bluuebunny/crossref_metadata_2025_split huggingface dataset:
A common human brain-derived neurotrophic factor polymorphism leads to sustained depression of excitatory synaptic transmission by isoflurane in hippocampus
Authors: Williams RA , Johnson KW , Lee FS , Hemmings HC , Platholi J 
Published: January 2022

AbstractMultiple presynaptic and postsynaptic targets have been identified for the reversible neurophysiological effects of general anesthetics on synaptic transmission and neuronal excitability. However, the synaptic mechanisms involved in persistent depression of synaptic transmission resulting in more prolonged neurological dysfunction following anesthesia are less clear. Here, we show that brain-derived neurotrophic factor (BDNF), a growth factor implicated in synaptic plasticity and dysfunction, enhances glutamate synaptic vesicle exocytosis, and that attenuation of vesicular BDNF release by isoflurane contributes to transient depression of excitatory synaptic transmission in mice. This reduction in synaptic vesicle exocytosis was irreversible in neurons that release less endogenous BDNF due to a polymorphism (BDNF Val66Met) compared to wild-type mouse hippocampal neurons following isoflurane exposure. These effects were prevented by exogenous application of BDNF. Our findings identify a role for a common human BDNF single nucleotide polymorphism (Val66Met; rs6265) in persistent changes of synaptic function following isoflurane exposure. These persistent alterations in excitatory synaptic transmission have important implications for the role of genotype in anesthetic effects on synaptic plasticity and neurocognitive function.
Mechanical gating of the auditory transduction channel TMC1 involves the fourth and sixth transmembrane helices
Authors: Akyuz Nurunisa , Karavitaki K. Domenica , Pan Bifeng , Tamvakologos Panos I. , Brock Kelly P. , Li Yaqiao , Marks Debora S. , Corey David P. 
Published: January 2022

AbstractThe transmembrane channel-like (TMC) 1 and 2 proteins play a central role in auditory transduction, forming ion channels that convert sound into electrical signals. However, the molecular mechanism of their gating remains unknown. Here, using predicted structural models as a guide, we probed the effects of twelve mutations on the mechanical gating of the transduction currents in native hair cells of Tmc1/2-null mice expressing virally introduced TMC1 variants. Whole-cell electrophysiological recordings revealed that mutations within the pore-lining transmembrane (TM) helices 4 and 6 modified gating, reducing the force sensitivity or shifting the open probability of the channels, or both. For some of the mutants, these changes were accompanied by a change in single-channel conductance. Our observations are in line with a model wherein conformational changes in the TM4 and TM6 helices are involved in the mechanical gating of the transduction channel.
The synaptic organization in the C. elegans neural network suggests significant local compartmentalized computations
Authors: Ruach Rotem , Ratner Nir , Emmons Scott W. , Zaslaver Alon 
Published: January 2022

AbstractNeurons are characterized by elaborate tree-like dendritic structures that support local computations by integrating multiple inputs from upstream presynaptic neurons. It is less clear if simple neurons, consisting of a few or even a single neurite, may perform local computations as well. To address this question, we focused on the compact neural network of C. elegans animals for which the full wiring diagram is available, including the coordinates of individual synapses. We find that the positions of the chemical synapses along the neurites are not randomly distributed, nor can they be explained by anatomical constraints. Instead, synapses tend to form clusters, an organization that supports local compartmentalized computations. In mutually-synapsing neurons, connections of opposite polarity cluster separately, suggesting that positive and negative feedback dynamics may be implemented in discrete compartmentalized regions along neurites. In triple-neuron circuits, the non-random synaptic organization may facilitate local functional roles, such as signal integration and coordinated activation of functionally-related downstream neurons. These clustered synaptic topologies emerge as a guiding principle in the network presumably to facilitate distinct parallel functions along a single neurite, effectively increasing the computational capacity of the neural network.
VRK1 is a Paralog Synthetic Lethal Target in VRK2-methylated Glioblastoma
Authors: Shields Julie A. , Meier Samuel R. , Bandi Madhavi , Ferdinez Maria Dam , Engel Justin L. , Mulkearns-Hubert Erin E. , Hajdari Nicole , Mitchell Kelly , Zhang Wenhai , Zhao Shan-chuan , Zhang Minjie , Tham Sjin Robert Tjin , Wilker Erik , Lathia Justin D. , Andersen Jannik N. , Chen Yingnan , Li Fang , Weber Barbara , Huang Alan , Emmanuel Natasha 
Published: January 2022

ABSTRACTSynthetic lethality — a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone — can be co-opted for cancer therapeutics. A pair of paralog genes is among the most straightforward synthetic lethal interaction by virtue of their redundant functions. Here we demonstrate a paralog-based synthetic lethality by targeting Vaccinia-Related Kinase 1 (VRK1) in Vaccinia-Related Kinase 2 (VRK2)-methylated glioblastoma (GBM). VRK2 is silenced by promoter methylation in approximately two-thirds of GBM, an aggressive cancer with few available targeted therapies. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells results in decreased activity of the downstream substrate Barrier to Autointegration Factor (BAF), a regulator of post-mitotic nuclear envelope formation. VRK1 knockdown, and thus reduced BAF activity, causes nuclear lobulation, blebbing and micronucleation, which subsequently results in G2/M arrest and DNA damage. The VRK1-VRK2 synthetic lethal interaction is dependent on VRK1 kinase activity and is rescued by ectopic VRK2 expression. Knockdown of VRK1 leads to robust tumor growth inhibition in VRK2-methylated GBM xenografts. These results indicate that inhibiting VRK1 kinase activity could be a viable therapeutic strategy in VRK2-methylated GBM.
Global ecomorphological restructuring of dominant marine reptiles prior to the K/Pg mass extinction
Authors: MacLaren Jamie A. , Bennion Rebecca F. , Bardet Nathalie , Fischer Valentin 
Published: January 2022

ABSTRACTMosasaurid squamates were the dominant amniote predators in marine ecosystems during most of the Late Cretaceous. Evidence from multiple sites worldwide of a global mosasaurid community restructuring across the Campanian–Maastrichtian transition may have wide-ranging implications for the evolution of diversity of these top oceanic predators. In this study, we use a suite of biomechanical traits and functionally descriptive ratios to investigate how the morphofunctional disparity of mosasaurids evolved through time and space prior to the Cretaceous-Palaeogene (K/Pg) mass extinction. Our results suggest that the worldwide taxonomic turnover in mosasaurid community composition from Campanian to Maastrichtian is reflected by a notable increase in morphofunctional disparity on a global scale, but especially driven the North American record. Ecomorphospace occupation becomes more polarised during the late Maastrichtian, as the morphofunctional disparity of mosasaurids plateaus in the Southern Hemisphere and decreases in the Northern Hemisphere. We show that these changes are not associated with strong modifications in mosasaurid size, but rather with the functional capacities of their skulls, and that mosasaurid morphofunctional disparity was in decline in several provincial communities before the K-Pg mass extinction. Our study highlights region-specific patterns of disparity evolution, and the importance of assessing vertebrate extinctions both globally and regionally. Ecomorphological differentiation in mosasaurid communities, coupled with declines in other formerly abundant marine reptile groups, indicates widespread restructuring of higher trophic levels in marine food webs was well underway when the K-Pg mass extinction took place.
Microglia influence neurofilament deposition in ALS iPSC-derived motor neurons
Authors: Allison Reilly L. , Adelman Jacob W. , Abrudan Jenica , Urrutia Raul A. , Zimmermann Michael T. , Mathison Angela J. , Ebert Allison D. 
Published: January 2022

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which upper and lower motor neuron loss is the primary phenotype, leading to muscle weakness and wasting, respiratory failure, and death. Although a portion of ALS cases are linked to one of over 50 unique genes, the vast majority of cases are sporadic in nature. However, the mechanisms underlying the motor neuron loss in either familial or sporadic ALS are not entirely clear. Here we used induced pluripotent stem cells derived from a set of identical twin brothers discordant for ALS to assess the role of astrocytes and microglia on the expression and accumulation of neurofilament proteins in motor neurons. We found that motor neurons derived from the affected twin exhibited increased transcript levels of all three neurofilament isoforms and increased expression of phosphorylated neurofilament puncta. We further found that treatment of the motor neurons with astrocyte conditioned medium and microglial conditioned medium significantly impacted neurofilament deposition. Together, these data suggest that glial-secreted factors can alter neurofilament pathology in ALS iPSC-derived motor neurons.
Acoustic and vibrational signaling in true katydid Nesoecia nigrispina: three means of sound production in the one species
Authors: Korsunovskaya Olga S. , Zhantiev Rustem D. 
Published: January 2022

AbstractThe males of Mexican katydids Nesoecia nigrispina (Stal, 1873) produce calling songs and protest sounds using the same stridulatory apparatus as in most of the other Ensifera at the base of the elytra. It includes pars stridens on the upper elytron and plectrum on the lower. Calling sounds of two types (fast and slow) are 2-pulse series, repeated with a frequency of 1.2-4.5 s−1. Protest signals in the form of short trills from the same pulse duration males produce with tactile stimulation. The pulse repetition rate is more higher than that of the calling sounds - up to 10 (mean c. 8) s−1. The frequency spectra of these signals have maxima in the band of 14–15 kHz. However, in addition to the sounds described, both males and females are capable to produce protest signals of the second type with the help of another sound apparatus, namely with the help of the wings. Insects with removed elytra are unable to produce an audible sound. Thus, the sound is produced by the friction of the wings on the elytra, but there are no specialized stridulatory structures on them. In individuals of both sexes, in response mainly to tactile stimulation, short clicks are recorded, which they make, apparently, by the mandibles. Vibrational signals at tremulation are emitted by individuals of both sexes during courtship and males, completing the calling signal cycle and after copulation. It is possible that vibrational signals are an additional factor in reproductive isolation in sympatric species, since the calling sound signals in representatives of the genus Nesoecia are similar and exhibit significant variability.
ZC3HC1 is a structural element of the nuclear basket effecting interlinkage of TPR polypeptides
Authors: Gunkel Philip , Cordes Volker C. 
Published: January 2022

AbstractThe nuclear basket (NB), anchored to the nuclear pore complex (NPC), is commonly thought of as built solely of protein TPR polypeptides, the latter thus regarded as the NB’s only scaffold-forming components. In the current study, we report ZC3HC1 as a second building element of the NB. Recently described as an NB-appended protein omnipresent in vertebrates, we now show that ZC3HC1, both in vivo and in vitro, enables in a step-wise fashion the recruitment of TPR subpopulations to the NB and their linkage to already NPC-anchored TPR polypeptides. We further demonstrate that the degron-mediated rapid elimination of ZC3HC1 results in the prompt detachment of the ZC3HC1-appended TPR polypeptides from the NB and their release back into the nucleoplasm again, underscoring the role of ZC3HC1 as a natural structural element of the NB. Finally, we show that ZC3HC1 can keep TPR polypeptides positioned even at sites remote from the NB, in line with ZC3HC1 functioning as a protein connecting TPR polypeptides.
Impaired endogenous neurosteroid signaling contributes to behavioral deficits associated with chronic stress
Authors: Walton Najah L. , Antonoudiou Pantelis , Barros Lea , DiLeo Alyssa , Gabby Jenah , Howard Samantha , Paracha Rumzah , Sánchez Edgardo J. , Weiss Grant L. , Kong Dong , Maguire Jamie L. 
Published: January 2022

AbstractChronic stress is a major risk factor for psychiatric illnesses, including depression; however, the pathophysiological mechanisms whereby stress leads to mood disorders remain unclear. The recent FDA approval of antidepressants with novel mechanisms of action, like Zulresso®, a synthetic neuroactive steroid analog with molecular pharmacology similar to allopregnanolone, has spurred interest in new therapeutic targets and, potentially, novel pathophysiological mechanisms for depression. Allopregnanolone acts as a positive allosteric modulator of GABAAreceptors (GABAARS), acting preferentially at δ subunit-containing receptors (δ-GABAARS). Accumulating clinical and preclinical evidence supports the antidepressant effects of exogenous administration of allopregnanolone and allopregnanolone analogs; however, the role of endogenous neurosteroids in the pathophysiology of depression remains unknown. Here, we examine whether altered neurosteroid signaling may contribute to behavioral deficits following chronic unpredictable stress (CUS) in mice. We first identified reductions in expression of δ-GABAARs, the predominant site of action of 5a-reduced neuroactive steroids, following CUS. Additionally, utilizing LC-MS/MS we discovered a decrease in levels of allopregnanolone in the BLA, but not plasma of mice following CUS, an indication of impaired neurosteroid synthesis. CRISPR knockdown the rate-limiting enzymes involved in allopregnanolone synthesis, 5α-reductase type 1 and 2, in the BLA mimicked the behavioral deficits associated with CUS in mice. Furthermore, overexpression expression of 5α-reductase type 1 and 2 in the BLA improved behavioral outcomes. Collectively, this suggests chronic stress impairs endogenous neurosteroid signaling in the BLA which is sufficient to induce behavioral deficits similar to those observed following CUS. Further, these studies suggest that the therapeutic efficacy of allopregnanolone-based treatments may be due to their ability to directly target the underlying pathophysiology of mood disorders. Therefore, targeting endogenous neurosteroidogenesis may offer a novel therapeutic strategy for the treatment of mood disorders.
NETISCE: A Network-Based Tool for Cell Fate Reprogramming
Authors: Marazzi Lauren , Shah Milan , Balakrishnan Shreedula , Patil Ananya , Vera-Licona Paola 
Published: January 2022

ABSTRACTThe search for effective therapeutic targets in fields like regenerative medicine and cancer research has generated interest in cell fate reprogramming. This cellular reprogramming paradigm can drive cells to a desired target state from any initial state. However, methods for identifying reprogramming targets remain limited for biological systems that lack large sets of experimental data or a dynamical characterization. We present NETISCE, a novel computational tool for identifying cell fate reprogramming targets in static networks. In combination with machine learning algorithms, NETISCE estimates the attractor landscape and predicts reprogramming targets using Signal Flow Analysis and Feedback Vertex Set Control, respectively. Through validations in studies of cell fate reprogramming from developmental, stem cell, and cancer biology, we show that NETISCE can predict previously identified cell fate reprogramming targets and identify potentially novel combinations of targets. NETISCE extends cell fate reprogramming studies to larger-scale biological networks without the need for full model parameterization and can be implemented by experimental and computational biologists to identify parts of a biological system relevant to the desired reprogramming task.
Normal Reproductive function in male mice lacking pituitary kisspeptin receptor
Authors: Ma Yaping , Awe Olubusayo , Radivick Sally , Yang Xiaofeng , Divall Sara , Wolfe Andrew , Wu Sheng 
Published: January 2022

AbstractThe anterior pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) regulate gonadal development, gametogenesis and the secretion of the gonadal steroid hormones. The gonadotroph is primarily regulated by hypothalamic secretion of gonadotropin-releasing hormone (GnRH) from neurons of the rostral hypothalamus and is mediated by GnRH receptor signaling. Kisspeptin (KISS1)/kisspeptin receptor (KISS1R) signaling in GnRH neurons plays an essential role in reproductive function. As the kisspeptin receptor is present in the pituitary, kisspeptin signaling via the Kiss1r may regulate reproductive function at the level of pituitary. Using Cre/Lox technology, we deleted the Kiss1r gene in pituitary gonadotropes (PKiRKO). PKiRKO male and females have normal genital development, puberty onset, and fertility. Females have normal LH, FSH and estradiol while males had significantly increased basal serum FSH levels with no differences in basal serum LH, or testosterone levels. Overall, these findings indicate that the pituitary KISS1R does not play a role in male reproduction.
Oxytocin modulates social brain network correlations in resting and task state
Authors: Wu Qingyuan , Huang Qi , Liu Chao , Wu Haiyan 
Published: January 2022

AbstractThe effects of oxytocin (OT) on the social brain can be tracked upon assessing the neural activity in resting and task states, and developing a system-level framework for characterizing the state-based functional relationships of its distinct effect. Here, we contribute to this framework by examining how OT modulates social brain network correlations during resting and task states, using fMRI. First, we investigated network activation, followed by an analysis of the relationships between networks and individual differences. Subsequently, we evaluated the functional connectivity in both states. Finally, the relationship between networks across states was represented by the predictive power of networks in the resting state for task-evoked activities. The differences in the predicted accuracy between the subjects displayed individual variations in this relationship. Our results showed that the activity of the dorsal default mode network (DDMN) in the resting state had the largest predictive power for task-evoked activation of the precuneus network (PN) only in the OT group. The results also demonstrated that OT reduced the individual variation in PN in the prediction process. These findings suggest a distributed but modulatory effect of OT on the association between resting and task-dependent brain networks.
Phenolic degradation by catechol dioxygenases is associated with pathogenic fungi with a necrotrophic lifestyle in the Ceratocystidaceae
Authors: Soal Nicole C , Coetzee Martin HA , van der Nest Magriet A , Hammerbacher Almuth , Wingfield Brenda D 
Published: January 2022

AbstractFungal species of the Ceratocystidaceae grow on their host plants using a variety of different lifestyles, from saprophytic to highly pathogenic. Although many genomes of fungi in the Ceratocystidaceae are publicly available, it is not known how the genes that encode catechol dioxygenases (CDOs), enzymes involved in the degradation of phenolic plant defence compounds, differ among members of the Ceratocystidaceae. The aim of this study was therefore to identify and characterize the genes encoding CDOs in the genomes of Ceratocystidaceae representatives. We found that genes encoding CDOs are more abundant in pathogenic necrotrophic species of the Ceratocystidaceae and less abundant in saprophytic species. The loss of the CDO genes and the associated 3-oxoadipate catabolic pathway appears to have occurred in a lineage-specific manner. Taken together, this study revealed a positive association between CDO gene copy number and fungal lifestyle in Ceratocystidaceae representatives.
Roles for Mitochondrial Complex I subunits in regulating synaptic transmission and growth
Authors: Mallik Bhagaban , Frank C. Andrew 
Published: January 2022

AbstractTo identify conserved components of synapse function that are also associated with human diseases, we conducted a genetic screen. We used the Drosophila melanogaster neuromuscular junction (NMJ) as a model. We employed RNA interference (RNAi) on selected targets and assayed synapse function and plasticity by electrophysiology. We focused our screen on genetic factors known to be conserved from human neurological or muscle functions (300 Drosophila lines screened). From our screen, knockdown of a Mitochondrial Complex I (MCI) subunit gene (ND-20L) lowered levels of NMJ neurotransmission. Due to the severity of the phenotype, we studied MCI function further. Knockdown of core MCI subunits concurrently in neurons and muscle led to impaired neurotransmission. We localized this neurotransmission function to the muscle. Pharmacology targeting MCI phenocopied the impaired neurotransmission phenotype. Finally, MCI subunit knockdowns or pharmacological inhibition led to profound cytological defects, including reduced NMJ growth and altered NMJ morphology. Mitochondria are essential for cellular bioenergetics and produce ATP through oxidative phosphorylation. Five multi-protein complexes achieve this task, and MCI is the largest. Impaired Mitochondrial Complex I subunits in humans are associated with disorders such as Parkinson’s disease, Leigh syndrome, and cardiomyopathy. Together, our data present an analysis of Complex I in the context of synapse function and plasticity. We speculate that in the context of human MCI dysfunction, similar neuronal and synaptic defects could contribute to pathogenesis.