Adv Exp Med Biol. 2021;1321:81-96. doi: 10.1007/978-3-030-59261-5_7.

ABSTRACT

The new coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), turned into a pandemic affecting more than 200 countries. Due to the high rate of transmission and mortality, finding specific and effective treatment options for this infection is currently of urgent importance. Emerging technologies have created a promising platform for developing novel treatment options for various viral diseases such as the SARS-CoV-2 virus. Here, we have described potential novel therapeutic options based on the structure and pathophysiological mechanism of the SARS-CoV-2 virus, as well as the results of previous studies on similar viruses such as SARS and MERS. Many of these approaches can be used for controlling viral infection by reducing the viral damage or by increasing the potency of the host response. Owing to their high sensitivity, specificity, and reproducibility, siRNAs, aptamers, nanobodies, neutralizing antibodies, and different types of peptides can be used for interference with viral replication or for blocking internalization. Receptor agonists and interferon-inducing agents are also potential options to balance and enhance the innate immune response against SARS-CoV-2. Solid evidence on the efficacy and safety of such novel technologies is yet to be established although many well-designed clinical trials are underway to address these issues.

PMID:33656715 | DOI:10.1007/978-3-030-59261-5_7

Adv Exp Med Biol. 2021;1321:53-68. doi: 10.1007/978-3-030-59261-5_5.

ABSTRACT

Following the outbreaks of SARS-CoV in 2002 and MERS-CoV in 2012, the COVID-19 pandemic caused by the SARS-CoV-2 virus has become an increasing threat to human health around the world. Numerous studies have shown that SARS-CoV-2 appears similar to the SARS-CoV as it uses angiotensin converting enzyme 2 (ACE2) as a receptor to gain entry into cells. The main aims of this scoping review were to identify the primary hosts of coronaviruses, the relationship between the receptor binding domain of coronaviruses and ACE2, the organ specificity of ACE2 expression compared with clinical manifestations of the disease, and to determine if this information can be used in the development of novel treatment approaches for the COVID-19 pandemic.

PMID:33656713 | DOI:10.1007/978-3-030-59261-5_5

Methods Mol Biol. 2021;2297:7-19. doi: 10.1007/978-1-0716-1370-2_2.

ABSTRACT

Light triggers changes in plant nuclear architecture to control differentiation, adaptation, and growth. A series of genetic, molecular, and imaging approaches have revealed that the nucleus forms a hub for photo-induced protein interactions and gene regulatory events. However, the mechanism and function of light-induced nuclear compartmentalization is still unclear. This chapter provides detailed experimental protocols for examining the morphology and potential functional significance of light signaling components that localize in light-induced subnuclear domains, also known as photobodies. We describe how immunolabeling of endogenous proteins and fluorescent in situ hybridization (FISH) could be combined with confocal imaging of fluorescently tagged proteins to assess co-localization in Arabidopsis nuclei. Furthermore, we employ a super-resolution imaging approach to study the morphology of photobodies at unprecedented detail.

PMID:33656665 | DOI:10.1007/978-1-0716-1370-2_2

J Cell Biol. 2021 May 3;220(5):e202006193. doi: 10.1083/jcb.202006193.

ABSTRACT

The polarisome is a cortical proteinaceous microcompartment that organizes the growth of actin filaments and the fusion of secretory vesicles in yeasts and filamentous fungi. Polarisomes are compact, spotlike structures at the growing tips of their respective cells. The molecular forces that control the form and size of this microcompartment are not known. Here we identify a complex between the polarisome subunit Pea2 and the type V Myosin Myo2 that anchors Myo2 at the cortex of yeast cells. We discovered a point mutation in the cargo-binding domain of Myo2 that impairs the interaction with Pea2 and consequently the formation and focused localization of the polarisome. Cells carrying this mutation grow round instead of elongated buds. Further experiments and biophysical modeling suggest that the interactions between polarisome-bound Myo2 motors and dynamic actin filaments spatially focus the polarisome and sustain its compact shape.

PMID:33656555 | DOI:10.1083/jcb.202006193

Microb Genom. 2021 Mar 3. doi: 10.1099/mgen.0.000541. Online ahead of print.

ABSTRACT

The RNA binding domain abundant in apicomplexans (RAP) is a protein domain identified in a diverse group of proteins, called RAP proteins, many of which have been shown to be involved in RNA binding. To understand the expansion and potential function of the RAP proteins, we conducted a hidden Markov model based screen among the proteomes of 54 eukaryotes, 17 bacteria and 12 archaea. We demonstrated that the domain is present in closely and distantly related organisms with particular expansions in Alveolata and Chlorophyta, and are not unique to Apicomplexa as previously believed. All RAP proteins identified can be decomposed into two parts. In the N-terminal region, the presence of variable helical repeats seems to participate in the specific targeting of diverse RNAs, while the RAP domain is mostly identified in the C-terminal region and is highly conserved across the different phylogenetic groups studied. Several conserved residues defining the signature motif could be crucial to ensure the function(s) of the RAP proteins. Modelling of RAP domains in apicomplexan parasites confirmed an ⍺/β structure of a restriction endonuclease-like fold. The phylogenetic trees generated from multiple alignment of RAP domains and full-length proteins from various distantly related eukaryotes indicated a complex evolutionary history of this family. We further discuss these results to assess the potential function of this protein family in apicomplexan parasites.

PMID:33656416 | DOI:10.1099/mgen.0.000541

Int J Environ Health Res. 2021 Mar 3:1-9. doi: 10.1080/09603123.2021.1892035. Online ahead of print.

ABSTRACT

Several observational studies have found an association between maternal Cadmium (Cd) exposure and Small for Gestational Age (SGA). However, these findings are inconsistent. We conducted this meta-analysis to evaluate the relationship between maternal cadmium exposure and SGA risk. A comprehensive search was performed through PubMed, Scopus, Embase, Web of Science, Cochrane Library and OpenGrey to retrieve all pertinent studies published before October 2020. A combined odds ratio (OR) and corresponding 95% confidence interval (CI) were employed to examine this correlation. As a result, nine eligible studies met the inclusion criteria and were included in a systematic review, of those six studies containing sample type of blood were included in meta-analysis, and present meta-analysis showed that maternal cadmium exposure increased the risk of SGA 1.31 times (OR = 1.31; 95% CI = 1.16-1.47 for highest versus lowest category of cadmium). This meta-analysis suggests that maternal Cd exposure may be a risk factor for SGA. However, large prospective studies from different ethnic populations with consideration of other influencing parameters are needed to confirm this finding.

PMID:33656412 | DOI:10.1080/09603123.2021.1892035

J Phys Chem B. 2021 Mar 3. doi: 10.1021/acs.jpcb.0c11253. Online ahead of print.

ABSTRACT

We used all-atom replica-exchange umbrella sampling molecular dynamics simulations to investigate the partitioning of the charged tetrapeptide KLVF and its neutral apolar counterpart VVIA into the blood-brain barrier (BBB)-mimetic bilayer. Our findings allowed us to reconstruct the partitioning mechanism for these two Aβ peptide fragments. Despite dissimilar sequences, their permeation shares significant common features. Computations of free energies and permeabilities show that partitioning of both peptides is highly unfavorable, ruling out passive transport. The peptides experience multiple rotational transitions within the bilayer and typically cause considerable lipid disorder and bilayer thinning. Near the bilayer midplane, they lose almost entirely their solvation shell and the interactions with the lipid headgroups. The peptides cause complex reorganization within the proximal bilayer region. Upon insertion, they induce striking cholesterol influx reversed by its depletion and the influx of DMPC when the peptides reach the midplane. The differences in partitioning mechanisms are due to the much higher polarity of KLVF peptide, the permeation of which is more unfavorable and which exclusively assumes vertical orientations within the bilayer. In contrast, VVIA positions itself flat between the leaflets, causing minor disorder and even thickening of the BBB-mimetic bilayer. Due to the high density of the cholesterol-rich BBB bilayer, the unfavorable work associated with the peptide insertion provides a significant, but not dominant, contribution to the partition free energy, which is still governed by dehydration and loss of peptide-headgroup interactions. Comparison with experiments indicates that KLVF and VVIA permeation is similar to that of proline tetrapeptide, mannitol, or cimetidine, all of which exhibit no passive transport.

PMID:33656350 | DOI:10.1021/acs.jpcb.0c11253

Environ Microbiol. 2021 Mar 2. doi: 10.1111/1462-2920.15437. Online ahead of print.

ABSTRACT

ESBL-/AmpC-producing Escherichia coli from organic fertilizers were previously detected on soil surfaces of arable land and might be emitted by wind erosion. To investigate this potential environmental transmission path, we exposed ESBL-/AmpC-positive chicken litter, incorporated in agricultural soils, to different wind velocities in a wind tunnel and took air samples for microbiological analysis. No data exist concerning the airborne tenacity of ESBL-/AmpC-producing E. coli. Therefore, we explored the tenacity of two ESBL/AmpC E. coli strains and E. coli K12 in aerosol chamber experiments at different environmental conditions. In the wind tunnel, ESBL/AmpC-producing E. coli were detected in none of the air samples (n = 66). Non-resistant E. coli were qualitatively detected in 40.7% of air samples taken at wind velocities exceeding 7.3 m s-1 . Significantly increased emission of total viable bacteria with increasing wind velocity was observed. In the aerosol chamber trials, recovery rates of airborne E. coli ranged from 0.003% to 2.8%, indicating a low airborne tenacity. Concluding, an emission of ESBL/AmpC E. coli by wind erosion in relevant concentrations appears unlikely because of the low concentration in chicken litter compared with non-resistant E. coli and their low airborne tenacity, proven in the aerosol chamber trials.

PMID:33655697 | DOI:10.1111/1462-2920.15437

NAR Genom Bioinform. 2021 Feb 23;3(1):lqab011. doi: 10.1093/nargab/lqab011. eCollection 2021 Mar.

ABSTRACT

RNA sequencing (RNA-seq) is widely used to identify differentially expressed genes (DEGs) and reveal biological mechanisms underlying complex biological processes. RNA-seq is often performed on heterogeneous samples and the resulting DEGs do not necessarily indicate the cell-types where the differential expression occurred. While single-cell RNA-seq (scRNA-seq) methods solve this problem, technical and cost constraints currently limit its widespread use. Here we present single cell Mapper (scMappR), a method that assigns cell-type specificity scores to DEGs obtained from bulk RNA-seq by leveraging cell-type expression data generated by scRNA-seq and existing deconvolution methods. After evaluating scMappR with simulated RNA-seq data and benchmarking scMappR using RNA-seq data obtained from sorted blood cells, we asked if scMappR could reveal known cell-type specific changes that occur during kidney regeneration. scMappR appropriately assigned DEGs to cell-types involved in kidney regeneration, including a relatively small population of immune cells. While scMappR can work with user-supplied scRNA-seq data, we curated scRNA-seq expression matrices for ∼100 human and mouse tissues to facilitate its stand-alone use with bulk RNA-seq data from these species. Overall, scMappR is a user-friendly R package that complements traditional differential gene expression analysis of bulk RNA-seq data.

PMID:33655208 | PMC:PMC7902236 | DOI:10.1093/nargab/lqab011

Eur Heart J Suppl. 2020 Nov 18;22(Suppl L):L105-L109. doi: 10.1093/eurheartj/suaa146. eCollection 2020 Nov.

ABSTRACT

Sudden cardiac death results from arrhythmias commonly caused by channelopathies and cardiomyopathies, often due to several genetic factors. An emerging concept is that these disease states may in fact overlap, with variants in traditionally classified 'cardiomyopathy genes' resulting in 'channelopathies phenotypes'. Another important concept is the influence of both genetic and non-genetic factors in disease expression, leading to the utilization of systems biology approaches, such as genomics/epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and glycomics, to understand the disease severity and progression and to determine the prognosis and the best course of treatment. In fact, our group has discovered significant differences in metabolites, proteins, and lipids between controls and Brugada syndrome patients. Omics approaches are useful in overcoming the dogma that both channelopathies and cardiomyopathies exist as Mendelian disorders (caused by a mutation in a single gene). This shift in understanding could lead to new diagnostic and therapeutic approaches.

PMID:33654474 | PMC:PMC7904073 | DOI:10.1093/eurheartj/suaa146

Nat Med. 2021 Mar 2. doi: 10.1038/s41591-020-01227-z. Online ahead of print.

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.

PMID:33654293 | DOI:10.1038/s41591-020-01227-z

Nat Rev Cardiol. 2021 Mar 2. doi: 10.1038/s41569-021-00520-9. Online ahead of print.

ABSTRACT

Conduction disorders and arrhythmias remain difficult to treat and are increasingly prevalent owing to the increasing age and body mass of the general population, because both are risk factors for arrhythmia. Many of the underlying conditions that give rise to arrhythmia - including atrial fibrillation and ventricular arrhythmia, which frequently occur in patients with acute myocardial ischaemia or heart failure - can have an inflammatory component. In the past, inflammation was viewed mostly as an epiphenomenon associated with arrhythmia; however, the recently discovered inflammatory and non-canonical functions of cardiac immune cells indicate that leukocytes can be arrhythmogenic either by altering tissue composition or by interacting with cardiomyocytes; for example, by changing their phenotype or perhaps even by directly interfering with conduction. In this Review, we discuss the electrophysiological properties of leukocytes and how these cells relate to conduction in the heart. Given the thematic parallels, we also summarize the interactions between immune cells and neural systems that influence information transfer, extrapolating findings from the field of neuroscience to the heart and defining common themes. We aim to bridge the knowledge gap between electrophysiology and immunology, to promote conceptual connections between these two fields and to explore promising opportunities for future research.

PMID:33654273 | DOI:10.1038/s41569-021-00520-9

Sci Rep. 2021 Mar 2;11(1):4951. doi: 10.1038/s41598-021-84329-z.

ABSTRACT

Encapsulins are recently discovered protein compartments able to specifically encapsulate cargo proteins in vivo. Encapsulation is dependent on C-terminal targeting peptides (TPs). Here, we characterize and engineer TP-shell interactions in the Thermotoga maritima and Myxococcus xanthus encapsulin systems. Using force-field modeling and particle fluorescence measurements we show that TPs vary in native specificity and binding strength, and that TP-shell interactions are determined by hydrophobic and ionic interactions as well as TP flexibility. We design a set of TPs with a variety of predicted binding strengths and experimentally characterize these designs. This yields a set of TPs with novel binding characteristics representing a potentially useful toolbox for future nanoreactor engineering aimed at controlling cargo loading efficiency and the relative stoichiometry of multiple concurrently loaded cargo proteins.

PMID:33654191 | DOI:10.1038/s41598-021-84329-z

Sci Rep. 2021 Mar 2;11(1):5407. doi: 10.1038/s41598-021-85105-9.

NO ABSTRACT

PMID:33654173 | DOI:10.1038/s41598-021-85105-9

Sci Data. 2021 Mar 2;8(1):71. doi: 10.1038/s41597-021-00860-8.

ABSTRACT

The impact of the gut microbiota in human health is affected by several factors including its composition, drug administrations, therapeutic interventions and underlying diseases. Unfortunately, many human microbiota datasets available publicly were collected to study the impact of single variables, and typically consist of outpatients in cross-sectional studies, have small sample numbers and/or lack metadata to account for confounders. These limitations can complicate reusing the data for questions outside their original focus. Here, we provide comprehensive longitudinal patient dataset that overcomes those limitations: a collection of fecal microbiota compositions (>10,000 microbiota samples from >1,000 patients) and a rich description of the "hospitalome" experienced by the hosts, i.e., their drug exposures and other metadata from patients with cancer, hospitalized to receive allogeneic hematopoietic cell transplantation (allo-HCT) at a large cancer center in the United States. We present five examples of how to apply these data to address clinical and scientific questions on host-associated microbial communities.

PMID:33654104 | DOI:10.1038/s41597-021-00860-8

Nat Commun. 2021 Mar 2;12(1):1396. doi: 10.1038/s41467-021-21636-z.

ABSTRACT

Increasing numbers of protein interactions have been identified in high-throughput experiments, but only a small proportion have solved structures. Recently, sequence coevolution-based approaches have led to a breakthrough in predicting monomer protein structures and protein interaction interfaces. Here, we address the challenges of large-scale interaction prediction at residue resolution with a fast alignment concatenation method and a probabilistic score for the interaction of residues. Importantly, this method (EVcomplex2) is able to assess the likelihood of a protein interaction, as we show here applied to large-scale experimental datasets where the pairwise interactions are unknown. We predict 504 interactions de novo in the E. coli membrane proteome, including 243 that are newly discovered. While EVcomplex2 does not require available structures, coevolving residue pairs can be used to produce structural models of protein interactions, as done here for membrane complexes including the Flagellar Hook-Filament Junction and the Tol/Pal complex.

PMID:33654096 | DOI:10.1038/s41467-021-21636-z

Transl Psychiatry. 2021 Mar 2;11(1):153. doi: 10.1038/s41398-020-01097-6.

ABSTRACT

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), yet their mechanisms of action are not fully understood and their therapeutic benefit varies among individuals. We used a targeted metabolomics approach utilizing a panel of 180 metabolites to gain insights into mechanisms of action and response to citalopram/escitalopram. Plasma samples from 136 participants with MDD enrolled into the Mayo Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) were profiled at baseline and after 8 weeks of treatment. After treatment, we saw increased levels of short-chain acylcarnitines and decreased levels of medium-chain and long-chain acylcarnitines, suggesting an SSRI effect on β-oxidation and mitochondrial function. Amines-including arginine, proline, and methionine sulfoxide-were upregulated while serotonin and sarcosine were downregulated, suggesting an SSRI effect on urea cycle, one-carbon metabolism, and serotonin uptake. Eighteen lipids within the phosphatidylcholine (PC aa and ae) classes were upregulated. Changes in several lipid and amine levels correlated with changes in 17-item Hamilton Rating Scale for Depression scores (HRSD17). Differences in metabolic profiles at baseline and post-treatment were noted between participants who remitted (HRSD17 ≤ 7) and those who gained no meaningful benefits (<30% reduction in HRSD17). Remitters exhibited (a) higher baseline levels of C3, C5, alpha-aminoadipic acid, sarcosine, and serotonin; and (b) higher week-8 levels of PC aa C34:1, PC aa C34:2, PC aa C36:2, and PC aa C36:4. These findings suggest that mitochondrial energetics-including acylcarnitine metabolism, transport, and its link to β-oxidation-and lipid membrane remodeling may play roles in SSRI treatment response.

PMID:33654056 | DOI:10.1038/s41398-020-01097-6

Trends Plant Sci. 2021 Feb 27:S1360-1385(21)00034-0. doi: 10.1016/j.tplants.2021.02.005. Online ahead of print.

ABSTRACT

The majority of the crops and vegetables of today were domesticated from their wild progenitors within the past 12 000 years. Considerable research effort has been expended on characterizing the genes undergoing positive and negative selection during the processes of crop domestication and improvement. Many studies have also documented how the contents of a handful of metabolites have been altered during human selection, but we are only beginning to unravel the true extent of the metabolic consequences of breeding. We highlight how crop metabolomes have been wittingly or unwittingly shaped by the processes of domestication, and highlight how we can identify new targets for metabolite engineering for the purpose of de novo domestication of crop wild relatives.

PMID:33653662 | DOI:10.1016/j.tplants.2021.02.005

Trends Biochem Sci. 2021 Feb 27:S0968-0004(21)00027-X. doi: 10.1016/j.tibs.2021.01.013. Online ahead of print.

ABSTRACT

The inability to make broad, minimally biased measurements of a cell's proteome stands as a major bottleneck for understanding how gene expression translates into cellular phenotype. Unlike sequencing for nucleic acids, there is no dominant method for making single-cell proteomic measurements. Instead, methods typically focus on either absolute quantification of a small number of proteins or highly multiplexed protein measurements. Advances in microfluidics and output encoding have led to major improvements in both aspects. Here, we review the most recent progress that has enabled hundreds of protein measurements and ultrahigh-sensitivity quantification. We also highlight emerging technologies such as single-cell mass spectrometry that may enable unbiased measurement of cellular proteomes.

PMID:33653632 | DOI:10.1016/j.tibs.2021.01.013

Clin Epigenetics. 2021 Mar 2;13(1):46. doi: 10.1186/s13148-021-01031-7.

ABSTRACT

BACKGROUND: Assessing functional ability is an important component of understanding healthy aging. Objective measures of functional ability include grip strength, gait speed, sit-to-stand time, and 6-min walk distance. Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Peripheral blood DNA methylation was measured (pre/post) with the Illumina HumanMethylationEPIC array and the Hannum, Horvath, and PhenoAge DNA methylation age clocks were used. Linear regression models adjusted for chronological age and sex tested the relationship between DNA methylation age and grip strength, gait speed, sit-to-stand, and 6-min walk.

RESULTS: Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively. Mean grip strength increased 3.2 kg. Decreased Hannum methylation age was significantly associated with increased grip strength (β = -0.30, p = 0.04), and increased gait speed (β = 0.02, p = 0.05), in adjusted models. Similarly, decreased methylation age using the PhenoAge clock was associated with significantly increased gait speed (β = 0.02, p = 0.04). A decrease in Horvath DNA methylation age and increase in physical functional ability did not demonstrate a significant association.

CONCLUSIONS: The observed relationship between increased physical functional ability and decreased biological age using DNA methylation clocks demonstrate the potential utility of DNA methylation clocks to assess interventional approaches to improve health in older obese adults.

TRIAL REGISTRATION: National Institute on Aging (NIA), NCT03104192. Posted April 7, 2017, https://clinicaltrials.gov/ct2/show/NCT03104192.

PMID:33653394 | DOI:10.1186/s13148-021-01031-7