bluuebunny/crossref_metadata_2025_split huggingface dataset:
Visuomotor information drives interference between the hands more than dynamic motor information during bimanual reaching
Authors: Desrochers Phillip C. , Brunfeldt Alexander T. , Kagerer Florian A. 
Published: March 2021

AbstractDuring complex bimanual movements, interference can occur in the form of one hand influencing the action of the contralateral hand. Interference likely results from conflicting sensorimotor information shared between brain regions controlling hand movements via neural crosstalk. However, how visual and force-related feedback processes interact with each other during bimanual reaching is not well understood. In this study, four groups experienced either a visuomotor perturbation, dynamic perturbation, combined visuomotor and dynamic perturbation, or no perturbation in their right hand during bimanual reaches, with each hand controlling its own cursor. The left hand was examined for interference as a consequence of the right-hand perturbation. The results indicated that the visuomotor and combined perturbations showed greater interference in the left hand than the dynamic perturbation, but that the combined and visuomotor perturbations were equivalent. This suggests that dynamic sensorimotor and visuomotor processes do not interact between hemisphere-hand systems, and that primarily visuomotor processes lead to interference between the hands.
Global effects ofade8deletion on budding yeast metabolism
Authors: Kokina Agnese , Tanilas Kristel , Ozolina Zane , Pleiko Karlis , Svirksts Karlis , Vamza Ilze , Liepins Janis 
Published: March 2021

AbstractPurine auxotrophy is a typical marker for many laboratory yeast strains. Supplementation of additional purine source (like adenine) is necessary to cultivate these strains. If not supplied in adequate amounts, purine starvation sets in. We tested purine starvation effects in budding yeastSaccharomyces cerevisiae ade8knockout. We explored effects brought by purine starvation in cellular, central carbon metabolism and in the global transcriptome level.We observed that cells cultivated in purine depleted media became significantly more tolerant to severe thermal, oxidative and desiccation stresses when compared to the cells cultivated in media with all necessary supplements. When starved for purine, cells stop their cell cycle in G1 or G0 state; intracellular concentration of ATP, ADP and AMP decreases, but adenylate charge remains stable. Intracellular RNA concentration decreases and massive downregulation of ribosomal RNA occurs.We think that purine auxotrophic starvation in a way mimics “natural” nitrogen or carbon starvations and therefore initiates elements of a transcriptional program typical for stationary phase cells (cell cycle arrest, increased stress resistance). Therefore our results demonstrate that organised metabolic response is initiated not only via “natural starvations”, but also when starving for metabolic intermediates, like purines.
BIONIC: Biological Network Integration using Convolutions
Authors: Forster Duncan T. , Li Sheena C. , Yashiroda Yoko , Yoshimura Mami , Li Zhijian , Isuhuaylas Luis Alberto Vega , Itto-Nakama Kaori , Yamanaka Daisuke , Ohya Yoshikazu , Osada Hiroyuki , Wang Bo , Bader Gary D. , Boone Charles 
Published: March 2021

AbstractBiological networks constructed from varied data, including protein-protein interactions, gene expression data, and genetic interactions can be used to map cellular function, but each data type has individual limitations such as bias and incompleteness. Network integration promises to address these limitations by combining and automatically weighting input information to obtain a more accurate and comprehensive representation of the underlying biology. However, existing network integration methods may fail to adequately scale to the number of nodes and networks present in genome-scale data, may perform poorly, and may not handle partial network overlap. To address these issues, we developed a deep learning-based network integration algorithm that incorporates a graph convolutional network (GCN) framework to effectively learn dependencies between any input network. Our method, BIONIC (BiologicalNetworkIntegration usingConvolutions), learns features which contain substantially more functional information compared to existing approaches, linking genes that share diverse functional relationships, including co-complex and shared bioprocess annotation. BIONIC can integrate networks in a fully unsupervised manner if functional gene annotations are not available, and it can also leverage available annotations in a semi-supervised manner. BIONIC is scalable in both size and quantity of the input networks, making it feasible to integrate numerous networks on the scale of the human genome. To demonstrate the utility of BIONIC in identifying novel biology, we predicted essential gene chemical-genetic interactions from a small set of diagnostic non-essential gene profiles in yeast, and experimentally validated these predictions. BIONIC correctly predicted many chemical-genetic interactions, and it correctly predicted genes that are required for proper β-1,6-glucan synthesis as significant interactions with the bioactive compound pseudojervine.
Assessing the Role of Calmodulin’s Linker Flexibility in Target Binding
Authors: Sun Bin , Kekenes-Huskey Peter M. 
Published: March 2021

1AbstractCalmodulin (CaM) is a universal Ca2+binding protein known to bind at least 300 targets. The selectivity and specificity towards these targets are partially attributed to the protein’s flexible alpha-helical linker that connects its N- and C-domains. How this flexible linker mediates the driving forces guiding CaM’s binding to regulatory targets is not well-established. Therefore, we utilized the Martini coarse-grained (CG) molecular dynamics simulations to probe interrelationships between CaM/target assembly and the role of its linker region. As a model system, we simulated the binding of CaM to the CaM binding region (CaMBR) of calcineurin (CaN). The simulations were conducted assuming a ‘wild-type’ calmodulin with normal flexibility of its linker, as well as a labile, highly flexible linker variant. For the wild-type model, 98% of the 600 simulations across three ionic strengths adopted a bound complex within 2µs of simulation time; of these, 1.7% sampled the fully-bound state observed in experimentally-determined crystallographic structure. By calculating the mean-first-passage-time for these simulations, we estimated the association rate to beka= 5.9 × 108M−1s−1, which is similar to the experimentally-determined rate of 2.2 × 108M−1s−1[1]. Further, our simulations recapitulated the inverse relationship between the association rate and solution ionic strength reported in the literature. In contrast, although over 97% of the labile linker simulations formed tightly-bound complexes, only 0.3% achieved the fully-bound configuration. This effect appears to stem from a difference in the ensembles of extended and collapsed states controlled by the linker properties. Specifically, the labile linker variant samples fewer extended states compatible with target peptide binding. Therefore, our simulations suggest that variations in the CaM linker’s propensity for alpha-helical secondary structure can modulate the kinetics of target binding. This finding is important, as the linker region houses several CaM variants sites for post-translational modifications, that may alter the protein’s normal regulatory functions.
Inflammatory signals are sufficient to elicit TOX expression in mouse and human CD8 T cells
Authors: Maurice Nicholas J , Berner Jacqueline , Taber Alexis K , Zehn Dietmar , Prlic Martin 
Published: March 2021

AbstractT cell receptor (TCR) stimulation leads to expression of the transcription factor TOX. Prolonged TCR signaling, such as encountered during chronic infections or in tumors, leads to sustained TOX expression, which induces a state of exhaustion or dysfunction. While CD8 memory T cells (Tmem) in specific pathogen-free laboratory mice typically do not express TOX, functional human Tmemshow heterogeneous TOX expression levels. Whether TCR-independent mechanisms can alter TOX expression in human and murine Tmemhas not been defined. We report that human and mouse Tmemincrease TOX expression following stimulation with inflammatory cytokines IL-12, IL-15, and IL-18. TOX and PD-1 expression patterns often appear to be directly correlated, however, we found that TOX is not necessary for cytokine-driven expression of PD-1. Together, these observations highlight that inflammation is sufficient to alter TOX and PD-1 expression and that the signals regulating TOX expression appear well conserved in human and murine Tmem.
Thermal preconditioning in a reef-building coral alleviates oxidative damage through a BI-1 mediated antioxidant response
Authors: Majerová Eva , Drury Crawford 
Published: March 2021

AbstractGlobal coral reef decline is largely driven by the breakdown of the coral-algal symbiosis during temperature stress. Corals can acclimatize to higher temperatures, but the cellular processes underlying this ability are poorly understood. We show that preconditioning-based improvements in thermal tolerance inPocillopora acutaare accompanied by increases in host glutathione reductase (GR) activity and expression, which prevents DNA damage. A strong correlation betweenGRandBI-1expression in heat-stressed preconditioned corals and the presence of an antioxidant response element (ARE) in theGRpromoter suggest BI-1 could regulateGRexpression through Nrf2/ARE pathway. To fortify this link, we developed an siRNA- mediated gene knockdown protocol and targeted the coral BI-1 gene. BI-1 knock-down specifically decreased GR expression and activity and increased oxidative DNA damage in heat- stressed preconditioned corals, showing that BI-1-mediated enhanced antioxidant response during acute heat stress is a key mechanism that prevents oxidative DNA damage after preconditioning.TeaserPreconditioning improves redox homeostasis and prevents oxidative stress in a thermally stressed reef-building coral
Methylation studies in Peromyscus: aging, altitude adaptation, and monogamy
Authors: Horvath Steve , Haghani Amin , Zoller Joseph A. , Naderi Asieh , Soltanmohammadi Elham , Farmaki Elena , Kaza Vimala , Chatzistamou Ioulia , Kiaris Hippokratis 
Published: March 2021

ABSTRACTDNA methylation-based biomarkers of aging have been developed for humans and many other mammals and could be used to assess how stress factors impact aging. Deer mice (Peromyscus) are long living rodents that have emerged as an informative model to study aging, adaptation at extreme environments, and monogamous behavior. In the present study we have undertaken an exhaustive, genome-wide analysis of DNA methylation in Peromyscus, spanning different species, stocks, sexes, tissues and age cohorts. We describe DNA methylation-based estimators of age for different species of deer mice based on novel DNA methylation data generated on highly conserved mammalian CpGs measured with a custom array. The multi-tissue epigenetic clock for deer mice was trained on 3 tissue sources (tail, liver, brain). Two dual species human-peromyscus clocks accurately measure age and relative age defined as the ratio of chronological age to maximum age. These analyses also allowed us to accurately manifest the increasing impact of age, sex, genetic relatedness, and ultimately tissue identity, in that order, in the acquisition of specific methylation patterns in the genome. Genes that were differentially methylated across different biological variables were determined and their potential impact is discussed. This study describes highly accurate DNA methylation-based estimators of age in deer mice and illustrates how differential methylation may be linked to adaptation at different conditions.
A gut-restricted lithocholic acid analog as an inhibitor of gut bacterial bile salt hydrolases
Authors: Adhikari Arijit A. , Ramachandran Deepti , Chaudhari Snehal N. , Powell Chelsea E. , McCurry Megan D. , Banks Alexander S. , Devlin A. Sloan 
Published: March 2021

AbstractBile acids play crucial roles in host physiology by acting as both detergents that aid in digestion and as signaling molecules that bind to host receptors. Gut bacterial bile salt hydrolase (BSH) enzymes perform the gateway reaction leading to the conversion of host-produced primary bile acids into bacterially modified secondary bile acids. Small molecule probes that target BSHs will help elucidate the causal roles of these metabolites in host physiology. We previously reported the development of a covalent BSH inhibitor with low gut permeability. Here, we build on our previous findings and describe the development of a second-generation gut-restricted BSH inhibitor with enhanced potency, reduced off-target effects, and durable in vivo efficacy. SAR studies focused on the bile acid core identified a compound,AAA-10, containing a C3-sulfonated lithocholic acid scaffold and an alpha-fluoromethyl ketone warhead as a potent pan-BSH inhibitor. This compound inhibits BSH activity in conventional mouse fecal slurries, bacterial cultures, and purified BSH proteins and displays reduced toxicity against mammalian cells compared to first generation compounds. Oral administration ofAAA-10to wild-type mice for 5 days resulted in a decrease in the abundance of the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) in the mouse GI tract with low systemic exposure ofAAA-10, demonstrating thatAAA-10is an effective tool for inhibiting BSH activity and modulating bile acid pool composition in vivo.
Natural Occurring Non-Synonymous Single Nucleotide Polymorphisms in Integrase and RNase H Regulate Assembly and Autoprocessing of HIV-1
Authors: Imamichi Tomozumi , Bernbaum John G. , Laverdure Sylvain , Yang Jun , Chen Qian , Highbarger Helene , Hao Ming , Sui Hongyan , Dewar Robin , Chang Weizhong , Lane H. Clifford 
Published: March 2021

AbstractRecently, a genome-wide association study using plasma HIV RNA reported that 14 naturally occurring non-synonymous single nucleotide polymorphisms (SNPs) in HIV derived from anti-retrovirus naïve patients were associated with virus load (VL). However, the impact of each mutation on viral fitness was not investigated. Here, we constructed a series of HIV variants encoding each SNP using site-directed mutagenesis and examined their replicative abilities and biological properties. An HIV variant containing Met-to-Ile change at codon 50 in integrase (HIV(IN:M50I)) was found an impaired virus. Despite the mutation being in integrase, a quantification assay demonstrated that the virus release was significantly suppressed (P<0.001). Transmission electron microscopy analyses revealed that the accumulation of abnormal shapes of buds on the plasma membrane and the released virus particles retained immature forms. Western blot analysis demonstrated a defect in autoprocessing of GagPol and Gag polyproteins in the HIV(IN:M50I) particles. Förster Resonance Energy Transfer (FRET) assay displayed that GagPol containing IN:M50I (GagPol(IN:M50I)) significantly increased the efficiency of homodimerization (P<0.05) and heterodimerization with Gag (P<0.001), compared to GagPol(WT). HIV replication assay using a series of variants of HIV(IN:M50I) elucidated that the C-terminus residues, Asn at codon 288, plays a key role in the defect and the impaired maturation and replication capability was rescued by two other VL-associated SNPs, Ser-to-Asn change at codon 17 in integrase or Asn-to-Ser change at codon 79 in RNase H. These data demonstrate that Gag and GagPol assembly, virus release and autoprocessing are not only regulated by integrase but also RNase H.ImportanceA nascent HIV-1 is noninfectious. To become an infectious virus, Gag and GagPol polyproteins in the particles need to be cleaved by mature HIV protease (PR). PR is initially translated as an inactive embedded enzyme in a GagPol polyprotein. The embedded PR in homodimerized GagPol polyproteins catalyzes a proteolytic reaction to release the mature PR. This excision step by a self-cleavage is called autoprocessing. Here, during the evaluation of roles of naturally emerging non-synonymous SNPs in HIV RNA, we found that autoprocessing is inhibited by Met-to-Ile change at codon 50 in integrase in GagPol which increases the efficiency of heterodimerization with Gag. This defect was recovered by co-existing of other SNPs: Ser-to-Asn change at codon 17 in integrase or Asn-to-Ser mutation at codon 79 in RNase H, suggesting that autoprocessing is regulated by not only integrase but also RNase H in GagPol polyprotein.
Amotosalen is a bacterial multidrug efflux pump substrate potentially affecting its pathogen inactivation activity
Authors: Green Alex B. , Zulauf Katelyn E. , Truelson Katherine A. , Chiaraviglio Lucius , Cui Meng , Zhang Zhemin , Ware Matthew P. , Flegel Willy A. , Haspel Richard L. , Yu Ed , Kirby James E 
Published: March 2021

AbstractPathogen inactivation is a strategy to improve the safety of transfusion products. The Cerus Intercept technology makes use of a psoralen compound called amotosalen in combination with UVA light to inactivate bacteria, viruses and protozoa. Psoralens have structural similarity to bacterial multidrug-efflux pump substrates. As these efflux pumps are often overexpressed in multidrug-resistant pathogens and with recent reported outbreaks of transfusion-associated sepsis withAcinetobacter, we tested whether contemporary drug-resistant pathogens might show resistance to amotosalen and other psoralens based on multidrug efflux mechanisms through microbiological, biophysical and molecular modeling analysis. The main efflux systems inEnterobacteralesandAcinetobacter baumannii, tripartite RND (resistance-nodulation-cell division) systems which span the inner and outer membranes of Gram-negative pathogens and expel antibiotics from the bacterial cytoplasm into the extracellular space, were specifically examined. We found that amotosalen was an efflux substrate for the TolC-dependent RND efflux pumps inE. coliand the AdeABC efflux pump fromAcinetobacter baumannii, and that minimal inhibitory concentrations for contemporary bacterial isolatesin vitroapproached and exceeded the concentration of amotosalen used in the approved platelet and plasma inactivation procedures. These findings suggest that otherwise safe and effective inactivation methods should be further studied to exclude possible gaps in their ability to inactivate contemporary, multidrug-resistant bacterial pathogens.ImportancePathogen inactivation is a strategy to enhance the safety of transfused blood products. We identify the compound, amotosalen, widely used for pathogen inactivation, as a bacterial multidrug efflux substrate. Specifically, experiments suggest that amotosalen is pumped out of bacteria by the major TolC-dependent RND efflux pumps inE. coliand the AdeABC efflux pump inAcinetobacter baumannii. Such efflux pumps are often overexpressed in multidrug-resistant pathogens. Importantly, the minimal inhibitory concentrations for contemporary multidrug-resistantEnterobacterales,Acinetobacter baumannii,Pseudomonas aeruginosa,Burkholderiaspp.,and Stenotrophomonas maltophiliaisolates approached or exceeded the amotosalen concentration used in approved platelet and plasma inactivation procedures, potentially as a result of efflux pump activity. Although there are important differences in methodology between our experiments and blood product pathogen inactivation, these findings suggest that otherwise safe and effective inactivation methods should be further studied to exclude possible gaps in their ability to inactivate contemporary, multidrug-resistant bacterial pathogens.
Finger representation in the cortex of the congenitally blind
Authors: Wesselink D.B. , Kikkert S. , Bridge H. , Makin T.R. 
Published: March 2021

AbstractHand representation in the primary somatosensory cortex (S1) is thought to be shaped by experience. Individuals with congenital blindness rely on their sense of touch for completing daily tasks that in sighted people would be informed by vision, and possess superior tactile acuity. It has therefore been proposed that their S1 hand representation should differ from that of sighted individuals. Alternatively, it has been proposed that the improved tactile acuity in blind individuals is due to cross-modal plasticity, when regions in the occipital and temporal cortex are typically used for processing vision become activated by touch. We probed finger representation using psychophysics and 7T fMRI (1 mm3resolution) in three individuals with bilateral anophthalmia, a rare condition in which both eyes fail to develop, as well as sighted controls. Despite anophthalmic individuals’ increased reliance on touch and superior tactile acuity, we found no evidence that they had more pronounced hand representation in S1. This is in line with recent research highlighting the stability of early sensory cortex, despite altered sensorimotor experience in adulthood. Unlike sighted controls, anophthalmic individuals activated the left human middle temporal complex (hMT+) during finger movement. This area did not express any hallmark of typical sensorimotor organisation, suggesting this and previously reported activity does not indicate low-level sensorimotor hand representation. However, left hMT+ contained some single finger information, beyond that found in sighted controls. This latter finding suggests that when the developmentally flexible area hMT+ is unaffected by retinal input, it can acquire novel cross-modal processes, which are potentially unrelated to the area’s function in sighted people. As such, our findings highlight the opportunity for other organising principles, beyond domain specific plasticity, in shaping cross-modal reorganisation.
Cannabidiol attenuates cognitive deficits and neuroinflammation induced by early alcohol exposure in a mice model
Authors: García-Baos Alba , Puig-Reyne Xavi , García-Algar Óscar , Valverde Olga 
Published: March 2021

SummaryFoetal alcohol spectrum disorder (FASD) is the umbrella term used to describe the physical and mental disabilities induced by alcohol exposure during development. Early alcohol exposure induces cognitive impairments resulting from damage to the central nervous system (CNS). The neuroinflammatory response accompanied by neurodegenerative mechanisms contribute to those detrimental alterations. Cannabidiol (CBD) has recently emerged as an anti-inflammatory drug that might be useful to treat several neuropsychiatric disorders. In our study, we assessed the effects of CBD on long-lasting cognitive deficits induced by early alcohol exposure. Furthermore, we analysed long-term pro-inflammatory and apoptotic markers within the prefrontal cortex and hippocampus. To model alcohol binge drinking during gestational and lactation periods, we used pregnant C57BL/6 female mice with time-limited access to 20% v/v alcohol solution. Following the prenatal and lactation alcohol exposure (PLAE), we treated the male and female offspring with CBD from post-natal day (PD) 25 until PD34, and we evaluated their cognitive performance at PD60. Our results showed that CBD treatment during peri-adolescence period ameliorates cognitive deficits observed in our FASD-like mouse model, without sex differences. Moreover, CBD restores the PLAE-induced increased levels of TNFα and IL-6 in the hippocampus. Thus, our study provides new insights for CBD as a therapeutic agent to counteract cognitive impairments and neuroinflammation caused by early alcohol exposure.