bluuebunny/crossref_metadata_2025_split huggingface dataset:
Strategies of developmental vestibular plasticity after unilateral embryonic ear removal in Xenopus laevis
Authors: Gordy Clayton , Straka Hans 
Published: June 2022

AbstractAppropriate gaze control mechanisms rely on bilateral mirror-symmetric vestibular endorgans, central circuits, and extraocular motor effectors. Embryonic removal of one inner ear prior to the formation of these structures was used to evaluate the extent to which animals can develop appropriate motor outputs in the presence of only a singular inner ear. Near-congenital one-eared tadpoles subjected to separate or combinatorial visuo-vestibular motion stimulation exhibited vestibular-ocular reflexes, though smaller in gain compared to controls, whereas isolated visuo-motor responses remained largely unaltered. Surprisingly, direction-specific responses in one-eared tadpoles revealed a spectrum of vestibulo-ocular reflex performance, where in many cases rather robust responses were observed during head motion towards the missing ear. Rotation toward the remaining ear elicited eye movements which were often severely attenuated. This suggests that embryonically generated one-eared animals develop bidirectional vestibular signal detection and downstream processing capacities that allow activation of robust compensatory eye movements. However, this capability seems to occur at the expense of performance of vestibular reflexes during motion in the canonical activation direction of the singular ear. Consequently, the development of central vestibulo-motor circuits in one-eared animals likely relies on strategies in which the outcome for gaze stabilization is driven by balanced homeostatic levels and individual temporal tuning of abducens motoneuron activity. Despite the lack of bilateral symmetric vestibular afferent input, the developing central nervous system is capable of creating a framework for symmetric sensorimotor transformations.
Co-occurrence of past and present shifts current neural representations and mediates serial biases
Authors: Zhang Huihui , Luo Huan 
Published: June 2022

AbstractThe regularities of the world render an intricate interplay between past and present. Even across independent trials, current-trial perception can be automatically shifted by preceding trials, namely the ‘serial bias’. Meanwhile, the neural implementation of the spontaneous shift of present by past that operates on multiple features remains unknown. In two auditory categorization experiments with human electrophysiology recordings, we demonstrate that serial bias arises from the co-occurrence of past-trial neural reactivation and the neural encoding of current-trial features. The meeting of past and present shifts the neural representation of current-trial features and modulates serial bias behavior. Critically, past-trial features (i.e., pitch, category, motor response) that constitute an ‘event-file’ keep their respective identities in working memory and are only reactivated by the corresponding features in the current trial, giving rise to dissociated feature-specific serial biases. This ’event-file’ reactivation might constitute a fundamental mechanism for adaptive past-to-present generalizations over multiple features.
“Genetic and chemical disruption of Amyloid Precursor Protein processing impairs zebrafish sleep maintenance”
Authors: Özcan Güliz Gürel , Lim Sumi , Canning Thomas , Tirathdas Lavitasha , Donnelly Joshua , Kundu Tanushree , Rihel Jason 
Published: June 2022

AbstractAmyloid precursor protein (APP) is a brain-rich, single pass transmembrane protein that is proteolytically processed into multiple products, including Amyloid-beta (Aβ), a major driver of Alzheimer’s disease (AD). Although both over-expression of APP, as in mouse models used to study AD, and exogenously delivered Aβ lead to changes in sleep behaviors, whether APP processing plays an endogenous role in regulating sleep is unknown. Here, we demonstrate that APP processing into Aβ40 and Aβ42 is conserved in zebrafish and then describe sleep/wake phenotypes in loss of functionappaandappbmutants. Larvae with mutations inappahad reduced waking activity but normal sleep patterns, while larvae that lackedappbhad shortened sleep bout durations at night. Treatment with the γ-secretase inhibitor DAPT also shortened sleep bouts at night, while the BACE-1 inhibitor lanabecestat lengthened sleep bouts. Since both drugs fail to further alter sleep inappbmutants, and intraventricular injection of the App cleavage product P3 also shortens night-time sleep bouts, we conclude that the proper balance of Appb proteolytic processing is required for normal sleep maintenance in zebrafish.
Alterations in neural stem cell quiescence and activation in the 3xTG-AD model of Alzheimer’s Disease
Authors: Liu Yubing , Fong Bensun C. , Harris Richard A. , McNicoll Marie-Michelle , Abdi Amaal A. , Cuthbert Jacob B. , Cook David P. , Figeys Daniel , Wang Jing , Vanderhyden Barbara C. , Slack Ruth S. 
Published: June 2022

AbstractAlzheimer’s Disease (AD) is the most common form of dementia with progressive cognitive deficits and mood disorders (Knopman et al., 2021). Recent studies have associated AD pathology with the impairment of adult neurogenesis, as indicated by impaired neural stem cell (NSCs) homeostasis (Bond et al., 2015). Recent work has further associated AD progression with a decline in the number and maturation of adult-born neurons in the SGZ, distinct from typical age-related decline (Moreno-Jiménez et al., 2019). In 3xTG-AD mice, a well-established mouse model of AD, our and other groups have demonstrated impairments to NSC pool and neural progenitor proliferation, as well as adult-born neurons, before the onset of Aβ plaques and NFTs (Hamilton et al., 2010, 2015; Rodríguez et al., 2008, 2009). However, the regulatory mechanisms underlying the functional impairment of adult NSCs remain to be resolved. Here, we employ single-cell RNA-Seq to establish population-specific defects in the 3xTG-AD mouse model during adult SGZ neurogenesis. Relative to control mice, we observe a dramatic AD-induced decrease in the primed and activated NSC population, which results in a progressive loss of cells committed to neurogenesis. Transcriptome measurements suggest that 3xTG-AD NSCs and their progeny represent enhanced ribosomal and mitochondrial biogenesis, and disturbed Notch signaling pathway. RNA velocity analysis reveals reduced NSC activation as evidenced by a large fraction of Ascl1-postive cells, instead of entering cell cycle, returning to the primed and quiescent state. This is further supported by reduced numbers of Lpar1-expressing cells, a marker of neural progenitor cells, in the SGZ. Our work explores, at a stage-specific resolution, changes in the regulatory networks guiding adult neurogenesis, and identifies niche disturbances in the regulation of NSC quiescence and activation. These NSC deficits underlying impaired neurogenesis identified in AD mice, may be key contributors underlying the compromised hippocampal function in AD.
Binding and unbinding pathways of peptide substrate on SARS-CoV-2 3CL protease
Authors: Moritsugu Kei , Ekimoto Toru , Ikeguchi Mitsunori , Kidera Akinori 
Published: June 2022

AbstractBased on many crystal structures of ligand complexes, much study has been devoted to understanding the molecular recognition of SARS-CoV-2 3C-like protease (3CLpro), a potent drug target for COVID-19. In this research, to extend this present static view, we examined the kinetic process of binding/unbinding of an eight-residue substrate peptide to/from 3CLpro by evaluating the path ensemble with the weighted ensemble simulation. The path ensemble showed the mechanism of how a highly flexible peptide folded into the bound form. At the early stage, the dominant motion was the diffusion on the protein surface showing a broad distribution, whose center was led into the cleft of the Chymotrypsin fold. We observed a definite sequential formation of the hydrogen bonds at the later stage occurring in the cleft, initiated between Glu166 (3CLpro) and P3_Val (peptide), followed by binding to the oxyanion hole and completed by the sequencespecific recognition at P1_Gln.
Cancers adapt to their mutational load by buffering protein misfolding stress
Authors: Tilk Susanne , Frydman Judith , Curtis Christina , Petrov Dmitri 
Published: June 2022

AbstractIn asexual populations that don’t undergo recombination, such as cancer, deleterious mutations are expected to accrue readily due to genome-wide linkage between mutations. Despite this mutational load of often thousands of deleterious mutations, many tumors thrive. How tumors survive the damaging consequences of this mutational load is not well understood. Here, we investigate the functional consequences of mutational load in 10,295 human tumors by quantifying their phenotypic response through changes in gene expression. Using a generalized linear mixed model (GLMM), we find that high mutational load tumors up-regulate proteostasis machinery related to the mitigation and prevention of protein misfolding. We replicate these expression responses in cancer cell lines and show that the viability in high mutational load cancer cells is strongly dependent on complexes that degrade and refold proteins. This indicates that upregulation of proteostasis machinery is causally important for high mutational burden tumors and uncovers new therapeutic vulnerabilities.Statement of SignificanceCancers can successfully survive an accumulation of thousands of protein-damaging mutations. Here, we show that high mutational load tumors mitigate these damaging consequences by up-regulating complexes that buffer against protein misfolding stress – providing novel therapeutic vulnerabilities and suggesting that disruption of proteostasis is a hallmark of somatic evolution.
C-terminal disulfide bond in SUN2 regulate dynamic remodeling of LINC complexes at the nuclear envelope
Authors: Sharma Rahul , Hetzer Martin W. 
Published: June 2022

AbstractThe LINC complex tethers the cell nucleus to the cytoskeleton to regulate mechanical forces during cell migration, differentiation, and diseases. The function of LINC complexes relies on the interaction between highly conserved SUN and KASH proteins that form higher-order assemblies capable of load bearing. These structural details have emerged from in vitro assembled LINC complexes however, the principles of in vivo assembly remain obscure. Here, we report a conformation-specific SUN2 antibody as a tool to visualize LINC complex dynamics in situ. Using imaging, biochemical and cellular methods, we find that conserved cysteines in SUN2 undergo KASH dependent inter- and intra- molecular disulfide bond rearrangements. Disruption of the SUN2 terminal disulfide bond compromises SUN2 localization, turnover, LINC complex assembly as well as cytoskeletal organization and cell migration. Moreover, using pharmacological and genetic interventions, we identify components of the ER lumen as SUN2 cysteines redox state regulators. Overall, we provide evidence for SUN2 disulfide bond rearrangement as a physiologically relevant structural modification that regulates LINC complex functions.
Mechanical properties of breast, kidney, and thyroid tumours measured by AFM: relationship with tissue structure
Authors: Levillain A. , Confavreux C.B. , Decaussin-Petrucci M. , Durieux E. , Paparel P. , Le-Bail Carval K. , Maillard L. , Bermond F. , Mitton D. , Follet H. 
Published: June 2022

AbstractThe mechanical properties of the extracellular matrix are essential for regulating cancer cell behaviour, but how they change depending on tumour type remains unclear. The aim of the current study was to determine how the mechanical properties of tumours that frequently metastasize to bones were affected depending on histological type. Human breast, kidney, and thyroid specimens containing tumour and normal tissue were collected during surgery. The elastic modulus and elastic fraction of each sample were characterised using atomic force microscopy and compared with histopathological markers. We observed that tumour mechanical properties were differentially affected depending on organ and histological type. Indeed, clear cell renal carcinoma and poorly differentiated thyroid carcinoma displayed a decrease in the elastic modulus compared to their normal counterpart, while breast tumours, papillary renal carcinoma and fibrotic thyroid tumours displayed an increase in the elastic modulus. Elastic fraction decreased only for thyroid tumour tissue, indicating an increase in the viscosity. These findings suggest a unique mechanical profile associated with each subtype of cancer. Therefore, viscosity could be a discriminator between tumour and normal thyroid tissue, while elasticity could be a discriminator between the subtypes of breast, kidney and thyroid cancers.Graphical abstract
ARF6 is a host factor for SARS-CoV-2 infectionin vitro
Authors: Mirabelli C. , Sherman E.J. , Cunha J. Bragazzi , Wotring J.W. , El Saghir J. , Harder J. , Kretzler M. , Sexton J.Z. , Emmer B.T. , Wobus C.E. 
Published: June 2022

AbstractSARS-CoV-2 is a newly emerged beta-coronavirus that enter cells via two routes, direct fusion at the plasma membrane or endocytosis followed by fusion with the late endosome/lysosome. While the viral receptor, ACE2, multiple entry factors, and the mechanism of fusion of the virus at the plasma membrane have been extensively investigated, viral entry via the endocytic pathway is less understood. By using a human hepatocarcinoma cell line, Huh-7, which is resistant to the antiviral action of the TMPRSS2 inhibitor camostat, we discovered that SARS-CoV-2 entry is not dependent on dynamin but dependent on cholesterol. ADP-ribosylation factor 6 (ARF6) has been described as a host factor for SARS-CoV-2 replication and it is involved in the entry and infection of several pathogenic viruses. Using CRISPR-Cas9 genetic deletion, we observed that ARF6 is important for SARS-CoV-2 uptake and infection in Huh-7. This finding was corroborated using a pharmacologic inhibitor, whereby the ARF6 inhibitor NAV-2729 showed a dose-dependent inhibition of viral infection. Importantly, NAV-2729 reduced SARS-CoV-2 viral loads also in more physiologic models of infection: Calu-3 and kidney organoids. This highlighted the importance of ARF6 in multiple cell contexts. Together, these experiments points to ARF6 as a putative target to develop antiviral strategies against SARS-CoV-2.
Glutamine metabolism modulates chondrocyte inflammatory response
Authors: Arra Manoj , Swarnkar Gaurav , Adapala Naga Suresh , Naqvi Syeda Kanwal , Cai Lei , Rai Farooq , Mbalaviele Gabriel , Brophy Robert , Abu-Amer Yousef 
Published: June 2022

AbstractOsteoarthritis is the most common joint disease in the world with significant societal consequences, but lacks effective disease modifying interventions. The pathophysiology consists of a prominent inflammatory component that can be targeted to prevent cartilage degradation and structural defects. Intracellular metabolism has emerged as a culprit of the inflammatory response in chondrocytes, with both processes co-regulating each other. The role of glutamine metabolism in chondrocytes, especially in the context of inflammation, lacks a thorough understanding and is the focus of this work. We display that chondrocytes utilize glutamine for energy production and anabolic processes. Furthermore, we show that glutamine deprivation itself causes metabolic reprogramming and decreases the inflammatory response of chondrocytes through inhibition of NF-κB activity. Finally, we display that glutamine deprivation promotes autophagy and that ammonia is an inhibitor of autophagy. Overall, we identify a relationship between glutamine metabolism and inflammatory signaling and display the need for increased study of chondrocyte metabolic systems.
Identification of a small chemical as a lysosomal calcium mobilizer and characterization of its ability to inhibit autophagy and viral infection
Authors: Zhang Kehui , Huang Lihong , Chen Nanjun , Yue Jianbo 
Published: June 2022

ABSTRACTWe previously identified GADPH as one of the cyclic adenosine diphosphoribose (cADPR)’s binding proteins and found that GADPH participates in cADPR-mediated Ca2+ release from ER via RyRs. Based on the simulated cADPR-GAPDH complex structure, we performed the structure-based drug screening, identified several small chemicals with high docking scores to cADPR’s binding pocket in GAPDH, and showed that two of these compounds, C244 and C346, are potential cADPR antagonists. We further synthesized several analogs of C346, and found that its analog, G42, also mobilized Ca2+ release from lysosomes. G42 alkalized lysosomal pH, and inhibited autophagosome-lysosome fusion. Moreover, G42 markedly inhibited Zika virus (ZIKV, a flavivirus) or murine hepatitis virus (MHV, a β-coronavirus) infections of host cells. These results suggest that G42 inhibits virus infection, likely by triggering lysosomal Ca2+ mobilization and inhibiting autophagy.
PTC2 region genotypes counteract Biomphalaria glabrata population differences between M-line and BS90 in resistance to infection by Schistosoma mansoni
Authors: Blouin Michael S. , Bollmann Stephanie R. , Tennessen Jacob A. 
Published: June 2022

AbstractBackgroundBiomphalaria glabrata is a snail intermediate host for Schistosoma mansoni, a trematode responsible for human schistosomiasis. BS90 is one of the most well studied strains of B. glabrata owing to its high resistance to infection by most strains of S. mansoni. An F2 mapping study from 1999 identified two RAPD markers that associated with what appeared to be single-locus, dominant resistance by the BS90 population relative to the susceptible M-line population. One marker cannot be mapped, but the other, OPM-04, maps to within 5 Mb of PTC2, a region we recently showed has a very large effect on resistance within another snail population challenged by the same strain of parasite (PR1). Here we tested the hypothesis that the PTC2 region contains the causal gene/s that explain the iconic resistance of BS90 snails.MethodsWe used marker-assisted backcrossing to drive the BS90 version of the PTC2 region (+/-∼ 1 Mb on either side) into an M-line (susceptible strain) genetic background, and the M-line version into a BS90 genetic background. We challenged the offspring with PR1-strain schistosomes and tested for effects of allelic variation in the PTC2 region in a common genetic background.ResultsRelative to M-line haplotypes, the BS90 haplotype actually confers enhanced susceptibility. So we reject our original hypothesis. One possible explanation for our result was that the causal gene linked to OPM-04 is near, but not in the PTC2 block that we introgressed into each line. So we used an F2 cross to independently test the effects of the PTC2 and OPM-04 regions in a randomized genetic background. We confirmed that the BS90 haplotype confers increased susceptibility, and we see a similar, although non-significant effect at OPM-04. We discuss possible reasons why our results differed so dramatically from those of the 1999 study. We also present PacBio assemblies of the PTC2 and flanking region in BS90 and M-line, compare with previously published PTC2 haplotypes, and discuss candidate genes that might be behind the enhanced susceptibility of the BS90 haplotype.
Decreasing photosystem antenna size: a double-edged sword for canopy photo-synthetic efficiency
Authors: Mao Linxiong , Song Qingfeng , Li Ming , Liu Xinyu , Shi Zai , Chen Faming , Chen Gen-yun , Zhu Xin-Guang 
Published: June 2022

AbstractOptimization of antenna size of photosynthetic systems is one strategy to increase plant canopy photosynthesis and crop yield potential. The relationship between antenna size and photosynthesis rate has been extensively studied recently. However, conflicting results have been obtained. Here we show that the extent of decrease in antenna size is a major factor determining the consequences of decreasing antenna on photosynthesis and growth-related parameters. Specifically, we constructed transgenic rice lines with artificial microRNA (amiRNA) targeting to Chlorophyll Synthesis (YGL1) to generate transgene heterozygous and homozygous lines with different leaf chlorophyll contents and antenna sizes. We found that canopy photosynthesis (Ac), biomass and grain yield of the heterozygote were not significantly different from those of WT while the Ac, biomass and grain yield of the homozygote were lower than those of WT. Further, when the maximal quantum yield of photosystem II (Fv/Fm) was larger than 0.8, decreasing antenna size by reducing chlorophyll biosynthesis did not affect leaf photosynthesis; but when Fv/Fm was lower than 0.8, there is a positive relationship between antenna size and leaf photosynthesis. There is large variation in both leaf chlorophyll content and antenna size in elite rice cultivars, suggesting that there is a large scope to decrease leaf chlorophyll content to increase nitrogen use efficiency as long as the quantum yield of PSII is not compromised.
The Cdc42 effector and non-receptor tyrosine kinase, ACK defines a distinct STAT5 transcription signature in a chronic myeloid leukaemia cell model
Authors: Corry Jessica , Jachimowicz Daniel , Keith Benjamin , Vicente-Garcia Jose Julio , Mott Helen R. , Wickson Kate , Owen Darerca 
Published: June 2022

SummaryActivated Cdc42-associated kinase (ACK) is a Rho family effector that is widely implicated in cancer. Here, we describe new roles for ACK in transcriptional regulation mediated by its relationship with the signal transducer and activators of transcription (STAT) family. We show that ACK can interact with STAT3, STAT5A and STAT5B, and augments phosphorylation at the conserved activation tyrosine on these STAT members. ACK stimulates oncogenic STAT nuclear relocation and transcriptional activation. We also identify endogenous relationships between ACK and STAT family members in haematopoietic disease cell lines. In the K562 chronic myeloid leukaemia cell line, we confirm that ACK contributes to the pool of active, nuclear STAT5. By interrogating ACK knock out cells we describe an ACK-driven STAT5 transcriptional signature in K562s. We propose ACK as a contributor to hyperactivated STAT5 signalling in this CML cell line and reveal a new route for therapeutic intervention.