bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative single-cell characterization of hypothalamus sex-differential and obesity-associated genes and regulatory elements
Authors: Nguyen Hai P. , Chan Candace S.Y , Cintron Dianne Laboy , Sheng Rory , Harshman Lana , Nobuhara Mai , Ushiki Aki , Biellak Cassidy , An Kelly , Gordon Gracie M. , Mifsud Francois , Blake Abbey , Huang Eric J. , Hemberg Martin , Vaisse Christian , Ahituv Nadav 
Published: November 2022

AbstractOver 500 noncoding genomic loci are associated with obesity. The majority of these loci reside near genes that are expressed in the hypothalamus in specific neuronal subpopulations that regulate food intake, hindering the ability to identify and functionally characterize them. Here, we carried out integrative single-cell analysis (RNA/ATAC-seq) on both mouse and human male and female hypothalamus to characterize genes and regulatory elements in specific cell subpopulations. Utilizing both transcriptome and regulome data, we identify over 30 different neuronal and non-neuronal cell subpopulations and a shared core of transcription factors that regulate cell cluster-specific genes between mice and humans. We characterize several sex-specific differentially expressed genes and the regulatory elements that control them in specific cell subpopulations. Overlapping cell-specific scATAC peaks with obesity-associated GWAS variants, identifies potential obesity-associated regulatory elements. Using reporter assays and CRISPR editing, we show that many of these sequences, including the top obesity-associated loci (FTOandMC4R), are functional enhancers whose activity is altered due to the obesity-associated variant and regulate known obesity genes. Combined, our work provides a catalog of genes and regulatory elements in hypothalamus cell subpopulations and uses obesity to showcase how integrative single-cell sequencing can identify functional variants associated with hypothalamus-related phenotypes.
Regenerative Agriculture Augments Bacterial Community Structure for a Healthier Soil and Agriculture
Authors: Singh Indira , Hussain Meeran , G Manjunath , Chandra Nagasuma , G Ravikanth 
Published: November 2022

AbstractUse of chemical fertilization and pesticides not only harm the environment but also have detrimental consequences on human health. In recent years, there has been a major emphasis worldwide on natural agriculture methods. Regenerative agriculture is known across the world as a combination of nature-friendly farming practices such as no-till, cover cropping, crop-rotation, agro-forestry and use of organic home-based/farm-based ingredients to revive soil health. In India, a number of farmers are slowly adopting these practices using home-based mixtures and farmyard manure for soil rejuvenation and pest management. In order to evaluate the efficacy of the regenerative agriculture practices, this study compared conventional and regenerative agriculture plots for their soil bacterial and nutrient profiles. Two crops - ragi and vegetable (tomato/beans), and different lengths (≤3 and >5 years) of regenerative practices were additional metrics considered to understand variabilities due to crop-type and period of application. We found that all regenerative practices were effective in bringing about an enrichment for soil bacteria with a more heterogeneous composition. Additionally, the regenerative vegetable (RV) plots had an enhanced representation ofActinobacteriota, Chloroflexi, CyanobacteriaandPatescibacteriain comparison to conventional vegetable (CV) plots and Barren land (BL). Similarly, the regenerative ragi (RR) plots saw higher representation ofFirmicutesandActinobacteriotain comparison to conventional ragi (CR) plots and BL. The RV plots were also found to be enriched for Plant Growth Promoting Rhizobacteria (PGPRs) -Pseudomonas sp., and RR plots were enriched forBacillus sp., andMesorhizobium sp., which are known to play significant roles in vegetable and ragi growth respectively. Interestingly, long-term regenerative agriculture was able to support good nutrient composition while enhancing Soil Organic Carbon (SOC) levels. In all, the regenerative agriculture practices were found to be effective in improving bacterial community structure and simultaneously improving soil health. We found that BL soil with eucalyptus plantation showed least bacterial diversity suggesting detrimental impact on soil health.
Transcriptomic cytoarchitecture reveals principles of human neocortex organization
Authors: Jorstad Nikolas L. , Close Jennie , Johansen Nelson , Yanny Anna Marie , Barkan Eliza R. , Travaglini Kyle J. , Bertagnolli Darren , Campos Jazmin , Casper Tamara , Crichton Kirsten , Dee Nick , Ding Song-Lin , Gelfand Emily , Goldy Jeff , Hirschstein Daniel , Kroll Matthew , Kunst Michael , Lathia Kanan , Long Brian , Martin Naomi , McMillen Delissa , Pham Trangthanh , Rimorin Christine , Ruiz Augustin , Shapovalova Nadiya , Shehata Soraya , Siletti Kimberly , Somasundaram Saroja , Sulc Josef , Tieu Michael , Torkelson Amy , Tung Herman , Ward Katelyn , Callaway Edward M. , Hof Patrick R. , Keene C. Dirk , Levi Boaz P. , Linnarsson Sten , Mitra Partha P. , Smith Kimberly , Hodge Rebecca D. , Bakken Trygve E. , Lein Ed S. 
Published: November 2022

AbstractVariation in cortical cytoarchitecture is the basis for histology-based definition of cortical areas, such as Brodmann areas. Single cell transcriptomics enables higher-resolution characterization of cell types in human cortex, which we used to revisit the idea of the canonical cortical microcircuit and to understand functional areal specialization. Deeply sampled single nucleus RNA-sequencing of eight cortical areas spanning cortical structural variation showed highly consistent cellular makeup for 24 coarse cell subclasses. However, proportions of excitatory neuron subclasses varied strikingly, reflecting differences in intra- and extracortical connectivity across primary sensorimotor and association cortices. Astrocytes and oligodendrocytes also showed differences in laminar organization across areas. Primary visual cortex showed dramatically different organization, including major differences in the ratios of excitatory to inhibitory neurons, expansion of layer 4 excitatory neuron types and specialized inhibitory neurons. Finally, gene expression variation in conserved neuron subclasses predicts differences in synaptic function across areas. Together these results provide a refined cellular and molecular characterization of human cortical cytoarchitecture that reflects functional connectivity and predicts areal specialization.
Malonyl-CoA is an ancient physiological ATP-competitive mTORC1 inhibitor
Authors: Nicastro Raffaele , Brohée Laura , Alba Josephine , Nüchel Julian , Figlia Gianluca , Kipschull Stefanie , Gollwitzer Peter , Romero-Pozuelo Jesus , Fernandes Stephanie A. , Lamprakis Andreas , Vanni Stefano , Teleman Aurelio A. , De Virgilio Claudio , Demetriades Constantinos 
Published: November 2022

AbstractCell growth is regulated primarily by the mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1) that functions both as a nutrient sensor and a master controller of virtually all biosynthetic pathways1. This ensures that cells are metabolically active only when conditions are optimal for growth. Notably, although mTORC1 is known to regulate fatty acid (FA) biosynthesis, how and whether the cellular lipid biosynthetic capacity signals back to fine-tune mTORC1 activity remains poorly understood. Here, we show that mTORC1 senses the capacity of a cell to synthesize FAs by detecting the levels of malonyl-CoA, an intermediate of this biosynthetic pathway. We find that, in both yeast and mammalian cells, this regulation is very direct, with malonyl-CoA binding to the mTOR catalytic pocket and acting as a specific ATP-competitive inhibitor. When ACC1 (acetyl-CoA carboxylase 1) is hyperactive or FASN (fatty acid synthase) is downregulated/inhibited, elevated malonyl-CoA levels are channelled to proximal mTOR molecules that form direct protein-protein interactions with ACC1 and FASN. Our findings represent a conserved, unique, homeostatic mechanism whereby impaired FA biogenesis leads to reduced mTORC1 activity to coordinatively link this metabolic pathway to the overall cellular biosynthetic output. Moreover, they reveal the first-described example of a physiological metabolite that directly inhibits the activity of a signalling kinase by competing with ATP for binding.
Partial Mimicry of the Microtubule Binding of Tau by Its Membrane Binding
Authors: MacAinsh Matthew , Zhou Huan-Xiang 
Published: November 2022

AbstractTau, as typical of intrinsically disordered proteins (IDPs), binds to multiple targets including microtubules and acidic membranes. The latter two surfaces are both highly negatively charged, raising the prospect of mimicry in their binding by tau. The tau-microtubule complex was recently determined by cryo-EM. Here we used molecular dynamics simulations to characterize the dynamic binding of tau K19 to an acidic membrane. This IDP can be divided into three repeats, each containing an amphipathic helix. The three amphipathic helices, along with flanking residues, tether the protein to the membrane interface. The separation between and membrane positioning of the amphipathic helices in the simulations are validated by published EPR data. The membrane contact probabilities of individual residues in tau show both similarities to and distinctions from native contacts with microtubules. In particular, a Lys that is conserved among the repeats forms similar interactions with membranes and with microtubules, as does a conserved Val. This partial mimicry facilitates both the membrane anchoring of microtubules by tau and the transfer of tau from membranes to microtubules.
Express visuomotor responses reflect knowledge of both target location and conscious intent during reaches of different amplitudes
Authors: Contemori Samuele , Loeb Gerald E. , Corneil Brian D. , Wallis Guy , Carroll Timothy J. 
Published: November 2022

ABSTRACTWhen humans reach to visual targets, extremely rapid (~90 ms) bursts of activity can be observed on task-relevant proximal muscles. Such express visuomotor responses are inflexibly locked in time and space to the target and have been proposed to reflect rapid visuomotor transformations conveyed subcortically via the tecto-reticulo-spinal pathway. Previously, we showed that express visuomotor responses are sensitive to explicit cue-driven information about the target, suggesting that the express pathway can be modulated by cortical signals affording contextual pre-stimulus expectations. Here, we show that the express visuomotor system incorporates information about the veridical target-directed reaching metrics and contextual instructions during visuospatial tasks requiring different movement amplitudes. In one experiment, we recorded the activity from two shoulder muscles as participants reached toward targets that appeared at different distances. Longer hand-to-target distances led to larger and more prevalent express visuomotor responses than short-reach targets. This suggests that both the direction and distance of veridical hand-to-target reaches are encoded along the putative subcortical express pathway. In a second experiment, we modulated the movement amplitude by asking the participants to deliberately undershoot, overshoot, or stop (control) at the target. The overshoot and undershoot tasks impaired the generation of large and frequent express visuomotor responses, consistent with the inability of the express pathway to generate responses directed toward non-veridical targets (e.g. anti-reach tasks). Our findings appear to reflect strategic, cortically-driven modulation of the express visuomotor circuit to facilitate rapid and effective response initiation during target-directed actions.SIGNIFICANCE STATEMENTExpress(~90 ms) arm muscle responses that are consistently tuned toward the location of visual stimuli suggest a subcortical contribution to target-directed visuomotor behaviour in humans, potentially via the tecto-reticulo-spinal pathway. This study shows that express muscle responses are modulated appropriately to reach targets at different distances, but generally suppressed when the task required non-veridical responses to overshoot/undershoot the real target. The data suggest that the tecto-reticulo-spinal pathway can be exploited strategically by the cerebral cortex to facilitate rapid initiation of effective responses during a visuospatial task.
Positive associations matter: microbial relationships drive tick microbiome composition
Authors: Fountain-Jones Nicholas M. , Khoo Benedict S. , Rau Austin , Berman Jesse D. , Burton Erin N. , Oliver Jonathan D. 
Published: November 2022

AbstractUntangling how factors such as environment, host, associations between species and dispersal predict microbial dynamics is a fundamental challenge. In this study, we use a robust sampling design coupled with complementary machine-learning approaches to quantify the relative role of these factors in shaping microbiome variation of the blacklegged tickIxodes scapularis. I. scapularisis the most important vector forBorrelia burgdorferi. (the causative agent for Lyme disease) in the U.S as well as a range of other important zoonotic pathogens. Yet the relative role of the interactions between pathogens and symbionts compared to other ecological forces is unknown. We found that positive associations between microbes where the occurrence of one microbe increases the probability of observing another, including between both pathogens and symbionts, was by far the most important factor shaping the tick microbiome. Microclimate and host factors played an important role for a subset of the tick microbiome includingBorrelia(Borreliella) andRalstonia, but for the majority of microbes, environmental and host variables were poor predictors at a regional scale. This study provides new hypotheses on how pathogens and symbionts might interact within tick species, as well as valuable predictions for how some taxa may respond to changing climate.
Biophysical modeling of actin-mediated structural plasticity reveals mechanical adaptation in dendritic spines
Authors: Bonilla-Quintana M. , Rangamani P. 
Published: November 2022

AbstractSynaptic plasticity is important for learning and memory formation; it describes the strengthening or weakening of connections between synapses. The postsynaptic part of excitatory synapses resides in dendritic spines, which are small protrusions on the dendrites. One of the key features of synaptic plasticity is its correlation with the size of these spines. A long-lasting synaptic strength increase (long-term potentiation, LTP) is only possible through the reconfiguration of the actin spine cytoskeleton. Here, we develop an experimentally-informed three-dimensional computational model in a moving boundary framework to investigate this reconfiguration. Our model describes the reactions between actin and actin-binding proteins (ABPs) leading to the cytoskeleton remodeling and their effect on the spine membrane shape to examine the spine enlargement upon LTP. Moreover, we find that the incorporation of perisynaptic elements enhances spine enlargement upon LTP, exhibiting the importance of accounting for these elements when studying structural LTP. Our model shows adaptation to repeated stimuli resulting from the interactions between spine proteins and mechanical forces.Significance StatementDendritic spines are small protrusions that receive stimulation from presynaptic neurons. Upon stimulation, the dendritic spines change their size, an important feature of synaptic plasticity. This change is achieved by modifications to the actin cytoskeleton and mediated by many actin-binding proteins. To investigate the fundamental mechanics of spine expansion, we developed a 3D biophysical model that accounts for the dynamics of cytoskeleton-membrane interactions. Our simulations predict that spine expansion due to actin remodeling can be enhanced by including the interaction with perisynaptic elements that affect the spine’s mechanical properties. We also found that mechanical properties can control spine expansion after repeated stimuli, which ensures physiological size. Thus, we predict that spine growth is regulated by its mechanical properties.
The soil microbiome reduces Striga infection of sorghum by modulation of host-derived signaling molecules and root development
Authors: Kawa Dorota , Thiombiano Benjamin , Shimels Mahdere , Taylor Tamera , Walmsley Aimee , Vahldick Hannah E , Leite Marcio FA , Musa Zayan , Bucksch Alexander , Dini-Andreote Francisco , Chen Alexander J , Daksa Jiregna , Etalo Desalegn , Tessema Taye , Kuramae Eiko E , Raaijmakers Jos M , Bouwmeester Harro , Brady Siobhan M 
Published: November 2022

AbstractSorghum bicoloris one of the most important cereals in the world and a staple crop for smallholder famers in sub-Saharan Africa. However approximately 20% of sorghum yield is annually lost on the African continent due to infestation with the root parasitic weedStriga hermonthica.Existing Striga management strategies often show an inconsistent to low efficacy. Hence, novel and integrated approaches are needed as an alternative strategy. Here, we demonstrate that the soil microbiome suppresses Striga infection in sorghum. We associate this suppression with microbiome-mediated induction of root endodermal suberization and aerenchyma formation, and depletion of haustorium inducing factors (HIFs), root exudate compounds that are critical for the initial stages of Striga infection. We further identify microbial taxa associated with reduced Striga infection with concomitant changes in root cellular anatomy and differentiation as well as HIF degradation. Our study describes novel microbiome-mediated mechanisms of Striga suppression, encompassing repression of haustorium formation and induction of physical barriers in the host root tissue. These findings open new avenues to broaden the effectiveness of Striga management practices.
PKM2-mediated epigenetic reprogramming regulates hypoxic expression ofPFKFB3to promote breast cancer progression
Authors: Pandkar Madhura R. , Raveendran Adarsh , Biswas Kajal , Mutnuru Srinivas Abhishek , Mishra Jharna , Samaiya Atul , Sharan Shyam K. , Shukla Sanjeev 
Published: November 2022

AbstractThe hypoxic milieu is a critical modulator of aerobic glycolysis, yet the regulatory mechanisms existing between the key glycolytic enzymes in hypoxic cancer cells are largely unexplored. In particular, M2 isoform of pyruvate kinase (PKM2) − the ratelimiting enzyme of glycolysis, is well-known to confer adaptive advantages under hypoxia. Herein, we report a non-canonical role of PKM2 in functioning as a co-activator of HIF-1α to govern the transcription of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Nuclear PKM2 enhances HIF-1α and p300 occupancy atPFKFB3hypoxia responsive elements (HREs) resulting in its upregulation. Consequently, absence of nuclear PKM2 fails to recruit HIF-1α which activates an opportunistic occupancy of HIF-2α atPFKFB3HREs. Enhanced binding of HDAC3 also occurs in the absence of PKM2 which prevents HIF-2α from efficiently inducing PFKFB3 to hamper proliferation of hypoxic breast cancer cells. In addition, clinical relevance of the study has been investigated by demonstrating that Shikonin blocks nuclear translocation of PKM2 to suppressPFKFB3expression. Furthermore, MCF7 cells-derived xenograft tumors in mice exhibited substantial tumor growth inhibition when treated with shikonin, highlighting the vitality of targeting PKM2. Taken in concert, this work provides novel insights into contributions of PKM2 in modulating hypoxic transcriptome and a previously unreported molecular axis exhibited by the hypoxic breast cancer cells for ensuring the maintenance of PFKFB3 expression essential for achieving high glycolytic flux.Statement of significanceNuclear PKM2 orchestrates the binding of histone modifiers to epigenetically alter PFKFB3 promoter and affects the binding of HIF-2α. Notably, targeting this axis attenuates proliferation of hypoxic breast cancer cells.
Charge-voltage curves of Shaker potassium channel are not hysteretic at steady state
Authors: Cowgill John , Chanda Baron 
Published: November 2022

AbstractCharged residues in transmembrane segments of voltage-gated ion channels (VGICs) sense and respond to changes in the electric field. The movement of these gating charges underpins voltage-dependent activation and is also a direct metric of the net free-energy of channel activation. However, for most voltage-gated ion channels, the charge-voltage (Q-V) curves appear to be dependent on initial conditions. For instance, Q-V curves of Shaker potassium channel obtained by hyperpolarizing from 0 mV is left shifted compared to those obtained by depolarizing from a holding potential of -80 mV. This hysteresis in Q-V curves is a common feature of channels in the VGIC superfamily and raises profound questions about channel energetics because the net free-energy of channel gating is a state function and should be path independent. Due to technical limitations, conventional gating current protocols are limited to test pulse durations of<500 ms which raises the possibility that the dependence of Q-V on initial conditions reflects a lack of equilibration. Others have suggested that the hysteresis is fundamental thermodynamic property of voltage-gated ion channels and reflects energy dissipation due to measurements under non-equilibrium conditions inherent to rapid voltage jumps (Villalba-Galea, 2017). Using an improved gating current and voltage-clamp fluorometry protocols, we show that the gating hysteresis arising from different initial conditions in Shaker potassium channel is eliminated with ultra-long (18-25 second) test pulses. Our study identifies a modified gating current recording protocol to obtain steady state Q-V curves of a voltage-gated ion channel. Above all, these findings demonstrate that the gating hysteresis in Shaker channel is a kinetic phenomenon rather than a true thermodynamic property of the channel and the charge-voltage curve is a true measure of the net-free energy of channel gating.