Incidence and Impact of Takotsubo Syndrome in Hospitalized Patients With COVID-19.

BACKGROUND: Takotsubo syndrome has been reported in patients with COVID-19, although minimal data are available. This investigation assessed the incidence and impact of takotsubo syndrome on patients hospitalized with COVID-19. METHODS: A retrospective cohort study was conducted using International Statistical Classification of Diseases, Tenth Revision, codes to identify patients with a primary diagnosis of COVID-19 with or without takotsubo syndrome in the National Inpatient Sample 2020 database. Outcomes between groups were compared after propensity score matching for patient and hospital demographics and comorbidities. RESULTS: A total of 211,448 patients with a primary diagnosis of COVID-19 were identified. Of these, 171 (0.08%) had a secondary diagnosis of takotsubo syndrome. Before matching, patients with COVID-19 and takotsubo syndrome, compared with patients without takotsubo syndrome, were older (68.95 vs 64.26 years; P < .001); more likely to be female (64.3% vs 47.2%; P < .001); and more likely to have anxiety (24.6% vs 12.8%; P < .001), depression (17.5% vs 11.4%; P = .02), and chronic obstructive pulmonary disease (24.6% vs 14.7%; P < .001). The takotsubo syndrome group had worse outcomes than the non-takotsubo syndrome group for death (30.4% vs 11.1%), cardiac arrest (7.6% vs 2.1%), cardiogenic shock (12.9% vs 0.4%), length of hospital stay (10.7 vs 7.5 days), and total charges ($152,685 vs $78,468) (all P < .001). After matching and compared with the non-takotsubo syndrome group (n = 508), the takotsubo syndrome group (n = 170) had a higher incidence of inpatient mortality (30% vs 14%; P < .001), cardiac arrest (7.6% vs 2.8%; P = .009), and cardiogenic shock (12.4% vs 0.4%; P < .001); a longer hospital stay (10.7 vs 7.6 days; P < .001); and higher total charges ($152,943 vs $79,523; P < .001). CONCLUSION: Takotsubo syndrome is a rare but severe in-hospital complication in patients with COVID-19.

Poplar glutathione S-transferase PtrGSTF8 contributes to reactive oxygen species scavenging and salt tolerance.

Glutathione S-transferases (GSTs) constitute a protein superfamily encoded by a large gene family and play a crucial role in plant growth and development. However, their precise functions in wood plant responses to abiotic stress are not fully understood. In this study, we isolated a Phi class glutathione S-transferase-encoding gene, PtrGSTF8, from poplar (Populus alba × P. glandulosa), which is significantly up-regulated under salt stress. Moreover, compared with wild-type (WT) plants, transgenic tobacco plants exhibited significant salt stress tolerance. Under salt stress, PtrGSTF8-overexpressing tobacco plants showed a significant increase in plant height and root length, and less accumulation of reactive oxygen species. In addition, these transgenic tobacco plants exhibited higher superoxide dismutase, peroxidase, and catalase activities and reduced malondialdehyde content compared with WT plants. Quantitative real-time PCR experiments showed that the overexpression of PtrGSTF8 increased the expression of numerous genes related to salt stress. Furthermore, PtrMYB108, a MYB transcription factor involved in salt resistance in poplar, was found to directly activate the promoter of PtrGSTF8, as demonstrated by yeast one-hybrid assays and luciferase complementation assays. Taken together, these findings suggest that poplar PtrGSTF8 contributes to enhanced salt tolerance and confers multiple growth advantages when overexpressed in tobacco.

The plant cell wall-dynamic, strong, and adaptable-is a natural shapeshifter.

Mythology is replete with good and evil shapeshifters, who, by definition, display great adaptability and assume many different forms-with several even turning themselves into trees. Cell walls certainly fit this definition as they can undergo subtle or dramatic changes in structure, assume many shapes, and perform many functions. In this review, we cover the evolution of knowledge of the structures, biosynthesis, and functions of the 5 major cell wall polymer types that range from deceptively simple to fiendishly complex. Along the way, we recognize some of the colorful historical figures who shaped cell wall research over the past 100 years. The shapeshifter analogy emerges more clearly as we examine the evolving proposals for how cell walls are constructed to allow growth while remaining strong, the complex signaling involved in maintaining cell wall integrity and defense against disease, and the ways cell walls adapt as they progress from birth, through growth to maturation, and in the end, often function long after cell death. We predict the next century of progress will include deciphering cell type-specific wall polymers; regulation at all levels of polymer production, crosslinks, and architecture; and how walls respond to developmental and environmental signals to drive plant success in diverse environments.

A century of studying plant secondary metabolism-From "what?" to "where, how, and why?"

Over the past century, early advances in understanding the identity of the chemicals that collectively form a living plant have led scientists to deeper investigations exploring where these molecules localize, how they are made, and why they are synthesized in the first place. Many small molecules are specific to the plant kingdom and have been termed plant secondary metabolites, despite the fact that they can play primary and essential roles in plant structure, development, and response to the environment. The past 100 yr have witnessed elucidation of the structure, function, localization, and biosynthesis of selected plant secondary metabolites. Nevertheless, many mysteries remain about the vast diversity of chemicals produced by plants and their roles in plant biology. From early work characterizing unpurified plant extracts, to modern integration of 'omics technology to discover genes in metabolite biosynthesis and perception, research in plant (bio)chemistry has produced knowledge with substantial benefits for society, including human medicine and agricultural biotechnology. Here, we review the history of this work and offer suggestions for future areas of exploration. We also highlight some of the recently developed technologies that are leading to ongoing research advances.

An unconventional proanthocyanidin pathway in maize.

Proanthocyanidins (PAs), flavonoid polymers involved in plant defense, are also beneficial to human health and ruminant nutrition. To date, there is little evidence for accumulation of PAs in maize (Zea mays), although maize makes anthocyanins and possesses the key enzyme of the PA pathway, anthocyanidin reductase (ANR). Here, we explore whether there is a functional PA biosynthesis pathway in maize using a combination of analytical chemistry and genetic approaches. The endogenous PA biosynthetic machinery in maize preferentially produces the unusual PA precursor (+)-epicatechin, as well as 4ß-(S-cysteinyl)-catechin, as potential PA starter and extension units. Uncommon procyanidin dimers with (+)-epicatechin as starter unit are also found. Expression of soybean (Glycine max) anthocyanidin reductase 1 (ANR1) in maize seeds increases the levels of 4ß-(S-cysteinyl)-epicatechin and procyanidin dimers mainly using (-)-epicatechin as starter units. Introducing a Sorghum bicolor transcription factor (SbTT2) specifically regulating PA biosynthesis into a maize inbred deficient in anthocyanin biosynthesis activates both anthocyanin and PA biosynthesis pathways, suggesting conservation of the PA regulatory machinery across species. Our data support the divergence of PA biosynthesis across plant species and offer perspectives for future agricultrural applications in maize.

Manipulating microRNA miR408 enhances both biomass yield and saccharification efficiency in poplar.

The conversion of lignocellulosic feedstocks to fermentable sugar for biofuel production is inefficient, and most strategies to enhance efficiency directly target lignin biosynthesis, with associated negative growth impacts. Here we demonstrate, for both laboratory- and field-grown plants, that expression of Pag-miR408 in poplar (Populus alba × P. glandulosa) significantly enhances saccharification, with no requirement for acid-pretreatment, while promoting plant growth. The overexpression plants show increased accessibility of cell walls to cellulase and scaffoldin cellulose-binding modules. Conversely, Pag-miR408 loss-of-function poplar shows decreased cell wall accessibility. Overexpression of Pag-miR408 targets three Pag-LACCASES, delays lignification, and modestly reduces lignin content, S/G ratio and degree of lignin polymerization. Meanwhile, the LACCASE loss of function mutants exhibit significantly increased growth and cell wall accessibility in xylem. Our study shows how Pag-miR408 regulates lignification and secondary growth, and suggest an effective approach towards enhancing biomass yield and saccharification efficiency in a major bioenergy crop.

Systematic approaches to C-lignin engineering in Medicago truncatula.

BACKGROUND: C-lignin is a homopolymer of caffeyl alcohol present in the seed coats of a variety of plant species including vanilla orchid, various cacti, and the ornamental plant Cleome hassleriana. Because of its unique chemical and physical properties, there is considerable interest in engineering C-lignin into the cell walls of bioenergy crops as a high-value co-product of bioprocessing. We have used information from a transcriptomic analysis of developing C. hassleriana seed coats to suggest strategies for engineering C-lignin in a heterologous system, using hairy roots of the model legume Medicago truncatula. RESULTS: We systematically tested strategies for C-lignin engineering using a combination of gene overexpression and RNAi-mediated knockdown in the caffeic acid/5-hydroxy coniferaldehyde 3/5-O-methyltransferase (comt) mutant background, monitoring the outcomes by analysis of lignin composition and profiling of monolignol pathway metabolites. In all cases, C-lignin accumulation required strong down-regulation of caffeoyl CoA 3-O-methyltransferase (CCoAOMT) paired with loss of function of COMT. Overexpression of the Selaginella moellendorffii ferulate 5-hydroxylase (SmF5H) gene in comt mutant hairy roots resulted in lines that unexpectedly accumulated high levels of S-lignin. CONCLUSION: C-Lignin accumulation of up to 15% of total lignin in lines with the greatest reduction in CCoAOMT expression required the strong down-regulation of both COMT and CCoAOMT, but did not require expression of a heterologous laccase, cinnamyl alcohol dehydrogenase (CAD) or cinnamoyl CoA reductase (CCR) with preference for 3,4-dihydroxy-substituted substrates in M. truncatula hairy roots. Cell wall fractionation studies suggested that the engineered C-units are not present in a heteropolymer with the bulk of the G-lignin.

FERONIA and wall-associated kinases coordinate defense induced by lignin modification in plant cell walls.

Altering the content or composition of the cell wall polymer lignin is a favored approach to valorize lignin toward biomaterial and chemical production in the biorefinery. However, modifying lignin or cellulose in transgenic plants can induce expression of defense responses and negatively affect growth. Through genetic screening for suppressors of defense gene induction in the low lignin ccr1-3 mutant of Arabidopsis thaliana, we found that loss of function of the receptor-like kinase FERONIA, although not restoring growth, affected cell wall remodeling and blocked release of elicitor-active pectic polysaccharides as a result of the ccr1-3 mutation. Loss of function of multiple wall-associated kinases prevented perception of these elicitors. The elicitors are likely heterogeneous, with tri-galacturonic acid the smallest but not necessarily the most active component. Engineering of plant cell walls will require development of ways to bypass endogenous pectin signaling pathways.

Therapeutic angiogenesis and tissue revascularization in ischemic vascular disease.

Ischemic vascular disease is a major healthcare problem. The keys to treatment lie in vascular regeneration and restoration of perfusion. However, current treatments cannot satisfy the need for vascular regeneration to restore blood circulation. As biomedical research has evolved rapidly, a variety of potential alternative therapeutics has been explored widely, such as growth factor-based therapy, cell-based therapy, and material-based therapy including nanomedicine and biomaterials. This review will comprehensively describe the main pathogenesis of vascular injury in ischemic vascular disease, the therapeutic function of the above three treatment strategies, the corresponding potential challenges, and future research directions.

Hippo pathway inhibition promotes metabolic adaptability and antioxidant response in myoblasts.

Metabolic plasticity in a hostile environment ensures cell survival. We investigated whether Hippo pathway inhibition contributed to cell adaptations under challenging conditions. We examined metabolic profiles and fuel substrate choices and preferences in C2C12 myoblasts after Hippo pathway inhibition via Salvador knockdown (SAV1 KD). SAV1 KD induced higher ATP production and a more energetic phenotype. Bioenergetic profiling showed enhanced key mitochondrial parameters including spare respiratory capacity. SAV1 KD cells showed markedly elevated glycolysis and glycolytic reserves; blocking other fuel-oxidation pathways enhanced mitochondrial flexibility of glucose oxidation. Under limited glucose, endogenous fatty acid oxidation increased to cope with bioenergetic stress. Gene expression patterns after SAV1 KD suggested transcriptional upregulation of key metabolic network regulators to promote energy production and free radical scavenging that may prevent impaired lipid and glucose metabolism. In SAV1 KD cells, sirtuin signaling was the top enriched canonical pathway linked with enhanced mitochondrial ATP production. Collectively, we demonstrated that Hippo pathway inhibition in SAV1 KD cells induces multiple metabolic properties, including enhancing mitochondrial spare respiratory capacity or glycolytic reserve to cope with stress and upregulating metabolic pathways supporting elevated ATP demand, bioenergetics, and glycolysis and counteracting oxidative stress. In response to metabolic challenges, SAV1 KD cells can increase fatty acid oxidation or glucose-coupled oxidative phosphorylation capacity to compensate for substrate limitations or alternative fuel oxidation pathway inhibition.

Association of atrial fibrillation burden with in-hospital outcomes in patients with Takotsubo cardiomyopathy.

BACKGROUND: The effects of atrial fibrillation (AF) and its burden on in-hospital mortality in patients with Takotsubo cardiomyopathy (TCM) are unclear. Here, we examined the effect of AF and paroxysmal AF on in-hospital outcomes in patients with TCM. METHODS: We used ICD-10 codes to retrospectively identify patients with a primary diagnosis of TCM in the National Inpatient Sample database 2016-2018. We compared in-hospital outcomes in TCM patients with and without AF before and after propensity score matching. The effect of AF burden on outcomes was assessed in patients with paroxysmal AF and no AF. RESULTS: Of the 4,733 patients with a primary diagnosis of TCM, 650 (13.7%) had AF, and 4,083 (86.3%) did not. Of TCM patients with AF, 368 (56.6%) had paroxysmal AF. In-hospital mortality was higher in patients with AF before (3.4% vs 1.2%, P <  0.001) and after propensity matching (3.4% vs 1.7%, P = 0.021) but did not differ between the paroxysmal AF and the no AF groups (P = 0.205). In the matched cohorts, both AF and paroxysmal AF groups were associated with a higher rate of cardiogenic shock (AF, P < 0.001; paroxysmal AF, P < 0.001), ventricular arrhythmia (AF, P = 0.002; paroxysmal AF, P = 0.02), acute kidney injury (AF, P = 0.007; paroxysmal AF, P = 0.008), and acute respiratory failure (AF, P < 0.001; paroxysmal AF, P < 0.001) compared with the no AF group. CONCLUSIONS: Although AF was associated with increased in-hospital mortality, paroxysmal AF did not affect in-hospital mortality, suggesting a higher AF burden is associated with worse clinical outcome in patients with TCM.

The complexities of proanthocyanidin biosynthesis and its regulation in plants.

Proanthocyanidins (PAs) are natural flavan-3-ol polymers that contribute protection to plants under biotic and abiotic stress, benefits to human health, and bitterness and astringency to food products. They are also potential targets for carbon sequestration for climate mitigation. In recent years, from model species to commercial crops, research has moved closer to elucidating the flux control and channeling, subunit biosynthesis and polymerization, transport mechanisms, and regulatory networks involved in plant PA metabolism. This review extends the conventional understanding with recent findings that provide new insights to address lingering questions and focus strategies for manipulating PA traits in plants.

Contractile Adaptation of the Left Ventricle Post-myocardial Infarction: Predictions by Rodent-Specific Computational Modeling.

Myocardial infarction (MI) results in cardiac myocyte death and the formation of a fibrotic scar in the left ventricular free wall (LVFW). Following an acute MI, LVFW remodeling takes place consisting of several alterations in the structure and properties of cellular and extracellular components with a heterogeneous pattern across the LVFW. The normal function of the heart is strongly influenced by the passive and active biomechanical behavior of the LVFW, and progressive myocardial structural remodeling can have a detrimental effect on both diastolic and systolic functions of the LV leading to heart failure. Despite important advances in understanding LVFW passive remodeling in the setting of MI, heterogeneous remodeling in the LVFW active properties and its relationship to organ-level LV function remain understudied. To address these gaps, we developed high-fidelity finite-element (FE) rodent computational cardiac models (RCCMs) of MI using extensive datasets from MI rat hearts representing the heart remodeling from one-week (1-wk) to four-week (4-wk) post-MI timepoints. The rat-specific models (n = 2 for each timepoint) integrate detailed imaging data of the heart geometry, myocardial fiber architecture, and infarct zone determined using late gadolinium enhancement prior to terminal measurements. The computational models predicted a significantly higher level of active tension in remote myocardium in early post-MI hearts (1-wk post-MI) followed by a return to near the control level in late-stage MI (3- and 4-wk post-MI). The late-stage MI rats showed smaller myofiber ranges in the remote region and in-silico experiments using RCCMs suggested that the smaller fiber helicity is consistent with lower contractile forces needed to meet the measured ejection fractions in late-stage MI. In contrast, in-silico experiments predicted that collagen fiber transmural orientation in the infarct region has little influence on organ-level function. In addition, our MI RCCMs indicated that reduced and potentially positive circumferential strains in the infarct region at end-systole can be used to infer information about the time-varying properties of the infarct region. The detailed description of regional passive and active remodeling patterns can complement and enhance the traditional measures of LV anatomy and function that often lead to a gross and limited assessment of cardiac performance. The translation and implementation of our model in patient-specific organ-level simulations offer to advance the investigation of individualized prognosis and intervention for MI.

The protein conformational basis of isoflavone biosynthesis.

Isoflavonoids play important roles in plant defense and also exhibit a range of mammalian health-promoting activities. Their biosynthesis is initiated by two enzymes with unusual catalytic activities; 2-hydroxyisoflavanone synthase (2-HIS), a membrane-bound cytochrome P450 catalyzing a coupled aryl-ring migration and hydroxylation, and 2-hydroxyisoflavanone dehydratase (2-HID), a member of a large carboxylesterase family that paradoxically catalyzes dehydration of 2-hydroxyisoflavanones to isoflavone. Here we report the crystal structures of 2-HIS from Medicago truncatula and 2-HID from Pueraria lobata. The 2-HIS structure reveals a unique cytochrome P450 conformation and heme and substrate binding mode that facilitate the coupled aryl-ring migration and hydroxylation reactions. The 2-HID structure reveals the active site architecture and putative catalytic residues for the dual dehydratase and carboxylesterase activities. Mutagenesis studies revealed key residues involved in substrate binding and specificity. Understanding the structural basis of isoflavone biosynthesis will facilitate the engineering of new bioactive isoflavonoids.

Multi-omic characterization of bifunctional peroxidase 4-coumarate 3-hydroxylase knockdown in Brachypodium distachyon provides insights into lignin modification-associated pleiotropic effects.

A bifunctional peroxidase enzyme, 4-coumarate 3-hydroxylase (C3H/APX), provides a parallel route to the shikimate shunt pathway for the conversion of 4-coumarate to caffeate in the early steps of lignin biosynthesis. Knockdown of C3H/APX (C3H/APX-KD) expression has been shown to reduce the lignin content in Brachypodium distachyon. However, like many other lignin-modified plants, C3H/APX-KDs show unpredictable pleiotropic phenotypes, including stunted growth, delayed senescence, and reduced seed yield. A system-wide level understanding of altered biological processes in lignin-modified plants can help pinpoint the lignin-modification associated growth defects to benefit future studies aiming to negate the yield penalty. Here, a multi-omic approach was used to characterize molecular changes resulting from C3H/APX-KD associated lignin modification and negative growth phenotype in Brachypodium distachyon. Our findings demonstrate that C3H/APX knockdown in Brachypodium stems substantially alters the abundance of enzymes implicated in the phenylpropanoid biosynthetic pathway and disrupt cellular redox homeostasis. Moreover, it elicits plant defense responses associated with intracellular kinases and phytohormone-based signaling to facilitate growth-defense trade-offs. A deeper understanding along with potential targets to mitigate the pleiotropic phenotypes identified in this study could aid to increase the economic feasibility of lignocellulosic biofuel production.

Toward product-based regulation of crops.

Current process-based approaches to regulation are no longer fit for purpose.

Evaluation of pathways to the C-glycosyl isoflavone puerarin in roots of kudzu (Pueraria montana lobata).

Kudzu (Pueraria montana lobata) is used as a traditional medicine in China and Southeast Asia but is a noxious weed in the Southeastern United States. It produces both O- and C-glycosylated isoflavones, with puerarin (C-glucosyl daidzein) as an important bioactive compound. Currently, the stage of the isoflavone pathway at which the C-glycosyl unit is added remains unclear, with a recent report of direct C-glycosylation of daidzein contradicting earlier labeling studies supporting C-glycosylation at the level of chalcone. We have employed comparative mRNA sequencing of the roots from two Pueraria species, one of which produces puerarin (field collected P. montana lobata) and one of which does not (commercial Pueraria phaseoloides), to identify candidate uridine diphosphate glycosyltransferase (UGT) enzymes involved in puerarin biosynthesis. Expression of recombinant UGTs in Escherichia coli and candidate C-glycosyltransferases in Medicago truncatula were used to explore substrate specificities, and gene silencing of UGT and key isoflavone biosynthetic genes in kudzu hairy roots employed to test hypotheses concerning the substrate(s) for C-glycosylation. Our results confirm UGT71T5 as a C-glycosyltransferase of isoflavone biosynthesis in kudzu. Enzymatic, isotope labeling, and genetic analyses suggest that puerarin arises both from the direct action of UGT71T5 on daidzein and via a second route in which the C-glycosidic linkage is introduced to the chalcone isoliquiritigenin.

Takotsubo syndrome and respiratory diseases: a systematic review.

Takotsubo syndrome (TTS) is a rare cardiovascular condition characterized by reversible ventricular dysfunction and a presentation resembling that of acute myocardial infarction. An increasing number of studies has shown the association of respiratory diseases with TTS. Here, we comprehensively reviewed the literature and examined the available evidence for this association. After searching PubMed, EMBASE, and Cochrane Library databases, two investigators independently reviewed 3117 studies published through May 2021. Of these studies, 99 met the inclusion criteria (n = 108 patients). In patients with coexisting respiratory disease and TTS, the most common TTS symptom was dyspnoea (70.48%), followed by chest pain (24.76%) and syncope (2.86%). The most common type of TTS was apical, accounting for 81.13% of cases, followed by the midventricular (8.49%), basal (8.49%), and biventricular (1.89%) types. Among the TTS cases, 39.82% were associated with obstructive lung disease and 38.89% were associated with pneumonia. Coronavirus disease 2019 (COVID-19), which has been increasingly reported in patients with TTS, was identified in 29 of 42 (69.05%) patients with pneumonia. The overall mortality rate for patients admitted for respiratory disease complicated by TTS was 12.50%. Obstructive lung disease and pneumonia are the most frequently identified respiratory triggers of TTS. Medications and invasive procedures utilized in managing respiratory diseases may also contribute to the development of TTS. Furthermore, the diagnosis of TTS triggered by these conditions can be challenging due to its atypical presentation. Future prospective studies are needed to establish appropriate guidelines for managing respiratory disease with concurrent TTS.