bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models
Authors: Laufer Benjamin I. , Hasegawa Yu , Zhang Zhichao , Hogrefe Casey E. , Del Rosso Laura A. , Haapanan Lori , Hwang Hyeyeon , Bauman Melissa D. , Van de Water Judy A. , Taha Ameer Y. , Slupsky Carolyn M. , Golub Mari S. , Capitanio John P. , VandeVoort Catherine A. , Walker Cheryl K. , LaSalle Janine M.
Published: August 2021

Maternal obesity during pregnancy is associated with neurodevelopmental disorder (NDD) risk. We utilized integrative multi-omics to examine maternal obesity effects on offspring neurodevelopment in rhesus macaques by comparison to lean controls and two interventions. Differentially methylated regions (DMRs) from longitudinal maternal blood-derived cell-free fetal DNA (cffDNA) significantly overlapped with DMRs from infant brain. The DMRs were enriched for neurodevelopmental functions, methylation-sensitive developmental transcription factor motifs, and human NDD DMRs identified from brain and placenta. Brain and cffDNA methylation levels from a large region overlapping mir-663 correlated with maternal obesity, metabolic and immune markers, and infant behavior. A DUX4 hippocampal co-methylation network correlated with maternal obesity, infant behavior, infant hippocampal lipidomic and metabolomic profiles, and maternal blood measurements of DUX4 cffDNA methylation, cytokines, and metabolites. Ultimately, maternal obesity altered infant brain and behavior, and these differences were detectable in pregnancy through integrative analyses of cffDNA methylation with immune and metabolic biomarkers.
Temporal scaling of dopamine neuron firing and dopamine release by distinct ion channels shape behavior
Authors: Juarez Barbara , Kong Mi-Seon , Jo Yong S. , Elum Jordan E. , Yee Joshua X. , Ng-Evans Scott , Cline Marcella , Hunker Avery C. , Quinlan Meagan A. , Baird Madison A. , Elerding Abigail J. , Johnson Mia , Ban Derek , Mendez Adriana , Goodwin Nastacia L. , Soden Marta E. , Zweifel Larry S.
Published: August 2021

Despite the widely known role of dopamine in reinforcement learning, how the patterns of dopamine release that are critical to the acquisition, performance, and extinction of conditioned responses are generated is poorly resolved. Here, we demonstrate that the coordinated actions of two ion channels, Kv4.3 and BKCa1.1, control the pattern of dopamine neuron firing and dopamine release on different time scales to regulate separate phases of reinforced behavior in mice. Inactivation of Kv4.3 in VTA dopamine neurons increasesex vivopacemaker activity and excitability that is associated with increasedin vivoramping dynamics prior to lever press in a learned instrumental response paradigm. Loss of Kv4.3 enhances performance of the learned response and facilitates extinction. In contrast, loss of BKCa1.1 increases burst firing and phasic dopamine release that enhances learning of an instrumental response. Inactivation of BKCa1.1 enhances extinction burst lever pressing in early extinction training that is associated with increased reward prediction error signals. These data demonstrate that temporally distinct patterns of dopamine release are governed by the intrinsic regulators of the cell to shape behavior.

Teaser

We show that ion channels in midbrain dopamine neurons are critical for patterning action potential firing at the cell body and governing neurotransmitter release to regulate reinforcement learning.
Binary outcomes of enhancer activity underlie stable random monoallelic expression
Authors: Kissiov Djem U. , Ethell Alexander , Chen Sean , Wolf Natalie K. , Zhang Chenyu , Dang Susanna M. , Jo Yeara , Madsen Katrine N. , Paranjpe Ishan D. , Lee Angus Y. , Chim Bryan , Muljo Stefan A. , Raulet David H.
Published: August 2021

Mitotically stable random monoallelic gene expression (RME) is documented for a small percentage of autosomal genes. Here we investigated the role of enhancers in the RME of natural killer (NK) cell receptor genes. Enhancers were accessible and enriched in H3K27ac on silent and active alleles alike, decoupling enhancer activation and expression. Enhancers controlled gene expression frequency, as predicted by the binary model of enhancer action, and enhancer deletion converted the broadly expressedNkg2dinto an RME gene, recapitulating natural variegation. The results suggested that RME is a consequence of general enhancer properties and therefore many genes may be subject to some degree of RME, which was borne out by analysis of a panel of genes previously thought to be universally expressed within defined hematopoietic lineages:Nkg2d,Cd45, Cd8aandThy1. We propose that previously documented RME is an extreme on a continuum of intrinsically probabilistic gene expression.
What do we gain when tolerating loss? The information bottleneck wrings out recombination
Authors: Narechania Apurva , Bobo Dean , DeSalle Rob , Mathema Barun , Kreiswirth Barry , Planet Paul J.
Published: August 2021

Most microbes have the capacity to acquire genetic material from their environment. Recombination of foreign DNA yields genomes that are, at least in part, incongruent with the vertical history of their species. Dominant approaches for detecting these transfers are phylogenetic, requiring a painstaking series of analyses including alignment and phylogenetic tree reconstruction. These traditional pan-genomic methods do not scale. Here we propose an unsupervised, alignment-free and tree-free technique based on the sequential information bottleneck (SIB), an optimization procedure designed to extract some portion of relevant information from one random variable conditioned on another. In our case, this joint probability distribution tabulates occurrence counts of k-mers against their genomes of origin with the expectation that recombination will create a strong signal that unifies certain sets of co-occuring k-mers. We conceptualize the technique as a rate-distortion problem, measuring distortion in the relevance information as k-mers are compressed into clusters based on their co-occurrence in the source genomes. The result is fast, model-free, lossy compression of k-mers into groups that learns tracts of shared genome sequence differentiating recombined elements from the vertically inherited core. We show that the technique yields a new recombination measure based purely on information, divorced from any biases and limitations inherent to alignment and phylogeny.

Significance

The information bottleneck, a lossy compression technique borrowed from the information theoretic and Natural Langauge Processing literature, is well suited to detecting evolutionary patterns in sets of co-occuring k-mers. Here we show that we can detect simulated and real recombination events while highlighting a core set of k-mers that comprise the vertically inherited portion of any set of genomes. Moreover, the compressibility of any given set of genomes offers a new way to compare the pangenomes of clades across the microbial tree of life. In our application, the bottleneck is informed by genome origin, our relevance variable, but the technique is general. The information bottleneck can be used for any biological contingency matrix where the goal is to learn groups from unstructured data.
Temporally dynamic antagonism between transcription and chromatin compaction controls stochastic photoreceptor specification
Authors: Voortman Lukas , Anderson Caitlin , Urban Elizabeth , Yuan Mini , Tran Sang , Neuhaus-Follini Alexandra , Derrick Josh , Gregor Thomas , Johnston Robert J.
Published: August 2021

Stochastic mechanisms diversify cell fates during development. How cells randomly choose between two or more fates remains poorly understood. In the Drosophila eye, the random mosaic of two R7 photoreceptor subtypes is determined by expression of the transcription factor Spineless (Ss). Here, we investigated how cis-regulatory elements and trans factors regulate nascent transcriptional activity and chromatin compaction at the ss gene locus during R7 development. We find that the ss locus is in a compact state in undifferentiated cells. An early enhancer drives ss transcription in all R7 precursors to open the ss locus. In differentiating cells, transcription ceases and the ss locus stochastically remains open or compacts. In SsON R7s, ss is open and competent for activation by a late enhancer, whereas in SsOFF R7s, ss is compact and repression prevents expression. Our results suggest that a temporally dynamic antagonism, in which transcription drives decompaction and then compaction represses transcription, controls stochastic cell fate specification.
Investigation of Chordwise Functionally Graded Flexural Rigidity in Flapping Wings Using a Two-Dimensional Pitch-Plunge Model
Authors: Reade Joseph , Jankauski Mark
Published: August 2021

Insect wings are heterogeneous structures, with flexural rigidity varying one to two orders of magnitude over the wing surface. This heterogeneity influences the deformation the flapping wing experiences during flight. However, it is not well understood how this flexural rigidity gradient affects wing performance. Here, we develop a simplified 2D model of a flapping wing as a pitching, plunging airfoil using the assumed mode method and unsteady vortex lattice method to model the structural and fluid dynamics, respectively. We conduct parameter studies to explore how variable flexural rigidity affects mean lift production, power consumption and the forces required to flap the wing. We find that there is an optimal flexural rigidity distribution that maximizes lift production; this distribution generally corresponds to a 3:1 ratio between the wing’s flapping and natural frequencies, though the ratio is sensitive to flapping kinematics. For hovering flight, the optimized flexible wing produces 20% more lift and requires 15% less power compared to a rigid wing but needs 20% higher forces to flap. Even when flapping kinematics deviate from those observed during hover, the flexible wing outperforms the rigid wing in terms of aerodynamic force generation and power across a wide range of flexural rigidity gradients. Peak force requirements and power consumption are inversely proportional with respect to flexural rigidity gradient, which may present a trade-off between insect muscle size and energy storage requirements. The model developed in this work can be used to efficiently investigate other spatially variant morphological or material wing features moving forward.
Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding
Authors: Furniss R. Christopher D. , Kadeřábková Nikol , Barker Declan , Bernal Patricia , Maslova Evgenia , Antwi Amanda A.A. , McNeil Helen E. , Pugh Hannah L. , Dortet Laurent , Blair Jessica M.A. , Larrouy-Maumus Gerald , McCarthy Ronan R. , Gonzalez Diego , Mavridou Despoina A.I.
Published: August 2021

Antimicrobial resistance in Gram-negative bacteria is one of the greatest threats to global health. New antibacterial strategies are urgently needed, and the development of antibiotic adjuvants that either neutralize resistance proteins or compromise the integrity of the cell envelope is of ever-growing interest. Most available adjuvants are only effective against specific resistance proteins. Here we demonstrate that disruption of cell envelope protein homeostasis simultaneously compromises several classes of resistance determinants. In particular, we find that impairing DsbA-mediated disulfide bond formation incapacitates diverse β-lactamases and destabilizes mobile colistin resistance enzymes. Furthermore, we show that chemical inhibition of DsbA sensitizes multidrug-resistant clinical isolates to existing antibiotics and that the absence of DsbA, in combination with antibiotic treatment, substantially increases the survival of Galleria mellonella larvae infected with multidrug- resistant Pseudomonas aeruginosa. This work lays the foundation for the development of novel antibiotic adjuvants that function as broad-acting resistance breakers.

IMPACT STATEMENT

Disruption of disulfide bond formation sensitizes resistant Gram- negative bacteria expressing β-lactamases and mobile colistin resistance enzymes to currently available antibiotics.
SNR-efficient distortion-free diffusion relaxometry imaging using ACcelerated Echo-train shifted EPTI (ACE-EPTI)
Authors: Dong Zijing , Wang Fuyixue , Wald Lawrence , Setsompop Kawin
Published: August 2021

Purpose

To develop an efficient acquisition technique for distortion-free diffusion MRI and diffusion-relaxometry.

Methods

A new ACcelerated Echo-train shifted Echo-Planar Time-resolved Imaging (ACE-EPTI) technique is developed to achieve high-SNR, distortion- and blurring-free diffusion and diffusion-relaxometry imaging. ACE-EPTI employs a newly designed variable density spatiotemporal encoding with self-navigation capability, that allows submillimeter in-plane resolution using only 3-shot. Moreover, an echo-train-shifted acquisition is developed to achieve minimal TE, together with an SNR-optimal readout length, leading to ~30% improvement in SNR efficiency over single-shot EPI. To recover the highly accelerated data with high image quality, a tailored subspace image reconstruction framework is developed, that corrects for odd/even-echo phase difference, shot-to-shot phase variation, and the B0 field changes due to field drift and eddy currents across different dynamics. After the phase-corrected subspace reconstruction, artifacts-free high-SNR diffusion images at multiple TEs are obtained with varying T2* weighting.

Results

Simulation, phantom and in-vivo experiments were performed, which validated the 3-shot spatiotemporal encoding provides accurate reconstruction at submillimeter resolution. The use of echo-train shifting and optimized readout length improves the SNR-efficiency by 27-36% over single-shot EPI. The reconstructed multi-TE diffusion images were demonstrated to be free from distortion (susceptibility and eddy currents) and phase/field variation induced artifacts. These improvements of ACE-EPTI enable improved diffusion tensor imaging and rich multi-TE information for diffusion-relaxometry analysis.

Conclusion

ACE-EPTI was demonstrated to be an efficient and powerful technique for high-resolution diffusion imaging and diffusion-relaxometry, which provides high SNR, distortion- and blurring-free, and time-resolved multi-echo images by a fast 3-shot acquisition.
Zika virus induces mitotic catastrophe in human neural progenitors by triggering unscheduled mitotic entry in the presence of DNA damage while functionally depleting nuclear PNKP
Authors: Rychlowska Malgorzata , Agyapong Abigail , Weinfeld Michael , Schang Luis M.
Published: August 2021

Vertical transmission of Zika virus (ZIKV) leads with high frequency to congenital ZIKV syndrome (CZS), whose worst outcome is microcephaly. However, the mechanisms of congenital ZIKV neurodevelopmental pathologies, including direct cytotoxicity to neural progenitor cells (NPC), placental insufficiency, and immune responses, remain incompletely understood. At the cellular level, microcephaly typically results from death or insufficient proliferation of NPC or cortical neurons. NPCs replicate fast, requiring efficient DNA damage responses to ensure genome stability. Like congenital ZIKV infection, mutations in the polynucleotide 5’-kinase 3’-phosphatase (PNKP) gene, which encodes a critical DNA damage repair enzyme, results in recessive syndromes often characterized by congenital microcephaly with seizures (MCSZ). We thus tested whether there were any links between ZIKV and PNKP.

Here we show that two PNKP phosphatase inhibitors or PNKP knockout inhibited ZIKV replication. PNKP relocalized from the nucleus to the cytoplasm in infected cells, co-localizing with the marker of ZIKV replication factories (RF) NS1 and resulting in functional nuclear PNKP depletion. Although infected NPC accumulated DNA damage, they failed to activate the DNA damage checkpoint kinases Chk1 and Chk2. ZIKV also induced activation of cytoplasmic CycA/CDK1 complexes, which trigger unscheduled mitotic entry. Inhibition of CDK1 activity inhibited ZIKV replication and the formation of RF, supporting a role of cytoplasmic CycA/CDK1 in RF morphogenesis. In brief, ZIKV infection induces mitotic catastrophe resulting from unscheduled mitotic entry in the presence of DNA damage. PNKP and CycA/CDK1 are thus host factors participating in ZIKV replication in NPC, and pathogenesis to neural progenitor cells.

Significance

The 2015-2017 Zika virus (ZIKV) outbreak in Brazil and subsequent international epidemic revealed the strong association between ZIKV infection and congenital malformations, mostly neurodevelopmental defects up to microcephaly. The scale and global expansion of the epidemic, the new ZIKV outbreaks (Kerala state, India, 2021), and the potential burden of future ones pose a serious ongoing risk. However, the cellular and molecular mechanisms resulting in microcephaly remain incompletely understood. Here we show that ZIKV infection of neuronal progenitor cells results in cytoplasmic sequestration of an essential DNA repair protein itself associated with microcephaly, with the consequent accumulation of DNA damage, together with an unscheduled activation of cytoplasmic CDK1/Cyclin A complexes in the presence of DNA damage. These alterations result in mitotic catastrophe of neuronal progenitors, which would lead to a depletion of cortical neurons during development.
COVID-19 infection among health care workers: Experience in Base Hospital Wathupitiwala, Sri Lanka
Authors: Samaranayake W.A.M.P. , Jayawardena G.P.C. , Roshan A.L.L. , Wijewardene M.A.M. , Siraj M.I.
Published: August 2021

Coronavirus disease 2019 (COVID-19) is a serious global health pandemic resulting in high mortality and morbidity. Frontline health care workers (HCWs) are at an increased risk of the acquisition of severe acute respiratory syndrome coronavirus-2 infection (SARS CoV-2) due to their close interaction with infected patients (1, 2). Also, HCWs can serve as reservoirs of SARS CoV-2 cross-transmission both in community and hospital settings (1). However, the extent of COVID-19 infection among HCWs in Sri Lanka is understudied.

Objectives

This study determined the incidence, demographic characteristics, and risk exposure behavior of HCWs who tested positive for SARS CoV-2 at Base Hospital Wathupitiwala. Furthermore, the rate of acquisition of SARS CoV-2 following COVISHIELD/ChAdOx1 nCoV-19 and Sinopharm /BBIBP-CorV vaccines in HCWs were studied.

Methods

A retrospective cross-sectional descriptive analysis was conducted from May 2021 to August 2021 for a total of 818 HCWs.

Results

Hundred and twenty-four HCWs (15.16%) were tested positive for COVID-19. The mean age of infected HCWs was 46.27 years and the majority were females (74.19%). Among all infected persons, 54 (43.55%) were nurses/midwives, 39 (31.45%) were clinical supportive staff and 12(9.68%) were medical officers. The number of infected HCWs rapidly escalated and a total of 64(51.61%) HCWs got an infection during August/2021. No source was identified in most of them (34.68%) followed by community acquisition (33.87%). Thirty-five HCWs (28.23%) had acquired infection during a hospital setting or had a high-risk exposure in recent history. Among hospital-related infections, 37.91% of HCWs had shared meals or shared sleeping rooms with an infected workmate. The majority of the HCWs were tested by the infection control unit as symptomatic screening (70.16%) followed by contact tracing (20.16%). Fifty-six (45.16%) HCWs had a history of single or multiple comorbidities. The vast majority of HCWs (95.97%) presented as mild to asymptomatic disease that followed an uneventful recovery. Body aches, headache, fever, and sore throat were the most commonly reported symptoms among them. Among the five HCWs required therapeutic oxygen supplementation, two unvaccinated HCWs succumbed to the infection. The rate of breakthrough infection among HCWs was 8.93%. The acquisition of disease was significantly higher among unvaccinated HCWs than partially (p<0.0001) or fully vaccinated (p<0.0001) HCWs with either type of vaccine.

Conclusions

Protecting HCWs remains a challenge in resource-poor settings. The risk of infection fueled by very contagious circulating variants is continuously high even though vaccination has shown clear benefits in preventing mortality and severe infection. Therefore, all healthcare workers should be vaccinated while ensuring continuous infection control measures in the hospital setting.
A toolkit for quantification of biological age from blood-chemistry and organ-function-test data: BioAge
Authors: Kwon Dayoon , Belsky Daniel W.
Published: August 2021

Methods to quantify biological aging are emerging as new measurement tools for epidemiology and population science and have been proposed as surrogate measures for healthy lifespan extension in geroscience clinical trials. Publicly available software packages to compute biological aging measurements from DNA methylation data have accelerated dissemination of these measures and generated rapid gains in knowledge about how different measures perform in a range of datasets. Biological age measures derived from blood chemistry data were introduced at the same time as the DNA methylation measures and, in multiple studies, demonstrate superior performance to these measures in prediction of healthy lifespan. However, their dissemination has been slow by comparison, resulting in a significant gap in knowledge. We developed a software package to help address this knowledge gap. The BioAge R package, available for download at GitHub (http://github.com/dayoonkwon/BioAge), implements three published methods to quantify biological aging based on analysis of chronological age and mortality risk: Klemera-Doubal Biological Age, PhenoAge, and homeostatic dysregulation. The package allows users to parametrize measurement algorithms using custom sets of biomarkers, to compare the resulting measurements to published versions of the Klemera-Doubal method and PhenoAge algorithms, and to score the measurements in new datasets. We applied BioAge to safety lab data from the CALERIE™ randomized controlled trial, the first-ever human trial of long-term calorie restriction in healthy, non-obese adults, to test effects of intervention on biological aging. Results contribute evidence that CALERIE intervention slowed biological aging. BioAge is a toolkit to facilitate measurement of biological age for geroscience.
Identification and Interaction Analysis of Molecular Markers in Myocardial Infarction by Integrated Bioinformatics Analysis
Authors: Vastrad Basavaraj , Vastrad Chanabasayya
Published: August 2021

Myocardial infarction (MI) is the leading cardiovascular diseases in worldwide, yet relatively little is known about the genes and signaling pathways involved in MI progression. The present investigation aimed to elucidate potential crucial candidate genes and pathways in MI. expression profiling by high throughput sequencing dataset (GSE132143) was downloaded from the Gene Expression Omnibus (GEO) database, which included data from 20 MI samples and 12 normal control samples. Differentially expressed genes (DEGs) were identified using t-tests in the DESeq2 R package. These DEGs were subsequently investigated by Gene Ontology (GO) and pathway enrichment analysis, a protein-protein interaction (PPI) network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network were constructed and analyzed. Hub genes were validated by receiver operating characteristic curve (ROC) analysis. In total, 958 DEGs were identified, of which 480 were up regulated and 478 were down regulated. GO and pathway enrichment analysis results revealed that the DEGs were mainly enriched in, immune system, neuronal system, response to stimulus, and multicellular organismal process. A PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network was constructed by using Cytoscape software, and CFTR, CDK1, RPS13, RPS15A, RPS27, NOTCH1, MRPL12, NOS2, CCDC85B and ATN1 were identified as the hub genes. Our results highlight the important roles of the genes including CFTR, CDK1, RPS13, RPS15A, RPS27, NOTCH1, MRPL12, NOS2, CCDC85B and ATN1 in MI pathogenesis or therapeutic management.
SampleQC: robust multivariate, multi-celltype, multi-sample quality control for single cell data
Authors: Macnair Will , Robinson Mark D.
Published: August 2021

Quality control (QC) is a critical component of single-cell RNA-seq (scRNA-seq) processing pipelines. Current approaches to QC implicitly assume that datasets are comprised of one celltype, potentially resulting in biased exclusion of rare celltypes. We introduce SampleQC, which robustly fits a Gaussian mixture model across multiple samples, and improves sensitivity and reduces bias compared to current approaches. We show via simulations that SampleQC is less susceptible to exclusion of rarer celltypes. We also demonstrate SampleQC on a complex real dataset (867k cells over 172 samples). SampleQC is general, is implemented in R, and could be applied to other data types.
Three-Dimensional Loop Extrusion
Authors: Bonato Andrea , Michieletto Davide
Published: August 2021

Loop extrusion convincingly describes how certain Structural Maintenance of Chromosome (SMC) proteins mediate the formation of large DNA loops. Yet, most of the existing computational models cannot reconcile recent in vitro observations showing that condensins can traverse each other, bypass large roadblocks and perform steps longer than its own size. To fill this gap, we propose a three-dimensional (3D) “trans-grabbing” model for loop extrusion which not only reproduces the experimental features of loop extrusion by one SMC complex, but also predicts the formation of so-called “Z-loops” via the interaction of two or more SMCs extruding along the same DNA substrate. By performing Molecular Dynamics simulations of this model we discover that the experimentally observed asymmetry in the different types of Z-loops is a natural consequence of the DNA tethering in vitro. Intriguingly, our model predicts this bias to disappear in absence of tethering and a third type of Z-loop, which has not yet been identified in experiments, to appear. Our model naturally explains road-block bypassing and the appearance of steps larger than the SMC size as a consequence of non-contiguous DNA grabbing. Finally, it is the first to our knowledge to address how Z-loops and bypassing might occur in a way that is broadly consistent with existing cis-only 1D loop extrusion models.
Cap analysis of gene expression (CAGE) sequencing reveals alternative promoter usage in complex disease
Authors: Dahale Sonal , Ruiz-Orera Jorge , Silhavy Jan , Hubner Norbert , van Heesch Sebastiaan , Pravenec Michal , Atanur Santosh S
Published: August 2021

The role of alternative promoter usage in tissue specific gene expression has been well established, however, its role in complex diseases is poorly understood. We performed cap analysis of gene expression (CAGE) tag sequencing from the left ventricle (LV) of a rat model of hypertension, the spontaneously hypertensive rat (SHR), and a normotensive strain, the Brown Norway (BN) to understand role of alternative promoter usage in complex disease. We identified 26,560 CAGE-defined transcription start sites (TSS) in the rat LV, including 1,970 novel cardiac TSS resulting in new transcripts. We identified 27 genes with alternative promoter usage between SHR and BN which could lead to protein isoforms differing at the amino terminus between two strains. Additionally, we identified 475 promoter switching events where a shift in TSS usage was within 100bp between SHR and BN, altering length of the 5’ UTR. Genomic variants located in the shifting promoter regions showed significant allelic imbalance in F1 crosses, confirming promoter shift. We found that the insulin receptor gene (Insr) showed a switch in promoter usage between SHR and BN in heart and liver. The Insr promoter shift was significantly associated with insulin levels and blood pressure within a panel of BXH/HXB recombinant inbred (RI) rat strains. This suggests that the hyperinsulinemia due to insulin resistance might lead to hypertension in SHR. Our study provides a preliminary evidence of alternative promoter usage in complex diseases.
Dynamic and Facilitated Binding of Topoisomerase Accelerates Topological Relaxation
Authors: Michieletto D. , Fosado Y. G. , Melas E. , Baiesi M. , Tubiana L. , Orlandini E.
Published: August 2021

How type 2 Topoisomerase (TopoII) proteins relax and simplify the topology of DNA molecules is one of the most intriguing open questions in genome and DNA biophysics. Most of the existing models neglect the dynamics of TopoII which is characteristics for proteins searching their targets via facilitated diffusion. Here, we show that dynamic binding of TopoII speeds up the topological relaxation of knotted substrates by enhancing the search of the knotted arc. Intriguingly, this in turn implies that the timescale of topological relaxation is virtually independent of the substrate length. We then discover that considering binding biases due to facilitated diffusion on looped substrates steers the sampling of the topological space closer to the boundaries between different topoisomers yielding an optimally fast topological relaxation. We discuss our findings in the context of topological simplification in vitro and in vivo.
Cardiomyocyte GSK-3β deficiency induces cardiac progenitor cell proliferation in the ischemic heart through paracrine mechanisms
Authors: Yusuf Ayesha M. , Qaisar Rizwan , Al-Tamimi Abaher O. , Jayakumar Manju Nidagodu , Woodgett James R. , Koch Walter J. , Ahmad Firdos
Published: August 2021

Cardiomyopathy is an irreparable loss and novel strategies are needed to induce resident cardiac progenitor cell (CPC) proliferation in situ to enhance the possibility of cardiac regeneration. Here we sought to identify the potential roles of glycogen synthase kinase-3β (GSK-3β), a critical regulator of cell proliferation and differentiation, in CPC proliferation post-myocardial infarction (MI).

Cardiomyocyte-specific conditional GSK-3β knockout (cKO) and littermate control mice were employed and challenged with MI. Though cardiac left ventricular chamber dimension (LVID) and contractile functions were comparable at two-week post-MI, cKO mice displayed significantly preserved LV chamber and contractile function vs. control mice at four-weeks post-MI. Consistent with protective phenotypes, an increased percentage of c-kit-positive cells (KPCs) were observed in the cKO hearts at four and six-weeks post-MI which was accompanied by increased levels of cardiomyocyte proliferation. Further analysis revealed that the observed increased number of KPCs in the ischemic cKO hearts was mainly from a cardiac lineage as the majority of identified KPCs were negative for the hematopoietic lineage marker, CD45. Mechanistically, cardiomyocyte-GSK-3β profoundly suppresses the expression and secretion of growth factors, including basic-FGF angiopoietin-2, erythropoietin, stem cell factor (SCF), PDGF-BB, G-CSF, and VEGF, post-hypoxia.

In conclusion, our findings strongly suggest that loss of cardiomyocyte-GSK-3β promotes cardiomyocyte and resident CPC proliferation post-MI. The induction of cardiomyocyte and CPC proliferation in the ischemic cKO hearts is potentially regulated by autocrine and paracrine signaling governed by dysregulated growth factors post-MI. A strategy to inhibit cardiomyocyte GSK-3β could be helpful for the promotion of in situ cardiac regeneration post-ischemic injury.
The rise of grasslands is linked to atmospheric CO2decline in the late Palaeogene
Authors: Palazzesi Luis , Hidalgo Oriane , Barreda Viviana D. , Forest Félix , Höhna Sebastian
Published: August 2021

Grasslands are predicted to experience a major biodiversity change by the year 2100 in part due to recent and projected increases in atmospheric CO2concentration. A better understanding of how grasslands have responded to past environmental changes will help predict the outcome of current and future environmental changes. Here, we explore the relationship between past atmospheric CO2and temperature fluctuations and the shifts in diversification rate of grasses (Poaceae) and daisies (Asteraceae), two exceptionally species-rich grassland families (∼11,000 and ∼23,000 species, respectively). To this end, we developed a novel Bayesian approach that simultaneously estimates diversification-rates through time from time-calibrated phylogenies and correlations between environmental variables and diversification rates. Additionally, we developed a new statistical approach that incorporates the information of the distribution of missing species in the phylogeny. We found strong evidence supporting a simultaneous increase in diversification rates for daisies and grasses after the most significant reduction of atmospheric CO2in the Cenozoic (∼34 Mya). The fluctuations of paleo-temperatures, however, appear not to have had a significant relationship with the diversification of these grassland families. Overall, our results shed new light on our understanding of the origin of grasslands in the context of past environmental changes.
Tailored extracellular electron transfer pathways enhance the electroactivity of Escherichia coli
Authors: Mouhib Mohammed , Reggente Melania , Li Lin , Schuergers Nils , Boghossian Ardemis A.
Published: August 2021

Extracellular electron transfer (EET) engineering in Escherichia coli holds great potential for bioremediation, energy and electrosynthesis applications fueled by readily available organic substrates. Due to its vast metabolic capabilities and availability of synthetic biology tools to adapt strains to specific applications, E. coli is of advantage over native exoelectrogens, but limited in electron transfer rates. We enhanced EET in engineered strains through systematic expression of electron transfer pathways differing in cytochrome composition, localization and origin. While a hybrid pathway harboring components of an E. coli nitrate reductase and the Mtr complex from the exoelectrogen Shewanella oneidensis MR-1 enhanced EET, the highest efficiency was achieved by implementing the complete Mtr pathway from S. oneidensis MR1 in E. coli. We show periplasmic electron shuttling through overexpression of a small tetraheme cytochrome to be central to the electroactivity of this strain, leading to enhanced degradation of the pollutant methyl orange and significantly increased electrical current to graphite electrodes.
Protein-Metabolite Interactomics Reveals Novel Regulation of Carbohydrate Metabolism
Authors: Hicks Kevin G. , Cluntun Ahmad A. , Schubert Heidi L. , Hackett Sean R. , Berg Jordan A. , Leonard Paul G. , Ajalla Aleixo Mariana A. , Blevins Aubrie , Barta Paige , Tilley Samantha , Fogarty Sarah , Winter Jacob M. , Ahn Hee-Chul , Allen Karen N. , Block Samuel , Cardoso Iara A. , Ding Jianping , Dreveny Ingrid , Gasper Clarke , Ho Quinn , Matsuura Atsushi , Palladino Michael J. , Prajapati Sabin , Sun PengKai , Tittmann Kai , Tolan Dean R. , Unterlass Judith , VanDemark Andrew P. , Vander Heiden Matthew G. , Webb Bradley A. , Yun Cai-Hong , Zhap PengKai , Hill Christopher P. , Nonato Maria Cristina , Muller Florian L. , Gottschling Daniel E. , Cox James E. , Rutter Jared
Published: August 2021

Metabolism is highly interconnected and also has profound effects on other cellular processes. However, the interactions between metabolites and proteins that mediate this connectivity are frequently low affinity and difficult to discover, hampering our understanding of this important area of cellular biochemistry. Therefore, we developed the MIDAS platform, which can identify protein-metabolite interactions with great sensitivity. We analyzed 33 enzymes from central carbon metabolism and identified 830 protein-metabolite interactions that were mostly novel, but also included known regulators, substrates, products and their analogs. We validated previously unknown interactions, including two atomic-resolution structures of novel protein-metabolite complexes. We also found that both ATP and long-chain fatty acyl-CoAs inhibit lactate dehydrogenase A (LDHA), but not LDHB, at physiological concentrations in vitro. Treating cells with long-chain fatty acids caused a loss of pyruvate/lactate interconversion, but only in cells reliant on LDHA. We propose that these regulatory mechanisms are part of the metabolic connectivity that enables survival in an ever-changing nutrient environment, and that MIDAS enables a broader and deeper understanding of that network.
Signaling network model of cardiomyocyte morphological changes in familial cardiomyopathy
Authors: Khalilimeybodi Ali , Riaz Muhammad , Campbell Stuart G. , Omens Jeffrey H. , McCulloch Andrew D. , Qyang Yibing , Saucerman Jeffrey J.
Published: August 2021

Familial cardiomyopathy is a precursor of heart failure and sudden cardiac death. Over the past several decades, researchers have discovered numerous gene mutations primarily in sarcomeric and cytoskeletal proteins causing two different disease phenotypes: hypertrophic (HCM) and dilated (DCM) cardiomyopathies. However, molecular mechanisms linking genotype to phenotype remain unclear. Here, we employ a systems approach by integrating experimental findings from preclinical studies (e.g., murine data) into a cohesive signaling network to scrutinize genotype to phenotype mechanisms. We developed an HCM/DCM signaling network model utilizing a logic-based differential equations approach and evaluated model performance in predicting experimental data from four contexts (HCM, DCM, pressure overload, and volume overload). The model has an overall prediction accuracy of 83.8%, with higher accuracy in the HCM context (90%) than DCM (75%). Global sensitivity analysis identifies key signaling reactions, with calcium-mediated myofilament force development and calcium-calmodulin kinase signaling ranking the highest. A structural revision analysis indicates potential missing interactions that primarily control calcium regulatory proteins, increasing model prediction accuracy. Combination pharmacotherapy analysis suggests that downregulation of signaling components such as calcium, titin and its associated proteins, growth factor receptors, ERK1/2, and PI3K-AKT could inhibit myocyte growth in HCM. In experiments with patient-specific iPSC-derived cardiomyocytes (MLP-W4R;MYH7-R723C iPSC-CMs), combined inhibition of ERK1/2 and PI3K-AKT rescued the HCM phenotype, as predicted by the model. In DCM, PI3K-AKT-NFAT downregulation combined with upregulation of Ras/ERK1/2 or titin or Gq protein could ameliorate cardiomyocyte morphology. The model results suggest that HCM mutations that increase active force through elevated calcium sensitivity could increase ERK activity and decrease eccentricity through parallel growth factors, Gq-mediated, and titin pathways. Moreover, the model simulated the influence of existing medications on cardiac growth in HCM and DCM contexts. This HCM/DCM signaling model demonstrates utility in investigating genotype to phenotype mechanisms in familial cardiomyopathy.
Local mechanical stimuli shape tissue growth in vertebrate joint morphogenesis
Authors: Comellas Ester , Farkas Johanna E , Kleinberg Giona , Lloyd Katlyn , Mueller Thomas , Duerr Timothy J , Muñoz Jose J , Monaghan James R , Shefelbine Sandra J
Published: August 2021

The correct formation of synovial joints is essential for proper motion throughout life. Movement-induced forces are critical to creating correctly shaped joints, but it is unclear how cells sense and respond to these mechanical cues. To determine how mechanical stimuli drive joint morphogenesis, we combined experiments on regenerating axolotl (Ambystoma mexicanum) forelimbs with a poroelastic model of bone rudiment growth. Animals either regrew forelimbs normally (control) or were injected with a TRPV4 agonist to impair chondrocyte mechanosensitivity during joint morphogenesis. We quantified growth and shape in regrown humeri from whole mount light sheet fluorescence images of the regenerated limbs. Results revealed statistically significant differences in morphology and cell proliferation between groups, indicating that mechanical stimuli play a role in the shaping of joints. We simulated local tissue growth in a finite element model with a biological contribution to growth proportional to chondrocyte density, and a mechanical contribution to growth proportional to fluid pressure. Computational predictions agreed with experimental outcomes, suggesting that interstitial pressure driven from cyclic mechanical stimuli promotes local tissue growth. Predictive computational models informed by experimental findings allow us to explore potential physical mechanisms involved in tissue growth to advance our understanding of the mechanobiology of joint morphogenesis.
Tip growth in the brown alga Ectocarpus is controlled by a RHO-GAP-BAR domain protein independently from F-actin organisation
Authors: Nehr Zofia , Chenivesse Sabine , Billoud Bernard , Genicot Sabine , Desban Nathalie , Theodorou Ioannis , Nasir Adeel , Le Bail Aude , Rabillé Hervé , Godfroy Olivier , Katsaros Christos , Charrier Bénédicte
Published: August 2021

The brown alga Ectocarpus is a filamentous seaweed that grows by tip growth and branching. In the morphometric mutant etoile, tip growth is slower than in the WT and eventually stops. In this paper, we show that the causal etoile mutation is a null mutation in a bi-domain BAR-RhoGAP gene. By quantitative RT-PCR, we showed that ETOILE is ubiquitously expressed in prostrate filaments of the Ectocarpus sporophyte, and is downregulated in the etoile mutant. We immunolocalised both domains of the protein in WT and etoile, as well as RAC1, the known target of Rho-GAP enzymes. Thus, ETOILE would be localised at the apical cell dome where it would control the localisation of EsRAC1 to the plasma membrane. Actin staining showed that the mutant is not affected in F-actin structures. Overall, these results suggest that in Ectocarpus, BAR-RhoGAP controls tip growth by controlling RAC1 localization and through an actin-independent mechanism.
Effect of urea–formaldehyde nanoparticles on the barrier property and delamination resistance for epoxy coating
Authors: Li Zhe , Zheng Hongpeng , Liu Li , Meng Fandi , Cui Yu , Wang Fuhui
Published: August 2021

Purpose

The purpose of this paper is to investigate the effect of urea–formaldehyde (UF) nanoparticles on the barrier property and delamination resistance for epoxy coating in a 3.5% NaCl aqueous solution.

Design/methodology/approach

The UF resin was synthesized via sol–gel method, and UF/epoxy composite coating was prepared through ball-milling process; the microstructure and chemical composition of UF resin were observed using the Fourier transform infrared spectroscopy, scanning electron microscopy and transmission electron microscopy; the bonding strength of coating/metal interface was investigated through adhesion test; the mechanical properties of the coatings were studied by tensile tests; and the barrier and corrosion resistance properties were verified using salt spray test, cathodic delamination test and electrochemical impedance spectroscopy measurements.

Findings

The experimental results indicated that the UF resin presented uniformly dispersed nanoparticles in the epoxy matrix and enhanced the bonding strength of coating/metal interface and then improved the delamination resistance for composite coating, which resulted in the enhancement of the barrier property and corrosion resistance for UF/epoxy composite coating.

Originality/value

In this paper, an easily prepared blending compounding coating with excellent corrosion resistance property was synthesized via sol–gel method and ball-milling process. The effects of UF nanoparticles on the barrier property and delamination resistance were investigated in detail.
Evaluation of enterprise technology innovation capability in prefabricated construction in China
Authors: Dou Yudan , Xue Xiaolong , Wang Yuna , Xue Weirui , Huangfu Wenbo
Published: August 2021

Purpose

This study aims to evaluate enterprise technology innovation capability in prefabricated construction (PC) from an input-output perspective, using six integrated enterprises in China as cases.

Design/methodology/approach

An evaluation system for enterprise technology innovation capability in PC was constructed, including total input, technology output (TO) and project output. All the evaluation indexes were quantified, and the subject and object indexes weights were determined using the fuzzy cognitive map and information entropy, respectively. The final scores and ranks were evaluated through gray relational analysis (GRA) based on the combined weights.

Findings

It was found that enterprise technology innovation capability in PC was low in China, with its unbalanced development in different dimensions and the poorest performance in TO, currently.

Originality/value

This research has developed an evaluation system for technology innovation capability in PC at the enterprise level and scientifically quantified all the indexes, which is a breakthrough over existing studies. The GRA model based on the combined weights proposed in this study can be applied to other comparable fields and regions, with its easy operation.
Operational challenges during a pandemic: an investigation in the electronics industry
Authors: Paul Sanjoy Kumar , Chowdhury Priyabrata , Chowdhury Md. Tarek , Chakrabortty Ripon Kumar , Moktadir Md. Abdul
Published: August 2021

Purpose

The recent coronavirus disease 2019 (COVID-19) pandemic poses numerous challenges to supply chains. This pandemic is quite unique when compared to previous epidemic disruptions and has had a severe impact on supply chains. As a result, the operational challenges (OCs) caused by COVID-19 are still unknown among practitioners and academics. It is critical to comprehensively document current OCs so that firms can plan and implement strategies to overcome them. Consequently, this study systematically identifies and ranks COVID-19-related OCs.

Design/methodology/approach

This study uses an integrated methodology combining expert interviews and the best-worst method (BWM) to analyze the results. The data have been collected from the electronics industry of Bangladesh, an emerging economy. This study also conducts a sensitivity analysis to check the robustness of the results.

Findings

The results reveal 23 COVID-19-related OCs under five categories: sourcing, production and inventory management, demand management and distribution, return management and after-sales service, and supply chain-wide challenges. The quantitative investigation reveals that overstock in finished goods inventory, low end-customer demands, order cancellations from dealers and retailers, high inventory holding costs and lack of transportation are the top five OCs.

Practical implications

The findings will help practitioners to understand the OCs and allow them to prepare for future major disruptions and formulate long-term strategies for operations during and after the COVID-19 pandemic.

Originality/value

This study contributes to the literature on supply chain complexity and challenges by considering a major pandemic outbreak. Moreover, the study also contributes to the knowledge on emerging economies, which have been largely neglected in the current literature.