bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resolving Individual-Atom of Protein Complex using Commonly Available 300-kV Cryo-electron Microscopes
Authors: Zhang Kaiming , Pintilie Grigore D. , Li Shanshan , Schmid Michael F. , Chiu Wah 
Published: August 2020

AbstractBreakthroughs in single-particle cryo-electron microscopy (cryo-EM) technology have made near-atomic resolution structure determination possible. Here, we report a ∼1.35-Å structure of apoferritin reconstructed from images recorded on a Gatan K3 or a Thermo Fisher Falcon 4 detector in a commonly available 300-kV Titan Krios microscope (G3i) equipped with or without a Gatan post-column energy filter. Our results demonstrate that the atomic-resolution structure determination can be achieved by single-particle cryo-EM with a fraction of a day of automated data collection. These structures resolve unambiguously each heavy atom (C, N, O, and S) in the amino acid side chains with an indication of hydrogen atoms’ presence and position, as well as the unambiguous existence of multiple rotameric configurations for some residues. We also develop a statistical and chemical based protocol to assess the positions of the water molecules directly from the cryo-EM map. In addition, we have introduced a B’ factor equivalent to the conventional B factor traditionally used by crystallography to annotate the atomic resolution model for determined structures. Our findings will be of immense interest among protein and medicinal scientists engaging in both basic and translational research.
A geometrical framework forf–statistics
Authors: Oteo–García Gonzalo , Oteo José–Angel 
Published: August 2020

AbstractA detailed derivation of thef–statistics formalism is made from a geometrical framework. It is shown that thef–statistics appear when a genetic distance matrix is constrained to describe a four population phylogenetic tree. The choice of genetic metric is crucial and plays an outstanding role as regards the tree–like–ness criterion. The case of lack of treeness is interpreted in the formalism as presence of population admixture. In this respect, four formulas are given to estimate the admixture proportions. One of them is the so–calledf4–ratio estimate and we show that a second one is related to a known result developed in terms of the fixation indexFST. An illustrative numerical simulation of admixture proportion estimates is included. Relationships of the formalism with coalescence times and pairwise sequence differences are also provided.
Primary visual cortex injury produces loss of inhibitory neurons and long-term visual circuit dysfunction
Authors: Frankowski Jan C. , Foik Andrzej T. , Machhor Jiana R. , Lyon David C. , Hunt Robert F. 
Published: August 2020

SummaryPrimary sensory areas of the mammalian neocortex have a remarkable degree of plasticity, allowing neural circuits to adapt to dynamic environments. However, little is known about the effect of traumatic brain injury on visual system function. Here we applied a mild focal contusion injury to primary visual cortex (V1) in adult mice. We found that, although V1 was largely intact in brain-injured mice, there was a reduction in the number of inhibitory interneurons that extended into deep cortical layers. In general, we found a preferential reduction of interneurons located in superficial layers, near the impact site, while interneurons positioned in deeper layers were better preserved. Three months after injury, V1 neurons showed dramatically reduced responses to visual stimuli and weaker orientation selectivity and tuning, consistent with the loss of cortical inhibition. Our results demonstrate that V1 neurons no longer robustly and stably encode visual input following a mild traumatic injury.HighlightsInhibitory neurons are lost throughout brain injured visual cortexVisually-evoked potentials are severely degraded after injuryInjured V1 neurons show weaker selectivity and tuning consistent with reduced interneurons
Genomic evolution of antibiotic resistance is contingent on genetic background following a long-term experiment withEscherichia coli
Authors: Card Kyle J. , Thomas Misty D. , Graves Joseph L. , Barrick Jeffrey E. , Lenski Richard E. 
Published: August 2020

AbstractAntibiotic resistance is a growing health concern. Efforts to control resistance would benefit from an improved ability to forecast when and how it will evolve. Epistatic interactions between mutations can promote divergent evolutionary trajectories, which complicates our ability to predict evolution. We recently showed that differences between genetic backgrounds can lead to idiosyncratic responses in the evolvability of phenotypic resistance, even among closely relatedEscherichia colistrains. In this study, we examined whether a strain’s genetic background also influences the genotypic evolution of resistance. Do lineages founded by different genotypes take parallel or divergent mutational paths to achieve their evolved resistance states? We addressed this question by sequencing the complete genomes of antibiotic-resistant clones that evolved from several different genetic starting points during our earlier experiments. We first validated our statistical approach by quantifying the specificity of genomic evolution with respect to antibiotic treatment. As expected, mutations in particular genes were strongly associated with each drug. Then, we determined that replicate lines evolved from the same founding genotypes had more parallel mutations at the gene level than lines evolved from different founding genotypes, although these effects were more subtle than those showing antibiotic specificity. Taken together with our previous work, we conclude that historical contingency can alter both genotypic and phenotypic pathways to antibiotic resistance.SignificanceA fundamental question in evolution is the repeatability of adaptation. Will independently evolving populations respond similarly when facing the same environmental challenge? This question also has important public-health implications related to the growing problem of antibiotic resistance. For example, efforts to control resistance might benefit from accurately predicting mutational paths to resistance. However, this goal is complicated when a lineage’s prior history alters its subsequent evolution. We recently found that differences between genetic backgrounds can lead to unpredictable responses in phenotypic resistance. Here, we report that genetic background can similarly alter genotypic paths to resistance. This historical contingency underscores the importance of accounting for stochasticity, in the past as well as at present, when designing evolutionarily informed treatment strategies.
Suboptimal intermediates underlie evolution of the Bicoid homeodomain
Authors: Onal Pinar , Gunasinghe Himari Imaya , Yui Umezawa Kristaley , Zheng Michael , Ling Jia , Azeez Leen , Dalmeus Anecine , Tazin Tasmima , Small Stephen 
Published: August 2020

AbstractChanges in regulatory networks generate materials for evolution to create phenotypic diversity. For transcription networks, multiple studies have shown that alterations in binding sites of cis-regulatory elements correlate well with the gain or loss of specific features of the body plan. Less is known about alterations in the amino acid sequences of the transcription factors (TFs) that bind these elements. Here we study the evolution of Bicoid (Bcd), a homeodomain (HD) protein that is critical for anterior embryo patterning inDrosophila. The ancestor of Bcd (AncBcd) emerged after a duplication of a Zerknullt (Zen)-like ancestral protein (AncZB) in a suborder of flies. AncBcd diverged from AncZB, gaining novel transcriptional and translational activities. We focus on the evolution of the HD of AncBcd, which binds DNA and RNA, and is comprised of four subdomains: an N-terminal arm (NT) and three helices; H1, H2, and Recognition Helix (RH). Using chimeras of subdomains and gene rescue assays inDrosophila, we show that robust patterning activity of the Bcd HD (high frequency rescue to adulthood) is achieved only when amino acid substitutions in three separate subdomains (NT, H1, and RH) are combined. Other combinations of subdomains also yield full rescue, but with lower penetrance, suggesting alternative suboptimal activities. Our results suggest a multi-step pathway for the evolution of the Bcd HD that involved intermediate HD sequences with suboptimal activities, which constrained and enabled further evolutionary changes. They also demonstrate critical epistatic forces that contribute to the robust function of a DNA-binding domain.
Exposing distinct subcortical components of the auditory brainstem response evoked by continuous naturalistic speech
Authors: Polonenko Melissa J , Maddox Ross K 
Published: August 2020

ABSTRACTSpeech processing is built upon encoding by the auditory nerve and brainstem, yet we know very little about how these processes unfold in specific subcortical structures. These structures are deep and respond quickly, making them difficult to study during ongoing speech. Recent techniques begin to address this problem, but yield temporally broad responses with consequently ambiguous neural origins. Here we describe a method that pairs re-synthesized “peaky” speech with deconvolution analysis of EEG recordings. We show that in adults with normal hearing, the method quickly yields robust responses whose component waves reflect activity from distinct subcortical structures spanning auditory nerve to rostral brainstem. We further demonstrate the versatility of peaky speech by simultaneously measuring bilateral and ear-specific responses across different frequency bands, and discuss important practical considerations such as talker choice. The peaky speech method holds promise as a tool for investigating speech encoding and processing, and for clinical applications.
Structural basis for CDK7 activation by MAT1 and Cyclin H
Authors: Peissert Stefan , Schlosser Andreas , Kendel Rafaela , Kuper Jochen , Kisker Caroline 
Published: August 2020

AbstractCDK7, Cyclin H, and MAT1 form the heterotrimeric CDK-activating kinase (CAK) complex. CAK is a vital factor for the two essential processes of transcription and cell cycle control. When associated with the general transcription factor II H (TFIIH) it activates RNA polymerase II by hyperphosphorylation of its C-terminal domain (CTD). In the absence of TFIIH it phosphorylates the T-loop of CDKs that control cell cycle progression. CAK holds a special position among the CDK branch due to this dual activity and the dependence on the MAT1 protein for activation in addition to Cyclin H. We solved the structure of the CAK complex from the model organismC. thermophilumat 2.6 Å resolution. Our structure reveals an intricate network of interactions between MAT1 and its two binding partners CDK7 and Cyclin H providing a structural basis for the mechanism of CDK7 activation and CAK activity regulation.In vitroactivity measurements combined with functional mutagenesis show that CDK7 activation can occur independently of T-loop phosphorylation and is thus exclusively MAT1 dependent by positioning the CDK7 T-loop in its active conformation. Finally, our structure of the active CAK with a peptide model provides a molecular rationale for heptad repeat phosphorylation.Significance StatementThe fundamental processes of cell cycle regulation and transcription are linked by the heterotrimeric CDK-activating kinase (CAK) complex. We have solved the crystal structure of the active CAK complex and provide a molecular rationale for CAK activation, regulation, and substrate recognition thereby highly advancing our understanding of this essential factor.
Social-like responses are inducible in asocial Mexican cavefish despite the exhibition of strong repetitive behaviour
Authors: Iwashita Motoko , Yoshizawa Masato 
Published: August 2020

AbstractSocial behaviour is a hallmark of complex animal systems; however, some species appear to have secondarily lost this social ability. In these non-social species, whether social abilities are permanently lost or suppressed is unclear. The blind cavefishAstyanax mexicanusis known to be asocial. Here, we reveal that cavefish exhibited social-like interactions in familiar environments but suppressed these interactions in stress-associated unfamiliar environments. Furthermore, the level of suppression in sociality was positively correlated with that of stereotypic repetitive behaviour, as seen in mammals. Treatment with a human antipsychotic drug targeting the dopaminergic system induced social-like interactions in cavefish, even in unfamiliar environments, while reducing repetitive behaviour. Overall, these results suggest that the antagonistic relationship between repetitive and social-like behaviours is deeply shared from teleosts through mammals.
Eurycomanone regulates lipid metabolism by activating the cAMP/PKA pathway
Authors: Jiang Zhihui , Han Haote , Li Shouxin , Tian Jingkui , Gao Zhiyuan , Huang Wenping , Zhang Dan , Ouyang Hui , Feng Yulin 
Published: August 2020

AbstractEurycoma longifolia Jack(ELJ) contains mainly alkaloids, and quassinoids, which are the main active ingredients. Eurycomanone (EN), one of the most common quassinoids, is said to have beneficial effects on lipid and glucose metabolism. In this study, we investigated the effects of EN on lipolysis by establishing a high-fat animal modelin vivoand evaluated its efficacy as a lipolytic and anti-fatty liver agent. Oil red O staining showed morphological changes of 3T3-L1 preadipocytes after EN treatment and confirmed the inhibitory effects of EN on adipocyte differentiation. The mechanism of EN promotes lipolysis in 3T3-L1 cells was analyzed by immunofluorescence, Western blotting, quantitative real-time PCR and siRNA transfection. In C57BL/6J mice fed a high-fat diet, intragastric administration of EN (5 mg/kg and 10 mg/kg) for two weeks, decreased fat droplet mass and size, and reduced fat accumulation in the liver. Furthermore, EN activated PKA and promoted the PKA/hormone sensitive lipase lipolysis signaling pathway, thereby increasing the release of glycerol and free fatty acids from adipocytes. Our findings indicate the potential of EN as a promising alternative pharmacologic agent for the prevention of obesity.
A failure to replicate the effect of visual symmetry on subjective duration
Authors: Makin Alexis D.J. , Rahman Afzal , Bertamini Marco 
Published: August 2020

AbstractPrevious work has shown that symmetrical or regular stimuli are judged as lasting longer than asymmetrical or irregular ones, even when actual duration is matched. This effect has been replicated with different methods and stimuli types, both in the UK and Japan. We aimed to a) replicate the effect of symmetry on subjective duration, and b) assess whether it was further modulated by the number of symmetrical axes. There was no evidence for either effect. This null result cannot be explained by reduced statistical power or enhanced floor or ceiling effects. There is no obvious stimulus-based explanation either. However, we are mindful of the reproducibility crisis and file drawer problems in psychology. Other symmetry and time perception researchers should be aware of this null result.
eDNA metabarcoding as a biomonitoring tool for marine protected areas
Authors: Gold Zachary , Sprague Joshua , Kushner David J. , Zerecero Erick , Barber Paul H. 
Published: August 2020

AbstractMonitoring of marine protected areas (MPAs) is critical for marine ecosystem management, yet current protocols rely on SCUBA-based visual surveys that are costly and time consuming, limiting their scope and effectiveness. Environmental DNA (eDNA) metabarcoding is a promising alternative for marine ecosystem monitoring, but more direct comparisons to visual surveys are needed to understand the strengths and limitations of each approach. This study compares fish communities inside and outside the Scorpion State Marine Reserve off Santa Cruz Island, CA using eDNA metabarcoding and underwater visual census surveys. Results from eDNA captured 76% (19/25) of fish species and 95% (19/20) of fish genera observed during pairwise underwater visual census. Species missed by eDNA were due to the inability of MiFish12Sbarcodes to differentiate species of rockfishes (Sebastes, n=4) or low site occupancy rates of crevice-dwellingLythrypnusgobies. However, eDNA detected an additional 30 fish species not recorded in paired visual surveys, but previously reported from prior visual surveys, highlighting the sensitivity of eDNA. Significant variation in eDNA signatures by location (50m) and site (~1000m) demonstrates the sensitivity of eDNA to address key questions such as community composition inside and outside MPAs. Interestingly, eDNA results recorded higher species richness outside the MPA while visual surveys observed the opposite pattern. This result is likely caused by swamping effects of high fish abundance in MPAs that reduce detection probabilities of pelagic and intertidal taxa. Results demonstrate the utility of eDNA metabarcoding for monitoring marine ecosystems, providing an important complementary tool to visual methods.
Circulating adiponectin mediates the association between omentin gene polymorphism and cardiometabolic health in Asian Indians
Authors: Vimaleswaran Karani S. , Jiang Juanjie , Bodhini Dhanasekaran , Ramya Kandaswamy , Mohan Deepa , Rani Coimbatore Subramanian Shanthi , Lakshmipriya Nagarajan , Sudha Vasudevan , Pradeepa Rajendra , Anjana Ranjit Mohan , Mohan Viswanathan , Radha Venkatesan 
Published: August 2020

AbstractBackgroundPlasma omentin levels have been shown to be associated with circulating adiponectin concentrations and cardiometabolic disease-related outcomes. However, the findings have been inconsistent due to high level of confounding. In this study, we aim to examine the association of omentin gene polymorphism with plasma adiponectin levels and cardiometabolic health status using a genetic approach, which is less prone to confounding, and investigate whether these associations are modified by lifestyle factors such as diet and physical activity.MethodsThe study included 945 normal glucose tolerant and 941 unrelated individuals with type 2 diabetes randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), in southern India. Study participants were further classified into cardiometabolically healthy and unhealthy, where cardiometabolically healthy were those without hypertension, diabetes, and dyslipidemia. Fasting serum adiponectin levels were measured by radioimmunoassay. The A326T (rs2274907) single nucleotide polymorphism (SNP) in the exon 4 of the omentin gene was screened by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing.ResultsThe ‘A’ allele of the omentin SNP was significantly associated with lower adiponectin concentrations after adjusting for age, sex, body mass index (BMI), waist circumference (WC) and cardiometabolic health status (p=1.90 x 10-47). There was also a significant association between circulating adiponectin concentrations and cardiometabolic health status after adjusting for age, sex, BMI, WC and Omentin SNP (p=7.47×10-10). However, after adjusting for age, sex, BMI, WC and adiponectin levels, the association of ‘A’ allele with cardiometabolic health status disappeared (p=0.79) suggesting that adiponectin serves as a mediator of the association between omentin SNP and cardiometabolic health status. There were no significant interactions between the SNP and dietary factors on adiponectin levels and cardiometabolic health status (p>0.25, for all comparisons).ConclusionsOur findings show that adiponectin might function as a mechanistic link between omentin SNP and increased risk of cardiometabolic diseases independent of common and central obesity in this Asian Indian population. Further studies are required to confirm the molecular mechanisms involved in this triangular relationship between omentin gene, adiponectin and cardiometabolic diseases.
Global prevalence of potentially pathogenic short-tandem repeats in an epilepsy cohort
Authors: Moreau Claudia , Michaud Jacques L. , Hamdan Fadi F. , Bouchard Joanie , Tremblay Vincent , Minassian Berge A. , Cossette Patrick , Girard Simon L. 
Published: August 2020

AbstractThis study aims to decipher the role of short tandem repeats (STRs) in epilepsy patients. Whole genome short-read sequencing data of 734 epileptic patients was used to look for known STR expansions associated with increased risk of neurodevelopmental diseases or epilepsy using three different software. Results show one hit of particular interest onARXgene associated with Early Infantile Encephalopathic Epilepsy that could be causal for one patient with developmental and epileptic encephalopathy. However, we show that the different software do not agree on most of the calls above the threshold and that experimental validation is still needed for diagnostic, although these algorithms could prove useful for pre-selection of samples to be validated.
Single cell tracking based on Voronoi partition via stable matching
Authors: Chang Young Hwan , Linsley Jeremy , Lamstein Josh , Kalra Jaslin , Epstein Irina , Barch Mariya , Daily Kenneth , Synder Phil , Omberg Larsson , Heiser Laura , Finkbeiner Steve 
Published: August 2020

AbstractLive-cell imaging is an important technique to study cell migration and proliferation as well as image-based profiling of drug perturbations over time. To gain biological insights from live-cell imaging data, it is necessary to identify individual cells, follow them over time and extract quantitative information. However, since often biological experiment does not allow the high temporal resolution to reduce excessive levels of illumination or minimize unnecessary oversampling to monitor long-term dynamics, it is still a challenging task to obtain good tracking results with coarsely sampled imaging data. To address this problem, we consider cell tracking problem as “stable matching problem” and propose a robust tracking method based on Voronoi partition which adapts parameters that need to be set according to the spatio-temporal characteristics of live cell imaging data such as cell population and migration. We demonstrate the performance improvement provided by the proposed method using numerical simulations and compare its performance with proximity-based tracking and nearest neighbor-based tracking.