bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cobalamin riboswitches are broadly sensitive to corrinoid cofactors to enable an efficient gene regulatory strategy
Authors: Kennedy Kristopher J. , Widner Florian J. , Sokolovskaya Olga M. , Innocent Lina V. , Procknow Rebecca R. , Mok Kenny C. , Taga Michiko E. 
Published: February 2022

AbstractIn bacteria, many essential metabolic processes are controlled by riboswitches, gene regulatory RNAs that directly bind and detect metabolites. Highly specific effector binding enables riboswitches to respond to a single biologically relevant metabolite. Cobalamin riboswitches are a potential exception because over a dozen chemically similar but functionally distinct cobalamin variants (corrinoid cofactors) exist in nature. Here, we measured cobalamin riboswitch activity in vivo using a Bacillus subtilis fluorescent reporter system and found that among 38 tested riboswitches, a subset responded to corrinoids promiscuously, while others were semi-selective. Analyses of chimeric riboswitches and structural models indicate that, unlike other riboswitch classes, cobalamin riboswitches indirectly differentiate among corrinoids by sensing differences in their structural conformation. This regulatory strategy aligns riboswitch-corrinoid specificity with cellular corrinoid requirements in a B. subtilis model. Thus, bacteria can employ broadly sensitive riboswitches to cope with the chemical diversity of essential metabolites.
Hormone levels increase in response to video playback in the Siamese fighting fish
Authors: Alex Deepa , Cardoso Sara D. , Ramos Andreia , Gonçalves David 
Published: February 2022

AbstractThe mechanisms of action of hormones regulating aggression in fish remain poorly understood. One possibly confounding variable is the lack of standardization in the type of stimuli used to elicit aggression. The presentation of controlled stimuli in videos, a.k.a. video playback, can provide better control of the fight components. However, this technique has produced conflicting results in animal behaviour studies and needs to be carefully validated. Here, the response of male Betta splendens to a matched for size conspecific fighting behind a one-way mirror presented live or through video playback was compared. Despite their non-interactive nature, both stimuli elicited a strong aggressive response by focal fish, which started with stereotypical threat displays and progressed to overt attacks. Overall, the frequency and duration of aggressive behaviours and swimming activity were similar towards live and video stimuli. Post-fight plasma levels of the androgen 11-ketotestosterone were elevated as compared to controls, regardless of the type of stimuli. Cortisol also increased in response to the video images, as previously described for interactive live fights in this species. The study shows for the first time in a fish a robust endocrine response to video stimuli and supports the use of this technique for researching aggressive behaviour in B. splendens.
The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria
Authors: Uyoga S , Watson JA , Wanjiku P , Rop JC , Makale J , Macharia AW , Kariuki SN , Nyutu GM , Shebe M , Mosobo M , Mturi N , Rockett KA , Woodrow CJ , Dondorp AM , Maitland K , White NJ , Williams TN 
Published: February 2022

AbstractSevere falciparum malaria is a major cause of preventable child mortality in sub-Saharan Africa. The sequestration of parasitized erythrocytes in the microvasculature of vital organs is a central pathophysiological feature. The plasma concentration of the parasite protein P. falciparum Histidine-Rich Protein 2 (PfHRP2) has diagnostic and prognostic value in severe malaria. In the current study we investigate the potential use of plasma PfHRP2 and the sequestration index (the ratio of plasma PfHRP2 to circulating parasites) as quantitative traits in the conduct of case-only genetic association studies of severe malaria. We demonstrate the utility of this approach using data from over 2,000 Kenyan children with severe malaria, genotyped for 14 major candidate genes that were found to be associated with protection against severe malaria in previous studies. We show that PfHRP2 is a more informative quantitative trait than peripheral parasite density, and that polymorphisms in four major red cell genes (the βS sickle mutation in HBB, the blood group mutation O in ABO, the α-thalassaemia mutation in HBA, and the Dantu blood group mutation in GYP) are associated with substantially lower concentrations of plasma PfHRP2 at admission. Further, the effect sizes we observed were considerably larger than those relating to peripheral parasite density. An unexpected outlier was the rs1541255 A>G polymorphism in ATP2B4 for which we saw higher plasma PfHRP2 concentrations, lower parasite densities and a higher sequestration index. We provide testable hypotheses for how this might be explained in the context of this specific protective allele.
Do we parse the background into separate streams in the cocktail party?
Authors: Szalárdy Orsolya , Tóth Brigitta , Farkas Dávid , Orosz Gábor , Winkler István 
Published: February 2022

AbstractIn the cocktail party situation, people with normal hearing usually follow a single speaker among multiple concurrent ones. However, there is no agreement in the literature as to whether the background is segregated into multiple streams/speakers. The current study varied the number of concurrent speech streams and investigated target detection and memory for the contents of a target stream as well as the processing of distractors. A male-spoken target stream was either presented alone (single-speech), together with one male-spoken (one-distractor), or a male- and a female-spoken distractor (two-distractor). Behavioral measures of target detection and content tracking performance as well as target- and distractor detection related ERPs were assessed. We found that the detection sensitivity and the target N2b amplitude decreased whereas the P3b amplitude increased from the single-speech to the concurrent speech streams conditions. Importantly, the behavioral distractor effect differed between the conditions with one- vs. two-distractor (distraction by the female speaker was lower than that of the male speaker in either condition) and the target N2b elicited in the presence of two distractors was significantly smaller than that elicited in the presence of one distractor. Further, the voltage in the N2b time window significantly differed between the one- and two-distractor conditions for the same (M2) speaker. These results show that speech processing was different in the presence of one vs. two distractors, and thus, the current data suggest that the two background speech streams were segregated from each other.
Gradients of orientation, composition and hydration of proteins for efficient light collection by the cornea of the horseshoe crab
Authors: Spaeker Oliver , Taylor Gavin , Wilts Bodo , Slabý Tomáš , Abdel-Rahman Mohamed Ashraf Khalil , Scoppola Ernesto , Schmitt Clemens NZ , Sztucki Michael , Liu Jiliang , Bertinetti Luca , Wagermaier Wolfgang , Scholtz Gerhard , Fratzl Peter , Politi Yael 
Published: February 2022

AbstractThe lateral eyes of the horseshoe crab, Limulus polyphemus, are the largest compound eyes within recent Arthropoda. While this visual system has been extensively described before, the precise mechanism allowing vision has remained controversial. Correlating quantitative refractive index (RI) mapping and detailed structural analysis, we demonstrate how gradients of RI in the cornea result from the hierarchical organization of chitin-protein fibers, heterogeneity in protein composition and bromine doping, as well as spatial variation in water content. Combining the realistic cornea structure and measured RI gradients with full-wave optical modelling and ray-tracing approaches, we show that the light collection mechanism depends on both refraction-based graded index (GRIN) optics and total internal reflection. The optical properties of the cornea are governed by different mechanisms at different hierarchical levels, demonstrating the remarkable versatility of arthropod cuticle.One-sentence summaryStructural hierarchy and protein hydration determine the optical performance of the cornea of L. polyphemus.
Monomeric α-Synuclein activates the Plasma Membrane Calcium Pump
Authors: Kowalski Antoni , Betzer Cristine , Larsen Sigrid Thirup , Gregersen Emil , Newcombe Estella Anne , Bermejo Montaña Caballero , Langkilde Annette Eva , Kragelund Birthe Brandt , Jensen Poul Henning , Nissen Poul 
Published: February 2022

ABSTRACTAlpha-synuclein (aSN) is a membrane-associated and intrinsically disordered protein, well-known for pathological aggregation in neurodegeneration. The physiological function of aSN however is disputed. Pull-down experiments have pointed to plasma membrane Ca2+-ATPase (PMCA) as a potential interaction partner. From proximity ligation assays we find that aSN and PMCA colocalize at neuronal synapses, and that calcium expulsion is activated by aSN and PMCA. From PMCA activity studies we show that soluble, monomeric aSN activates PMCA at par with CaM, yet independent of the autoinhibitory domain of PMCA, but highly dependent on acidic phospholipids and membrane-anchoring of aSN. On PMCA, the key site is mapped to the acidic lipid-binding site, located within a disordered PMCA-specific loop region connecting the cytosolic A domain and transmembrane segment 3. Our studies point towards a novel physiological role of monomeric aSN as a stimulator of calcium clearance in neurons through activation of PMCA.
Retinoic acid-induced protein 14 controls dendritic spine dynamics associated with depressive-like behaviors
Authors: Kim Soo Jeong , Woo Youngsik , Kim Hyun Jin , Goo Bon Seong , Nhung Troung Thi My , Lee Seol-Ae , Suh Bo Kyoung , Mun Dong Jin , Kim Joung-Hun , Park Sang Ki 
Published: February 2022

AbstractDendritic spines are the central postsynaptic machinery that determines synaptic function. The F-actin within dendritic spines regulates their dynamic formation and elimination. Rai14 is an F-actin-regulating protein with a membrane-shaping function. Here, we identified the roles of Rai14 for the regulation of dendritic spine dynamics associated with stress-induced depressive-like behaviors. Rai14-deficient neurons failed to maintain a proper dendritic spine density in the Rai14+/- mouse brain, resulting in impaired functional synaptic activity. Rai14 was protected from degradation by complex formation with Tara, and accumulated in the dendritic spine neck, thereby enhancing spine maintenance. Concurrently, Rai14 deficiency in mice altered gene expression profile relevant to depressive conditions and increased depressive-like behaviors. Moreover, Rai14 expression was reduced in the prefrontal cortex of the mouse stress model, which was blocked by antidepressant treatment. Thus, we propose that Rai14-dependent regulation of dendritic spines may underlie the plastic changes of neuronal connections relevant to depressive-like behaviors.
A Facile Method to Produce N-Terminally Truncated α-Synuclein
Authors: Thrush Rebecca J. , Vadukul Devkee M. , Aprile Francesco A. 
Published: February 2022

Abstractα-Synuclein is a key protein of the nervous system, which regulates the release and recycling of neurotransmitters in the synapses. It is also involved in several neurodegenerative conditions, including Parkinson’s disease and Multiple System Atrophy, where it forms toxic aggregates. The N-terminus of α-synuclein is of particular interest as it has been linked to both the physiological and pathological functions of the protein and undergoes post-translational modification. One such modification, N-terminal truncation, affects the aggregation propensity of the protein in vitro and is also found in aggregates from patients’ brains. To date, our understanding of the role of this modification has been limited by the many challenges of introducing biologically relevant N-terminal truncations with no overhanging starting methionine. Here, we present a method to produce N-terminally truncated variants of α-synuclein that do not carry extra terminal residues. We show that our method can generate highly pure protein to facilitate the study of this modification and its role in physiology and disease. Thanks to this method, we have determined that the first six residues of α-synuclein play an important role in the formation of the amyloids.
c-Src-dependent phosphorylation of Mfn2 regulates endoplasmic reticulum-mitochondria tethering
Authors: Zhang Peng , Ford Kara , Sung Jae Hwi , Suzuki Yuta , Landherr Maria , Moeller Jacob , Chaput Isabel , Polina Iuliia , Kelly Madeline , Nieto Bridget , Tachibana Toshiaki , Kusakari Yoichiro , Cypress Michael W. , Drenkova Kamelia , Adaniya Stephanie M. , Mishra Jyotsna , Mende Ulrike , Jhun Bong Sook , O-Uchi Jin 
Published: February 2022

AbstractContact sites between the mitochondria and endoplasmic reticulum (ER) regulate the exchange of lipids, Ca2+, and reactive oxygen species (ROS) across the two organelles. Mitofusin 2 (Mfn2) has been identified as one of the major components tethering these two organelles together. Several post-translational modifications (PTMs) of Mfn2 have been shown to modulate canonical (i.e., mitochondrial fusion) and non-canonical Mfn2 functions, such as mitophagy and activation of ER stress signaling. However, there is little information about whether any PTMs can regulate mitochondrial and ER tethering. Basal tyrosine phosphorylation of Mfn2 was detected by mass spectroscopy, but it is unknown whether Mfn2 is a substrate of mitochondria-localized tyrosine kinases. Here, we show that mitochondria-localized c-Src can phosphorylate the C-terminal tail of Mfn2, which decreases the distance between the mitochondria and ER and facilitates Ca2+transfer from the ER to mitochondria, followed by changes in ROS generation and mitochondrial bioenergetics. Our findings suggest that tyrosine phosphorylation of Mfn2 may uniquely work to fine-tune ER-mitochondrial Ca2+transport under physiological and pathological conditions.
Network profiling of hepatocellular carcinoma targets for evidence based pharmacological approach to improve clinical efficacy
Authors: Manchukonda Bhavya , Kumar Arun HS 
Published: February 2022

AbstractIntroductionHepatocellular carcinoma (HCC) is the most prevalent malignancy of the liver with limited clinical efficacy of currently used drugs such as sorafenib. Hence in this study we assessed the network proteins of HCC targets to identify the target/s which can achieve optimal clinical efficacy.Materials and MethodsThe reported HCC targets and their network proteins were identified in the string database. The interactions of the network proteins based on the number of hydrogen bonds formed were evaluated using the chimera software and used to merit the network protein interactions. The merit of network protein interactions in clinical efficacy was assessed based on the expression pattern of the network proteins and corelating their targeting by sorafenib.Results22 potential HCC targets were identified along with their 152 unique network proteins. The following HCC targets; PDGFRB, IFNA2, VEGFR2, PD1, C-MET, RAR and IGF1R were observed to be among the top networks with the most number of hydrogen bond interactions between them. Among these, C-MET, RAR and IGF1R were significantly expressed in hepatocytes, making them relevant HCC targets. PD-1 and PD-L1, which are immune checkpoint regulators and hence used as part of immune therapy, were observed to form higher numbers of hydrogen bonds with HCC network proteins.ConclusionOur analysis suggest that selectively targeting IGF1R, C-MET and RAR in hepatocytes together with immunotherapy will result in optimal clinical efficacy in the management of HCC.
Granulocyte Colony Stimulating Factor causes cerebellar deficits and anxiety in a mouse model of CSF-1 receptor-related leukoencephalopathy
Authors: Biundo Fabrizio , Chitu Violeta , Tindi Jaafar , Burghardt Nesha S. , Shlager Gabriel G. L. , Ketchum Harmony C. , DeTure Michael A. , Dickson Dennis W. , Wszolek Zbignew K. , Khodakhah Kamran , Stanley E. Richard 
Published: February 2022

AbstractColony stimulating factor (CSF) receptor-1 (CSF-1R)-related leukoencephalopathy (CRL) is an adult-onset, demyelinating neurodegenerative disease caused by autosomal dominant mutations in CSF1R, modeled by the Csf1r+/- mouse. The expression of Csf2, encoding granulocyte- macrophage CSF (GM-CSF) and of Csf3, encoding granulocyte CSF (G-CSF), are elevated in both mouse and human CRL brains. While monoallelic targeting of Csf2 has been shown to attenuate many behavioral and histological deficits of mouse CRL, including cognitive dysfunction and demyelination, the contribution of Csf3 has not been explored. In this manuscript, we investigate the behavioral, electrophysiological and histopathological phenotypes of CRL mice following monoallelic targeting of Csf3. We show that Csf3 heterozygosity normalized the Csf3 levels in Csf1r+/- mouse brains and ameliorated anxiety-like behavior, motor coordination and social interaction deficits, but not their cognitive impairment. Consistent with this, Csf3 heterozygosity attenuated microglial activation in the cerebellum and in the ventral but not in the dorsal hippocampus. Csf3 heterozygosity also failed to prevent demyelination. Csf1r+/- mice exhibited altered synaptic activity in the deep cerebellar nuclei (DCN) associated with increased deposition of the complement factor C1q on glutamatergic synapses and with increased engulfment of glutamatergic synapses by DCN microglia. These phenotypes were significantly ameliorated by monoallelic deletion of Csf3. Our findings indicate that G-CSF and GM-CSF play non-overlapping roles in mouse CRL development and suggest that G-CSF could be an additional therapeutic target in CRL.
On the Mental Status of Stargazer Mice
Authors: Schirmer Catharina , Abboud Mark A , Lee Samuel C , Bass John S , Mazumder Arindam G , Kamen Jessica L , Krishnan Vaishnav 
Published: February 2022

SummaryIn many childhood-onset genetic epilepsies, seizures are accompanied by neurobehavioral impairments and motor disability. In the Stargazer mutant mouse, genetic disruptions of Cacng2 result in absence-like spike-wave seizures, cerebellar gait ataxia and vestibular dysfunction. Here, we combine videotracking and instrumented home-cage monitoring to resolve the neurobehavioral facets of the murine Stargazer syndrome. We find that despite their gait ataxia, stargazer mutants display horizontal hyperactivity and variable rates of repetitive circling behavior. While feeding rhythms, circadian or ultradian oscillations in activity are unchanged, mutants exhibit fragmented sleep bouts, atypical licking dynamics and lowered sucrose preference. Mutants also display an attenuated response to visual and auditory home-cage perturbations, together with profound reductions in voluntary wheel-running. Our results reveal that the seizures and ataxia of Stargazer mutants occur in the context of a more pervasive behavioral syndrome with elements of encephalopathy, repetitive behavior and anhedonia. These findings expand our understanding of the function of Cacng2/CACNG2, variants in which have been identified in patients with bipolar disorder and schizophrenia.
Inositol depletion regulates phospholipid metabolism and activates stress signaling in HEK293T cells
Authors: Suliman Mahmoud , Case Kendall C. , Schmidtke Michael W. , Lazcano Pablo , Onu Chisom J. , Greenberg Miriam L. 
Published: February 2022

ABSTRACTInositol plays a significant role in cellular function and signaling. Studies in yeast have demonstrated an “inositol-less death” phenotype, suggesting that inositol is an essential metabolite. In yeast, inositol synthesis is highly regulated, and inositol levels have been shown to be a major metabolic regulator, with its abundance affecting the expression of hundreds of genes. Abnormalities in inositol metabolism have been associated with several human disorders. Despite its importance, very little is known about the regulation of inositol synthesis and the pathways regulated by inositol in human cells. The current study aimed to address this knowledge gap. Knockout of ISYNA1 (encoding myo-inositol-3-P synthase 1) in HEK293T cells generated a human cell line that is deficient in de novo inositol synthesis. ISYNA1-KO cells exhibited inositol-less death when deprived of inositol. Lipidomic analysis identified inositol depletion as a global regulator of phospholipid levels in human cells, including downregulation of phosphatidylinositol (PI) and upregulation of the phosphatidylglycerol (PG)/cardiolipin (CL) branch of phospholipid metabolism. RNA-Seq analysis revealed that inositol depletion induced substantial changes in the expression of genes involved in cell signaling, including extracellular signal-regulated kinase (ERK), and genes controlling amino acid transport and protein processing in the endoplasmic reticulum (ER). This study provides the first in-depth characterization of the effects of inositol depletion on phospholipid metabolism and gene expression in human cells, establishing an essential role for inositol in maintaining cell viability and regulating cell signaling and metabolism.
Landscape diversity and local temperature, but not climate, affect arthropod predation among habitat types
Authors: Fricke Ute , Steffan-Dewenter Ingolf , Zhang Jie , Tobisch Cynthia , Rojas-Botero Sandra , Benjamin Caryl S. , Englmeier Jana , Ganuza Cristina , Haensel Maria , Riebl Rebekka , Uhler Johannes , Uphus Lars , Ewald Jörg , Kollmann Johannes , Redlich Sarah 
Published: February 2022

AbstractArthropod predators are important for ecosystem functioning by providing top-down regulation of insect herbivores. As predator communities and activity are influenced by biotic and abiotic factors on different spatial scales, the strength of top-down regulation (‘arthropod predation’) is also likely to vary. Understanding the combined effects of potential drivers on arthropod predation is urgently needed with regard to anthropogenic climate and land-use change. In a large-scale study, we recorded arthropod predation rates using artificial caterpillars on 113 plots of open herbaceous vegetation embedded in contrasting habitat types (forest, grassland, arable field, settlement) along climate and land-use gradients in Bavaria, Germany. As potential drivers we included habitat characteristics (habitat type, plant species richness, local mean temperature and mean relative humidity during artificial caterpillar exposure), landscape diversity (0.5–3.0-km, six scales), climate (multi-annual mean temperature, ‘MAT’) and interactive effects of habitat type with other drivers. We observed no substantial differences in arthropod predation rates between the studied habitat types, related to plant species richness and across the Bavarian-wide climatic gradient, but predation was limited when local mean temperatures were low and tended to decrease towards higher relative humidity. Arthropod predation rates increased towards more diverse landscapes at a 2-km scale. Interactive effects of habitat type with local weather conditions, plant species richness, landscape diversity and MAT were not observed. We conclude that landscape diversity favours high arthropod predation rates in open herbaceous vegetation independent of the dominant habitat in the vicinity. This finding may be harnessed to improve top-down control of herbivores, e.g. agricultural pests, but further research is needed for more specific recommendations on landscape management. The absence of MAT effects suggests that high predation rates may occur independent of moderate increases of MAT in the near future.