bluuebunny/crossref_metadata_2025 huggingface dataset:
Leaf water relations reflect canopy phenology rather than leaf life span in Sonoran Desert trees
Authors: González-Rebeles Georgina , Terrazas Teresa , Méndez-Alonzo Rodrigo , Paz Horacio , Brodribb Tim J , Tinoco-Ojanguren Clara
Published: February 2021

Plants from arid environments display covarying traits to survive or resist drought. Plant drought resistance and ability to survive long periods of low soil water availability should involve leaf phenology coordination with leaf and stem functional traits related to water status. This study tested correlations between phenology and functional traits involved in plant water status regulation in 10 Sonoran Desert tree species with contrasting phenology. Species seasonal variation in plant water status was defined by calculating their relative positions along the iso/anisohydric regulation continuum based on their hydroscape areas (HA)—a metric derived from the relationship between predawn and midday water potentials—and stomatal and hydraulic traits. Additionally, functional traits associated with plant water status regulation, including lamina vessel hydraulic diameter (DHL), stem-specific density (SSD) and leaf mass per area (LMA) were quantified per species. To characterize leaf phenology, leaf longevity (LL) and canopy foliage duration (FD) were determined. Hydroscape area was strongly correlated with FD but not with leaf longevity (LL); HA was significantly associated with SSD and leaf hydraulic traits (DHL, LMA) but not with stem hydraulic traits (vulnerability index, relative conductivity); and FD was strongly correlated with LMA and SSD. Leaf physiological characteristics affected leaf phenology when it was described as canopy FD better than when described as LL. Stem and leaf structure and hydraulic functions were not only relevant for categorizing species along the iso/anisohydric continuum but also allowed identifying different strategies of desert trees within the ‘fast–slow’ plant economics spectrum. The results in this study pinpoint the set of evolutionary pressures that shape the Sonoran Desert Scrub physiognomy.
Seasonal changes in carbohydrates and water content predict dynamics of frost hardiness in various temperate tree species
Authors: Baffoin Romain , Charrier Guillaume , Bouchardon Anne-Emilie , Bonhomme Marc , Améglio Thierry , Lacointe André
Published: February 2021

Predicting tree frost tolerance is critical to select adapted species according to both the current and predicted future climate. The relative change in water to carbohydrate ratio is a relevant trait to predict frost acclimation in branches from many tree species. The objective of this study is to demonstrate the interspecific genericity of this approach across nine tree species. In the studied angiosperm species, frost hardiness dynamics were best correlated to a decrease in water content at the early stage of acclimation (summer and early autumn). Subsequently, frost hardiness dynamics were more tightly correlated to soluble carbohydrate contents until spring growth resumption. Based on different model formalisms, we predicted frost hardiness at different clade levels (angiosperms, family, genus and species) with high to moderate accuracy (1.5–6.0 °C root mean squared error (RMSE)) and robustness (2.8–6.1 °C prediction RMSE). The TOT model, taking all soluble carbohydrate and polyols into account, was more effective and adapted for large scale studies aiming to explore frost hardiness across a wide range of species. The ISC model taking the individual contribution of each soluble carbohydrate molecule into account was more efficient at finer scale such as family or species. The ISC model performance also suggests that the role of solutes cannot be reduced to a ‘bulk’ osmotic effect as could be computed if all of them were located in a single, common, compartment. This study provides sets of parameters to predict frost hardiness in a wide range of species, and clues for targeting specific carbohydrate molecules to improve frost hardiness.
Hexosylceramides and glycerophosphatidylcholine GPC(36:1) increase in Multi-Organ Dysfunction Syndrome patients with Pediatric Intensive Care Unit Admission over 8-day hospitalization
Authors: Leimanis-Laurens Mara L. , Wolfrum Emily , Ferguson Karen , Grunwell Jocelyn R. , Sanfilippo Dominic , Prokop Jeremy W , Lydic Todd A. , Rajasekaran Surender
Published: February 2021

Glycero- and sphingo-lipids are important in plasma membrane structure, caloric storage and signaling. An un-targeted lipidomics approach for a cohort of critically ill pediatric intensive care unit (PICU) patients, undergoing multi-organ dysfunction syndrome (MODS) was compared to sedation controls. After IRB approval, patients meeting criteria for MODS were screened, consented (n=24), and blood samples were collected from the PICU at HDVCH, Michigan; eight patients needed veno-arterial extracorporeal membrane oxygenation (VA ECMO). Sedation controls were presenting for routine sedation (n=4). Plasma lipid profiles were determined by nano-electrospray (nESI) direct infusion high resolution/accurate mass spectrometry (MS) and tandem mass spectrometry (MS/MS). Biostatistics analysis was performed using R v 3.6.0. 61 patient samples over 3 time points revealed a ceramide metabolite, hexosylceramide (Hex-Cer) was high across all time points (mean 1.63% - 3.19%; vs. controls 0.22%). Fourteen species statistically differentiated from sedation controls (P-value ≤0.05); sphingomyelin (SM) [SM(d18:1/23:0), SM(d18:1/22:0), SM(d18:1/23:1), SM(d18:1/21:0), SM(d18:1/24:0)]; and glycerophosphotidylcholine (GPC) [GPC(36:01), GPC(18:00), GPC(O:34:02), GPC(18:02), GPC(38:05), GPC(O:34:03), GPC(16:00), GPC(40:05), GPC(O:36:03)]. Hex-Cer has been shown to be involved in viral infection and may be at play during acute illness. GPC(36:01) was elevated in all MODS patients at all time points and is associated with inflammation and brain injury.
A disproportionate epidemic: COVID-19 cases and deaths among essential workers in Toronto, Canada
Authors: Rao Amrita , Ma Huiting , Moloney Gary , Kwong Jeffrey C , Jüni Peter , Sander Beate , Kustra Rafal , Baral Stefan D , Mishra Sharmistha
Published: February 2021

Shelter-in-place mandates and closure of non-essential businesses have been central to COVID-19 response strategies including in Toronto, Canada. Approximately half of the working population in Canada are employed in occupations that do not allow for remote work suggesting potentially limited impact of some of the strategies proposed to mitigate COVID-19 acquisition and onward transmission risks and associated morbidity and mortality. We compared per-capita rates of COVID-19 cases and deaths from January 23, 2020 to January 24, 2021, across neighborhoods in Toronto by proportion of the population working in essential services. We used person-level data on laboratory-confirmed COVID-19 community cases (N=74,477) and deaths (N=2319), and census data for neighborhood-level attributes. Cumulative per-capita rates of COVID-19 cases and deaths were 3-fold and 2.5-fold higher, respectively, in neighborhoods with the highest versus lowest concentration of essential workers. Findings suggest that the population who continued to serve the essential needs of society throughout COVID-19 shouldered a disproportionate burden of transmission and deaths. Taken together, results signal the need for active intervention strategies to complement restrictive measures to optimize both the equity and effectiveness of COVID-19 responses.
Similar neural and perceptual masking effects of low-power optogenetic stimulation in primate V1
Authors: Chen Spencer , Benvenuti Giacomo , Chen Yuzhi , Kumar Satwant , Ramakrishnan Charu , Deisseroth Karl , Geisler Wilson S. , Seidemann Eyal
Published: February 2021

Can direct stimulation of primate V1 substitute for a visual stimulus and mimic its perceptual effect? To address this question, we developed an optical-genetic toolkit to “read” neural population responses using widefield calcium imaging, while simultaneously using optogenetics to “write” neural responses into V1 of behaving macaques. We focused on the phenomenon of visual masking, where detection of a dim target is significantly reduced by a co-localized medium-brightness pedestal. Using our toolkit, we tested whether V1 optogenetic stimulation can recapitulate the perceptual masking effect of a visual pedestal. We find that, similar to a visual pedestal, low-power optostimulation can significantly reduce visual detection sensitivity, that a sublinear interaction between visual and optogenetic evoked V1 responses could account for this perceptual effect, and that these neural and behavioral effects are spatially selective. Our toolkit and results open the door for further exploration of perceptual substitutions by direct stimulation of sensory cortex.
Affinity requirements for control of synaptic targeting and neuronal cell survival by heterophilic IgSF cell adhesion molecules
Authors: Xu Shuwa , Sergeeva Alina P , Katsamba Phinikoula S. , Mannepalli Seetha , Bahna Fabiana , Bimela Jude , Zipursky S. L , Shapiro Lawrence , Honig Barry , Zinn Kai
Published: February 2021

Neurons in the developing brain express many different cell adhesion molecules (CAMs) on their surfaces, and CAM interactions are essential for the determination of synaptic connectivity patterns. CAM binding affinities can vary by more than 200-fold, but the significance of affinity differences among CAMs is unknown. Here we provide a systematic characterization of thein vivoconsequences of altering CAM affinity. Interactions between DIP-α and its binding partners Dpr6 and Dpr10 control synaptic targeting and cell survival forDrosophilaoptic lobe neurons. We generated mutations that change DIP-α::Dpr10 binding affinity and introduced these into the endogenous loci. We show that cell survival and synaptic targeting have different affinity requirements, and that there is a threshold affinity required for targeting. Reducing affinity causes graded loss-of-function phenotypes, while increasing affinity rescues cells that would normally die. Affinity reduction can be compensated for by increasing gene copy number.
MK-801-induced behavioral and dopaminergic responses in the shell part of the nucleus accumbens in adult rats are disrupted after neonatal blockade of the ventral subiculum
Authors: Saoud Hana , Kereselidze Elora , Eybrard Séverine , Louilot Alain
Published: February 2021

The present study was conducted in the context of animal modeling of schizophrenia. It investigated in adult rats, after transient neonatal blockade of the ventral subiculum (VSub), the impact of a very specific non-competitive antagonist of NMDA receptors (MK-801) on locomotor activity and dopaminergic (DAergic) responses in the dorsomedialshellpart of the nucleus accumbens (Nacc), a striatal subregion described as the common target region for antipsychotics.

The functional neonatal inactivation of the VSub was achieved by local microinjection of tetrodotoxin (TTX) at postnatal day 8 (PND8). Control pups were microinjected with the solvent phosphate buffered saline (PBS). Locomotor responses and DAergic variations in the dorsomedialshellpart of the Nacc were measured simultaneously usingin vivovoltammetry in awake, freely moving animals after sc administration of MK-801. The following results were obtained: 1) a dose-dependent increase in locomotor activity in PBS and TTX animals, greater in TTX rats/PBS rats; and 2) divergent DAergic responses for PBS and TTX animals. A decrease in DA levels with a return to around basal values was observed in PBS animals. An increase in DA levels was obtained in TTX animals. The present data suggest that neonatal blockade of the VSub results in disruption in NMDA glutamatergic transmission, causing a disturbance in DA release in the dorsomedialshellin adults rats. In the context of animal modeling of schizophrenia using the same approach it would be interesting to investigate possible changes in postsynaptic NMDA receptors-related proteins in the dorsomedialshellregion in the Nacc.
Regulation of ribosomal protein synthesis in mycobacteria: autogenous control ofrpsO
Authors: Aseev Leonid V , Koledinskaya Ludmila S , Bychenko Oksana S , Boni Irina V
Published: February 2021

Autogenous regulation of ribosomal protein (r-protein) synthesis plays a key role in maintaining the stoichiometry of ribosomal components in bacteria. Our main goal was to develop techniques for investigating the r-protein synthesis regulation in mycobacteria, Gram-positive organisms with a high GC-content, which has never been addressed. We started with therpsOgene known to be autoregulated by its product, r-protein S15, in a broad range of bacterial species. To study the in vivo regulation ofrpsOfromMycobacterium smegmatis(Msm), we first applied an approach based on chromosomally integratedMsm rpsO’-’lacZreporters by usingE. colias a surrogate host. The β-galactosidase assay has shown that mycobacterialrpsOexpression is feedback regulated at the translation level in the presence ofMsmS15 in trans, like inE. coli. Next, to overcome difficulties caused by the inefficiency of mycobacterial gene expression inE. coli, we created a fluorescent reporter system based onM. smegmatis. To this end, the integrative shuttle plasmid pMV306 was modified to provide insertion of theMsmorMtb(M. tuberculosis)rpsO-egfpreporters into theMsmchromosome, and a novelE. coli-mycobacteria replicative shuttle vector, pAMYC, a derivative of pACYC184, was built. Analysis of the eGFP expression in the presence of the pAMYC derivative expressingMsm rpsO vsan empty vector confirms the autogenous regulation of therpsOgene in mycobacteria. Additionally, we have revealed that the mycobacterialrpsOcore promoters are rather weak and require upstream activating elements to enhance their strength.

IMPORTANCE

Bacterial ribosomes are targets for a majority of as-yet reported antibiotics, hence ribosome biogenesis and its regulation are central for development of new antimicrobials. One of the key mechanisms regulating ribosome biogenesis in bacteria is the autogenous control of r-protein synthesis, which has been so far explored forE. coliandBacillus spp. but not yet for mycobacteria. Here, we describe experimental approaches for in vivo analysis of mechanisms regulating r-protein synthesis in mycobacteria, includingM. tuberculosis, and show, for the first time, that the autogenous control at the translation level is really functioning in these microorganisms. The developed system paves the way for studying various regulatory circuits involving proteins or sRNAs as mRNA- targetingtrans-regulators in mycobacteria as well as in other actinobacterial species.
Tax induces the recruitment of NF-kB to unintegrated HIV-1 DNA to rescue viral gene expression and replication
Authors: Irwan Ishak D. , Cullen Bryan R.
Published: February 2021

We have previously reported that the normally essential step of integration of the HIV-1 proviral DNA intermediate into the host cell genome becomes dispensable in T cells that express the Human T cell leukemia virus 1 (HTLV-1) Tax protein. The rescue of integrase (IN) deficient HIV-1 replication by Tax results from the strong activation of transcription from the long terminal repeat (LTR) promoter on episomal HIV-1 DNA, an effect that is closely correlated with the recruitment of activating epigenetic marks, such as H3Ac, and depletion of repressive epigenetic marks, such as H3K9me3, from chromatinized unintegrated proviruses. In addition, activation of transcription from unintegrated HIV-1 DNA coincides with the recruitment of NF-kB to the two NF-kB binding sites found in the HIV-1 LTR enhancer. Here we report that the recruitment of NF-kB to unintegrated viral DNA precedes, and is a prerequisite for, Tax-induced changes in epigenetic marks, so that an IN-HIV-1 mutant lacking both LTR NF-kB sites is entirely non-responsive to Tax and fails to undergo the epigenetic changes listed above. We also report that heterologous promoters introduced into IN-HIV-1-based vectors are transcriptionally active even in the absence of Tax. Finally, we failed to reproduce a recent report arguing that heterologous promoters introduced into IN-vectors based on HIV-1 are more active if the HIV-1 promoter and enhancer, located in the LTR U3 region, are deleted, in a so-called self inactivating or SIN lentivector design.

Importance

Integrase-deficient expression vectors based on HIV-1 are becoming increasingly popular as tools for gene therapyin vivodue to their inability to cause insertional mutagenesis. However, many IN-lentiviral vectors are able to achieve only low levels of gene expression and methods to increase this low level have not been extensively explored. Here we analyze how the HTLV-1 Tax protein is able to rescue the replication of IN-HIV-1 in T cells and describe IN-lentiviral vectors that are able to express a heterologous gene effectively.
A transient postnatal quiescent period precedes emergence of mature cortical dynamics
Authors: Domínguez Soledad , Ma Liang , Yu Han , Pouchelon Gabrielle , Mayer Christian , Spyropoulos George D. , Cea Claudia , Buzsáki György , Fishell Gord , Khodagholy Dion , Gelinas Jennifer N.
Published: February 2021

Mature neural networks synchronize and integrate spatiotemporal activity patterns to support cognition. Emergence of these activity patterns and functions is believed to be developmentally regulated, but the postnatal time course for neural networks to perform complex computations remains unknown. We investigate the progression of large-scale synaptic and cellular activity patterns across development using high spatiotemporal resolutionin vivoelectrophysiology in immature mice. We reveal that mature cortical processes emerge rapidly and simultaneously after a discrete but volatile transition period at the beginning of the second postnatal week of rodent development. The transition is characterized by relative neural quiescence, after which spatially distributed, temporally precise, and internally organized activity occurs. We demonstrate a similar developmental trajectory in humans, suggesting an evolutionarily conserved mechanism to transition network operation. We hypothesize that this transient quiescent period is a requisite for the subsequent emergence of coordinated cortical networks.
The MS remyelinating drug bexarotene (an RXR agonist) promotes induction of human Tregs and suppresses Th17 differentiationin vitro
Authors: Gaunt Christof , Rainbow Daniel , Mackenzie Ruairi , Jarvis Lorna , Mousa Hani , Cunniffe Nicholas , Georgieva Zoya , Brown J. William , Coles Alasdair , Jones Joanne
Published: February 2021

The retinoid X receptor (RXR) agonist bexarotene has recently been shown to promote remyelination in individuals with multiple sclerosis. Murine studies demonstrated that RXR agonists can have anti-inflammatory effects by enhancing the ability of all-trans-retinoic acid (αtRA), the primary active metabolite of vitamin A, to promote T regulatory cell (Treg) induction and reduce Th17 differentiationin vitro, following stimulation of naïve CD4 cells in the presence of TGF-β.

Stimulating naïve human CD4 T cells for 7 days, in the presence of either Treg or Th17 skewing cytokines ± bexarotene (1 μM), ± other RXR agonists (9CisRA and NRX 194204), or ±αtRA (100 nM) shows that RXR agonists, including bexarotene, are capable of tipping the human Treg/Th17 axis in favour of Treg induction. Furthermore, this occurs independently ofαtRA and retinoic acid receptor (RAR) signalling. Tregs induced in the presence of bexarotene express many of the canonical markers of T cell regulation and are functionally suppressivein vitro.

These findings support a potential immunomodulatory role for bexarotene and highlight the possible therapeutic application of RXR agonists in autoimmune disease, with bexarotene’s pro-remyelinating effects making multiple sclerosis a particularly attractive disease target.

Significance Statement

The pan-retinoid X receptor (RXR) agonist bexarotene has recently been shown to promote remyelination in patients with multiple sclerosis. Here we demonstrate that bexarotene, and other RXR agonists have immunomodulating effects, tipping the Th17/T regulatory cell (Treg) differentiation axis in favour of Treg development.

These findings lend support to the idea of developing RXR agonists as treatments of autoimmune diseases, in particular multiple sclerosis.
Ancient Migrations - The first complete genome assembly, annotation and variants of the Zoroastrian-Parsi community of India
Authors: Pasha Naseer , Krishnasamy Kashyap , Nagarajan Naveenkumar , Mutya Seshank , Mam Bhavika , Sonnekhan Kouser , Gopalakrishnan Chellappa , Jain Renuka , Morawala-Patell Villoo
Published: February 2021

With the advent of Next Generation Sequencing, many population specific whole genome sequences published thus far, predominantly represent individuals of European ancestry. While sequencing efforts of underrepresented communities in genomes datasets, like the Yoruba West-African, Han Chinese, Tibetan, South Korean, Egyptian and Japanese have recently added to the public genomic repositories, a comprehensive understanding of human genomic diversity and discovery of trait-associated variants necessitates the need for additional population specific analysis. In this context, the genomics of the population from the Indian sub-continent, given its genetic heterogeneity needs further elucidation.

In this context, the endogamous Zoroastrian-Parsi community of India, offer an exceptional insight into a homogenous population that has culturally, socially, and genetically remained intact, for 13 centuries amidst the genomic, social and cultural Indian landscape, consequent to their migration from the ancient Persian plateau.

Notwithstanding longevity as a trait, this endangered community is highly susceptible to cancers, rare genetic disorders, and display a documented high incidence of neurodegenerative and autoimmune conditions. The community as a matter of cultural practice abstains from smoking.

Here, we describe the assembly and annotation of the genome of an adult female, Zoroastrian-Parsi individual sequenced at a high depth of 173X using a combination of short Illumina reads (160X) and long nanopore reads (13X). Using a combination of hybrid assemblers, we created a new, population-specific human reference genome, The Zoroastrian-Parsi Genome Reference Female, AGENOME-ZPGRF, contains 2,778,216,114 nucleotides as compared to 3,096,649,726 in GRCh38 constituting 93.235% of the total genomic fraction. Annotation identified 20833 genomic features, of which 14996 are almost identical to their counterparts on GRCh38 while 5837 genomic features were covered in partial. AGENOME-ZPGRF contained 5,426,310 variants of which the majority were SNP’s (4,291,601) and 960,867 SNPs were AGENOME-ZPGRF specific personal variants not listed in dbSNP.

We present, AGENOME-ZPGRF as a whole reference for any genetic studies involving Zoroastrian-Parsi individuals extending their application to identify disease relevant prognostic biomarkers and variants in global population genomics studies.
Biomolecular recognition of the glycan neoantigen CA19-9 by distinct antibodies
Authors: Borenstein-Katz Aliza , Warszawski Shira , Amon Ron , Tasnima Nova , Yu Hai , Chen Xi , Padler-Karavani Vered , Fleishman Sarel Jacob , Diskin Ron
Published: February 2021

Glycans decorate cell surface, secreted glycoproteins and glycolipids. Altered glycans are often found in cancers. Despite their high diagnostic and therapeutic potentials, glycans are polar and flexible molecules that are quite challenging for the development and design of high-affinity binding antibodies. To understand the mechanisms by which glycan neoantigens are specifically recognized by antibodies, we analyze the biomolecular recognition of a single tumor-associated carbohydrate antigen CA19-9 by two distinct antibodies using X-ray crystallography. Despite the plasticity of glycans and the very different antigen-binding surfaces presented by the antibodies, both structures reveal an essentially identical extended CA19-9 conformer, suggesting that this conformer’s stability selects the antibodies. Starting from the bound structure of one of the antibodies, we use the AbLIFT computational method to design a variant with seven core mutations that exhibited tenfold improved affinity for CA19-9. The results reveal strategies used by antibodies to specifically recognize glycan antigens and show how automated antibody-optimization methods may be used to enhance the clinical potential of existing antibodies.
Impaired pattern separation in Tg2576 mice is associated with hyperexcitable dentate gyrus caused by Kv4.1 downregulation
Authors: Kim Kyung-Ran , Kim Yoonsub , Jeong Hyeon-Ju , Kang Jong-Sun , Lee Sang Hun , Kim Yujin , Lee Suk-Ho , Ho Won-Kyung
Published: February 2021

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that causes memory loss. Most AD researches have focused on neurodegeneration mechanisms. Considering that neurodegenerative changes are not reversible, understanding early functional changes before neurodegeneration is critical to develop new strategies for early detection and treatment of AD. We found that Tg2576 mice exhibited impaired pattern separation at the early preclinical stage. Based on previous studies suggesting a critical role of dentate gyrus (DG) in pattern separation, we investigated functional changes in DG of Tg2576 mice. We found that granule cells in DG (DG-GCs) in Tg2576 mice showed increased action potential firing in response to long depolarizations and reduced 4-AP sensitive K+-currents compared to DG-GCs in wild-type (WT) mice. Among Kv4 family channels, Kv4.1 mRNA expression in DG was significantly lower in Tg2576 mice. We confirmed that Kv4.1 protein expression was reduced in Tg2576, and this reduction was restored by antioxidant treatment. Hyperexcitable DG and impaired pattern separation in Tg2576 mice were also recovered by antioxidant treatment. These results highlight the hyperexcitability of DG-GCs as a pathophysiologic mechanism underlying early cognitive deficits in AD and Kv4.1 as a new target for AD pathogenesis in relation to increased oxidative stress.
Pharmacological inhibition of PAI-1 alleviates cardiopulmonary pathologies induced by exposure to air pollutants PM2.5
Authors: Ghosh Asish K , Soberanes Saul , Lux Elizabeth , Shang Meng , Piseaux-Aillon Raul , Eren Mesut , Budinger G.R. Scott , Miyata Toshio , Vaughan Douglas E
Published: February 2021

OBJECTIVE

Exposure to air pollutants leads to the development of pulmonary and cardiovascular diseases, and thus air pollution is one of the major global threats to human health. Air pollutant particulate matter 2.5 (PM2.5)-induced cellular dysfunction impairs tissue homeostasis and causes vascular and cardiopulmonary damage. To test a hypothesis that elevated plasminogen activator inhibitor-1 (PAI-1) levels play a pivotal role in air pollutant-induced cardiopulmonary pathologies, we examined the efficacy of a drug-like novel inhibitor of PAI-1, TM5614, in treating PM2.5-induced vascular and cardiopulmonary pathologies.

APPROACH AND RESULTS

Results from biochemical, histological, and immunohistochemical studies revealed that PM2.5increases the circulating levels of PAI-1 and thrombin and that TM5614 treatment completely abrogates these effects in plasma. PM2.5significantly augments levels of pro-inflammatory cytokine IL-6 in bronchoalveolar lavage fluid, and this also can be reversed by TM5614, indicating its efficacy in amelioration of PM2.5-induced increases in inflammatory and pro-thrombotic factors. TM5614 reduces PM2.5-induced increased levels of inflammatory markers Mac3 and pSTAT3, adhesion molecule VCAM1, and apoptotic marker cleaved caspase 3. Longer exposure to PM2.5induces pulmonary and cardiac thrombosis, but TM5614 significantly ameliorates PM2.5-induced vascular thrombosis. TM5614 also reduces PM2.5-induced increased blood pressure and heart weight.In vitrocell culture studies revealed that PM2.5induces the levels of PAI-1, type I collagen, fibronectin, and SREBP-1/2, a transcription factor that mediates profibrogenic signaling, in cardiac fibroblasts. TM5614 abrogated that stimulation, indicating that it may block PM2.5-induced PAI-1 and profibrogenic signaling through suppression of SREBP-1. Furthermore, TM5614 blocked PM2.5-mediated suppression of Nrf2, a major antioxidant regulator in cardiac fibroblasts.

CONCLUSIONS

Pharmacological inhibition of PAI-1 with TM5614 is a promising therapeutic approach to control air pollutant PM2.5-induced cardiopulmonary and vascular pathologies.

Abstract Figure
High-throughput and high-efficiency sample preparation for single-cell proteomics using a nested nanowell chip
Authors: Woo Jongmin , Williams Sarah M. , Aguilera-Vazquez Victor , Sontag Ryan L. , Moore Ronald J. , Markillie Lye Meng , Mehta Hardeep S. , Cantlon Joshua , Adkins Joshua N. , Smith Richard D. , Clair Geremy C. , Pasa-Tolic Ljiljana , Zhu Ying
Published: February 2021

Global quantification of protein abundances in single cells would provide more direct information on cellular function phenotypes and complement transcriptomics measurements. However, single-cell proteomics (scProteomics) is still immature and confronts technical challenges, including limited proteome coverage, poor reproducibility, as well as low throughput. Here we describe a nested nanoPOTS (N2) chip to dramatically improve protein recovery, operation robustness, and processing throughput for isobaric-labeling-based scProteomics workflow. The N2 chip allows reducing cell digestion volume to <30 nL and increasing processing capacity to > 240 single cells in one microchip. In the analysis of ∼100 individual cells from three different cell lines, we demonstrate the N2 chip-based scProteomics platform can robustly quantify ∼1500 proteins and reveal functional differences. Our analysis also reveals low protein abundance variations (median CVs < 16.3%), highlighting the utility of such measurements, and also suggesting the single-cell proteome is highly stable for the cells cultured under identical conditions.
Dopamine receptor DOP-1 engages a sleep pathway to modulate swimming inC. elegans
Authors: Xu Ye , Zhang Lin , Liu Yan , Topalidou Irini , Hassinan Cera , Ailion Michael , Zhao Zhenqiang , Wang Tan , Chen Zhibin , Bai Jihong
Published: February 2021

Animals require robust yet flexible programs to support locomotion. While it is clear that a variety of processes must be engaged to ensure rhythmic actions, the exact mechanisms remain largely unknown. Here we report a novel pathway that connects the D1-like dopamine receptor DOP-1 with a sleep mechanism to modulate swimming inC. elegans. We show that DOP-1 plays a negative role in sustaining swimming behavior. By contrast, a pathway through the D2-like dopamine receptor DOP-3 negatively regulates the initiation of swimming, but its impact fades quickly over a few minutes. We find that DOP-1 and the GPCR kinase GRK-2 function in the sleep interneuron RIS, where DOP-1 modulates the secretion of a sleep neuropeptide FLP-11. Our genetic studies further show that DOP-1 and FLP-11 act in the same pathway to modulate swimming. Together, these results delineate a functional connection between a dopamine receptor and a sleep program to regulate swimming inC. elegans. The temporal transition between DOP-3 and DOP-1 pathways highlights the dynamic nature of neuromodulation for rhythmic movements that persist over time.

HIGHLIGHTS

The D1-like dopamine receptor DOP-1 regulates swimming at 10 minutes

An integrated function of DOP-1 and DOP-3 is required for the continuity of swimming

DOP-1 and GRK-2 act in the sleep neuron RIS

FLP-11, a neuropeptide that promotes sleep, negatively regulates swimming

IN BRIEF

Xu et al. investigated genetic programs that modulate swimming behavior in the nematodeC. elegans. They identified a functional link that couples a D1-like dopamine receptor to a sleep program that modulates the sustained phase rather than the initial phase of swimming.
Immune characterization and profiles of SARS-CoV-2 infected patients reveals potential host therapeutic targets and SARS-CoV-2 oncogenesis mechanism
Authors: Policard Martine , Jain Sidharth , Rego Samantha , Dakshanamurthy Sivanesan
Published: February 2021

The spread of SARS-CoV-2 and the increasing mortality rates of COVID-19 create an urgent need for treatments, which are currently lacking. Although vaccines have been approved by the FDA for emergency use in the U.S., patients will continue to require pharmacologic intervention to reduce morbidity and mortality as vaccine availability remains limited. The rise of new variants makes the development of therapeutic strategies even more crucial to combat the current pandemic and future outbreaks. Evidence from several studies suggests the host immune response to SARS-CoV-2 infection plays a critical role in disease pathogenesis. Consequently, host immune factors are becoming more recognized as potential biomarkers and therapeutic targets for COVID-19. To develop therapeutic strategies to combat current and future coronavirus outbreaks, understanding how the coronavirus hijacks the host immune system during and after the infection is crucial. In this study, we investigated immunological patterns or characteristics of the host immune response to SARS-CoV-2 infection that may contribute to the disease severity of COVID-19 patients. We analyzed large bulk RNASeq and single cell RNAseq data from COVID-19 patient samples to immunoprofile differentially expressed gene sets and analyzed pathways to identify human host protein targets. We observed an immunological profile of severe COVID-19 patients characterized by upregulated cytokines, interferon-induced proteins, and pronounced T cell lymphopenia, supporting findings by previous studies. We identified a number of host immune targets including PERK, PKR, TNF, NF-kB, and other key genes that modulate the significant pathways and genes identified in COVID-19 patients. Finally, we identified genes modulated by COVID-19 infection that are implicated in oncogenesis, including E2F transcription factors and RB1, suggesting a mechanism by which SARS-CoV-2 infection may contribute to oncogenesis. Further clinical investigation of these targets may lead to bonafide therapeutic strategies to treat the current COVID-19 pandemic and protect against future outbreaks and viral escape variants.
Plant responses to multiple antagonists are mediated by order of attack and phytohormone crosstalk
Authors: Basu Saumik , Clark Robert E. , Bera Sayanta , Casteel Clare L. , Crowder David W.
Published: February 2021

Plants are often attacked by multiple antagonists, and traits of the attacking organisms, and their order of arrival onto hosts, may affect plant defenses. However, few studies have assessed how multiple antagonists, and varying attack order, affect plant defense or nutrition. To address this, we assessed defensive and nutritional responses ofPisum sativumplants after attack by a vector herbivore (Acrythosiphon pisum), a non-vector herbivore (Sitona lineatus), and a pathogen (Pea enation mosaic virus, PEMV). We show PEMV-infectiousA. pisuminduced several pathogen-specific plant defense signals, but these defenses were inhibited whenS. lineatuswas present in peas infected with PEMV. In contrast, feeding byS. lineatusinduced anti-herbivore defense signals, but these defenses were enhanced by PEMV.Sitona lineatusalso increased abundance of plant amino acids, but only when they attacked after PEMV-infectiousA. pisum. Our results suggest that diverse communities of biotic antagonists alter defense and nutritional traits of plants through complex pathways that depend on the identity of attackers and their order of arrival onto hosts. Moreover, we show interactions among a group of biotic stressors can vary along a spectrum from antagonism to enhancement/synergism based on the identity and order of attackers, and these interactions are mediated by a multitude of phytohormone pathways.
coupleCoC+: an information-theoretic co-clustering-based transfer learning framework for the integrative analysis of single-cell genomic data
Authors: Zeng Pengcheng , Lin Zhixiang
Published: February 2021

Technological advances have enabled us to profile multiple molecular layers at unprecedented single-cell resolution and the available datasets from multiple samples or domains are growing. These datasets, including scRNA-seq data, scATAC-seq data and sc-methylation data, usually have different powers in identifying the unknown cell types through clustering. So, methods that integrate multiple datasets can potentially lead to a better clustering performance. Here we proposecoupleCoC+ for the integrative analysis of single-cell genomic data.coupleCoC+ is a transfer learning method based on the information-theoretic co-clustering framework. IncoupleCoC+, we utilize the information in one dataset, the source data, to facilitate the analysis of another dataset, the target data.coupleCoC+ uses the linked features in the two datasets for effective knowledge transfer, and it also uses the information of the features in the target data that are unlinked with the source data. In addition,coupleCoC+ matches similar cell types across the source data and the target data. By applyingcoupleCoC+ to the integrative clustering of mouse cortex scATAC-seq data and scRNA-seq data, mouse and human scRNA-seq data, mouse cortex sc-methylation and scRNA-seq data, and human blood dendritic cells scRNA-seq data from two batches, we demonstrate thatcoupleCoC+ improves the overall clustering performance and matches the cell subpopulations across multimodal single-cell genomic datasets.coupleCoC+ has fast convergence and it is computationally efficient. The software is available athttps://github.com/cuhklinlab/coupleCoC_plus.
Peak shifts and extinction under sex-specific selection
Authors: De Lisle Stephen P.
Published: February 2021

A well-known property of sexual selection combined with a cross sex genetic correlation (rmf), is that it can facilitate a peak shift on the adaptive landscape. How do these diversifying effects of sexual selection +rmfbalance with the constraints imposed by such sexual antagonism, to affect macroevolution of sexual dimorphism? Here, I extend existing quantitative genetic models of evolution on complex adaptive landscapes. Beyond recovering classical predictions for the conditions promoting a peak shift, I show that whenrmfis moderate to strong, relatively weak sexual selection is required to induce a peak shift in males only. Increasing the strength of sexual selection leads to a sexually-concordant peak shift, suggesting that macroevolutionary rates of sexual dimorphism may be largely decoupled from the strength of within-population sexual selection. Accounting explicitly for demography further reveals that sex-specific peak shifts may be more likely to be successful than concordant shifts in the face of extinction, especially when natural selection is strong. An overarching conclusion is that macroevolutionary patterns of sexual dimorphism are unlikely to be readily explained by within-population estimates of selection or constraint alone.
XPO7 is a tumor suppressor regulating p21CIP1-dependent senescence
Authors: Innes Andrew J. , Sun Bin , Wagner Verena , Brookes Sharon , McHugh Domhnall , Pombo Joaquim , Porreca Rosa María , Dharmalingam Gopuraja , Vernia Santiago , Zuber Johannes , Vannier Jean-Baptiste , García-Escudero Ramón , Gil Jesús
Published: February 2021

Senescence is a key barrier to neoplastic transformation. To identify senescence regulators relevant to cancer, we screened a genome-wide shRNA library. Here, we describe exportin 7 (XPO7) as a novel regulator of senescence and validate its function in telomere-induced, replicative, and oncogene-induced senescence (OIS). XPO7 is a bidirectional transporter that regulates the nuclear-cytoplasmic shuttling of a broad range of substrates. Depletion of XPO7 results in reduced levels of TCF3 and an impaired induction of the cyclin-dependent kinase inhibitor p21CIP1 during OIS. Deletion of XPO7 correlates with poorer overall survival in several cancer types. Moreover, depletion of XPO7 alleviated OIS and increased tumor formation in a mouse model of liver cancer. Our results suggest that XPO7 is a novel tumor suppressor that regulates p21CIP1 expression to control senescence and tumorigenesis.
Early behavioral and molecular events leading to caste switching in the ant Harpegnathos
Authors: Opachaloemphan Comzit , Mancini Giacomo , Konstantinides Nikos , Parikh Apurva , Mlejnek Jakub , Yan Hua , Reinberg Danny , Desplan Claude
Published: February 2021

Ant societies show a division of labor in which a queen is in charge of reproduction while nonreproductive workers maintain the colony. In Harpegnathos saltator, workers retain reproductive ability, inhibited by the queen pheromones. Following the queen loss, the colony undergoes social unrest with an antennal dueling tournament. Most workers quickly abandon the tournament while a few workers continue the dueling for months and become gamergates (pseudoqueens). However, the temporal dynamics of the social behavior and molecular mechanisms underlining the caste transition and social dominance remain unclear. By tracking behaviors, we show that the gamergate fate is accurately determined 3 d after initiation of the tournament. To identify genetic factors responsible for this commitment, we compared transcriptomes of different tissues between dueling and nondueling workers. We found that juvenile hormone is globally repressed, whereas ecdysone biosynthesis in the ovary is increased in gamergates. We show that molecular changes in the brain serve as earliest caste predictors compared with other tissues. Thus, behavioral and molecular data indicate that despite the prolonged social upheaval, the gamergate fate is rapidly established, suggesting a robust re-establishment of social structure.
Polycomb complexes redundantly maintain epidermal stem cell identity during development
Authors: Cohen Idan , Bar Carmit , Liu Hequn , Valdes Victor J. , Zhao Dejian , Galbo Phillip M. , Silva Jose M. , Koseki Haruhiko , Zheng Deyou , Ezhkova Elena
Published: February 2021

Polycomb repressive complex 1 (PRC1) and PRC2 are critical epigenetic developmental regulators. PRC1 and PRC2 largely overlap in their genomic binding and cooperate to establish repressive chromatin domains demarcated by H2AK119ub and H3K27me3. However, the functional contribution of each complex to gene repression has been a subject of debate, and understanding of its physiological significance requires further studies. Here, using the developing murine epidermis as a paradigm, we uncovered a previously unappreciated functional redundancy between Polycomb complexes. Coablation of PRC1 and PRC2 in embryonic epidermal progenitors resulted in severe defects in epidermal stratification, a phenotype not observed in the single PRC1-null or PRC2-null epidermis. Molecular dissection indicated a loss of epidermal identity that was coupled to a strong derepression of nonlineage transcription factors, otherwise repressed by either PRC1 or PRC2 in the absence of its counterpart. Ectopic expression of subsets of PRC1/2-repressed nonepidermal transcription factors in wild-type epidermal stem cells was sufficient to suppress epidermal identity genes, highlighting the importance of functional redundancy between PRC1 and PRC2. Altogether, our studies show how PRC1 and PRC2 function as two independent counterparts, thereby providing a repressive safety net that protects and preserves lineage identity.
SARS-CoV-2 genomic diversity and the implications for qRT-PCR diagnostics and transmission
Authors: Sapoval Nicolae , Mahmoud Medhat , Jochum Michael D. , Liu Yunxi , Elworth R.A. Leo , Wang Qi , Albin Dreycey , Ogilvie Huw A. , Lee Michael D. , Villapol Sonia , Hernandez Kyle M. , Maljkovic Berry Irina , Foox Jonathan , Beheshti Afshin , Ternus Krista , Aagaard Kjersti M. , Posada David , Mason Christopher E. , Sedlazeck Fritz J. , Treangen Todd J.
Published: February 2021

The COVID-19 pandemic has sparked an urgent need to uncover the underlying biology of this devastating disease. Though RNA viruses mutate more rapidly than DNA viruses, there are a relatively small number of single nucleotide polymorphisms (SNPs) that differentiate the main SARS-CoV-2 lineages that have spread throughout the world. In this study, we investigated 129 RNA-seq data sets and 6928 consensus genomes to contrast the intra-host and inter-host diversity of SARS-CoV-2. Our analyses yielded three major observations. First, the mutational profile of SARS-CoV-2 highlights intra-host single nucleotide variant (iSNV) and SNP similarity, albeit with differences in C > U changes. Second, iSNV and SNP patterns in SARS-CoV-2 are more similar to MERS-CoV than SARS-CoV-1. Third, a significant fraction of insertions and deletions contribute to the genetic diversity of SARS-CoV-2. Altogether, our findings provide insight into SARS-CoV-2 genomic diversity, inform the design of detection tests, and highlight the potential of iSNVs for tracking the transmission of SARS-CoV-2.
On Compton scattering as a source of background in coherent diffraction imaging experiments
Authors: Bikondoa Oier , Carbone Dina
Published: February 2021

Compton scattering is generally neglected in diffraction experiments because the incoherent radiation it generates does not give rise to interference effects and therefore is negligible at Bragg peaks. However, as the scattering volume is reduced, the difference between the Rayleigh (coherent) and Compton (incoherent) contributions at Bragg peaks diminishes and the incoherent part may become substantial. The consequences can be significant for coherent diffraction imaging at high scattering angles: the incoherent radiation produces background that smears out the secondary interference fringes, affecting thus the achievable resolution of the technique. Here, a criterion that relates the object shape and the resolution is introduced. The Compton contribution for several object shapes is quantified, and it is shown that the maximum achievable resolution along different directions has a strong dependence on the crystal shape and size.
Pushing the limits of accountability: big data analytics containing and controlling COVID-19 in South Korea
Authors: Ahn Paul D. , Wickramasinghe Danture
Published: February 2021

Purpose

The purpose of this paper is to illustrate how big data analytics pushed the limits of individuals' accountability as South Korea tried to control and contain coronavirus disease 2019 (COVID-19).

Design/methodology/approach

The authors draw upon Deleuzo-Guattarian framework elaborating how a surveillant assemblage was rhizomatically created and operated to monitor a segment of the population holding them accountable. Publicly available secondary data, such as press release from the government and media coverage, were used.

Findings

A COVID-19 Smart Management System and a Self-Quarantine Safety Protection App constituted a surveillance assemblage operating in a “state-form”. This comprises the central government departments, local councils, policing systems, providers of telecommunication and financial services, and independent groups of people. This assemblage pushed the limits of accountability as individuals who tested positive or might bear possible future risks of the infection and transmission were held accountable for their locations and health conditions.

Practical implications

Policymakers may consider constructing this type of state-form for containing and controlling pandemics, such as COVID-19, while dealing with the issue of undermined privacy.

Social implications

The mass may consider to what extent individuals' personal information should be protected and how to hold the governments accountable for the legitimate use of such information.

Originality/value

While accountability studies have largely focussed on formal organisations, the authors illustrated how a broader context of a state-form, harnessing big data analytics, pushes the limits of accountability.