bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct neocortical mechanisms underlie human SI responses to median nerve and laser evoked peripheral activation
Authors: Thorpe Ryan V. , Black Christopher J. , Borton David A. , Hu Li , Saab Carl Y. , Jones Stephanie R.
Published: October 2021

Magneto- and/or electro-encephalography (M/EEG) are non-invasive clinically-relevant tools that have long been used to measure electromagnetic fields in somatosensory cortex evoked by innocuous and noxious somatosensory stimuli. Two commonly applied stimulation paradigms that produce distinct responses in primary somatosensory cortex (SI) linked to innocuous and noxious sensations are electrical median nerve (MN) stimulation and cutaneous laser-evoked (LE) stimulation to the dorsum of the hand, respectively. Despite their prevalence, the physiological mechanisms that produce stereotypic macroscale MN and LE responses have yet to be fully articulated, limiting their utility in understanding brain dynamics associated with non-painful and/or painful somatosensation. Through a literature review, we detailed features of MN and LE responses source-localized to SI that are robust and reproducible across studies. We showed that the first peak in the MN response at ∼20 ms post-stimulus (i.e., MN N1) corresponds to outward-directed deep-to-superficial electrical current flow through the cortical laminae, which is followed by inward-directed current at ∼30 ms (i.e., MN P1). In contrast, the initial LE response occurs later at ∼170 ms (i.e., LE N1) and is oriented inward and opposite the direction of the MN N1. We then examined the neocortical circuit mechanisms contributing to the robust features of each response using the Human Neocortical Neurosolver (HNN) neural modeling software tool (Neymotin et al., 2020). Using HNN as a hypothesis development and testing tool, model results predicted the MN response can be simulated with a sequence of layer specific thalamocortical and cortico-cortical synaptic drive similar to that previously reported for tactile evoked responses (Jones et al., 2007; Neymotin et al., 2020), with the novel discovery that an early excitatory input to supragranular layers at ∼30 ms is an essential mechanism contributing to the inward current flow of the MN P1. Model results further predicted that the initial ∼170 ms inward current flow of the LE N1 was generated by a burst of repetitive gamma-frequency (∼40 Hz) excitatory synaptic drive to supragranular layers, consistent with prior reports of LE gamma-frequency activity. These results make novel and detailed multiscale predictions about the dynamic laminar circuit mechanisms underlying temporal and spectral features of MN and LE responses in SI and can guide further investigations in follow-up studies. Ultimately, these findings may help with the development of targeted therapeutics for pathological somatosensation, such as somatic sensitivity and acute neuropathic pain.
Anatomy of the Heart with the Highest Heart Rate
Authors: Chang Yun Hee , Sheftel Boris I. , Jensen Bjarke
Published: October 2021

Shrews occupy the lower extreme of the seven orders of magnitude mammals range in size. Their hearts are large relative to body weight and heart rate can exceed a thousand beats a minute. To investigate whether cardiac traits that are typical mammalian scale to these extremes, we assessed the heart of three species of shrew (genusSorex) following the sequential segmental analysis developed for human hearts. Using micro-computed tomography we describe the overall structure and find, in agreement with previous studies, a large and elongate ventricle. The atrial and ventricular septums and the atrioventricular and arterial valves are typically mammalian. The ventricular walls comprise mostly compact myocardium and especially the right ventricle has few trabeculations on the luminal side. A developmental process of compaction is thought to reduce trabeculations in mammals, but in embryonic shrews the volume of trabeculations increase for every gestational stage, only slower than the compact volume. By expression of Hcn4, we identify a sinus node and an atrioventricular conduction axis which is continuous with the ventricular septal crest. Outstanding traits include pulmonary venous sleeve myocardium that reaches farther into the lungs than in any other mammals. Typical proportions of coronary arteries-to-aorta do not scale and the shrew coronary arteries are proportionally enormous, presumably to avoid the high resistance to blood flow of narrow vessels. In conclusion, most cardiac traits do scale to the miniscule shrews. The shrew heart, nevertheless, stands out by its relative size, elongation, proportionally large coronary vessels, and extent of pulmonary venous myocardium.
Distinct dendritic Ca2+ spike forms produce opposing input-output transformations in rat CA3 pyramidal cells
Authors: Magó Ádám , Kis Noémi , Lükő Balázs , Makara Judit K.
Published: October 2021

Proper integration of different inputs targeting the dendritic tree of CA3 pyramidal cells (CA3PCs) is critical for associative learning and recall. Dendritic Ca2+ spikes have been proposed to perform associative computations in other PC types, by detecting conjunctive activation of different afferent input pathways, initiating afterdepolarization (ADP) and triggering burst firing. Implementation of such operations fundamentally depends on the actual biophysical properties of dendritic Ca2+ spikes; yet little is known about these properties in dendrites of CA3PCs. Using dendritic patch-clamp recordings and two-photon Ca2+ imaging in acute slices from male rats we report that, unlike CA1PCs, distal apical trunk dendrites of CA3PCs exhibit distinct forms of dendritic Ca2+ spikes. Besides ADP-type global Ca2+ spikes, a majority of dendrites expresses a novel, fast Ca2+ spike type that is initiated locally without backpropagating action potentials, can recruit additional Na+ currents, and is compartmentalized to the activated dendritic subtree. Occurrence of the different Ca2+ spike types correlates with dendritic structure, indicating morpho-functional heterogeneity among CA3PCs. Importantly, ADPs and dendritically initiated spikes produce opposing somatic output: bursts versus strictly single action potentials, respectively. The uncovered variability of dendritic Ca2+ spikes may underlie heterogeneous input-output transformation and bursting properties of CA3PCs, and might specifically contribute to key associative and non-associative computations performed by the CA3 network.
Highly resolved spatial transcriptomics for detection of rare events in cells
Authors: Groiss Silvia , Pabst Daniela , Faber Cynthia , Meier Andreas , Bogdoll Annette , Unger Conny , Nilges Benedikt , Strauss Sascha , Föderl-Höbenreich Esther , Hardt Melina , Geipel Andreas , Reinecke Frank , Korfhage Christian , Zatloukal Kurt
Published: October 2021

Single-cell spatial transcriptomics technologies leveraged the potential to transcriptionally landscape sophisticated reactions in cells. Current methods to delineate such complex interplay lack the flexibility in rapid target adaptation and are particularly restricted in detecting rare transcripts. We developed a multiplex single-cell RNA In-situ hybridization technique, called ‘Molecular Cartography’ (MC) that can be easily tailored to specific applications and, by providing unprecedented sensitivity, specificity and resolution, is particularly suitable in tracing rare events at a subcellular level. Using a SARS-CoV-2 infection model, MC allows the discernment of single events in host-pathogen interactions, dissects primary from secondary responses, and illustrates differences in antiviral signaling pathways affected by SARS-CoV-2, simultaneously in various cell types.
Hypertrophic cardiomyopathy mutations in the pliant and light chain-binding regions of the lever arm of human β-cardiac myosin have divergent effects on myosin function
Authors: Morck Makenna M. , Bhowmik Debanjan , Dawood Aminah , Spudich James A. , Ruppel Kathleen M.
Published: October 2021

Mutations in the lever arm of β-cardiac myosin are a frequent cause of hypertrophic cardiomyopathy (HCM), a disease characterized by hypercontractility and eventual hypertrophy of the left ventricle. Here, we studied five such mutations: three in the pliant region of the lever arm (D778V, L781P, and S782N) and two in the light chain-binding region (A797T and F834L). We investigated their effects on both motor function and myosin S2 tail-based autoinhibition. The pliant region mutations had varying effects on the motor function of a myosin construct lacking the S2 tail: overall, D778V increased power output, L781P reduced power output, and S782N had little effect on power output, while all three reduced the external force sensitivity of the actin detachment rate. With a myosin containing the motor domain and the proximal S2 tail, the pliant region mutations also attenuated autoinhibition in the presence of filamentous actin but had no impact in the absence of actin. By contrast, the light chain-binding region mutations had little effect on motor activity but produced marked reductions in autoinhibition in both the presence and absence of actin. Thus, mutations in the lever arm of β-cardiac myosin have divergent allosteric effects on myosin function, depending on whether they are in the pliant or light chain-binding regions.
Specific N-glycans regulate an extracellular adhesion complex during somatosensory dendrite patterning
Authors: Rahman Maisha , Ramirez-Suarez Nelson J. , Diaz-Balzac Carlos A. , Bülow Hannes E.
Published: October 2021

N-glycans are molecularly diverse sugars borne by over 70% of proteins transiting the secretory pathway and have been implicated in protein folding, stability, and localization. Mutations in genes important for N-glycosylation result in congenital disorders of glycosylation that are often associated with intellectual disability. Here, we show that structurally distinct N-glycans regulate the activity of an extracellular protein complex involved in patterning of somatosensory dendrites in Caenorhabditis elegans. Specifically, aman-2/Golgi alpha-mannosidase II, a conserved key enzyme in the biosynthesis of specific N-glycans regulates the activity of the Menorin adhesion complex without obviously affecting protein stability and localization of its components. AMAN-2 functions cell-autonomously to ensure decoration of the neuronal transmembrane receptor DMA-1/LRR-TM with high-mannose/hybrid N-glycans. Moreover, distinct types of N-glycans on specific N-glycosylation sites regulate the DMA-1/LRR-TM receptor, which together with three other extracellular proteins forms the Menorin adhesion complex. In summary, specific N-glycan structures regulate dendrite patterning by coordinating the activity of an extracellular adhesion complex suggesting that the molecular diversity of N-glycans can contribute to developmental specificity in the nervous system.
Interactions between natural selection and recombination shape the genomic landscape of introgression
Authors: Duranton Maud , Pool John
Published: October 2021

Hybridization between lineages that have not reached complete reproductive isolation appears more and more like a common phenomenon. Indeed, speciation genomics studies have now extensively shown that many species’ genomes have hybrid ancestry. However, genomic patterns of introgression are often heterogeneous across the genome. In many organisms, a positive correlation between introgression levels and recombination rate has been observed. It is usually explained by the purging of deleterious introgressed material due to incompatibilities. However, the opposite relationship was observed in a North American population of Drosophila melanogaster with admixed European and African ancestry. In order to explore how directional and epistatic selection can impact the relationship between introgression and recombination, we performed forward simulations of whole D. melanogaster genomes reflecting the North American population’s history. Our results revealed that the simplest models of positive selection often yield negative correlations between introgression and recombination such as the one observed in D. melanogaster. We also confirmed that incompatibilities tend to produce positive introgression-recombination correlations. And yet, we identify parameter space under each model where the predicted correlation is reversed. These findings deepen our understanding of the evolutionary forces that may shape patterns of ancestry across genomes, and they strengthen the foundation for future studies aimed at estimating genome-wide parameters of selection in admixed populations.
Ferroptosis Regulation by the NGLY1/NFE2L1 Pathway
Authors: Forcina Giovanni C. , Pope Lauren , Murray Magdalena , Dong Wentao , Abu-Remaileh Monther , Bertozzi Carolyn R. , Dixon Scott J.
Published: October 2021

Ferroptosis is an oxidative form of non-apoptotic cell death whose transcriptional regulation is poorly understood. Cap’n’collar (CNC) transcription factors including Nuclear Factor Erythroid-2 Related Factor 1 (NFE2L1/NRF1) and NFE2L2 (NRF2) are important regulators of oxidative stress responses. Here, we report that NFE2L1 expression inhibits ferroptosis, independent of NFE2L2. NFE2L1 inhibits ferroptosis by promoting expression of the key anti-ferroptotic lipid hydroperoxidase glutathione peroxidase 4 (GPX4). NFE2L1 abundance and function are regulated post-translationally by N-glycosylation. Functional maturation of NFE2L1 requires deglycosylation by cytosolic peptide:N-glycanase 1 (NGLY1). We find that loss of NGLY1 or NFE2L1 enhances ferroptosis sensitivity. Expression of wild-type NGLY1 but not a disease-associated NGLY1 mutant inhibits ferroptosis, and this effect is dependent on the presence of NFE2L1. Enhanced ferroptosis sensitivity in NFE2L1 and NFE2L2 knockout cells can be potently reverted by expression of an NFE2L1 mutant containing eight asparagine-to-aspartate protein sequence substitutions, which mimic NGLY1-catalyzed sequence editing. Enhanced ferroptosis sensitivity in NGLY1/NFE2L1 pathway mutants could also be reversed by overexpression of NFE2L2. These results suggest that ferroptosis sensitivity is regulated by NGLY1-catalyzed NFE2L1 deglycosylation, and highlight a broad role for CNC transcription factors in ferroptosis regulation.

Significance Statement

Ferroptosis is an oxidative form of cell death whose biochemical regulation remains incompletely understood. NFE2L1/NRF1 is a cap’n’collar (CNC) transcription factor whose role in ferroptosis regulation is unclear. Unlike the CNC family member NFE2L2/NRF2, NFE2L1 is an N-glycoprotein whose abundance is regulated by post-translational deglycosylation catalyzed by the enzyme peptide:N-glycanase 1 (NGLY1). Our results indicate that NGLY1-mediated NFE2L1 deglycosylation, resulting in ‘editing’ of the NFE2L1 amino acid sequence, is necessary for NFE2L1 to inhibit ferroptosis. Mechanistically, NFE2L1 inhibits ferroptosis by via the anti-ferroptotic protein GPX4. This work demonstrates that CNC transcription factors beyond NFE2L2 can regulate ferroptosis. This work may suggest a role of misregulation of ferroptosis in NGLY1 deficiency, an ultrarare genetic disorder.
Histone H1 regulates non-coding RNA turnover on chromatin in a m6A-dependent manner
Authors: Fernández-Justel José Miguel , Santa-María Cristina , Ferrera-Lagoa Alberto , Salinas-Pena Mónica , Maslon Magdalena M. , Jordan Albert , Cáceres Javier F. , Gómez María
Published: October 2021

Linker histones are highly abundant chromatin-associated proteins with well-established structural roles in chromatin and as general transcriptional repressors. In addition, it has been long proposed that histone H1 exerts context-specific effects on gene expression. Here, we have identified a new function of histone H1 in chromatin structure and transcription using a range of genomic approaches. We show that histone H1-depleted cells accumulate nascent non-coding RNAs on chromatin, suggesting that histone H1 prevents non-coding RNA transcription and regulates non-coding transcript turnover on chromatin. Accumulated non-coding transcripts have reduced levels of m6A modification and cause replication-transcription conflicts. Accordingly, altering the m6A RNA methylation pathway rescues the replicative phenotype of H1 loss. This work unveils unexpected regulatory roles of histone H1 on non-coding RNA turnover and m6A deposition, highlighting the intimate relationship between chromatin conformation, RNA metabolism and DNA replication to maintain genome performance.
Transcriptome-wide Association Study and eQTL colocalization identify potentially causal genes responsible for bone mineral density GWAS associations
Authors: Al-Barghouthi Basel M. , Rosenow Will T. , Du Kang-Ping , Heo Jinho , Maynard Robert , Mesner Larry , Calabrese Gina , Nakasone Aaron , Senwar Bhavya , Gerstenfeld Louis , Ferguson Virginia , Ackert-Bicknell Cheryl , Morgan Elise , Brautigan David L. , Farber Charles R.
Published: October 2021

Genome-wide association studies (GWASs) for bone mineral density (BMD) have identified over 1,100 associations to date. However, identifying causal genes implicated by such studies has been challenging. Recent advances in the development of transcriptome reference datasets and computational approaches such as transcriptome-wide association studies (TWASs) and expression quantitative trait loci (eQTL) colocalization have proven to be informative in identifying putatively causal genes underlying GWAS associations. Here, we used TWAS/eQTL colocalization in conjunction with transcriptomic data from the Genotype-Tissue Expression (GTEx) project to identify potentially causal genes for the largest BMD GWAS performed to date. Using this approach, we identified 512 genes as significant (Bonferroni <= 0.05) using both TWAS and eQTL colocalization. This set of genes was enriched for regulators of BMD and members of bone relevant biological processes. To investigate the significance of our findings, we selected PPP6R3, the gene with the strongest support from our analysis which was not previously implicated in the regulation of BMD, for further investigation. We observed that Ppp6r3 deletion in mice decreased BMD. In this work, we provide an updated resource of putatively causal BMD genes and demonstrate that PPP6R3 is a putatively causal BMD GWAS gene. These data increase our understanding of the genetics of BMD and provide further evidence for the utility of combined TWAS/colocalization approaches in untangling the genetics of complex traits.
Modulation of pre-mRNA structure by hnRNP proteins regulates alternative splicing of MALT1
Authors: Jones Alisha N , Graß Carina , Meininger Isabel , Geerlof Arie , Klostermann Melina , Zarnack Kathi , Krappmann Daniel , Sattler Michael
Published: October 2021

Alternative splicing is controlled by differential binding of trans-acting RNA binding proteins (RBPs) to cis-regulatory elements in intronic and exonic pre-mRNA regions 1-3. How secondary structure in the pre-mRNA transcripts affects recognition by RBPs and determines alternative exon usage is poorly understood. The MALT1 paracaspase is a key component of signaling pathways that mediate innate and adaptive immune responses 4. Alternative splicing of MALT1 exon7 is critical for controlling optimal T cell activation 5,6. Here, we demonstrate that processing of the MALT1 pre-mRNA depends on RNA structural elements that shield the 5’ and 3’ splice sites of the alternatively spliced exon7. By combining biochemical analyses with chemical probing and NMR we show that the RBPs hnRNP U and hnRNP L bind competitively and with comparable affinities to identical stem-loop RNA structures flanking the 5’ and 3’ splice sites of MALT1 exon7. While hnRNP U stabilizes RNA stem-loop conformations that maintain exon7 skipping, hnRNP L unwinds these RNA elements to facilitate recruitment of the essential splicing factor U2AF2 to promote exon7 inclusion. Our data represent a paradigm for the control of splice site selection by differential RBP binding and modulation of pre-mRNA structure.
Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma
Authors: Marcus Rebecca , Ferri-Borgogno Sammy , Hosein Abdel , Foo Wai Chin , Ghosh Bidyut , Zhao Jun , Rajapakshe Kimal , Brugarolas James , Maitra Anirban , Gupta Sonal
Published: October 2021

Intrahepatic cholangiocarcinoma (ICC) is a primary biliary malignancy that harbors a dismal prognosis. Oncogenic mutations of KRAS and loss of function mutations of BRCA1-associated protein 1 (BAP1) have been identified as recurrent somatic alterations in ICC. However, an autochthonous genetically engineered mouse model of ICC that genocopies the co-occurrence of these mutations has never been developed. By crossing Albumin-Cre mice bearing conditional alleles of mutant Kras and/or floxed Bap1, Cre-mediated recombination within the liver was induced. Mice with hepatic expression of mutant KrasG12D alone (KA), bi-allelic loss of hepatic Bap1 (BhomoA), and heterozygous loss of Bap1 in conjunction with mutant KrasG12D expression (BhetKA) developed primary hepatocellular carcinoma (HCC), but no discernible ICC. In contrast, mice with homozygous loss of Bap1 in conjunction with mutant KrasG12D expression (BhomoKA) developed discrete foci of HCC and ICC. Further, the median survival of BhomoKA mice was significantly shorter at 24 weeks, when compared to median survival of ≥40 weeks in BhetKA mice and approximately 50 weeks in BhomoA and KA mice (p <0.001). Microarray analysis performed on liver tissue from KA and BhomoKA mice identified differentially expressed genes in the setting of BAP1 loss and suggests that deregulation of ferroptosis might be one mechanism by which loss of BAP1 cooperates with oncogenic Ras in hepato-biliary carcinogenesis. Our autochthonous model provides an in vivo platform to further study this lethal class of neoplasm.
Shorter constant work rate cycling tests as proxies for longer tests in highly trained cyclists
Authors: Plessis Chantelle du , Andrews Mark , Mitchell Lachlan J G , Wilkie Jodie Cochrane , King Trish , Blazevich Anthony J
Published: October 2021

Severe-intensity constant work rate (CWR) cycling tests are useful for monitoring training progression and adaptation as they impose significant physiological and psychological strain and thus simulate the high-intensity competition environment. However, fatiguing tests require substantial recovery and may disrupt athlete training or competition preparation. Therefore, the development of a brief, minimally fatiguing test providing comparable information is desirable.

Purpose

To determine whether physiological variables measured during, and functional decline in maximal power output immediately after, a 2-min CWR test can act as a proxy for 4-min test outcomes.

Methods

Physiological stress was monitored and pre-to-post-CWR changes in 10-s sprint power computed (to estimate performance fatigability) during 2- and 4-min CWR tests in high-level cyclists.

Results

The 2-min CWR test evoked a smaller decline in sprint mechanical power (32% vs. 47%, p<0.001), however both the physiological variables and sprint mechanical power were independently and strongly correlated between 2- and 4-min tests. Differences in V·O2peak and blood lactate concentration in both CWR tests were strongly associated with the decline in sprint mechanical power.

Conclusion

Physiological variables measured during, and the loss in sprint mechanical power measured after, a severe-intensity 2-min CWR test were less than in the 4-min test. Yet strong correlations between 2- and 4-min test outcomes indicated that the 2-min test can be used as a proxy for the longer test. Because shorter tests are less strenuous, they should have less impact on training and competition preparation and may therefore be more practically applicable within the elite performance environment.
Multimodal tubulin binding by the yeast kinesin-8, Kip3, underlies its motility and depolymerization
Authors: Arellano-Santoyo Hugo , Hernandez-Lopez Rogelio A. , Stokasimov Emma , Wang Ray Yu-Ruei , Pellman David , Leschziner Andres E.
Published: October 2021

The microtubule (MT) cytoskeleton is central to cellular processes including axonal growth, intracellular transport, and cell division, all of which rely on precise spatiotemporal control of MT organization. Kinesin-8s play a key role in regulating MT length by combining highly processive directional motility with MT-end disassembly. However, how kinesin-8 switches between these two apparently opposing activities remains unclear. Here, we define the structural features underlying this molecular switch through cryo-EM analysis of the yeast kinesin-8, Kip3 bound to MTs, and molecular dynamics simulations to approximate the complex of Kip3 with the curved tubulin state found at the MT plus-end. By integrating biochemical and single-molecule biophysical assays, we identified specific intra- and intermolecular interactions that modulate processive motility and MT disassembly. Our findings suggest that Kip3 undergoes conformational changes in response to tubulin curvature that underlie its unique ability to interact differently with the MT lattice than with the MT-end.
Haplotype mapping uncovers unexplored variation in wild and domesticated soybean at the major protein locus cqProt-003
Authors: Marsh Jacob I. , Hu Haifei , Petereit Jakob , Bayer Philipp E. , Valliyodan Babu , Batley Jacqueline , Nguyen Henry T. , Edwards David
Published: October 2021

Here, we present association and linkage analysis of 985 wild, landrace and cultivar soybean accessions in a pan genomic dataset to characterize the major high-protein/low-oil associated locus cqProt-003 located on chromosome 20. A significant trait associated region within a 173 kb linkage block was identified and variants in the region were characterised, identifying 34 high confidence SNPs, 4 insertions, 1 deletion and a larger 304 bp structural variant in the high-protein haplotype. Trinucleotide tandem repeats of variable length present in the third exon of gene 20G085100 are strongly correlated with the high-protein phenotype and likely represent causal variation. Structural variation has previously been found in the same gene, for which we report the global distribution of the 304bp deletion and have identified additional nested variation present in high-protein individuals. Mapping variation at the cqProt-003 locus across demographic groups suggests that the high-protein haplotype is common in wild accessions (94.7%), rare in landraces (10.6%) and near absent in cultivated breeding pools (4.1%), suggesting its decrease in frequency primarily correlates with domestication and continued during subsequent improvement. However, the variation that has persisted in under-utilized wild and landrace populations holds high breeding potential for breeders willing to forego seed oil to maximise protein content. The results of this study include the identification of distinct haplotype structures within the high-protein population, and a broad characterization of the genomic context and linkage patterns of cqProt-003 across global populations, supporting future functional characterisation and modification.

Key message

The major soy protein QTL, cqProt-003, was analysed for haplotype diversity and global distribution, results indicate 304bp deletion and variable tandem repeats in protein coding regions are likely causal candidates.
Structural and functional asymmetry of the neonatal cerebral cortex
Authors: Williams Logan Z. J. , Fitzgibbon Sean P. , Bozek Jelena , Winkler Anderson M. , Dimitrova Ralica , Poppe Tanya , Schuh Andreas , Makropoulos Antonios , Cupitt John , O’Muircheartaigh Jonathan , Duff Eugene P. , Cordero-Grande Lucilio , Price Anthony N. , Hajnal Joseph V. , Rueckert Daniel , Smith Stephen M. , Edwards A. David , Robinson Emma C.
Published: October 2021

Features of brain asymmetry have been implicated in a broad range of cognitive processes; however, their origins are still poorly understood. Using a new left-right symmetric, spatiotemporal cortical surface atlas, we investigated cortical asymmetries in 442 healthy term-born neonates using structural and functional magnetic resonance images from the Developing Human Connectome Project. Cortical asymmetries observed in the term cohort were contextualised in two ways: by comparing them against cortical asymmetries observed in 103 preterm neonates scanned at term-equivalent age, and by comparing structural asymmetries against those observed in 1110 healthy young adults from the Human Connectome Project. Our results demonstrate that the neonatal cortex is markedly asymmetric in both structure and function, and while associations with preterm birth and biological sex were minimal, significant differences exist between birth and adulthood. Although these changes may represent experience-dependent developmental milestones, longitudinal studies across the lifespan are required to fully address these hypotheses.
The fungicide Tebuconazole induces electromechanical cardiotoxicity in murine hearts
Authors: Santos-Miranda Artur , Joviano-Santos Julliane V. , Cruz-Nascimento Taynara , Souza Diego Santos , Marques Leisiane , Roman-Campos Danilo
Published: October 2021

Tebuconazole (TEB) is an important fungicide that belongs to the triazole family. It is largely applied in agriculture and its use has increased in the last decade. Since TEB is stable in water and soil, long-term exposure of humans to this pesticide is a real threat. Acute toxicological studies to uncover the toxicity of TEB are limited, and there is evidence of an association between long-term exposure to TEB and damage of several biological systems, including hepatotoxicity and cardiotoxicity. In this paper, the effects of acute exposure of cardiomyocytes and murine hearts to TEB were addressed to elucidate its impact on electromechanical properties of the cardiac tissue. In whole-cell patch-clamp records, TEB inhibited both the total outward potassium current (IC50=5.7±1.5 μmol.l-1) and the L-type calcium current (IC50=33.2±7.4 μmol.l-1). Acute exposure to TEB at 30 μmol.l-1 prolonged the action potential duration as well as an induced out-of-pace action potential, and increased the sodium/calcium exchanger current in its forward and reverse modes. Moreover, sarcomere shortening and calcium transient in isolated cardiomyocytes was enhanced when cells were exposed to TEB at 30 μmol.l-1. In ex vivo experiments, TEB 30 μmol.l-1 caused significant electrocardiogram remodeling with prolonged PR, QRS, and QT interval duration. Accordingly, TEB exposure was prone to the appearance of arrhythmias. Combined, our results demonstrate that acute TEB exposure affects the cardiomyocyte’s electro-contractile properties and triggers the appearance of ECG abnormalities, including conduction defects and arrhythmias.
Production structure, income distribution and macroeconomic efficiency: an analysis framework and empirical study of the Marxist political economy
Authors: Li Bangxi , Liu Chong , Zhao Feng , Huang Yanghua
Published: October 2021

Purpose

In the current literature, there is little systematic research on the relationship among adjustment of the income distribution, change in economic structure and improvement of macroeconomic efficiency.

Design/methodology/approach

This paper expands Marx's reproduction schema into the “Marx–Sraffa” three-department structure table comprising fixed capital, general means of production and means of consumption and employs China's input–output table from 1987 to 2015 to portray the relationship between income distribution and macroeconomic efficiency under investment-driven growth.

Findings

This paper calculates the wage–profit curve of China's economy and evaluates the space of macroeconomic efficiency improvement in China based on the deviation between actual and potential income distribution structure.

Originality/value

The results show that there is a downward trend of the profit rate, which meets Marx's theoretical prediction, and the decline in the profit rate is mainly attributed to an increase in the organic composition of capital arising from the rapid growth of fixed capital investment under extended growth. The analysis of macroeconomic efficiency shows that the space for improving macroeconomic efficiency is extremely limited under traditional growth pattern and that China must transform its economic development pattern and foster new economic growth drivers.
The National Security Law: political and social effects on the governance of the Hong Kong Special Administrative Region
Authors: Lau Siu-kai
Published: October 2021

Purpose

The purpose of this paper is to identify the major political and social effects of the Hong Kong National Security Law on Hong Kong. It is argued that the enactment of this Law allows Hong Kong not only to end its protracted political turmoil since its return to China in 1997, but also will generate the favorable conditions for long-term stability and effective governance in the territory.

Design/methodology/approach

This paper is based on the author’s close observation of what had happened in Hong Kong in the year since the Hong Kong National Security Law came into effect on 1 July 2020.

Findings

The Hong Kong National Security Law has brought about significant changes in the political psychology of Hongkongers, the balance of power among different political forces, the ability of external forces to interfere in Hong Kong politics, the way Hong Kong is governed, the relationship between the government and the legislature, the activities in the educational and cultural sectors, and the behavior of the judiciary.

Originality/value

This paper would be of interest to scholars and people who are interested in the implementation of “One Country, Two Systems” in the Hong Kong Special Administrative Region (SAR) as well as Beijing’s new policy towards Hong Kong in the aftermath of Hong Kong’s unprecedented riots and violence.
Effects of systemic therapies on pruritus in adults with atopic dermatitis: a systematic review and meta-analysis
Authors: Tan X. L. , Thomas B. R. , Tan Y. J. , O’Toole E. A.
Published: October 2021

Pruritus is a hallmark of atopic dermatitis (AD), which affects disease severity and patient quality of life. In AD uncontrolled with first-line topical therapies or in moderate to severe AD, systemic therapies are used; however, there is a paucity of head-to-head trials comparing the effectiveness of these therapies. The aim of this study was to compare the effectiveness of systemic therapies in relieving pruritus in moderate to severe AD in adults, using a meta-analysis. The PubMed, EMBASE, Medline and CINAHL databases were searched from inception up to 31 May 2020 for randomized, placebo-controlled trials investigating the effectiveness of systemic therapies on pruritus with moderate to severe AD in patients aged ≥ 16 years. In total, 26 studies (n = 5190 participants) were identified. Compared with placebo, there was a large and statistically significant (P < 0.001 for all) reduction in pruritus [standard mean difference (SMD); 95% CI] with dupilumab every 2 weeks (−0.88; −1.13 to −0.63), dupilumab every 2 weeks plus topical corticosteroids (−0.77; −0.91 to −0.62), dupilumab once weekly (−0.99; −1.29 to −0.68), dupilumab once weekly plus topical corticosteroids (−0.70; −0.81 to −0.59). There was also a large and statistically significant reduction with ciclosporin (−1.30; −2.34 to −0.26; P = 0.01) and a large, although not statistically significant reduction with azathioprine (−0.85; −2.07 to 0.35). There was a small reduction with both mepolizumab (−0.27; −0.89 to 0.35) and interferon-γ (−0.31; −0.75 to 0.12). Of the investigational drugs, nemolizumab 2.0 mg/kg was the most effective (−8.13; −9.31 to −6.94). The majority of systemic therapies were superior to placebo in reducing pruritus. In particular, the dupilumab studies consistently showed large improvements in pruritus, while nemolizumab showed the strongest antipruritic effects. However, future head-to-head trials are required for conclusive evidence.
Study on the effect of mental health nursing intervention after gynecological tumour operation based on clustering model
Authors: Li Li , Lu Yi , Li Hongmei , Liu Ai Lan
Published: October 2021

In order to explore scientific and effective mental health nursing intervention methods after gynecological tumour surgery, this paper combines the clustering algorithm to process the nursing method data. Aiming at the type of comprehensive design structure matrix, this paper compares and analyzes the pros and cons of current intelligent clustering algorithms and selects a high‐fit density algorithm as the clustering algorithm of the module division method. Moreover, this paper explains the relative meaning of module cohesion and coupling and uses the smallest ratio of cohesion and coupling as the criterion of the module division method to select the best results from the clustering. In addition, this paper combines the actual situation of mental health nursing intervention after gynecological tumour surgery to set the nursing intervention effect and analyzes the effectiveness of the centralized nursing intervention method through the contrast method. From the test results, it can be seen that the joint intervention nursing method has the best effect on the mental health nursing intervention after gynecological tumour surgery, which provides theoretical guidance for the subsequent mental health intervention after gynecological tumour surgery.
Young Adults Rehabilitation Needs and Experiences following Stroke (YARNS): A review of digital accounts to inform the development of age‐appropriate support and rehabilitation
Authors: Holloway Aisha , Chandler Colin , Aviles Reinso Lissette , Clarissa Catherine , Putri Arcellia , Choi HyeRi , Pan Jo‐Fan , Mitra Udita , Hewitt Jonathan , Cluckie Gillian , Smart Alison , Noble Helen , Harris Ruth , Reid Joanne , Kelly Daniel M.
Published: October 2021

Aims

To explore younger adults' experiences of stroke rehabilitation to inform practice, education and future health policy.

Design

Qualitative analysis of digital and other media sources on public platforms.

Methods

Between March and June 2020, the experiences of younger adult stroke survivors aged 18 to 45 at the time of the stroke were collected. Data were gathered from publicly available sources, including social media, and from English‐speaking users. In total, 117 accounts from 103 participants were identified from films, autobiographical books, blogs, websites, videos, Twitter and Instagram. Data analysis followed narrative and multimodal analysis with a focus on rehabilitation needs.

Results

Younger adult stroke survivors make sense of their experience by reflecting on how stroke has impacted their lives. Accounts reflected an emotional journey between the past self, the present self and evolving self, as well as associated challenges such as the impact on relationships and careers. The majority of accounts presented transitions as problematic, including the receipt of the initial diagnosis, or sometimes misdiagnosis, to returning home and achieving long‐term rehabilitation goals. Specialist stroke nurses were considered essential in the rehabilitation process.

Conclusion

A complex process of recovery follows stroke for younger adult stroke populations. Challenges to the rehabilitation process need to be better understood and the role of nursing highlighted in future service provision. A series of age‐related challenges were highlighted that require attention to improve the care and support offered.

Impact

This article informs clinicians, educators, and policymakers of the age‐related needs of young adult stroke survivors. Focusing on the individual and the development of age‐appropriate person‐centred stroke care is important. The study highlights the role of stroke nursing and challenges the current policy focus on older stroke populations as well as arguing for greater awareness of age‐appropriate stroke rehabilitation in younger adults following stroke.
Neutralisation of SARS‐CoV‐2 by anatomical embalming solutions
Authors: Quondamatteo Fabio , Corzo‐Leon Dora E. , Brassett Cecilia , Colquhoun Ian , Davies David C. , Dockery Peter , Grenham Sue , Guild Simon , Hunter Amanda , Jones James , Lee Thomas C. , Tracey Chris , Wilkinson Tracey , Munro Carol A. , Gillingwater Thomas H. , Parson Simon H.
Published: October 2021

Teaching and learning anatomy by using human cadaveric specimens has been a foundation of medical and biomedical teaching for hundreds of years. Therefore, the majority of institutions that teach topographical anatomy rely on body donation programmes to provide specimens for both undergraduate and postgraduate teaching of gross anatomy. The COVID‐19 pandemic has posed an unprecedented challenge to anatomy teaching because of the suspension of donor acceptance at most institutions. This was largely due to concerns about the potential transmissibility of the SARS‐CoV‐2 virus and the absence of data about the ability of embalming solutions to neutralise the virus. Twenty embalming solutions commonly used in institutions in the United Kingdom and Ireland were tested for their ability to neutralise SARS‐CoV‐2, using an established cytotoxicity assay. All embalming solutions tested neutralised SARS‐CoV‐2, with the majority of solutions being effective at high‐working dilutions. These results suggest that successful embalming with the tested solutions can neutralise the SARS‐CoV‐2 virus, thereby facilitating the safe resumption of body donation programmes and cadaveric anatomy teaching.
Double nail of the second toe: A case report with sonographic and radiological correlation
Authors: Pons Benavent Martí , Salgüero Fernández Irene , Lopez Negrete Elena , Roustan Gullon Gaston , Alfageme Roldán Fernando
Published: October 2021

Double toenail is a rare abnormality that usually affects the fifth toe. It is considered as an inherited condition that may represent an incomplete form of polydactyly. Underlying bone abnormalities should be ruled out. We present a case of a double toenail of the second toe, a location that has not previously been described, with underlying bone involvement noted on ultrasound and plain films.
Maturing papillomatous nevoid melanoma in the scalp mimicking recurrent melanocytic nevus: A case report of previously undescribed subtype of nevoid melanoma
Authors: Tsujimura Marina , Kaku Yo , Takeuchi Yasuhide , Ishida Yoshihiro , Fujimoto Masakazu , Usui Shunya , Yamada Yosuke , Ogawa Seishi , Shea Christopher R. , Haga Hironori
Published: October 2021

Nevoid melanoma is a subtype of melanoma that histologically resembles a melanocytic nevus. Two subtypes have been proposed for nevoid melanoma, namely papillomatous and maturing. Here, we report the case of a 67‐year‐old woman who developed two nevoid melanomas on her scalp with composite histological features of papillomatous and maturing subtypes after electrocautery of a nearby solitary scalp papule. The histology of both lesions was very similar, papillary in shape, and both comprised two melanocyte populations, including large atypical melanocytes and small non‐atypical melanocytes. Whole‐exome sequencing was performed in one of the two lesions, which revealed a high mutation burden (17 mutations/megabase) with co‐deletion of CDKN2A. Additional immunohistochemistry revealed that the large and small melanocytes in both lesions were completely negative for p16 and MTAP. A final diagnosis of nevoid melanoma was made. To our knowledge, this is the first report of a nevoid melanoma with both features of papillomatous and maturing subtypes. Pathologists should be aware of this subtype of melanoma to avoid misdiagnosis as a mitotically active melanocytic nevus. In this case, immunohistochemistry for p16 and MTAP, in addition to molecular analysis, helped in the final diagnosis.
Autopsy case with concurrent transthyretin and immunoglobulin amyloidosis
Authors: Shintani‐Domoto Yukako , Ishino Kousuke , Naiki Hironobu , Sakatani Takashi , Ohashi Ryuji
Published: October 2021

An 85‐year‐old man with a history of aortic dissection suddenly fainted, underwent cardiac heart arrest, and died. An autopsy was performed, but the cause of death was not grossly identified. Congo red staining detected amyloid deposits in systemic organs, including the heart, lungs, liver, and kidneys. Immunohistochemical (IHC) analysis revealed immunoglobulin (Ig) λ light chain (‐λ) in systemic blood vessels and transthyretin (TTR) in the heart and lungs. Ig‐λ was predominantly positive in the blood vessels of the lungs, while TTR was detected in the alveolar septum. In the heart, Ig‐λ was positive in the endocardium and blood vessels, and TTR was positive in nodular deposits between cardiomyocytes. The concurrent deposition of Ig‐λ and TTR in the heart was further substantiated by laser microdissection (LMD)‐liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) at each deposition site. Despite systemic deposition of Ig‐λ, bone marrow biopsy findings were not diagnostic for multiple myeloma. In summary, we present an autopsy case of concurrent Ig‐λ and TTR deposition as revealed by IHC and LC‐MS/MS. When Congo red staining and IHC results are indeterminate due to the deposition of multiple amyloid proteins, LMD‐LC‐MS/MS is useful for determining the precursor protein.
TaIAA21 represses TaARF25‐mediated expression of TaERFs required for grain size and weight development in wheat
Authors: Jia Meiling , Li Yanan , Wang Zhenyu , Tao Shu , Sun Guoliang , Kong Xingchen , Wang Ke , Ye Xingguo , Liu Shaoshuai , Geng Shuaifeng , Mao Long , Li Aili
Published: October 2021

Auxin signaling is essential for the development of grain size and grain weight, two important components for crop yield. However, no auxin/indole acetic acid repressor (Aux/IAA) has been functionally characterized to be involved in the development of wheat (Triticum aestivum L.) grains to date. Here, we identified a wheat Aux/IAA gene, TaIAA21, and studied its regulatory pathway. We found that TaIAA21 mutation significantly increased grain length, grain width, and grain weight. Cross‐sections of mutant grains revealed elongated outer pericarp cells compared to those of the wild type, where the expression of TaIAA21 was detected by in situ hybridization. Screening of auxin response factor (ARF) genes highly expressed in early developing grains revealed that TaARF25 interacts with TaIAA21. In contrast, mutation of the tetraploid wheat (Triticum turgidum) ARF25 gene significantly reduced grain size and weight. RNA sequencing analysis revealed upregulation of several ethylene response factor genes (ERFs) in taiaa21 mutants which carried auxin response cis‐elements in their promoter. One of them, ERF3, was upregulated in the taiaa21 mutant and downregulated in the ttarf25 mutant. Transactivation assays showed that ARF25 promotes ERF3 transcription, while mutation of TtERF3 resulted in reduced grain size and weight. Analysis of natural variations identified three TaIAA21‐A haplotypes with increased allele frequencies in cultivars relative to landraces, a signature of breeding selection. Our work demonstrates that TaIAA21 works as a negative regulator of grain size and weight development via the ARF25–ERFs module and is useful for yield improvement in wheat.
La teoría de la voluntad de José Eusebio Caro: el concepto de hombre en el pensamiento colombiano del siglo XIX y su relación con la filosofía liberal francesa
Authors: Gélvez Higuera Carlos Rubén
Published: October 2021

En 1836, a los 19 años, el filósofo colombiano José Eusebio Caro compuso un tratado sociológico y antropológico titulado Mecánica social, en el que se muestra en contexto la acogida que tuvo la filosofía francesa (sensualismo, ideología y fisiología) en el pensamiento colombiano del siglo xix. El propósito de este artículo es exponer críticamente la teoría de la voluntad diseñada por José Eusebio Caro en dicha obra y, en conjunto, poner en evidencia las fuentes filosóficas en las que se apoyó, particularmente la fisiología y su papel como base teórica tanto para la ideología como para la construcción de una novedosa “antropología científica”, sobre la cual se fundamenta la ciencia de la moral y la legislación, objetivos propios del pensamiento liberal radical francés.