx). However, the circuit mechanisms responsible for age-related auditory dysfunction remain unknown. Here we investigated how auditory cortical microcircuits change with age. We performed laser-scanning photostimulation (LSPS) combined with whole-cell patch clamp recordings from Layer (L) 2/3 cells in primary auditory cortex (A1) in young adult (postnatal day (P) 47-P72) and aged (P543 to P626) male and female CBA/CaJ mice. We found that L2/3 cells in aged male animals display functional hypoconnectivity of both excitatory and inhibitory circuits originating from L4. Compared to cells from young adult mice, cells from aged male mice have fewer inhibitory connections from L4 while female mice show weaker connection strength. These results suggest a sex-specific reduction in excitatory and inhibitory intralaminar cortical circuits in aged mice compared with young adult animals. We speculate that these unbalanced changes in cortical circuits contribute to the functional manifestations of age-related hearing loss in both males and females.