Sm Domain Research Articles

Contribution of reduced skeletal muscle perfusion reserve to exercise intolerance in heart failure with preserved ejection fraction

BackgroundSkeletal muscle (SM)-associated mechanisms of exercise intolerance in HFpEF are insufficiently defined, and inadequate augmentation of SM blood flow during physical effort may be one of the contributors. Therefore, we sought to investigate the association of SM perfusion response to exertion with exercise capacity in this clinical condition. MethodsEchocardiography and SM microvascular perfusion by contrast-enhanced ultrasound were performed at rest and immediately post-exercise test in 77 HFpEF patients in NYHA class II and III, and in 25 subjects with normal exercise tolerance (stage B). Exercise reserve of cardiac function and SM perfusion was calculated by subtracting resting value from exercise value. ResultsIn addition to decreased cardiac functional reserve, HFpEF patients demonstrated significantly reduced SM perfusion reserve as compared to HF stage B, with the degree of impairment being greater in the subgroup with more profound left ventricular (LV) diastolic abnormalities (E/e’ > 15 and TRV > 2.8 m/s).SM perfusion reserve was significantly associated with exercise capacity (beta = 0.33; SE 0.11; p = 0.003), cardiac output reserve (beta = 0.24; SE 0.12; p = 0.039), resting E/e’ (beta = −0.33; SE 0.11; p = 0.006), and patient frailty expressed by the PRISMA 7 score (beta = −0.30; SE 0.11; p = 0.008). In multivariable analysis including clinical, demographic and cardiac functional variables, SM perfusion reserve was in addition to patient frailty, sex and LV longitudinal strain reserve among the independent correlates of exercise capacity. ConclusionsSM perfusion reserve is impaired in HFpEF, and is associated with reduced exercise capacity independent of clinical, demographic and “central” cardiac factors. This supports the need to consider the SM domain in patient management strategies in HFpEF.

Application of Multi-Criteria Decision-Making Methods in Sustainable Manufacturing Management: A Systematic Literature Review and Analysis of the Prospects

Due to increasing environmental regulation and customers’ demand for environmentally friendly products, organizations have been required to adopt sustainable manufacturing practices by implementing clean technology (Cleantec) to manufacture green products. By adopting environmental practices, organizations can also achieve qualitative and quantitative benefits that help them remain competitive in the market while meeting governmental environmental policies, such as lowering energy and the cost of materials. The significant number of articles addressing sustainability in manufacturing published in the past few years attests to the importance of the topic. However, not many studies have been developed to understand the decision-making process in sustainable manufacturing. Therefore, the objective of this paper is to conduct a systematic literature review on the application of multi-attribute decision-making (MADM) methods in sustainable manufacturing. A total of 158 papers, published between 2009 and 2018, met the criteria set in the research methodology. The 158 papers were then analyzed and classified into seven categories: (i) SM domain, (ii) activity within the organization, (iii) decision goals, (iv) decision-makers involved (group or individual), (v) uncertain data, (vi) SM aspects (social, environmental, and economic), and (vii) MADM methods. Among the results, we identified that AHP is the most applied MADM method and, regarding the activities of the organization, MADM methods have been the most frequently applied to strategy management and supply chain. We also identified a tendency to consider uncertain and imprecise data in the decision-making process. Another result is that all the three domains — economic, environmental and social — were considered in most of the papers, followed by the combination of the economic and environmental perspectives. In the conclusion, some recent trends and future research directions are highlighted.

Self-Management Apps for People With Epilepsy: Systematic Analysis.

BackgroundPatients with epilepsy (PWEs) are motivated to manage and cope with their disorder themselves (ie, self-management [SM] is encouraged). Mobile health (mHealth) apps have multiple features that have a huge potential to improve SM of individuals with chronic disorders such as epilepsy.ObjectiveThis study aimed to review all freely available apps related to the SM of PWEs and to determine the SM domains covered in these apps.MethodsWe performed a search of apps on Google Play and App Store using the keywords “epilepsy” or “seizures” from May to August 2018. Apps were included if they were free and in English language. We excluded apps with installation-related issues and not related to epilepsy self-management (eSM).ResultsA total of 22 eSM apps were identified in our search: 6 of these run only on iOS, 7 only on Android, and 9 run on both operating systems. Of the 11 domains of SM, seizure tracking and seizure response features were covered by most apps (n=22 and n=19, respectively), followed by treatment management (n=17) and medication adherence (n=15). Three apps (Epilepsy Journal, Epilepsy Tool Kit, and EpiDiary) were installed more than 10,000 times, with features focused specifically on a few domains (treatment management, medication adherence, health care communication, and seizure tracking). Two apps (Young Epilepsy and E-Epilepsy Inclusion) covered more than 6 SM domains but both had lower installation rates (5000+ and 100+, respectively).ConclusionsBoth Android and iOS mHealth apps are available to improve SM in epilepsy, but the installation rate of most apps remains low. The SM features of these apps were different from one another, making it difficult to recommend a single app that completely fulfills the needs of PWEs. The common features of the apps evaluated included seizure tracking and seizure response. To improve the efficacy and availability of these apps, we propose the following: (1) involve the stakeholders, such as physicians, pharmacists, and PWEs, during the development of mHealth apps; (2) assess the efficacy and acceptance of the apps objectively by performing a usability analysis; and (3) promote the apps so that they benefit more PWEs.

Acidic C-terminal domains autoregulate the RNA chaperone Hfq.

The RNA chaperone Hfq is an Sm protein that facilitates base pairing between bacterial small RNAs (sRNAs) and mRNAs involved in stress response and pathogenesis. Hfq possesses an intrinsically disordered C-terminal domain (CTD) that may tune the function of the Sm domain in different organisms. In Escherichia coli, the Hfq CTD increases kinetic competition between sRNAs and recycles Hfq from the sRNA-mRNA duplex. Here, de novo Rosetta modeling and competitive binding experiments show that the acidic tip of the E. coli Hfq CTD transiently binds the basic Sm core residues necessary for RNA annealing. The CTD tip competes against non-specific RNA binding, facilitates dsRNA release, and prevents indiscriminate DNA aggregation, suggesting that this acidic peptide mimics nucleic acid to auto-regulate RNA binding to the Sm ring. The mechanism of CTD auto-inhibition predicts the chaperone function of Hfq in bacterial genera and illuminates how Sm proteins may evolve new functions.

Structural and dynamic properties of the C-terminal region of the Escherichia coli RNA chaperone Hfq: integrative experimental and computational studies.

In Escherichia coli, hexameric Hfq is an important RNA chaperone that facilitates small RNA-mediated post-transcriptional regulation. The Hfq monomer consists of an evolutionarily conserved Sm domain (residues 1-65) and a flexible C-terminal region (residues 66-102). It has been recognized that the existence of the C-terminal region is important for the function of Hfq, but its detailed structural and dynamic properties remain elusive due to its disordered nature. In this work, using integrative experimental techniques, such as nuclear magnetic resonance spectroscopy and small-angle X-ray scattering, as well as multi-scale computational simulations, new insights into the structure and dynamics of the C-terminal region in the context of the Hfq hexamer are provided. Although the C-terminal region is intrinsically disordered, some residues (83-86) are motionally restricted. The hexameric core may affect the secondary structure propensity of the C-terminal region, due to transient interactions between them. The residues at the rim and the proximal side of the core have significantly more transient contacts with the C-terminal region than those residues at the distal side, which may facilitate the function of the C-terminal region in the release of double-stranded RNAs and the cycling of small non-coding RNAs. Structure ensembles constructed by fitting the experimental data also support that the C-terminal region prefers to locate at the proximal side. From multi-scale simulations, we propose that the C-terminal region may play a dual role of steric effect (especially at the proximal side) and recruitment (at the both sides) in the binding process of RNA substrates. Interestingly, we have found that these motionally restricted residues may serve as important binding sites for the incoming RNAs that is probably driven by favorable electrostatic interactions. These integrative studies may aid in our understanding of the functional role of the C-terminal region of Hfq.

Mutagenic Analysis of the C-Terminal Extension of Lsm1.

The Sm-like proteins (also known as Lsm proteins) are ubiquitous in nature and exist as hexa or heptameric RNA binding complexes. They are characterized by the presence of the Sm-domain. The Lsm1 through Lsm7 proteins are highly conserved in eukaryotes and they form a hetero-octameric complex together with the protein Pat1. The Lsm1-7-Pat1 complex plays a key role in mRNA decapping and 3’-end protection and therefore is required for normal mRNA decay rates in vivo. Lsm1 is a key subunit that is critical for the unique RNA binding properties of this complex. We showed earlier that unlike most Sm-like proteins, Lsm1 uniquely requires both its Sm domain and its C-terminal extension to contribute to the function of the Lsm1-7-Pat1 complex and that the C-terminal segment can associate with the rest of the complex and support the function even in trans. The studies presented here identify a set of residues at the very C-terminal end of Lsm1 to be functionally important and suggest that these residues support the function of the Lsm1-7-Pat1 complex by facilitating RNA binding either directly or indirectly.

THE STRONG MORI PROPERTY IN RINGS WITH ZERO DIVISORS

An SM domain is an integral domain which satisfies the ascending chain condition on w-ideals. Then an SM domain also satisfies the descending chain condition on those chains of v-ideals whose intersection is not zero. In this paper, a study is begun to extend these properties to commutative rings with zero divisors. A <TEX>$Q_0$</TEX>-SM ring is defined to be a ring which satisfies the ascending chain condition on semiregular w-ideals and satisfies the descending chain condition on those chains of semiregular v-ideals whose intersection is semiregular. In this paper, some properties of <TEX>$Q_0$</TEX>-SM rings are discussed and examples are provided to show the difference between <TEX>$Q_0$</TEX>-SM rings and SM rings and the difference between <TEX>$Q_0$</TEX>-SM rings and <TEX>$Q_0$</TEX>-Mori rings.

A NOTE ON w-NOETHERIAN RINGS

Let R be a commutative ring. An R-module M is called a w-Noetherian module if every submodule of M is of w-finite type. R is called a w-Noetherian ring if R as an R-module is a w-Noetherian module. In this paper, we present an exact version of the Eakin-Nagata Theorem on w-Noetherian rings. To do this, we prove the Formanek Theorem for w-Noetherian rings. Further, we point out by an example that the condition (<TEX>${\dag}$</TEX>) in the Chung-Ha-Kim version of the Eakin-Nagata Theorem on SM domains is essential.

A NOTE ON ZERO DIVISORS IN w-NOETHERIAN-LIKE RINGS

We introduce the concept of w-zero-divisor (w-ZD) rings and study its related rings. In particular it is shown that an integral domain R is an SM domain if and only if R is a w-locally Noetherian w-ZD ring and that a commutative ring R is w-Noetherian if and only if the polynomial ring in one indeterminate R[X] is a w-ZD ring. Finally we characterize universally zero divisor rings in terms of w-ZD modules.

Interpreting a Low Resolution Map of Human U1 snRNP Using Anomalous Scatterers

SummaryWe recently determined the crystal structure of the functional core of human U1 snRNP, consisting of nine proteins and one RNA, based on a 5.5 Å resolution electron density map. At 5–7 Å resolution, α helices and β sheets appear as rods and slabs, respectively, hence it is not possible to determine protein fold de novo. Using inverse beam geometry, accurate anomalous signals were obtained from weakly diffracting and radiation sensitive P1 crystals. We were able to locate anomalous scatterers with positional errors below 2 Å. This enabled us not only to place protein domains of known structure accurately into the map but also to trace an extended polypeptide chain, of previously undetermined structure, using selenomethionine derivatives of single methionine mutants spaced along the sequence. This method of Se-Met scanning, in combination with structure prediction, is a powerful tool for building a protein of unknown fold into a low resolution electron density map.

Analysis of Lsm1p and Lsm8p domains in the cellular localization of Lsm complexes in budding yeast

In eukaryotes, two heteroheptameric Sm-like (Lsm) complexes that differ by a single subunit localize to different cellular compartments and have distinct functions in RNA metabolism. The cytoplasmic Lsm1–7p complex promotes mRNA decapping and localizes to processing bodies, whereas the Lsm2–8p complex takes part in a variety of nuclear RNA processing events. The structural features that determine their different functions and localizations are not known. Here, we analyse a range of mutant and hybrid Lsm1 and Lsm8 proteins, shedding light on the relative importance of their various domains in determining their localization and ability to support growth. Although no single domain is either essential or sufficient for cellular localization, the Lsm1p N-terminus may act as part of a nuclear exclusion signal for Lsm1–7p, and the shorter Lsm8p N-terminus contributes to nuclear accumulation of Lsm2–8p. The C-terminal regions seem to play a secondary role in determining localization, with little or no contribution coming from the central Sm domains. The essential Lsm8 protein is remarkably resistant to mutation in terms of supporting viability, whereas Lsm1p appears more sensitive. These findings contribute to our understanding of how two very similar protein complexes can have different properties.

Promiscuous Modification of the Nuclear Poly(A)-binding Protein by Multiple Protein-arginine Methyltransferases Does Not Affect the Aggregation Behavior

The mammalian nuclear poly(A)-binding protein, PABPN1, carries 13 asymmetrically dimethylated arginine residues in its C-terminal domain. By fractionation of cell extracts, we found that protein-arginine methyltransferases (PRMTs)-1, -3, and -6 are responsible for the modification of PABPN1. Recombinant PRMT1, -3, and -6 also methylated PABPN1. Our data suggest that these enzymes act on their own, and additional polypeptides are not involved in recognizing PABPN1 as a substrate. PRMT1 is the predominant methyltransferase acting on PABPN1. Nevertheless, PABPN1 was almost fully methylated in a Prmt1(-/-) cell line; thus, PRMT3 and -6 suffice for methylation. In contrast to PABPN1, the heterogeneous nuclear ribonucleoprotein (hnRNP) K is selectively methylated only by PRMT1. Efficient methylation of synthetic peptides derived from PABPN1 or hnRNP K suggested that PRMT1, -3, and -6 recognize their substrates by interacting with local amino acid sequences and not with additional domains of the substrates. However, the use of fusion proteins suggested that the inability of PRMT3 and -6 to modify hnRNP K is because of structural masking of the methyl-accepting amino acid sequences by neighboring domains. Mutations leading to intracellular aggregation of PABPN1 cause the disease oculopharyngeal muscular dystrophy. The C-terminal domain containing the methylated arginine residues is known to promote PAPBN1 self-association, and arginine methylation has been reported to inhibit self-association of an orthologous protein. Thus, arginine methylation might be relevant for oculopharyngeal muscular dystrophy. However, in two different types of assays we have been unable to detect any effect of arginine methylation on the aggregation of bovine PABPN1.

A Divergent Sm Fold in EDC3 Proteins Mediates DCP1 Binding and P-Body Targeting

Members of the (L)Sm (Sm and Sm-like) protein family are found across all kingdoms of life and play crucial roles in RNA metabolism. The P-body component EDC3 (enhancer of decapping 3) is a divergent member of this family that functions in mRNA decapping. EDC3 is composed of a N-terminal LSm domain, a central FDF domain, and a C-terminal YjeF-N domain. We show that this modular architecture enables EDC3 to interact with multiple components of the decapping machinery, including DCP1, DCP2, and Me31B. The LSm domain mediates DCP1 binding and P-body localization. We determined the three-dimensional structures of the LSm domains of Drosophila melanogaster and human EDC3 and show that the domain adopts a divergent Sm fold that lacks the characteristic N-terminal alpha-helix and has a disrupted beta4-strand. This domain remains monomeric in solution and lacks several features that canonical (L)Sm domains require for binding RNA. The structures also revealed a conserved patch of surface residues that are required for the interaction with DCP1 but not for P-body localization. The conservation of surface and of critical structural residues indicates that LSm domains in EDC3 proteins adopt a similar fold that has separable novel functions that are absent in canonical (L)Sm proteins.

A complex containing the Sm protein CAR-1 and the RNA helicase CGH-1 is required for embryonic cytokinesis in Caenorhabditis elegans

Cytokinesis completes cell division and partitions the contents of one cell to the two daughter cells. Here we characterize CAR-1, a predicted RNA binding protein that is implicated in cytokinesis. CAR-1 localizes to germline-specific RNA-containing particles and copurifies with the essential RNA helicase, CGH-1, in an RNA-dependent fashion. The atypical Sm domain of CAR-1, which directly binds RNA, is dispensable for CAR-1 localization, but is critical for its function. Inhibition of CAR-1 by RNA-mediated depletion or mutation results in a specific defect in embryonic cytokinesis. This cytokinesis failure likely results from an anaphase spindle defect in which interzonal microtubule bundles that recruit Aurora B kinase and the kinesin, ZEN-4, fail to form between the separating chromosomes. Depletion of CGH-1 results in sterility, but partially depleted worms produce embryos that exhibit the CAR-1–depletion phenotype. Cumulatively, our results suggest that CAR-1 functions with CGH-1 to regulate a specific set of maternally loaded RNAs that is required for anaphase spindle structure and cytokinesis.

Toward an Assembly Line for U7 snRNPs: INTERACTIONS OF U7-SPECIFIC Lsm PROTEINS WITH PRMT5 AND SMN COMPLEXES

The survival of motor neurons (SMN) complex mediates the assembly of small nuclear ribonucleoproteins (snRNPs) involved in splicing and histone RNA processing. A crucial step in this process is the binding of Sm proteins onto the SMN protein. For Sm B/B', D1, and D3, efficient binding to SMN depends on symmetrical dimethyl arginine (sDMA) modifications of their RG-rich tails. This methylation is achieved by another entity, the PRMT5 complex. Its pICln subunit binds Sm proteins whereas the PRMT5 subunit catalyzes the methylation reaction. Here, we provide evidence that Lsm10 and Lsm11, which replace the Sm proteins D1 and D2 in the histone RNA processing U7 snRNPs, associate with pICln in vitro and in vivo without receiving sDMA modifications. This implies that the PRMT5 complex is involved in an early stage of U7 snRNP assembly and hence may have a second snRNP assembly function unrelated to sDMA modification. We also show that the binding of Lsm10 and Lsm11 to SMN is independent of any methylation activity. Furthermore, we present evidence for two separate binding sites in SMN for Sm/Lsm proteins. One recognizes Sm domains and the second one, the sDMA-modified RG-tails, which are present only in a subset of these proteins.

Some Remarks on Pseudo-Krull Domains#

ABSTRACT Using an example of Heinzer-Ohm-Pendleton we show that the integral closure of a pseudo-Krull domain (respectively, an SM domain) need not be a Krull domain. This example also shows that there exists a non-Noetherian non-Krull pseudo-Krull domain (and therefore an SM domain). It is shown that for a one-dimensional domain R, R is a PKD if and only if R is a t-closed SM domain. Finally, we characterize pseudo-Krull group rings.

U7 snRNP-specific Lsm11 protein: dual binding contacts with the 100 kDa zinc finger processing factor (ZFP100) and a ZFP100-independent function in histone RNA 3' end processing

The 3′ cleavage generating non-polyadenylated animal histone mRNAs depends on the base pairing between U7 snRNA and a conserved histone pre-mRNA downstream element. This interaction is enhanced by a 100 kDa zinc finger protein (ZFP100) that forms a bridge between an RNA hairpin element upstream of the processing site and the U7 small nuclear ribonucleoprotein (snRNP). The N-terminus of Lsm11, a U7-specific Sm-like protein, was shown to be crucial for histone RNA processing and to bind ZFP100. By further analysing these two functions of Lsm11, we find that Lsm11 and ZFP100 can undergo two interactions, i.e. between the Lsm11 N-terminus and the zinc finger repeats of ZFP100, and between the N-terminus of ZFP100 and the Sm domain of Lsm11, respectively. Both interactions are not specific for the two proteins in vitro, but the second interaction is sufficient for a specific recognition of the U7 snRNP by ZFP100 in cell extracts. Furthermore, clustered point mutations in three phylogenetically conserved regions of the Lsm11 N-terminus impair or abolish histone RNA processing. As these mutations have no effect on the two interactions with ZFP100, these protein regions must play other roles in histone RNA processing, e.g. by contacting the pre-mRNA or additional processing factors.

Structure and assembly of an augmented Sm-like archaeal protein 14-mer.

To better understand the roles of Sm proteins in forming the cores of many RNA-processing ribonucleoproteins, we determined the crystal structure of an atypical Sm-like archaeal protein (SmAP3) in which the conserved Sm domain is augmented by a previously uncharacterized, mixed alpha/beta C-terminal domain. The structure reveals an unexpected SmAP3 14-mer that is perforated by a cylindrical pore and is bound to 14 cadmium (Cd(2+)) ions. Individual heptamers adopt either "apical" or "equatorial" conformations that chelate Cd(2+) differently. SmAP3 forms supraheptameric oligomers (SmAP3)(n = 7,14,28) in solution, and assembly of the asymmetric 14-mer is modulated by differential divalent cation-binding in apical and equatorial subunits. Phylogenetic and sequence analyses substantiate SmAP3s as a unique subset of SmAPs. These results distinguish SmAP3s from other Sm proteins and provide a model for the structure and properties of Sm proteins >100 residues in length, e.g., several human Sm proteins.

The methylosome, a 20S complex containing JBP1 and pICln, produces dimethylarginine-modified Sm proteins.

snRNPs, integral components of the pre-mRNA splicing machinery, consist of seven Sm proteins which assemble in the cytoplasm as a ring structure on the snRNAs U1, U2, U4, and U5. The survival motor neuron (SMN) protein, the spinal muscular atrophy disease gene product, is crucial for snRNP core particle assembly in vivo. SMN binds preferentially and directly to the symmetrical dimethylarginine (sDMA)-modified arginine- and glycine-rich (RG-rich) domains of SmD1 and SmD3. We found that the unmodified, but not the sDMA-modified, RG domains of SmD1 and SmD3 associate with a 20S methyltransferase complex, termed the methylosome, that contains the methyltransferase JBP1 and a JBP1-interacting protein, pICln. JBP1 binds SmD1 and SmD3 via their RG domains, while pICln binds the Sm domains. JBP1 produces sDMAs in the RG domain-containing Sm proteins. We further demonstrate the existence of a 6S complex that contains pICln, SmD1, and SmD3 but not JBP1. SmD3 from the methylosome, but not that from the 6S complex, can be transferred to the SMN complex in vitro. Together with previous results, these data indicate that methylation of Sm proteins by the methylosome directs Sm proteins to the SMN complex for assembly into snRNP core particles and suggest that the methylosome can regulate snRNP assembly.

On overrings of Strong Mori domains

We show that if R is a Strong Mori domain (SM domain) and T is a w-overdomain of R such that T⊆ R wg , then T is an SM domain; if R is an SM domain, then R S is an SM domain for any generalized multiplicative system S of R. Finally, we give an example such that an intersection with finiteness condition of SM domains is not an SM domain.