Nanowired human cardiac organoid transplantation enables highly efficient and effective recovery of infarcted hearts

Human cardiac organoids hold remarkable potential for cardiovascular disease modeling and human pluripotent stem cell–derived cardiomyocyte (hPSC-CM) transplantation. Here, we show cardiac organoids engineered with electrically conductive silicon nanowires (e-SiNWs) significantly enhance the therapeutic efficacy of hPSC-CMs to treat infarcted hearts. We first demonstrated the biocompatibility of e-SiNWs and their capacity to improve cardiac microtissue engraftment in healthy rat myocardium. Nanowired human cardiac organoids were then engineered with hPSC-CMs, nonmyocyte supporting cells, and e-SiNWs. Nonmyocyte supporting cells promoted greater ischemia tolerance of cardiac organoids, and e-SiNWs significantly improved electrical pacing capacity. After transplantation into ischemia/reperfusion–injured rat hearts, nanowired cardiac organoids significantly improved contractile development of engrafted hPSC-CMs, induced potent cardiac functional recovery, and reduced maladaptive left ventricular remodeling. Compared to contemporary studies with an identical injury model, greater functional recovery was achieved with a 20-fold lower dose of hPSC-CMs, revealing therapeutic synergy between conductive nanomaterials and human cardiac organoids for efficient heart repair

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling, in inflammation and in vascular biology. The human family includes 19 members that can be sub-grouped on the basis of their known substrates, namely the aggrecanases or proteoglycanases (ADAMTS1, 4, 5, 8, 9, 15 and 20), the procollagen N-propeptidases (ADAMTS2, 3 and 14), the cartilage oligomeric matrix protein-cleaving enzymes (ADAMTS7 and 12), the von-Willebrand Factor proteinase (ADAMTS13) and a group of orphan enzymes (ADAMTS6, 10, 16, 17, 18 and 19). Control of the structure and function of the extracellular matrix (ECM) is a central theme of the biology of the ADAMTS, as exemplified by the actions of the procollagen-N-propeptidases in collagen fibril assembly and of the aggrecanases in the cleavage or modification of ECM proteoglycans. Defects in certain family members give rise to inherited genetic disorders, while the aberrant expression or function of others is associated with arthritis, cancer and cardiovascular disease. In particular, ADAMTS4 and 5 have emerged as therapeutic targets in arthritis. Multiple ADAMTSs from different sub-groupings exert either positive or negative effects on tumorigenesis and metastasis, with both metalloproteinase-dependent and -independent actions known to occur. The basic ADAMTS structure comprises a metalloproteinase catalytic domain and a carboxy-terminal ancillary domain, the latter determining substrate specificity and the localization of the protease and its interaction partners; ancillary domains probably also have independent biological functions. Focusing primarily on the aggrecanases and proteoglycanases, this review provides a perspective on the evolution of the ADAMTS family, their links with developmental and disease mechanisms, and key questions for the future

Role Of Phosphoglucan Phosphatases In Regulating Starch Degradation In Plants

Starch is the major carbohydrate reserve in plants. Sugars are assimilated into storage granules during photosynthesis and released for continual growth at night from the chloroplast. Breakdown of leaf starch is initiated through reversible glucan phosphorylation by novel dikinases and phosphatases at the granule surface. This phosphorylation disrupts the semi-crystalline structure of starch, and removal of these phosphates provides access for β- amylases to release maltose. The phosphoglucan phosphatases are members of the dual- specificity protein phosphatase (DSP) family, which includes starch excess 4 (SEX4) and like-SEX4 1 (LSF1). SEX4 is required for proper glucan dephosphorylation; however, whether LSF1 participates in starch degradation is unknown. Moreover, how the activity of these phosphatases regulate reversible glucan phosphorylation is unclear. SEX4 and LSF1 both contain phosphatase and carbohydrate-binding domains, but LSF1 also possesses a protein-protein interaction PDZ domain. I show that LSF1 is chloroplastic and necessary for proper starch breakdown, as lsf1 mutants accumulate starch at the end of night. LSF1 lacks phosphatase activity and contains an irregular catalytic motif from known DSPs. The PDZ domain of LSF1 alone forms dimers and can disrupt protein complexes with β-amylases that include LSF1. In the end, these results indicate LSF1 acts as an inactive, scaffold protein that associates with starch degradative enzymes at the granule surface of starch. SEX4 activity is sensitive to oxidation, suggesting this phosphatase might undergo reversible oxidation like other mammalian DSPs. I show that SEX4 phosphatase activity can be modulated between reduced (active) and oxidized (inactive) states, and the endogenous SEX4 can exist in these forms. Oxidation of SEX4 promotes the formation of a disulfide linkage between the catalytic cysteine 198 (Cys198) and Cys130 within the phosphatase domain, and mutation of the latter residue renders SEX4 redox-impaired. Not only does this disulfide bridge protect Cys198 from irreversible oxidation, these data provide the first biochemical evidence for the redox-dependent structural switch that regulates SEX4 activity. Altogether, these results expand our understanding of the protein biology of leaf starch degradation and provide new insights into manipulating the phosphorylation state of starch in planta for industrial applications

Acute Kidney Injury: Preclinical Innovations, Challenges, and Opportunities for Translation

Background: Acute kidney injury (AKI) is a clinically important condition that has attracted a great deal of interest from the biomedical research community. However, acute kidney injury AKI research findings have yet to be translated into significant changes in clinical practice. Objective: This article reviews many of the preclinical innovations in acute kidney injury AKI treatment, and explores challenges and opportunities to translate these finding into clinical practice. Sources of Information: MEDLINE, ISI Web of Science Findings: This paper details areas in biomedical research where translation of pre-clinical findings into clinical trials is ongoing, or nearing a point where trial design is warranted. Further, the paper examines ways that best practice in the management of AKI can reach a broader proportion of the patient population experiencing this condition. Limitations: This review highlights pertinent literature from the perspective of the research interests of the authors for new translational work in AKI. As such, it does not represent a systematic review of all of the AKI literature. Implications: Translation of findings from biomedical research into AKI therapy presents several challenges. These may be partly overcome by targeting populations for interventional trials where the likelihood of AKI is very high, and readily predictable. Further, specific clinics to follow-up with patients after AKI events hold promise to provide best practice in care, and to translate therapies into treatment for the broadest possible patient populations

Acute kidney injury: preclinical innovations, challenges, and opportunities for translation

Abstract Background Acute kidney injury (AKI) is a clinically important condition that has attracted a great deal of interest from the biomedical research community. However, acute kidney injury AKI research findings have yet to be translated into significant changes in clinical practice. Objective This article reviews many of the preclinical innovations in acute kidney injury AKI treatment, and explores challenges and opportunities to translate these finding into clinical practice. Sources of Information MEDLINE, ISI Web of Science Findings This paper details areas in biomedical research where translation of pre-clinical findings into clinical trials is ongoing, or nearing a point where trial design is warranted. Further, the paper examines ways that best practice in the management of AKI can reach a broader proportion of the patient population experiencing this condition. Limitations This review highlights pertinent literature from the perspective of the research interests of the authors for new translational work in AKI. As such, it does not represent a systematic review of all of the AKI literature. Implications Translation of findings from biomedical research into AKI therapy presents several challenges. These may be partly overcome by targeting populations for interventional trials where the likelihood of AKI is very high, and readily predictable. Further, specific clinics to follow-up with patients after AKI events hold promise to provide best practice in care, and to translate therapies into treatment for the broadest possible patient populations

"PP2C7s", Genes Most Highly Elaborated in Photosynthetic Organisms, Reveal the Bacterial Origin and Stepwise Evolution of PPM/PP2C Protein Phosphatases

<div><p>Mg⁺²/Mn⁺²-dependent type 2C protein phosphatases (PP2Cs) are ubiquitous in eukaryotes, mediating diverse cellular signaling processes through metal ion catalyzed dephosphorylation of target proteins. We have identified a distinct PP2C sequence class (“PP2C7s”) which is nearly universally distributed in Eukaryotes, and therefore apparently ancient. PP2C7s are by far most prominent and diverse in plants and green algae. Combining phylogenetic analysis, subcellular localization predictions, and a distillation of publically available gene expression data, we have traced the evolutionary trajectory of this gene family in photosynthetic eukaryotes, demonstrating two major sequence assemblages featuring a succession of increasingly derived sub-clades. These display predominant expression moving from an ancestral pattern in photosynthetic tissues toward non-photosynthetic, specialized and reproductive structures. Gene co-expression network composition strongly suggests a shifting pattern of PP2C7 gene functions, including possible regulation of starch metabolism for one homologue set in Arabidopsis and rice. Distinct plant PP2C7 sub-clades demonstrate novel amino terminal protein sequences upon motif analysis, consistent with a shifting pattern of regulation of protein function. More broadly, neither the major events in PP2C sequence evolution, nor the origin of the diversity of metal binding characteristics currently observed in different PP2C lineages, are clearly understood. Identification of the PP2C7 sequence clade has allowed us to provide a better understanding of both of these issues. Phylogenetic analysis and sequence comparisons using Hidden Markov Models strongly suggest that PP2Cs originated in Bacteria (Group II PP2C sequences), entered Eukaryotes through the ancestral mitochondrial endosymbiosis, elaborated in Eukaryotes, then re-entered Bacteria through an inter-domain gene transfer, ultimately producing bacterial Group I PP2C sequences. A key evolutionary event, occurring first in ancient Eukaryotes, was the acquisition of a conserved aspartate in classic Motif 5. This has been inherited subsequently by PP2C7s, eukaryotic PP2Cs and bacterial Group I PP2Cs, where it is crucial to the formation of a third metal binding pocket, and catalysis.</p></div

Mental health symptom changes in pregnant individuals across the COVID-19 pandemic: a prospective longitudinal study

Abstract Background Initial studies found that mental health symptoms increased in pregnant and postpartum individuals during the COVID-19 pandemic. Less research has focused on if these putative increases persist over time and what factors influence these changes. We examined the longitudinal change in mental health symptoms in pregnant and postpartum individuals and investigated moderation by maternal emotion dysregulation and the incidence of coronavirus. Methods Pregnant and postpartum individuals at the University of Utah were invited to join the COVID-19 and Perinatal Experiences (COPE) Study. Beginning on April 23, 2020 participants were sent a survey comprised of demographics, medical and social history, pregnancy information and self-assessments (Time 1). Participants were contacted 90 days later and invited to participate in a follow-up questionnaire (Time 2). Daily coronavirus case counts were accessed from the state of Utah and a 7-day moving average calculated. Within-subject change in mental health symptom scores, as measured by the Brief Symptom Inventory, was calculated. Linear mixed effects regression modeling adjusted for history of substance abuse and mental health disorders. Results 270 individuals responded between April 23rd, 2020 and July 15th, 2021. Mental health symptom scores improved by 1.36 points (0.7-2.0 p < 0.001). The decrease in mental health symptoms was not moderated by the prevalence of COVID-19 cases (p = 0.19) but was moderated by emotion dysregulation (p = 0.001) as defined by the Difficulties in Emotion Regulation Scale short form. Participants with higher emotion dysregulation also had higher mental health symptom scores. Conclusion Mental health symptoms improved over the course of the pandemic in the same pregnant or postpartum participant. Our findings do not negate the importance of mental health care during the pandemic. Rather, we believe this identifies some aspect of resiliency and adaptability. Examining emotion dysregulation, or asking about a history of mental health, may be helpful in identifying persons at higher risk of heightened responses to stressors

Inhibition Stabilized Network models

Models of Inhibition Stabilized Networks in mammalian neocortex. Theoretical, firing-rate and spiking models of cortical networks with increasing realism, to explore how networks respond to perturbation of neural activity.<div><br></div><div>Provided as supplementary material to the paper Sadeh et al. 2017 <i>J Neurosci (in press).</i></div

Topological uncertainty in the phylogenetic tree summarizing PP2C sequence evolutionary history.

<p>This tree is an alternate display of the same BEAST analysis data used to generate <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132863#pone.0132863.g001" target="_blank">Fig 1</a>. Green lines represent traces of individual trees from amongst the posterior distribution tree sample. In blue is the consensus tree with the highest clade support (“root canal”). Points 1, 2, and 3 are discussed in the text. Each represents a node with a black bar indicating the 95% high posterior density interval.</p

Structure-guided alignment of bacterial Group II, PP2C7, bacterial Group I, and eukaryotic PP2C sequences.

<p>Information from solved structures of bacterial Group II, bacterial Group I, and eukaryotic PP2Cs (indicated by their four-character PDB codes) was used to guide this alignment, as detailed in “Materials and Methods”. Above the sequences are shown conserved beta-strand and α-helical secondary structure elements. “Box” refers to a more variable region in multiple solved structures. For a secondary structure diagram, including element numbering, see Fig F in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132863#pone.0132863.s002" target="_blank">S2 File</a>. Sequence motifs are as given in [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132863#pone.0132863.ref084" target="_blank">84</a>]. Universally conserved aspartates involved in metal coordination are given in red. Aspartates conserved in some but not all sequences are given in purple and orange (see text for <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132863#sec021" target="_blank">discussion</a>). The inset shows a simplified phylogenetic tree, with the proposed evolutionary advent of critical aspartate residues indicated. See Table A in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132863#pone.0132863.s001" target="_blank">S1 File</a> for a listing of PP2C7 sequences. Bacterial Group II sequences without solved structures are from UniProt. Species for sequences are as follows: Bs (Bacillus subtilis); Ssp (Synechocystis sp.); Pa (Pseudomonas aeruginosa); Mt (Moorella thermoacetica); Tb (Trypanosoma brucei); Lm (Leishmania major); Tt (Tetrahymena thermophila); Ppa (Physcomitrella patens); At (Arabidopsis thaliana); Cr (Chlamydomonas reinhardtii); Vc (Volvox carteri); Ps (Phytophthora sojae); Ng (Naegleria gruberi); Xl (Xenopus laevis); Hs (Homo sapiens); Dm (Drosophila melanogaster); Fg (Fusarium graminearum); An (Aspergillus niger); Sc (Saccharomyces cerevisiae); Mtu (Mycobacterium tuberculosis); Sa (Streptococcus agalactiae); Ms (Mycobacterium smegmatis); Te (Thermosynechococcus elongatus); Ag (Anopheles gambiae).</p