bluuebunny/crossref_metadata_2025 huggingface dataset:
7-Tesla Functional Cardiovascular MR Using Vectorcardiographic Triggering – overcoming the magnetohydrodynamic effect
Authors: Hamilton-Craig Christian , Stäeb Daniel , Najjar Aiman Al , O’Brien Kieran , Crawford William , Fletcher Sabine , Barth Markus , Galloway Graham
Published: May 2021

Objective

Ultra-high-field (B0 ≥ 7 Tesla) cardiovascular magnetic resonance (CMR) offers increased resolution. However, ECG gating is impacted by the magneto-hydrodynamic (MHD) effect distorting the ECG trace. We explored the technical feasibility of a 7T MR scanner using ECG trigger learning algorithm to quantitatively assess cardiac volumes and vascular flow.

Methods

7T scans performed on 10 healthy volunteers on a whole-body research MRI (Siemens Healthcare, Erlangen, Germany) with 8 channel Tx/32 channel Rx cardiac coil (MRI Tools GmbH, Berlin, Germany). Vectorcardiogram ECG was performed using a learning phase outside of the magnetic field, with a trigger algorithm overcoming severe ECG signal distortions.

Vectorcardiograms were quantitatively analyzed for false negative and false positive events. Cine CMR was performed after 3rd-order B0 shimming using a high-resolution breath-held ECG-retro-gated segmented spoiled gradient echo, and 2D phase contrast flow imaging. Artefacts were assessed using a semi-quantitative scale.

Results

7T CMR scans were acquired in all patients (100%) using the VCG learning method. 3,142 R-waves were quantitatively analyzed, yielding sensitivity 97.6%, specificity 98.7%. Mean image quality score was 0.9, sufficient to quantitate both cardiac volumes, ejection fraction (EF), aortic and pulmonary blood flow. Mean LVEF was 56.4%, RVEF 51.4%.

Conclusion

Reliable cardiac ECG triggering is feasible in healthy volunteers at 7T utilizing a state-of-the-art 3-lead trigger device despite signal distortion from the MHD effect. This provides sufficient image quality for quantitative analysis. Other ultra-high-field imaging applications such as human brain functional MRI with physiologic noise correction may benefit from this method of ECG triggering.

Key points

Ultra-high field 7 Tesla cardiac MRI is challenging due to the impact of the magneto-hydrodynamic (MHD) effect causing severe distortions in the ECG trace.

Using VCG with a learning phase outside the ultra-high field magnet, the R waves can be adequately detected to perform high quality Cardiac MRI scans, overcoming signal distortion from the MHD effect.
COVID-19 case definitions, diagnostic testing criteria, and surveillance across the pandemic’s 25 highest burden countries
Authors: Suthar Amitabh B. , Schubert Sara , Garon Julie , Couture Alexia , Brown Amy M. , Charania Sana
Published: May 2021

Objective

We compared suspect, probable, and confirmed case definitions, as well as diagnostic testing criteria, used in the COVID-19 pandemic’s 25 highest burden countries to aid interpretation of global and national surveillance data.

Methods

We identified the COVID-19 pandemic’s 25 countries with the highest disease burden based on the number of cumulative reported cases to the World Health Organization (WHO) as of 1 October 2020. We searched official websites of these countries for suspect, probable, and confirmed case definitions. Given that confirmation of COVID-19 usually requires diagnostic testing, we also searched for diagnostic testing eligibility criteria in these countries. Extracted case definitions and testing criteria were managed in a database and analyzed in Microsoft Excel.

Findings

We identified suspect, probable, and confirmed case definitions in 96%, 64%, and 100% of countries, respectively. Testing criteria were identified in 100% of countries. 56% of identified countries followed WHO recommendations for using a combination of clinical and epidemiological criteria as part of the suspect case definition. 75% of identified countries followed WHO recommendations on using clinical, epidemiological, and diagnostic criteria for probable cases. 72% of countries followed WHO recommendations on using PCR testing for confirming a case of COVID-19. Finally, 64% of countries used testing eligibility criteria at least as permissive as WHO.

Conclusion

There is marked heterogeneity in who is eligible for testing in countries and how countries define a case of COVID-19. This affects the ability to compare burden, transmission, and response impact estimates derived from case surveillance data across countries.
A protein microarray-based in vitro transglutaminase assay platform for epitope mapping and immunogen design: implication for transglutaminase-mediated immunodominant determination
Authors: Liu Chen
Published: May 2021

Transglutaminases (TGs) are a family of crosslinking enzymes catalyzing the formation of intra- and inter-molecular glutamine-lysine isopeptide bonds in a calcium dependent manner. Activation of transglutaminases is pathogenically associated with severe human diseases including neurodegenerations, cardiovascular diseases, and autoimmune diseases. Although continuous efforts determining the enzymes’ substrate preference have been witnessed, a high-throughput assay platform with the “omic” efficiency is still missing for the global identification of substrate-specific TG modification sites. In this study we report a protein microarray-based in vitro TG assay platform for rapid and large-scale (up to 30000 reactions per chip) determination of the glutamine (Q)-bearing TG modification motifs. With this platform we identified the Q16 in superoxide dismutase 1 and Q109 in alpha-synuclein as the primary modification sites for tissue transglutaminase (TG2), the most ubiquitous member of the enzyme family. Of particular interest, we found a close match between the modification motifs and published vaccine epitope sequences in alpha-synuclein, implying an essential and intrinsic role transglutaminase might play in the determination of immunodominant epitopes. Our data collectively suggest the glutamine and its follow-up five residues on the C terminal of a protein compose a minimal determinant motif for TG2 modification and, more importantly, the TG2 modification motifs determined by our platform could finally correspond to the substrate’s immunodominant epitope sequences in antigen processing. To establish an efficient approach to optimize the enzyme modification motifs and screen for site-specific interfering peptides, we scanned the known TG2 modification motifs with onchip amino-acid swapping and glutamine repeat addition, and obtained multiple variants with significantly upregulated TG2 reactivity. This approach could also be employed to improve the target peptide’s immunogenicity. Taken together, our synthetic transglutaminase assay platform might be able to deliver a precise epitope blueprint for immunotherapeutic targeting and provide pilot and directional studies for TG-based peptide discovery and immunogen design.
The Origin of Bladder Cancer from Mucosal Field Effects
Authors: Bondaruk Jolanta , Jaksik Roman , Wang Ziqiao , Cogdell David , Lee Sangkyou , Chen Yujie , Dinh Khanh Ngoc , Majewski Tadeusz , Zhang Li , Cao Shaolong , Yao Hui , Weinstein John N. , Navai Neema , Dinney Colin , Gao Jianjun , Theodorescu Dan , Logothetis Christopher , Guo Charles C. , Wang Wenyi , McConkey David , Wei Peng , Kimmel Marek , Czerniak Bogdan
Published: May 2021

We used whole-organ mapping to study loco-geographic molecular changes in evolution of human bladder cancer from mucosal field effects. The integrative multi-platform analyses based on genome-wide RNA sequencing, methylation, copy number variations, and whole exome sequencing identified over 100 dysregulated canonical pathways involving immunity, tissue differentiation and transformation as initiators of bladder carcinogenesis. Widespread dysregulation of interleukin signaling was the dominant change signifying the important role of inflammation and immunity in the incipient phases of urothelial carcinogenesis. The analyses of mutational patterns identified three types of mutations based on their geographic distribution and variant allele frequencies. The most common were low frequency subclonal mutations restricted to individual mucosal samples which were the progeny of their respective uroprogenitor cells. The two additional types of mutations were associated with clonal expansion and involved large areas of bladder mucosa. The first group referred to as α mutations, showed a low mutational frequency across the mucosa. The second group referred to as β mutations increased in their frequencies with disease progression and a large proportion of them represented mutated transcriptional regulators controlling proliferation. Time modeling revealed that bladder carcinogenesis is spanning 10-15 years and can be divided into dormant and progressive phases. The progressive phase lasted 1-2 years and was primarily driven by β mutations with high proliferative advantage. This is the first detailed molecular characterization of mucosal field effects initiating bladder carcinogenesis on the whole-organ scale. It provides novel insights into incipient phases of bladder carcinogenesis and biomarkers for early detection of bladder cancer as well as targets for preventive therapies.
Neural cell injury pathology due to high-rate mechanical loading
Authors: Estrada Jonathan B. , Cramer Harry C. , Scimone Mark T. , Buyukozturk Selda , Franck Christian
Published: May 2021

Successful detection and prevention of brain injuries relies on the quantitative identification of cellular injury thresholds associated with the underlying pathology. Here, by combining a recently developed inertial microcavitation rheology technique with a 3D in vitro neural tissue model, we quantify and resolve the structural pathology and critical injury strain thresholds of neural cells occurring at high loading rates such as encountered in blast, cavitation or directed energy exposures. We find that neuronal dendritic spines characterized by MAP2 displayed the lowest physical failure strain at 7.3%, whereas microtubules and filamentous actin were able to tolerate appreciably higher strains (14%) prior to injury. Interestingly, while these critical injury thresholds were similar to previous literature values reported for moderate and lower strain rates (< 100 1/s), the pathology of primary injury reported here was distinctly different by being purely physical in nature as compared to biochemical activation during apoptosis or necrosis.

Teaser

Controlled microcavitation enables quantitative identification of injury thresholds in neural cells.
Variable brain wiring through scalable and relative synapse formation inDrosophila
Authors: Kiral F. Ridvan , Dutta Suchetana B. , Linneweber Gerit Arne , Poppa Caroline , von Kleist Max , Hassan Bassem A. , Hiesinger Peter Robin
Published: May 2021

Variability of synapse numbers and partners despite identical genes reveals limits of genetic determinism. Non-genetic perturbation of brain wiring can therefore reveal to what extent synapse formation is precise and absolute, or promiscuous and relative. Here, we show the role of relative partner availability for synapse formation in the fly brain through perturbation of developmental temperature. Unexpectedly, slower development at lower temperatures substantially increases axo-dendritic branching, synapse numbers and non-canonical synaptic partnerships of various neurons, while maintaining robust ratios of canonical synapses. Using R7 photoreceptors as a model, we further show that scalability of synapse numbers and ratios is preserved when relative availability of synaptic partners is changed in a DIPγ mutant that ablates R7’s preferred synaptic partner. Behaviorally, movement activity scales inversely with synapse numbers, while movement precision and relative connectivity are congruently robust. Hence, the fly genome encodes scalable relative connectivity to develop functional, but not identical, brains.

One-Sentence Summary

Non-identical connectivity and behavior result from temperature-dependent synaptic partner availability inDrosophila.
Complex introgression among three diverged largemouth bass lineages
Authors: Silliman Katherine , Zhao Honggang , Justice Megan , Thongda Wilawan , Bowen Bryant , Peatman Eric
Published: May 2021

Hybrid zones between diverged lineages offer an unique opportunity to study evolutionary processes related to speciation. Natural and anthropogenic hybridization in the black basses (Micropterus spp.) is well documented, including an extensive intergrade zone between the widespread northern Largemouth Bass (M. salmoides) and the Florida Bass (M. floridanus). Phenotypic surveys have identified an estuarine population of Largemouth Bass (M. salmoides) in the Mobile-Tensaw Delta, with larger relative weight and smaller adult size compared to inland populations, suggesting a potential third lineage of largemouth bass. To determine the evolutionary relationships between these Mobile Delta bass populations, M. salmoides, and M. floridanus, putative pure and intergrade populations of all three groups were sampled across the eastern United States. Phylogenetic analyses of 8,582 nuclear SNPs derived from genotype-by-sequencing and the ND2 mitochondrial gene determined that Delta bass populations stem from a recently diverged lineage of Largemouth Bass. Using a novel quantitative pipeline, a panel of 73 diagnostic SNPs was developed for the three lineages, evaluated for accuracy, and then used to screen 881 samples from 52 sites for genetic integrity and hybridization on the Agena MassARRAY platform. These results strongly support a redrawing of native ranges for both the intergrade zone and M. floridanus, which has significant implications for current fisheries management. Furthermore, Delta bass ancestry was shown to contribute significantly to the previously described intergrade zone between northern Largemouth Bass and Florida Bass, suggesting a more complex pattern of secondary contact and introgression among these diverged Micropterus lineages.
Developmental single-cell transcriptomics of hypothalamic POMC progenitors reveal the genetic trajectories of multiple neuropeptidergic phenotypes
Authors: Yu Hui , Rubinstein Marcelo , Low Malcolm J
Published: May 2021

Proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus are essential to regulate food intake and energy balance. However, the ontogenetic transcriptional programs that specify the identity and functioning of these neurons are poorly understood. Here, we use scRNAseq to define the transcriptomes characterizing POMC progenitors in the developing hypothalamus and TRAP-seq to analyze the subsequent translatomes of mature POMC neurons. Our data show that Pomc-expressing neurons originate from multiple developmental pathways expressing distinct combinations of transcription factors. The predominant cluster, featured by high levels of Pomc and Prdm12 transcripts represents the precursor of canonical arcuate POMC neurons. Additional clusters of progenitors expressing lower levels of Pomc mature into different neuronal phenotypes characterized by distinct combinations of transcription factors, neuropeptides, processing enzymes, cell surface and nuclear receptors. We conclude that the genetic programs specifying the identity and differentiation of arcuate POMC neurons are diverse and generate a heterogeneous repertoire of neuronal phenotypes early in development that continue to evolve postnatally.
Mice lacking the cAMP effector protein POPDC1 show enhanced hippocampal synaptic plasticity
Authors: Shetty Mahesh Shivarama , Ris Laurence , Schindler Roland F. R. , Mizuno Keiko , Fedele Laura , Giese Karl Peter , Brand Thomas , Abel Ted
Published: May 2021

Extensive research has uncovered diverse forms of synaptic plasticity and a wide array of molecular signaling mechanisms that act as positive or negative regulators. Specifically, cAMP-dependent signaling pathways have been crucially implicated in long-lasting synaptic plasticity. In this study, we examine the role of POPDC1 (or BVES), a cAMP effector protein expressed in brain, in modulating hippocampal synaptic plasticity. Unlike other cAMP effectors, such as PKA and EPAC, POPDC1 is membrane-bound and the sequence of the cAMP-binding cassette differs from canonical cAMP-binding domains. These properties suggest that POPDC1 may have a unique role in cAMP-mediated signaling underlying synaptic plasticity. Our results show that POPDC1 is enriched in hippocampal synaptoneurosomes. Acute hippocampal slices from Popdc1 knockout (KO) mice exhibit enhanced long-term potentiation (LTP) induced by a variety of stimulation paradigms, particularly in response to weak stimulation paradigms that in slices from wildtype mice induce only transient LTP. Furthermore, Popdc1 KO mice did not display any further enhancement in forskolin-induced LTP observed following inhibition of phosphodiesterases (PDEs), suggesting a possible modulation of cAMP-PDE signaling by POPDC1. Taken together, these data reveal POPDC1 as a novel player in the regulation of hippocampal synaptic plasticity and as a potential target for cognitive enhancement strategies.
IL-31 uncouples skin inflammation from itch sensation in allergic dermatitis
Authors: Fassett Marlys S. , Braz Joao M. , Castellanos Carlos A. , Schroeder Andrew W. , Sadeghi Mahsa , Mar Darryl J. , Zhou Connie J. , Shin Jeoung-Sook , Basbaum Allan I. , Ansel K. Mark
Published: May 2021

Despite a robust literature associating IL-31 with pruritic inflammatory skin diseases, its influence on cutaneous inflammation and on the interplay between inflammatory and neurosensory pathways remain unmapped. Here, we examined the effects of IL-31 and its receptor IL31RA on both inflammation and pruritus in mouse models of dermatitis, including chronic topical house dust mite (HDM) exposure. Unexpectedly, Il31 deficiency increased cutaneous adaptive type 2 cytokine-producing cells and serum IgE. In addition, M2-like macrophages capable of fueling feedforward pro-inflammatory loops were selectively enriched in Il31ra-deficient skin. Thus, IL-31 is not strictly a pro-inflammatory cytokine, but rather an immunoregulatory factor that limits the magnitude of allergic skin inflammation. In contrast, Il31-deficient mice displayed a deficit in HDM-induced scratching. Itch reduction occurred despite intact – and in some cases increased – responsiveness of sensory neurons to other pruritogens released during HDM challenge, highlighting the non-redundant contribution of IL-31-receptive sensory afferents to pruritus in environmental allergen-induced dermatitis. When present, therefore, IL-31 uncouples circuits driven by sensory neurons and immune cells that converge in inflamed skin.
Structural basis for template switching by a group II intron-encoded non-LTR-retroelement reverse transcriptase
Authors: Lentzsch Alfred M. , Stamos Jennifer L. , Yao Jun , Russell Rick , Lambowitz Alan M.
Published: May 2021

Reverse transcriptases (RTs) can template switch during cDNA synthesis, enabling them to join discontinuous nucleic acid sequences. Template switching plays crucial roles in retroviral replication and recombination, is used for adapter addition in RNA-seq, and may contribute to retroelement fitness by enabling continuous cDNA synthesis on damaged templates. Here, we determined an X-ray crystal structure of a template-switching complex of a group II intron RT bound simultaneously to an acceptor RNA and donor RNA template/DNA heteroduplex with a 1-nt 3’-DNA overhang. The latter mimics a completed cDNA after non-templated addition (NTA) of a nucleotide complementary to the 3’ nucleotide of the acceptor as required for efficient template switching. The structure showed that the 3’ end of the acceptor RNA binds in a pocket formed by an N-terminal extension (NTE) present in non-long-terminal-repeat (LTR)-retroelement RTs and the RT fingertips loop, with the 3’ nucleotide of the acceptor base paired to the 1-nt 3’-DNA overhang and its penultimate nucleotide base paired to the incoming dNTP at the RT active site. Analysis of structure-guided mutations identified amino acids that contribute to acceptor RNA binding and a phenylalanine near the RT active site that mediates NTA. Mutation of the latter residue decreased multiple sequential template switches in RNA-seq. Our results provide new insights into the mechanisms of template switching and NTA by RTs, suggest how these reactions could be improved for RNA-seq, and reveal common structural features for template switching by non-LTR-retroelement RTs and viral RNA-dependent RNA polymerases.
Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression
Authors: Bruinstroop Eveline , Zhou Jin , Tripathi Madhulika , Yau Winifred W. , Boelen Anita , Singh Brijesh Kumar , Yen Paul M.
Published: May 2021

Objective

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum ranging from hepatosteatosis to progressive non-alcoholic steatohepatitis that can lead to cirrhosis. Humans with low levels of the prohormone thyroxine (T4) have a higher incidence of NAFLD and thyroid hormone treatment is very promising in all patients with NAFLD. Deiodinase 1 (Dio1) is a hepatic enzyme that converts T4 to the bioactive T3, and therefore regulates intracellular thyroid hormone availability in the liver. The role of this intracellular regulation was investigated during the progression of NAFLD.

Methods

We investigated intracellular thyroid hormone metabolism in two NAFLD models: wildtype mice fed Western diet with fructose and Leprdp mice fed a methionine- and choline-deficient diet. AAV8-mediated liver-specific Dio1 knockdown was employed to investigate the role of Dio1 during the progression of NAFLD. Intrahepatic thyroid hormone levels, deiodinase activity and metabolic parameters were measured.

Results

Dio1 expression and activity were increased in the early stages of NAFLD and were associated with an increased T3/T4 ratio. Prevention of this increase by AAV8-mediated liverspecific Dio1 knockdown increased hepatic triglycerides and cholesterol as well as decreased pACC/ACC ratio and acylcarnitine levels suggesting there was lower β-oxidation. Dio1 siRNA KD in hepatic cells treated with fatty acids showed increased lipid accumulation and decreased oxidative phosphorylation.

Conclusion

Hepatic Dio1 gene expression was modulated by dietary conditions, increased during hepatosteatosis and early NASH, and regulated hepatic triglyceride content. These early adaptations likely represent compensatory mechanisms to reduce hepatosteatosis and prevent NASH progression.
Nerve recovery from treatment with a vascularized nerve graft compared to an autologous non-vascularized nerve graft in animal models: a systematic review and meta-analysis
Authors: Broeren Berend O. , Duraku Liron S. , Hundepool Caroline A. , Walbeehm Erik T. , Zuidam J. Michiel , Hooijmans Carlijn R. , De Jong Tim
Published: May 2021

Background

Treatment of nerve injuries proves to be a worldwide clinical challenge. Vascularized nerve grafts are suggested to be a promising alternative for bridging a nerve gap to the current gold standard, an autologous non-vascularized nerve graft. However, there is no adequate clinical evidence for the beneficial effect of vascularized nerve grafts and they are still disputed in clinical practice.

Objective

To systematically review whether vascularized nerve grafts give a superior nerve recovery compared to non-vascularized nerve autografts regarding histological and electrophysiological outcomes in animal models.

Material and methods

PubMed and Embase were systematically searched. The inclusion criteria were as follows: 1) the study was an original full paper which presented unique data; 2) a clear comparison between a vascularized and a non-vascularized autologous nerve transfer was made; 3) the population study were animals of all genders and ages. A standardized mean difference and 95% confidence intervals for each comparison was calculated to estimate the overall effect. Subgroup analyses were conducted on graft length, species and time frames.

Results

Fourteen articles were included in this review and all of them were included in the meta-analyses. A vascularized nerve graft resulted in a significantly larger diameter, higher nerve conduction velocity and axonal count compared to an autologous non-vascularized nerve

graft. However, during sensitivity analysis the effect on axonal count disappeared. No significant difference was observed in muscle weight.

Conclusion

Treating a nerve gap with a vascularized graft results in superior nerve recovery compared to non-vascularized nerve autografts in three out of four outcome measurements. However, this conclusion needs to be taken with some caution due to the inherent limitations of this meta-analysis. We recommend future studies to be performed under conditions more closely resembling human circumstances and to use long nerve defects.
Discovery of potential drug-like compounds against Viral protein (VP40) of Marburg Virus using pharmacophoric based virtual screening from ZINC database
Authors: Quazi Sameer , Malik Javed , Suman Komal Singh , Capuzzo Arnaud Martino , Haider Zeshan
Published: May 2021

Marburg virus (MARV) has been confirmed to cause extreme hemorrhagic fever (HFM) in human and animals. The effective and suitable vaccine to treat the MARV virus is not commercialized in public and demands rigorously tested on several scales. This research used a CADD (Computer-Aided Drug Design) computational based technology to find novel drug-like compounds that could inhibit the replicating of the VP40. The pharmacophoric features bases screening was done using an online computational based software, “ZINC Pharmer”. We retrieved about 32456 compounds mainly focused on the properties of pharmacophores from the ZINC database. Lipinski’s rule was also used to predict these drug-like compounds. as well as molecular coupling-dependent screening and selection of VP40 screening ligand complexes based on S-rank (lower than reference) and value of root, mean square (RMSD) (bottom) to examine for reference) using the Molecular Working Environment (MOE) machine. As a result, 100 compounds were found to have a close interaction with MARV VP40, followed by the Binding energy (BE) analysis of these 100 compounds. Only 50 were the strongest binding energy than favipiravir [reference inhibitor] after using the MOE-LigX algorithm to compare their binding energy. After that, ADMET analysis predicted only five compounds (ZINC95457352, ZINC38752258, ZINC38752253, ZINC39272175, and ZINC38752377) passed the ADMET parameters and have the strongest inhibitory effect against the MARV’s VP40. It has been suggested that these “drug-like” candidates have an increased ability to inhibit MARV replication, leading to treatment of MARVD.
Sex differences in microRNA expression in first and third trimester human placenta
Authors: Flowers Amy E. , Gonzalez Tania L. , Joshi Nikhil V. , Eisman Laura E. , Clark Ekaterina L. , Buttle Rae A. , Sauro Erica , DiPentino Rosemarie , Lin Yayu , Wu Di , Wang Yizhou , Santiskulvong Chintda , Tang Jie , Lee Bora , Sun Tianyanxin , Chan Jessica L. , Wang Erica T. , Jefferies Caroline , Lawrenson Kate , Zhu Yazhen , Afshar Yalda , Tseng Hsian-Rong , Williams John , Pisarska Margareta D.
Published: May 2021

Maternal and fetal pregnancy outcomes related to placental function vary based on fetal sex, which may be the result of sexually dimorphic epigenetic regulation of RNA expression. We identified sexually dimorphic miRNA expression throughout gestation in human placentae. Next-generation sequencing was used to identify miRNA expression profiles in first and third trimester uncomplicated pregnancies using tissue obtained at chorionic villous sampling (n=113) and parturition (n=47). Sequencing and differential expression (DE) analysis identified 432 mature miRNAs expressed in the first trimester female, 425 in the first trimester male, 400 in the third trimester female, and 508 in the third trimester male placenta (baseMean >10). Of these, 11 sexually dimorphic (FDR<0.05, baseMean >10) miRNAs were identified in the first and 4 miRNAs were identified in the third trimester, including miR-361-5p, significant in both trimesters, all upregulated in females. Across gestation, 207 miRNAs were DE across gestation, common to both females and males, miR-4483, the most DE across gestation. There were twice as many female-specific differences across gestation as male-specific (44 miRNAs vs 21 miRNAs), indicating that miRNA abundance across human gestation is sexually dimorphic. Pathway enrichment analysis identified significant pathways that were differentially regulated in first and third trimester as well as across gestation. This work provides the normative sex dimorphic miRNA atlas in first and third trimester, as well as the sex independent and sex specific placenta miRNA atlas across gestation which may be used to identify biomarkers of placental function and direct functional studies investigating placental sex differences.

Summary Sentence

Sex dimorphism in miRNA expression is more pronounced in first compared to third trimester placenta, and there are twice as many female-specific gestational differences, indicating miRNA abundance across human gestation is also sexually dimorphic.
Chaperones directly and efficiently disperse stress-triggered biomolecular condensates
Authors: Yoo Haneul , Bard Jared A.M. , Pilipenko Evgeny , Drummond D. Allan
Published: May 2021

Heat shock triggers formation of intracellular protein aggregates and induction of a molecular disaggregation system. Although this system (Hsp100/Hsp70/Hsp40 in most cellular life) can disperse aggregates of model misfolded proteins, its activity on these model substrates is puzzlingly weak, and its endogenous heat-induced substrates have largely eluded biochemical study. Recent work has revealed that several cases of apparent heat-induced aggregation instead reflect evolved, adaptive biomolecular condensation. In budding yeast Saccharomyces cerevisiae, the resulting condensates depend on molecular chaperones for timely dispersal in vivo, hinting that condensates may be major endogenous substrates of the disaggregation system. Here, we show that the yeast disaggregation system disperses heat-induced biomolecular condensates of poly(A)-binding protein (Pab1) orders of magnitude more rapidly than aggregates of the most commonly used model substrate, firefly luciferase. Pab1 condensate dispersal also differs from aggregate dispersal in its molecular requirements, showing no dependence on small heat-shock proteins and a strict requirement for type II Hsp40. Unlike luciferase, Pab1 is not fully threaded (and thus not fully unfolded) by the disaggregase Hsp104 during dispersal, which we show can contribute to the extreme differences in dispersal efficiency. The Hsp70-related disaggregase Hsp110 shows some Pab1 dispersal activity, a potentially important link to animal systems, which lack cytosolic Hsp104. Finally, we show that the long-observed dependence of the disaggregation system on excess Hsp70 stems from the precise mechanism of the disaggregation system, which depends on the presence of multiple, closely spaced Hsp70s for Hsp104 recruitment and activation. Our results establish heat-induced biomolecular condensates of Pab1 as a direct endogenous substrate of the disaggregation machinery which differs markedly from previously studied foreign substrates, opening a crucial new window into the native mechanistic behavior and biological roles of this ancient system.
Piezo1 activation using Yoda1 inhibits macropinocytosis and proliferation of cancer cells
Authors: Kuriyama Masashi , Hirose Hisaaki , Masuda Toshihiro , Shudou Masachika , Arafiles Jan Vincent V. , Imanishi Miki , Maekawa Masashi , Hara Yuji , Futaki Shiroh
Published: May 2021

Macropinocytosis is a type of endocytosis accompanied by actin rearrangement-driven membrane deformation, such as lamellipodia formation and membrane ruffling, followed by macropinosome formation. A certain number of mammalian mechanosensors are sensitive to membrane deformation and tension. However, it remains unclear whether macropinocytosis is regulated by mechanosensors. Focusing on the mechanosensitive ion channel Piezo1, we found that Yoda1, a Piezo1 agonist, potently inhibits macropinocytosis induced by epidermal growth factor (EGF). Although studies with Piezo1 knockout cells suggest that Piezo1 itself is not physiologically indispensable for macropinocytosis regulation, Yoda1 inhibited ruffle formation depending on the extracellular Ca2+ influx through Piezo1 and on the activation of the calcium-activated potassium channel KCa3.1. This suggests that Ca2+ ions can regulate EGF-stimulated macropinocytosis. Moreover, Yoda1 impaired cancer cell proliferation, suggesting the impact of macropinocytosis inhibition. We propose the potential for cancer therapy by macropinocytosis inhibition through the regulation of a mechanosensitive channel activity.
Nitric oxide synthase neurons in the preoptic hypothalamus are sleep-active and contribute to regulating NREM and REM sleep and lowering body temperature
Authors: Harding Edward C. , Ba Wei , Zahir Reesha , Yu Xiao , Yustos Raquel , Hsieh Bryan , Lignos Leda , Vyssotski Alexei L. , Constandinou Timothy , Franks Nicholas P. , Wisden William
Published: May 2021

When mice are exposed to external warmth, nitric oxide synthase (NOS1) neurons in the median and medial preoptic (MnPO/MPO) hypothalamus induce sleep and concomitant body cooling. However, how these neurons regulate baseline sleep and body temperature is unknown. Using calcium photometry, we show that NOS1 neurons in MnPO/MPO are predominantly NREM active. This is the first instance of a predominantly NREM-active population in the PO area, or to our knowledge, elsewhere in the brain. In addition to releasing nitric oxide, NOS1 neurons in MnPO/MPO can release GABA, glutamate and peptides. We expressed tetanus-toxin light-chain in MnPO/MPO NOS1 cells to reduce vesicular release of transmitters. This induced changes in sleep structure: over 24 hours, mice had less NREM sleep in their dark (active) phase, and more NREM sleep in their light (sleep) phase. REM sleep episodes in the dark phase were longer, and there were fewer REM transitions between other vigilance states. REM sleep had less theta power. Mice with synaptically blocked MnPO/MPO NOS1 neurons were also warmer. In particular, mice were warmer than control mice at the dark-light transition (ZT0), as well as during the dark phase siesta (ZT16-20), where there is usually a body temperature dip. Also, at this siesta point of cooled body temperature, mice usually have more NREM, but mice with synaptically blocked MnPO/MPO NOS1 cells showed reduced NREM sleep at this time. Overall, MnPO/MPO NOS1 neurons promote both NREM and REM sleep and contribute to chronically lowering body temperature, particularly at transitions where the mice normally enter NREM sleep.
The environmental stress response regulates ribosome content in cell cycle-arrested S. cerevisiae
Authors: Terhorst Allegra , Sandikci Arzu , Neurohr Gabriel E. , Whittaker Charles A. , Szórádi Tamás , Holt Liam J. , Amon Angelika
Published: May 2021

Temperature sensitive cell division cycle (cdc-ts) cells are unable to progress through the cell cycle at the restrictive temperature due to mutations in genes essential to cell cycle progress. Cells harboring cdc-ts mutations increase in cell volume upon arrest but eventually stop growing. We found that this attenuation in growth was due to selective downregulation of ribosome concentration. We saw similar ribosome downregulation in cells arrested in the cell cycle through alpha factor addition, rapamycin addition, and entrance into stationary phase. In all cell cycle arrests studied, cells activated the Environmental Stress Response (ESR), a key transcriptional response to many stressors in S. cerevisiae. When we combined cell cycle arrest with hyperactivation of the Ras/PKA pathway, ESR activation was prevented, cells were unable to downregulate their ribosomes, and cell viability was decreased. Our work uncovers a key role for the environmental stress response in coupling cell cycle progression to biomass accumulation.
Crystal structure and Hirshfeld surface analysis of bis(6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-5-ium) tetrachloridozincate
Authors: Tojiboev Akmaljon , Okmanov Rasul , Englert Ulli , Wang Ruimin , Pan Fangfang , Turgunov Kambarali , Tashkhodjaev Bakhodir
Published: May 2021

The title compound, (C12H15N2)2[ZnCl4], is a salt with two symmetrically independent, essentially planar heterocyclic cations and a slightly distorted tetrahedral chlorozincate dianion. N—H...Cl hydrogen bonds link these ionic constituents into a discrete aggregate, which comprises one formula unit. The effect of hydrogen bonding is reflected in the minor distortions of the [ZnCl4]2− moiety: distances between the cation and chlorido ligands engaged in classical hydrogen bonds are significantly longer than the others. Secondary interactions comprise C—H...π hydrogen bonding and weak π–π stacking. A Hirshfeld surface analysis indicates that the most abundant contacts in packing stem from H...H (47.8%) and Cl...H/H...Cl (29.3%) interactions.
The effects of internal and external innovation strategies on process innovation in Vietnamese firms
Authors: Phung Thuy Minh Thu , Tran Dat Tho , Vermeulen Patrick Alexander Maria , Knoben Joris
Published: May 2021

Purpose

This paper aims to investigate the antecedents of process innovation to provide more alternates for Vietnamese firms as they are still struggling to find an appropriate innovation strategy.

Design/methodology/approach

The research analyzes the separate impacts of each innovation strategy on process innovation using logistic regression models. Data were collected using a stratified random sampling method.

Findings

The results show that having an innovation strategy is good for innovation, regardless of whether the strategy is internal or external. Internal and external strategies are proved not complements but substitutes. However, the internal strategy seems to be most beneficial. Weak institutional settings further strengthen the importance of internal strategies, whereas strong institutional settings favor external strategies.

Originality/value

This paper analyzes the impact of different innovation strategies on process innovation in Vietnamese firms using firm-level data. The findings strongly recommend that in weak institutional settings such as Vietnam, firms should focus on an internal strategy because the emphasis on external innovation strategies might be a western bias stemming from research in mostly strong institutional contexts.
Mode identification method of low-frequency oscillation for power system based on ambient data
Authors: Yan Hong-Yan , Hwang Jin Kwon
Published: May 2021

Purpose

The purpose of this paper is to improve the online monitoring level of low-frequency oscillation in the power system. A modal identification method of discrete Fourier transform (DFT) curve fitting based on ambient data is proposed in this study.

Design/methodology/approach

An autoregressive moving average mathematical model of ambient data was established, parameters of low-frequency oscillation were designed and parameters of low-frequency oscillation were estimated via DFT curve fitting. The variational modal decomposition method is used to filter direct current components in ambient data signals to improve the accuracy of identification. Simulation phasor measurement unit data and measured data of the power grid proved the correctness of this method.

Findings

Compared with the modified extended Yule-Walker method, the proposed approach demonstrates the advantages of fast calculation speed and high accuracy.

Originality/value

Modal identification method of low-frequency oscillation based on ambient data demonstrated high precision and short running time for small interference patterns. This study provides a new research idea for low-frequency oscillation analysis and early warning of power systems.
Soccer game optimization-based power flow for distribution networks
Authors: Venkatesan Yogambari , Palanivelu Aravindhababu
Published: May 2021

Purpose

The purpose of the paper is to develop a simple, efficient and robust power flow (PF) method for ill-conditioned distribution networks (DNs).

Design/methodology/approach

It first formulates the PF problem as an optimization problem of minimizing the node power mismatches, while treating the corrections of node voltages as problem variables and then uses soccer game optimization (SGO), an artificial intelligent algorithm simulating the behavior of soccer game players in scoring goals, in solving the formulated PF problem.

Findings

It studies the performances of the developed method on four standard test DNs and exhibits that the method is superior in respect of accuracy, robustness and computational speed than those of existing methods.

Originality/value

It suggests a novel and new PF method using SGO and portrays that the proposed method is as accurate as any other PF method, robust like non-Newton type of PF methods and faster than Newton type of PF methods.
Negotiation complexity: a review and an integrative model
Authors: Zhang Hong , Zhang Kai , Warsitzka Marco , Trötschel Roman
Published: May 2021

Purpose

This paper aims to review and synthesize the existing literature related to negotiation complexity and provides an integrative model to systematically identify and examine factors contributing to negotiation complexity and how they affect negotiating parties’ behaviors and economic and subjective outcomes.

Design/methodology/approach

The approach was to combine relevant literature from negotiation in general and from negotiation complexity in particular and to develop and support an integrative model of complexity in real-world negotiations.

Findings

The literature on negotiation complexity and previous analytical frameworks are reviewed from a cross-disciplinary perspective. Based on the integrative review, an integrative model of negotiation complexity is proposed for identifying important complexity contributory factors. Six contributory factors are distinguished based on the three negotiation components – negotiation task, dynamic variables of negotiators and negotiation context. Their effects on negotiation complexity are examined and discussed with respect to four complexity dimensions (i.e. informational and computational, procedural, social and strategic dimensions). Finally, the effects of negotiation complexity on parties’ behaviors and outcomes are examined based on previous theoretical and empirical research and practical tools for managing negotiation complexity are delineated.

Originality/value

The integrative review and conceptualization of negotiation complexity are helpful for gaining a better understanding of negotiation complexity and its management in various real-world domains.
Waqf governance in the Republic of Guinea: legal framework, issues, challenges and way forward
Authors: Sano Mohamed Al Amine , Kassim Salina
Published: May 2021

Purpose

The purpose of this paper is to seek to establish an effective governance framework for waqf (Islamic endowment) in the Republic of Guinea that would assist in enhancing socio-economic activities and eradicating poverty in the country.

Design/methodology/approach

It examines key governing features within the said country’s waqf legal framework and undertakes a comparison with other countries’ legal frameworks. This paper also examines waqf-related legal references of Guinea and other countries and analyses relevant online sources such as journal articles, research papers, webpages as well as informal discussions with persons informed on the subject matter within and outside the Republic of Guinea.

Findings

This paper identifies a number of prevailing issues affecting the development of the institution of waqf in the Republic of Guinea and, thereafter, proposes key reformatory measures. These include the passing of general codified legislation that comprehensively governs waqf affairs in the country and the setting up of a dedicated supervisory entity and competent managerial bodies to ensure the smooth and effective operation of the institution in the country.

Originality/value

This research proposes an innovative and befitting governance framework for waqf operations in the Republic of Guinea. These recommendations, if correctly adopted, would ensure the viability and efficacy of the institution of waqf in the Republic of Guinea and would lead to socio-economic development, as has been the case in other nations. Moreover, other countries with underdeveloped waqf governance systems could also model their waqf operations based on these recommendations, as they are most likely already encountering or going to encounter identical issues in this particular field.
Experiences of COVID-19 isolation in Northern Ireland prisons: a qualitative study
Authors: Gray Ruth , Rooney Barry , Connolly Clare
Published: May 2021

Purpose

The purpose of this study was to capture the experience of people after completing their period of COVID-19 14-day isolation in prison. This study used in-depth interviews to assess the impact of the restricted regime.

Design/methodology/approach

This was a cross-sectional qualitative study using an adapted regional survey to record people’s experiences of COVID-19 isolation on entry into prison. This study began in April 2020 and continued to run over eight months. A weekly capture of people’s stories was conducted using a convenience sample. A total of 168 people participated in the study, with in-depth interviews conducted by the health-care team. Content conceptual analysis was used to quantify and analyse the themes of impact of COVID-19 isolation. This information was then used to shape iterative health-care service development.

Findings

A number of key themes have emerged from the experiences of COVID-19 isolation, including connection, communication and support. Stories highlighted how isolation had exacerbated depression, anxiety or feelings of self-harm. This was amplified by the uncertainty of the pandemic and lack of information about accessing services in the altered prison regime. A priority for people in COVID-19 isolation was contact with family. Telephone calls and virtual visits were cited as mitigating the mental health impact of social isolation. People who felt supported by health-care or prison staff reported coping with their time in isolation better. Timely, accessible information was pivotal in support, leading to development of Engagement Lead check-ins on the isolation landings. It is crucial that a public health approach is core to the COVID-19 response in prisons. The thematic analysis of the experiences has enabled a focused understanding of the impact of COVID-19 isolation and an accountability of care provision through organisational collaboration and iterative improvements to service delivery.

Originality/value

There is a paucity of real-time evidence of the impact of restricted regimes in prison owing to COVID-19. This study gives an important insight.