bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment with Tumor-Treating Fields (TTFields) Suppresses Intercellular Tunneling Nanotube FormationIn Vitroand Upregulates Immuno-Oncologic BiomarkersIn Vivoin Malignant Mesothelioma
Authors: Sarkari Akshat , Korenfeld Sophie , Deniz Karina , Ladner Katherine , Wong Phillip , Padmanabhan Sanyukta , Vogel Rachel I , Sherer Laura , Courtemanche Naomi , Steer Clifford J , Wainer-Katsir Kerem , Lou Emil 
Published: December 2022

AbstractIntercellular communication is critical for the development of invasive cancers. Multiple forms of intercellular communication have been well characterized, involving diffusible soluble factors or contact-dependent channels for immediately adjacent cells. Over the past 1-2 decades, the emergence of a unique form of F-actin-based cellular protrusion known as tunneling nanotubes (TNTs) has filled the niche of long-range cell-contact dependent intercellular communication that facilitates cell growth, differentiation, and in the case of invasive cancer phenotypes, a more chemoresistant phenotype. The cellular machinery of TNT-mediated transport is an area of active investigation, and microtubules have been implicated in this process as they are in other membranous protrusions. Tumor-Treating Fields (TTFields) therapy is a novel therapeutic strategy in clinical use for patients with advanced cancers, based on the principle of using low-intensity alternating electric fields to disrupt microtubules in cancer cells undergoing mitosis. Other mechanisms of action have also been demonstrated. In this study, we investigated the effects of TTFields on TNTs in malignant pleural mesothelioma (MPM)in vitroand also on the spatial transcriptomic landscapein vivo. We found that applying TTFields at 1.0 V/cm significantly suppressed TNT formation in a biphasic MPM cell line (MSTO-211H), but not in sarcomatoid MPM (VAMT). At these parameters, TTFields significantly reduced cell count in MSTO-211H, but did not significantly alter intercellular transport of mitochondria via intact TNTs. To understand how TTFields may impact expression of genes with known involvement to TNT formation and overall tumor growth, we performed spatial genomic assessment of TTFields-treated tumors from anin vivoanimal model of MPM, and detected upregulation of immuno-oncologic biomarkers with simultaneous downregulation of pathways associated with cell hyperproliferation, invasion, and other critical regulators of oncogenic growth. Several molecular classes and pathways coincide with markers that we and others have found to be differentially expressed in cancer cell TNTs, including MPM specifically. In this study, we report novel cellular and molecular effects of TTFields in relation to tumor communication networks enabled by TNTs and related molecular pathways. These results position TNTs as potential therapeutic targets for TTFields-directed cancer treatment strategies; and also identify the ability of TTFields to potentially remodel the tumor microenvironment, thus enhancing response to immunotherapeutic drugs.
Structural titration reveals Ca2+-dependent conformational landscape of the IP3receptor
Authors: Paknejad Navid , Sapuru Vinay , Hite Richard K. 
Published: December 2022

SummaryInositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+-permeable cation channels whose biphasic dependence on cytoplasmic Ca2+gives rise to cytosolic Ca2+oscillations that regulate fertilization, cell division and cell death. Despite the critical roles of IP3R-mediated Ca2+oscillations, the structural underpinnings of the biphasic Ca2+dependence that underlies Ca2+oscillations are incompletely understood. Here, we collected images of an IP3R with Ca2+at concentrations spanning five orders of magnitude. Unbiased image analysis revealed that Ca2+binding does not explicitly induce conformational changes but rather biases a complex conformational landscape consisting of resting, preactivated, activated, and inhibited states. Using particle counts as a proxy for free energy, we demonstrate that Ca2+binding at a high-affinity site allows IP3Rs to activate by escaping a low-energy resting state through an ensemble of preactivated states. At high Ca2+, IP3Rs preferentially enter an inhibited state stabilized by a second, low-affinity Ca2+binding site. Together, these studies provide a mechanistic basis for the biphasic Ca2+-dependence of IP3R channel activity.
A ubiquitin-proteasome pathway degrades the inner nuclear membrane protein Bqt4 to maintain nuclear membrane homeostasis
Authors: Le Toan Khanh , Hirano Yasuhiro , Asakawa Haruhiko , Okamoto Koji , Fukagawa Tatsuo , Haraguchi Tokuko , Hiraoka Yasushi 
Published: December 2022

AbstractAberrant accumulation of inner nuclear membrane (INM) proteins is associated with deformed nuclear morphology and mammalian diseases. However, the mechanisms underlying the maintenance of INM homeostasis remain poorly understood. In this study, we explored the degradation mechanisms of the INM protein, Bqt4, in the fission yeastSchizosaccharomyces pombe. We have previously shown that Bqt4 interacts with the transmembrane protein Bqt3 at the INM and is degraded in the absence of Bqt3. Here, we revealed that excess Bqt4, unassociated with Bqt3, was targeted for degradation by the ubiquitin-proteasome system localized in the nucleus and Bqt3 antagonized this process. The degradation process involved the Doa10 E3 ligase complex at the INM. Bqt4 is a tail-anchored protein and extraction from the membrane by the Cdc48 complex is required for its degradation. The C-terminal transmembrane domain of Bqt4 is necessary and sufficient for proteasome-dependent protein degradation. Accumulation of Bqt4 at the INM impaired cell viability with nuclear envelope deformation, suggesting that quantity control of Bqt4 plays an important role in nuclear membrane homeostasis.Summary statementAppropriate levels of the inner nuclear membrane protein Bqt4 are maintained by ubiquitin-proteasome-mediated degradation. Aberrant accumulation of Bqt4 disturbs nuclear membrane homeostasis.
A concerted increase in readthrough and intron retention drives transposon expression during aging and senescence
Authors: Pabis Kamil , Barardo Diogo , Sirbu Olga , Selvarajoo Kumar , Gruber Jan , Kennedy Brian K. 
Published: December 2022

Aging and senescence are characterized by pervasive transcriptional dysfunction, including increased expression of transposons and introns. Our aim was to elucidate mechanisms behind this increased expression. Most transposons are found within genes and introns, with a large minority being close to genes. This raises the possibility that transcriptional readthrough and intron retention are responsible for age-related changes in transposon expression rather than expression of autonomous transposons.To test this, we compiled public RNA-seq datasets from aged human fibroblasts, replicative and drug-induced senescence in human cells and RNA-seq from aging mice and senescent mouse cells. Indeed, our reanalysis revealed a correlation between transposons expression, intron retention and transcriptional readthrough across samples and within samples. Both intron retention and readthrough increased with aging or cellular senescence and these transcriptional defects were more pronounced in human samples as compared to those of mice.In support of a causal connection between readthrough and transposon expression, analysis of models showing induced transcriptional readthrough confirmed that they also show elevated transposon expression. Taken together, our data suggests that elevated transposon reads during aging seen in various RNA-seq dataset are concomitant with multiple transcriptional defects. Intron retention and transcriptional readthrough are the most likely explanation for the expression of transposable elements that lack a functional promoter.
Natural Shortwave UV-B Radiation Increases UV absorbing pigments levels in Texas native grassesChasmanthium latifoliumandBouteloua curtipendula
Authors: Nebhut AN , Semro MR , Worley CA , Shinkle JR 
Published: December 2022

AbstractPlants are routinely exposed to UV-B radiation (280–315 nm) as a natural component of incident solar radiation. UV-B radiation is relevant to plants as both a source of damage and as a photomorphogenic cue, but the relative impacts of different wavelengths within the UV-B waveband are largely unresolved. Previous studies indicate that the full spectrum of solar UV-B radiation elicits unique responses in model plants under laboratory conditions compared to photons within the longwave UV-B band (300–315 nm), but the impacts of shortwave UV-B radiation (SW-UVB; 280–300 nm) remain unknown in a field environment. In this study, we examine the impact of shortwave UV-B radiation on the pigmentation and morphology of C3shade-adapted inland sea oats (Chasmanthium latifolium) and C4sun-adapted side-oats grama (Bouteloua curtipendula) in field conditions. We characterized the responses of these grasses to SW-UVB radiation by placing UV-naive individuals under SW-UVB excluding or transmitting filters at three field sites in Central Texas and measuring their responses through leaf pigment extract absorbance, leaf surface reflectance, and whole leaf chlorophyll and flavonoid content. We found that both species exhibited changes to their UV-B associated traits following exposure to the field environment, which were influenced by field site location, maximum daily temperature, and SW-UVB exposure. In particular,C. latifoliumincreased the ratio of its maximum to minimum absorbance in response to SW-UVB, whileB. curtipendulaexhibited higher flavonoid content in response to SW-UVB exposure. We believe this is the first time that the effects of SW-UVB radiation have been documented in a field environment.
Dorsal pulvinar inactivation leads to spatial selection bias without perceptual deficit
Authors: Kaduk Kristin , Wilke Melanie , Kagan Igor 
Published: December 2022

AbstractThe dorsal pulvinar has been implicated in visuospatial attentional and perceptual confidence processing. Pulvinar lesions in humans and monkeys lead to spatial neglect symptoms, including an overt spatial saccade bias during free choices. But it remains unclear whether disrupting the dorsal pulvinar during target selection that relies on a perceptual decision leads to a perceptual impairment or a more general spatial orienting and choice deficit. To address this question, we reversibly inactivated the unilateral dorsal pulvinar by injecting GABA-A agonist THIP while two macaque monkeys performed a color discrimination saccade task with varying perceptual difficulty. We used Signal Detection Theory and simulations to dissociate perceptual sensitivity (d-prime) and spatial selection bias (response criterion) effects. We expected a decrease in d-prime if dorsal pulvinar affects perceptual discrimination and a shift in response criterion if dorsal pulvinar is mainly involved in spatial orienting. After the inactivation, we observed response criterion shifts away from contralesional stimuli, especially when two competing stimuli in opposite hemifields were present. Notably, the d-prime and overall accuracy remained largely unaffected. Our results underline the critical contribution of the dorsal pulvinar to spatial orienting and action selection while showing it to be less important for visual perceptual discrimination.
Ventral posterolateral and ventral posteromedial thalamus neurons have distinct synaptic and cellular physiology
Authors: Studtmann Carleigh , Ladislav Marek , Safari Mona , Chen Yang , Topolski Mackenzie A. , Khondaker Rabeya , Tomović Eni , Balík Aleš , Swanger Sharon A. 
Published: December 2022

AbstractSomatosensory information is propagated from the periphery to the cerebral cortex by two parallel pathways through the ventral posterolateral (VPL) and ventral posteromedial (VPM) thalamus. VPL and VPM neurons receive somatosensory signals from the body and head, respectively. VPL and VPM neurons also receive cell-type-specific GABAergic input from the reticular nucleus of the thalamus (nRT). Although VPL and VPM neurons have distinct connectivity and physiological roles, differences in the functional properties of VPL and VPM neurons remain unclear as they are often studied as one ventrobasal (VB) thalamus neuron population. Here, we directly compared synaptic and intrinsic properties of VPL and VPM neurons in C57Bl/6J mice of both sexes aged P25-P32. Recordings of spontaneous synaptic transmission suggested that VPL neurons receive excitatory synaptic input with higher frequency and strength than VPM neurons, while VPL neurons exhibited weaker inhibitory synapse strength than VPM neurons. Furthermore, VPL neurons showed enhanced depolarization-induced spike firing and greater spike frequency adaptation than VPM neurons. VPL and VPM neurons fired similar numbers of spikes during hyperpolarization rebound bursts, but VPM neurons exhibited shorter burst latency compared to VPL neurons, which correlated with increased sag potential during hyperpolarization. This work indicates that VPL and VPM thalamocortical neurons are functionally distinct populations. The observed functional differences could have important implications for their specific physiological and pathophysiological roles within the somatosensory thalamocortical network.
A thermally stable protein nanoparticle that stimulates long lasting humoral immune response
Authors: Wong Ten-Tsao , Liou Gunn-Guang , Kan Ming-Chung 
Published: December 2022

AbstractThermally stable vaccine platform is considered to be the missing piece of vaccine technology. In this article, we are reporting the development of a novel protein nanoparticle and evaluating its ability in withstanding extended high temperature incubation and stimulating long lasting humoral immune response. This protein nanoparticle is assembled from a fusion protein composed of an amphipathic helical peptide derived from M2 protein of H5N1 influenza virus (AH3) and a super folder green fluorescent protein(sfGFP). The proposed structure of this protein nanoparticle is modeled according to transmission electronic microscope (TEM) images of protein nanoparticle. From this proposed protein model, we have generated a mutant with two gain-of-function mutations that function synergistically on particle stability. Protein nanoparticle assembled from this gain-of-function mutant is able to remove a hydrophobic patch from the surface of protein nanoparticle. This gain-of-function mutant also contributes to higher thermostability of protein nanoparticle and stimulates long lasting humoral immune response after single immunization. This protein nanoparticle shows increasing particle stability in higher temperature and higher salt concentration. This novel protein nanoparticle may serve as a thermal-stable platform for vaccine development.
A thalamo-parietal cortex circuit is critical for place-action coordination
Authors: Simmons Christine M. , Moseley Shawn C. , Ogg Jordan D. , Johnson Madeline , Clark Benjamin J. , Wilber Aaron A. 
Published: December 2022

AbstractThe anterior and lateral thalamus (ALT) contains head direction cells that signal the directional orientation of an animal within an environment. ALT has direct and indirect connections with the parietal cortex (PC), an area hypothesized to play a role in coordinating viewer-dependent and viewer-independent spatial reference frames. This coordination between reference frames would allow an individual to translate movements toward a desired location from memory. Thus ALT-PC functional connectivity would be critical for moving toward remembered locations. This hypothesis was tested with a place-action task that requires associating an appropriate action (left or right turn) with a spatial location. There are four arms, each offset by 90 degrees, positioned around a central starting point. A trial begins in the central starting point. After exiting a pseudorandomly selected arm, the rat had to displace the correct object covering one of two (left versus right) feeding stations to receive a reward. For a pair of arms facing opposite directions, the reward was located on the left, and for the other pair, the reward was located on the right. Thus, each reward location had a different combination of allocentric location and egocentric action. Removal of an object was scored as correct or incorrect. Trials in which the rat did not displace any objects were scored as ‘no response’ trials. After an object was removed, the rat returned to the center starting position and the maze was reset for the next trial. To investigate the role of the ALT-PC network, muscimol inactivation infusions targeted bilateral PC, bilateral ALT, or the ALT-PC network. Muscimol sessions were counterbalanced and compared to saline sessions within the same animal. All inactivations resulted in decreased accuracy. Only bilateral PC inactivations resulted in increased no response trials, increased errors, and longer latency responses on the remaining trials. Thus, the ALT-PC network is critical for linking an action with a spatial location for successful navigation.
An integrated systems-biology platform for power-to-gas technology
Authors: Casini Isabella , McCubbin Tim , Esquivel-Elizondo Sofia , Luque Guillermo G. , Evseeva Daria , Fink Christian , Beblawy Sebastian , Youngblut Nicholas D. , Aristilde Ludmilla , Huson Daniel H. , Dräger Andreas , Ley Ruth E. , Marcellin Esteban , Angenent Largus T. , Molitor Bastian 
Published: December 2022

AbstractMethanogenesis allows methanogenic archaea (methanogens) to generate cellular energy for their growth while producing methane. Hydrogenotrophic methanogens thrive on carbon dioxide and molecular hydrogen as sole carbon and energy sources. Thermophilic and hydrogenotrophicMethanothermobacterspp. have been recognized as robust biocatalysts for a circular carbon economy and are now applied in power-to-gas technology. Here, we generated the first manually curated genome-scale metabolic reconstruction for threeMethanothermobacterspp‥ We investigated differences in the growth performance of three wild-type strains and one genetically engineered strain in two independent chemostat bioreactor experiments. In the first experiment, with molecular hydrogen and carbon dioxide, we found the highest methane production rate forMethanothermobacter thermautotrophicusΔH, whileMethanothermobacter marburgensisMarburg reached the highest biomass growth rate. Systems biology investigations, including implementing a pan-model that contains combined reactions from all three microbes, allowed us to perform an interspecies comparison. This comparison enabled us to identify crucial differences in formate anabolism. In the second experiment, with sodium formate, we found stable growth with anM. thermautotrophicusΔH plasmid-carrying strain with similar performance parameters compared to wild-typeMethanothermobacter thermautotrophicusZ-245. Our findings reveal that formate anabolism influences the diversion of carbon to biomass and methane with implications for biotechnological applications ofMethanothermobacterspp. in power-to-gas technology and for chemical production.Graphical AbstractBroader contextRenewable energy sources (e.g., wind and solar) provide carbon-free electric power. However, their intermittency and offset between peak production and demand generate the need to store this electric power. Furthermore, these technologies alone do not satisfy the demand for carbon-based commodities. Power-to-gas technology provides a means to store intermittent renewable electric power with concomitant carbon dioxide recycling into a chemical energy carrier, such as methane, on a centralized and decentralized scale. This is particularly important to establish equitable energy strategies forallcountries, as is highlighted by the United Nations Sustainable Development Goals. With this work, we provide an integrated systems-biology platform forMethanothermobacterspp. to optimize biological power-to-gas technology and formulate strategies to produce other value-added products besides methane.
Determinants of Viscoelasticity and Flow Activation Energy in Biomolecular Condensates
Authors: Alshareedah Ibraheem , Singh Anurag , Quinn Alexander , Banerjee Priya R. 
Published: December 2022

AbstractThe form and function of biomolecular condensates, which are phase-separated intracellular granules of proteins and RNAs, are regulated by their material and dynamical properties. Emerging reports suggest that biomolecular condensates are viscoelastic network fluids, and the primary sequence and structure of the constituent biopolymers govern their bulk fluid phase properties. Here, we employ a multi-parametric approach to dissect the molecular determinants of condensate viscoelasticity by studying a series of condensates formed by engineered multivalent arginine-rich polypeptides and single-stranded DNA. By measuring the terminal relaxation time of the condensate network through optical tweezer-based microrheology and the activation energy of viscous flow through temperature-controlled video particle tracking, we show that condensate viscoelasticity is controlled by two distinct factors − sequence-encoded inter-chain interactions of associative polymers and entropic factors emerging from their intrinsic polymer properties such as the chain length. The biomolecular diffusion in the dense phase shows a strong dependence on the flow activation energy, indicating that the intra-condensate transport properties are primarily reaction-dominant. These results provide a glimpse of the multifaceted control of viscoelasticity and transport properties within biomolecular condensates. Flow activation energy measurement of single and multicomponent condensates by thermo-rheology provides a direct route to quantify inter-chain interactions in the dense phase and dissect the roles of chain entropy and valence in dictating the viscoelastic behavior of biomolecular condensates.
A Sensory-Motor Theory of the Neocortex based on Active Predictive Coding
Authors: Rao Rajesh P. N. 
Published: December 2022

AbstractWe propose that the neocortex implements active predictive coding (APC), a form of predictive coding that incorporates hierarchical dynamics and actions. In this model, each neocortical area estimates both sensory states and actions, and the cortex as whole learns to predict the sensory consequences of actions at multiple hierarchical levels. “Higher” cortical areas maintain more abstract representations at larger spatiotemporal scales compared to “lower” areas. Feedback from higher areas modulate the dynamics of both state and action networks in lower areas. This allows the cortical network to model the complex dynamics and physics of the world in terms of simpler compositional elements (state transition functions). Simultaneously, current higher level goals invoke sequences of lower level sub-goals and actions, allowing the network to solve complex planning problems by composing simpler solutions. Planning (“system 2” thinking) in turns allows the network to learn, over time, perception-to-action mappings (policies; “system 1” thinking) at multiple abstraction levels. We provide examples from simulations illustrating how the same APC architecture can solve problems that, at first blush, seem very different from each other: (1) how do we recognize an object and its parts using eye movements? (2) why does perception seem stable despite eye movements? (3) how do we learn compositional representations, e.g., part-whole hierarchies, and nested reference frames for equivariant vision? (4) how do we model the “physics” of a complex environment by decomposing it into simpler components? (5) how do we plan actions in a complex domain to achieve a goal by composing sequences of sub-goals and simpler actions? and (6) how do we form episodic memories of sensory-motor experiences? We propose a mapping of the APC network to the laminar architecture of the cortex and suggest possible roles for cortico-cortical, cortico-thalamic, cortico-hippocampal and cortico-subcortical pathways.