bluuebunny/crossref_metadata_2025_split huggingface dataset:
On the demographic history of chimpanzees and some consequences of integrating population structure in chimpanzees and other great apes
Authors: Steux Camille , Couloigner Clément , Arredondo Armando , Rodríguez Willy , Mazet Olivier , Tournebize Rémi , Chikhi Lounès 
Published: June 2024

AbstractReconstructing the evolutionary history of great apes is of particular importance for our understanding of the demographic history of humans. The reason for this is that modern humans and their hominin ancestors evolved in Africa and thus shared the continent with the ancestors of chimpanzees and gorillas. Common chimpanzees (Pan troglodytes) are our closest relatives with bonobos (Pan paniscus) and most of what we know about their evolutionary history comes from genetic and genomic studies. Most evolutionary studies of common chimpanzees have assumed that the four currently recognised subspecies can be modelled using simple tree models where each subspecies is panmictic and represented by one branch of the evolutionary tree. However, several studies have identified the existence of significant population structure, both within and between subspecies, with evidence of isolation-by-distance (IBD) patterns. This suggests that demographic models integrating population structure may be necessary to improve our understanding of their evolutionary history. Here we propose to usen-island models within each subspecies to infer a demographic history integrating population structure and changes in connectivity (i.e.gene flow). For each subspecies, we use SNIF (structured non-stationary inference framework), a method developed to infer a piecewise stationaryn-island model using PSMC (pairwise sequentially Markovian coalescent) curves as summary statistics. We then propose a general model integrating the four subspecies metapopulations within a phylogenetic tree. We find that this model correctly predicts estimates of within subspecies genetic diversity and differentiation, but overestimates genetic differentiation between subspecies as a consequence of the tree structure. We argue that spatial models integrating gene flow between subspecies should improve the prediction of between subspecies differentiation and IBD patterns. We also use a simple spatially structured model for bonobos and chimpanzees (without admixture) and find that it explains signals of admixture between the two species that have been reported and could thus be spurious. This may have implications for our understanding of the evolutionary history of theHomogenus.
Marcks and Marcks-like 1 proteins promote spinal cord development and regeneration inXenopus
Authors: El Amri Mohamed , Pandit Abhay , Schlosser Gerhard 
Published: June 2024

AbstractMarcks and Marcksl1 are abundant proteins that shuttle between the cytoplasm and membrane to modulate multiple cellular processes, including cytoskeletal dynamics, proliferation, and secretion. Here, we performed loss- and gain-of-function experiments inXenopus laevisto reveal the novel roles of these proteins in spinal cord development and regeneration. We show that Marcks and Marcksl1 have partly redundant functions and are required for normal neurite outgrowth and proliferation of neuro-glial progenitors during embryonic spinal cord development and for its regeneration during tadpole stages. Rescue experiments in Marcks and Marcksl1 knockout animals further suggested that some of the functions of Marcks and Marcksl1 in the spinal cord are mediated by phospholipase D (PLD) signaling. Taken together, these findings identify Marcks and Marcksl1 as critical new players in spinal cord development and regeneration and suggest new pathways to be targeted for therapeutic stimulation of spinal cord regeneration in human patients.
Ultrastructural sublaminar-specific diversity of excitatory synaptic boutons in layer 1 of the adult human temporal lobe neocortex
Authors: Rollenhagen Astrid , Sadeghi Akram , Walkenfort Bernd , Hilgetag Claus C. , Sätzler Kurt , Lübke Joachim HR 
Published: June 2024

AbstractLayer (L)1, beside receiving massive cortico-cortical, commissural and associational projections, is the termination zone of tufted dendrites of pyramidal neurons and the area of Ca2+spike initiation. However, its synaptic organization in humans is not known. Quantitative 3D-models of synaptic boutons (SBs) in L1 of the human temporal lobe neocortex were generated from non-epileptic neocortical biopsy tissue using transmission electron microscopy, 3D-volume reconstructions and TEM tomography. Particularly, the size of active zones (AZs) and the readily releasable, recycling and resting pool of synaptic vesicles (SVs) were quantified.The majority of SBs contained numerous mitochondria comprising ∼7% of the total volume of SBs, had a large macular, non-perforated AZs (∼0.20 µm2) and were predominantly located on dendritic spines. SBs had a total pool of ∼3500 SVs, a comparably large readily releasable (∼4 SVs), recycling (∼470 SVs) and resting (∼2900 SVs) pool. Astrocytic coverage of SBs suggests both synaptic cross talk or removal of spilled glutamate by astrocytic processes at synaptic complexes.The structural composition of SBs in L1 may underlie the function of L1 networks that mediate, integrate and synchronize contextual and cross-modal information, enabling flexible and state-dependent processing of feedforward sensory inputs from other layers of the cortical column.
The effects of 17α-estradiol treatment on endocrine system revealed by single-nucleus transcriptomic sequencing of hypothalamus
Authors: Li Lei , Wu Guanghao , Xu Xiaolei , Yang Junling , Yi Lirong , Yang Ziqing , Mo Zheng , Xing Li , Shan Ying , Yu Zhuo , Li Yinchuan 
Published: June 2024

AbstractIn this study, we investigated the role of 17α-estradiol in lifespan extension and its potential side effects from long-term administration. Pooled hypothalami from aged male Norway brown rats treated with 17α-estradiol (O.T), aged male controls (O), and young male controls (Y) were subjected to single-nucleus transcriptomic sequencing (snRNA-seq). To evaluate the effects of 17α-estradiol on aging neurons, supervised clustering of neurons based on neuropeptides and their receptors were used to evaluate the responses of each neuron subtype during aging and after 17α-estradiol treatment. The elevated cellular metabolism, stress and decreased expression levels of pathways involved in synapse formation in neurons initiated by aging were significantly attenuated by 17α-estradiol. Assessment of changes in neuron populations showed that neurons related to food intake, reproduction, blood pressure, stress response, and electrolyte balance were sensitive to 17α-estradiol treatment. 17α-estradiol treatment not only increased serum Oxytocin (Oxt), but also heightened the activity of hypothalamic-pituitary-gonadal (HPG) axis, as evidenced by significantly elevated levels of plasma Gnrh, total testosterone, and decreased estradiol. Elevated Gnrh1 was confirmed to be one of the causal effects mediating the role of 17α-estradiol in energy homeostasis, neural synapse, and stress response. Notably,Crhneurons exhibited prominent stressed phenotype among all the checked neuron subtypes in O.T, which may indicate a potential side effect of 17α-estradiol treatment. Therefore, the HPG axis and energy metabolism may be key targets of 17α-estradiol in male hypothalamus. Additionally, supervised clustering of neurons was shown to be a useful method for assessing treatment responses among different neuron subtypes in the hypothalamus.
Cell- and state-specific plasticity of striatal glutamatergic synapses is critical to the expression of levodopa-induced dyskinesia
Authors: Shen Weixing , Zhai Shenyu , Francardo Veronica , Cui Qiaoling , Xie Zhong , Tkatch Tatiana , Cenci M. Angela , Surmeier D. James 
Published: June 2024

AbstractLevodopa-induced dyskinesia (LID) is a debilitating complication of symptomatic therapy in Parkinson’s disease (PD). Although there is compelling evidence that striatal pathophysiology is a major driver of LID, the circuit-specific mechanisms contributing to dysfunction remain obscure. This lack of clarity is reflected in the limited options for diminishing established LID. To address this gap, molecular, cellular, and behavioral strategies were used to interrogate striatal indirect pathway spiny projection neurons (iSPNs) in a mouse model of LID. These studies revealed that LID induction led to an up-regulation of GluN2B-containing N-methyl-d-aspartate receptors (NMDARs) specifically at iSPN glutamatergic synapses. This up-regulation was correlated with increased numbers of ‘silent’ glutamatergic synapses in the hours after levodopa treatment. In this ‘off-state’, long-term potentiation (LTP) of iSPN glutamatergic synapses was readily induced and this induction was blocked by antagonists of adenosine type 2 receptors (A2aRs) or GluN2B-containing NMDARs. Systemic administration of the A2aR antagonist tozedenant at the beginning of the off-state significantly reduced the development of LID. More importantly, specifically knocking down the expression ofGRIN2BmRNA in iSPNs dramatically attenuated both development and expression of LID, without compromising the beneficial effects of levodopa on movement. Taken together, these studies demonstrate that dyskinesiogenic doses of levodopa trigger cell-specific synaptic adaptations during the off-state that make an important contribution to the network pathophysiology underlying LID and suggest that targeting GluN2B-containing NMDARs in iSPNs could be therapeutically useful.
Differential effects of diphenyl diselenide (PhSe)2on mitochondria-related pathways depending on the cellular energy status in Bovine Vascular Endothelial Cells
Authors: Galant Letícia Selinger , Doblado Laura , Radi Rafael , da Rocha João Batista Teixeira , de Bem Andreza Fabro , Monsalve Maria 
Published: June 2024

AbstractCellular energy metabolism varies depending on tissue and cell type, as well as the availability of energy substrates and energy demands. We recently investigated the variations in cellular metabolism and antioxidant responses in primary bovine vascular endothelial cells (BAECs) under different energetic substrate conditions in vitro, specifically glucose or galactose. In this context, pharmacological agents may exert different effects on cells depending on their energy metabolism status. In this study, we aimed to characterize the effects of (PhSe)2, a redox-active molecule known for its prominent cardiovascular effects, on redox-bioenergetic cellular pathways under glycolytic or oxidative conditions in BAECs. Under glucose conditions, (PhSe)2positively impacted mitochondrial oxidative capacity, as assessed by respirometry, and was associated with changes in mitochondrial cellular dynamics. However, these changes were not observed in cells cultured with galactose. Although (PhSe)2induced the nuclear translocation of NRF2 in both glucose and galactose media, NRF2 remained in the nuclei of cells cultured in galactose for a longer duration. Additionally, activation of FOXO3a was only detected in galactose media. Notably, (PhSe)2strongly induced the expression of genes controlling mitochondrial antioxidant capacity and glutathione synthesis and recycling in glucose media, whereas its effects in galactose media were primarily focused on glutathione homeostasis. In conclusion, our findings underscore the critical influence of cellular metabolic status on the antioxidant capacity of redox-active molecules such as (PhSe)2.
A higher order PUF complex is central to regulation of
C. elegans
germline stem cells
Authors: Qiu Chen , Crittenden Sarah L. , Carrick Brian H. , Dillard Lucas B. , Costa Dos Santos Stephany J. , Dandey Venkata P. , Dutcher Robert C. , Viverette Elizabeth G. , Wine Robert N. , Woodworth Jennifer , Campbell Zachary T. , Wickens Marvin , Borgnia Mario J. , Kimble Judith , Tanaka Hall Traci M. 
Published: June 2024

Abstract

PUF RNA-binding proteins are broadly conserved stem cell regulators. Nematode PUF proteins maintain germline stem cells (GSCs) and, with key partner proteins, repress differentiation mRNAs, including
gld-1
. Here we report that PUF protein FBF-2 and its partner LST-1 form a ternary complex that represses
gld-1
via a pair of adjacent FBF-2 binding elements (FBEs) in its 3’UTR. One LST-1 molecule links two FBF-2 molecules via motifs in the LST-1 intrinsically-disordered region; the
gld-1
FBE pair includes a well-established ‘canonical’ FBE and a newly-identified noncanonical FBE. Remarkably, this FBE pair drives both full RNA repression in GSCs and full RNA activation upon differentiation. Discovery of the LST-1–FBF-2 ternary complex, the
gld-1
adjacent FBEs, and their
in vivo
significance predicts an expanded regulatory repertoire of different assemblies of PUF-partner complexes in nematode germline stem cells. It also suggests analogous PUF controls may await discovery in other biological contexts and organisms.
Iterative deep learning-design of human enhancers exploits condensed sequence grammar to achieve cell type-specificity
Authors: Yin Christopher , Hair Sebastian Castillo , Byeon Gun Woo , Bromley Peter , Meuleman Wouter , Seelig Georg 
Published: June 2024

SummaryAn important and largely unsolved problem in synthetic biology is how to target gene expression to specific cell types. Here, we apply iterative deep learning to design synthetic enhancers with strong differential activity between two human cell lines. We initially train models on published datasets of enhancer activity and chromatin accessibility and use them to guide the design of synthetic enhancers that maximize predicted specificity. We experimentally validate these sequences, use the measurements to re-optimize the predictor, and design a second generation of enhancers with improved specificity. Our design methods embed relevant transcription factor binding site (TFBS) motifs with higher frequencies than comparable endogenous enhancers while using a more selective motif vocabulary, and we show that enhancer activity is correlated with transcription factor expression at the single cell level. Finally, we characterize causal features of top enhancers via perturbation experiments and show enhancers as short as 50bp can maintain specificity.
Improvement of the potency of a N1-methylpseudouridine-modified self-amplifying RNA through mutations in the RNA-dependent-RNA-polymerase
Authors: Quintana Verónica , Caillava Josefina , Byk Laura A. , Mondotte Juan A. , Battini Leandro , Tarte Prutha , Samsa Marcelo M. , Filomatori Claudia V. , Alvarez Diego E. 
Published: June 2024

ABSTRACTRNA vaccines are sensed as non-self molecules by the innate immune system, and balancing control of the immune activation and vaccine safety and efficacy has remained a challenge, especially for self-amplifying RNAs (saRNAs). Incorporation of modified nucleotides has been widely used to temper immune activation of RNA vaccines. However, it was previously reported that incorporation of modified nucleotides to saRNAs impeded antigen expression. Here, we used a reporter replicon of the attenuated TC-83 strain of Venezuelan equine encephalitis virus (VEEV) to investigate the impact of modified nucleotide incorporation on the replication capacity of the saRNA in transfected cells. ψ and ψ-modified molecules showed a profound defect in RNA synthesis compared to unmodified saRNA. Interestingly, the levels of RNA synthesis of m5C-modified RNAs were similar to unmodified molecules, positioning m5C as a promising candidate for saRNA modification. To overcome the impact of ψ or m1ψ-modified nucleotide incorporation in RNA synthesis, we explored two alternative approaches: engineering the UTR sequences and tuning polymerase fidelity. Our results uncover a previously unappreciated link between polymerase fidelity and saRNA amplification. Overall, we provide new insights for the design of saRNAs with high levels of heterologous protein expression and potential vaccine applications.
Addition of Soil Protists Enhances Performance of Agrochemical Seed Treatments
Authors: Hawxhurst Christopher J. , McClure Travis , Kirk Daniel , Shor Mikhael , Gage Daniel J. , Shor Leslie M. 
Published: June 2024

AbstractChemicals are an integral part of modern agriculture, and are applied through a variety of methods. Some agrochemicals applied for crop protection function by absorption through the root before translocation to the rest of the plant. To be absorbed by the root, the agrochemical must first be transported through the soil, often by water. Some agrochemicals suffer from poor water-based soil transmission due to their chemical properties, limiting their application as a traditional seed treatment. Two such agrochemicals are chlorantraniliprole and spinosad. Soil protists are an important component of the soil microbial community. Certain soil protists have been previously shown to facilitate transport and targeted delivery of suspended particles and cells through soil and microfluidic devices. We provide practical evidence that a soil protist,Colpoda sp., when co-inoculated with an agrochemical seed treatment, can substantially and robustly reduce subsequent pest feeding damage compared with the agrochemical alone. Using maize (Zea maysL.) and fall armyworm,Spodoptera frugiperda(J. E. Smith, 1797) (Lepidoptera: Noctuidae), in a plant damage assay, we directly compare pest feeding damage and mortality in plants that received no additional treatment, only protists, only agrochemical, and co-inoculation of agrochemical with protists. We discover for both agrochemicals tested, the co-inoculation of protists with the agrochemical increases protection in leaves when the efficacy of the agrochemical alone declines. Protist amendment is a simple, natural, inexpensive, chemical-free, soil-based transport enhancer that thus may be widely useful in a variety of contexts including more sustainable and cost-effective integrated pest management.ImportancePest resistance, regulatory pressure, and environmental concerns are limiting many classes of pesticides which can be effectively used to protect valuable crops from pests. Other classes of pesticides, however, are limited by physical characteristics – water solubility or octane-water partition coefficient (KOW) fall outside the limit for an effective seed coating, or the per-unit cost is high enough to discourage broad application. Here, we provide data which supports the co-inoculation of a high value, low solubility, high KOWpesticides with a naturally-occurring soil protist as a seed treatment can enhance crop protection relative to the pesticide alone. This co-formulation reduced feeding damage by up to 30% compared with the pesticide alone. Co-inoculation of crop-protecting agrochemicals with natural soil protists may be employed as a more sustainable agriculture biotechnology, enabling the use of classes of agrochemicals which may not otherwise show sufficient performance for use as a seed treatment.
A BTB extension and ion-binding domain contribute to the pentameric structure and TFAP2A binding of KCTD1
Authors: Pinkas Daniel M. , Bufton Joshua C. , Hunt Alice E. , Manning Charlotte E. , Richardson William , Bullock Alex N. 
Published: June 2024

SUMMARYKCTD family proteins typically assemble into Cullin-RING E3 ligases. KCTD1 is an atypical member that functions instead as a transcriptional repressor. Mutations in KCTD1 cause developmental abnormalities and kidney fibrosis in scalp-ear-nipple syndrome. Here, we present unexpected mechanistic insights from the structure of full-length KCTD1. Disease-causing mutation P20S maps to an unrecognized extension of the BTB domain that contributes both to its pentameric structure and TFAP2A binding. The C-terminal domain (CTD) shares its fold and pentameric assembly with the protein GFRP despite lacking discernible sequence similarity. Most surprisingly, the KCTD1 CTD establishes a central channel occupied by alternating sodium and iodide ions that restrict TFAP2A dissociation. The elucidation of the structure redefines the KCTD family BTB domain fold and identifies an unexpected ion pore for future study of KCTD1’s function in the ectoderm, neural crest and kidney.
Long-read RNA-seq demarcatescis- andtrans-directed alternative RNA splicing
Authors: Quinones-Valdez Giovanni , Amoah Kofi , Xiao Xinshu 
Published: June 2024

AbstractGenetic regulation of alternative splicing constitutes an important link between genetic variation and disease. Nonetheless, RNA splicing is regulated by bothcis-acting elements andtrans-acting splicing factors. Determining splicing events that are directed primarily by thecis- ortrans-acting mechanisms will greatly inform our understanding of the genetic basis of disease. Here, we show that long-read RNA-seq, combined with our new method isoLASER, enables a clear segregation ofcis- andtrans-directed splicing events for individual samples. The genetic linkage of splicing is largely individual-specific, in stark contrast to the tissue-specific pattern of splicing profiles. Analysis of long-read RNA-seq data from human and mouse revealed thousands ofcis-directed splicing events susceptible to genetic regulation. We highlight such events in the HLA genes whose analysis was challenging with short-read data. We also highlight novelcis-directed splicing events in Alzheimer’s disease-relevant genes such asMAPTandBIN1. Together, the clear demarcation ofcis- andtrans-directed splicing paves ways for future studies of the genetic basis of disease.
A Path Integral Approach for Allele Frequency Dynamics Under Polygenic Selection
Authors: Anderson Nathan W. , Kirk Lloyd , Schraiber Joshua G. , Ragsdale Aaron P. 
Published: June 2024

AbstractMany phenotypic traits have a polygenic genetic basis, making it challenging to learn their genetic architectures and predict individual phenotypes. One promising avenue to resolve the genetic basis of complex traits is through evolve-and-resequence experiments, in which laboratory populations are exposed to some selective pressure and trait-contributing loci are identified by extreme frequency changes over the course of the experiment. However, small laboratory populations will experience substantial random genetic drift, and it is difficult to determine whether selection played a roll in a given allele frequency change. Predicting how much allele frequencies change under drift and selection had remained an open problem well into the 21stcentury, even those contributing to simple, monogenic traits. Recently, there have been efforts to apply the path integral, a method borrowed from physics, to solve this problem. So far, this approach has been limited to genic selection, and is therefore inadequate to capture the complexity of quantitative, highly polygenic traits that are commonly studied. Here we extend one of these path integral methods, the perturbation approximation, to selection scenarios that are of interest to quantitative genetics. In particular, we derive analytic expressions for the transition probability (i.e., the probability that an allele will change in frequency fromx, toyin timet) of an allele contributing to a trait subject to stabilizing selection, as well as that of an allele contributing to a trait rapidly adapting to a new phenotypic optimum. We use these expressions to characterize the use of allele frequency change to test for selection, as well as explore optimal design choices for evolve-and-resequence experiments to uncover the genetic architecture of polygenic traits under selection.