gulati

Arabidopsis retrotransposon virus-like particles and their regulation by epigenetically activated small RNA [RESEARCH]

In Arabidopsis, LTR retrotransposons are activated by mutations in the chromatin gene DECREASE in DNA METHYLATION 1 (DDM1), giving rise to 21- to 22-nt epigenetically activated siRNA (easiRNA) that depend on RNA DEPENDENT RNA POLYMERASE 6 (RDR6). We purified virus-like particles (VLPs) from ddm1 and ddm1rdr6 mutants in which genomic RNA is reverse transcribed into complementary DNA. High-throughput short-read and long-read sequencing of VLP DNA (VLP DNA-seq) revealed a comprehensive catalog of active LTR retrotransposons without the need for mapping transposition, as well as independent of genomic copy number. Linear replication intermediates of the functionally intact COPIA element EVADE revealed multiple central polypurine tracts (cPPTs), a feature shared with HIV in which cPPTs promote nuclear localization. For one member of the ATCOPIA52 subfamily (SISYPHUS), cPPT intermediates were not observed, but abundant circular DNA indicated transposon "suicide" by auto-integration within the VLP. easiRNA targeted EVADE genomic RNA, polysome association of GYPSY (ATHILA) subgenomic RNA, and transcription via histone H3 lysine-9 dimethylation. VLP DNA-seq provides a comprehensive landscape of LTR retrotransposons and their control at transcriptional, post-transcriptional, and reverse transcriptional levels.




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Complex Rab4-Mediated Regulation of Endosomal Size and EGFR Activation

Early sorting endosomes are responsible for the trafficking and function of transferrin receptor (TfR) and EGFR. These receptors play important roles in iron uptake and signaling and are critical for breast cancer development. However, the role of morphology, receptor composition, and signaling of early endosomes in breast cancer remains poorly understood. A novel population of enlarged early endosomes was identified in breast cancer cells and tumor xenografts but not in noncancerous MCF10A cells. Quantitative analysis of endosomal morphology, cargo sorting, EGFR activation, and Rab GTPase regulation was performed using super-resolution and confocal microscopy followed by 3D rendering. MDA-MB-231 breast cancer cells have fewer, but larger EEA1-positive early endosomes compared with MCF10A cells. Live-cell imaging indicated dysregulated cargo sorting, because EGF and Tf traffic together via enlarged endosomes in MDA-MB-231, but not in MCF10A. Large EEA1-positive MDA-MB-231 endosomes exhibited prolonged and increased EGF-induced activation of EGFR upon phosphorylation at tyrosine-1068 (EGFR-p1068). Rab4A overexpression in MCF10A cells produced EEA1-positive enlarged endosomes that displayed prolonged and amplified EGF-induced EGFR-p1068 activation. Knockdown of Rab4A lead to increased endosomal size in MCF10A, but not in MDA-MB-231 cells. Nevertheless, Rab4A knockdown resulted in enhanced EGF-induced activation of EGFR-p1068 in MDA-MB-231 as well as downstream signaling in MCF10A cells. Altogether, this extensive characterization of early endosomes in breast cancer cells has identified a Rab4-modulated enlarged early endosomal compartment as the site of prolonged and increased EGFR activation.

Implications:

Enlarged early endosomes play a Rab4-modulated role in regulation of EGFR activation in breast cancer cells.




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Circular RNA hsa_circ_0014130 Inhibits Apoptosis in Non-Small Cell Lung Cancer by Sponging miR-136-5p and Upregulating BCL2

Previous studies indicated that circular RNAs (circRNA) played vital roles in the development of non–small cell lung cancer (NSCLC). Although hsa_circ_0014130 might be a potential NSCLC biomarker, its function in NSCLC remains unknown. Thus, this study aimed to investigate the role of hsa_circ_0014130 in the progression of NSCLC. The levels of hsa_circ_0014130 in NSCLC tissues and adjacent normal tissues were determined by qRT-PCR. In addition, the expressions of Bcl-2 and cleaved caspase-3 in A549 cells were detected with Western blot analysis. Meanwhile, the dual luciferase reporter system assay was used to determine the interaction of hsa_circ_0014130 and miR-136-5p or Bcl-2 and miR-136-5p in NSCLC, respectively. The level of hsa_circ_0014130 was significantly upregulated in NSCLC tissues. Downregulation of hsa_circ_0014130 markedly inhibited the proliferation and invasion of A549 cells via inducing apoptosis. In addition, downregulation of hsa_circ_0014130 inhibited the tumorigenesis of subcutaneous A549 xenograft in mice in vivo. Meanwhile, mechanistic analysis indicated that downregulation of hsa_circ_0014130 decreased the expression of miR-136-5p–targeted gene Bcl-2 via acting as a competitive "sponge" of miR-136-5p. In this study, we found that hsa_circ_0014130 was upregulated in NSCLC tissues. In addition, hsa_circ_0014130 functions as a tumor promoter in NSCLC to promote tumor growth through upregulating Bcl-2 partially via "sponging" miR-136-5p.

Implications:

In conclusion, hsa_circ_0014130 might function as a prognostic factor for patients with NSCLC and might be a therapeutic target for the treatment of NSCLC in future.




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Cinnamaldehyde Inhibits Inflammation of Human Synoviocyte Cells Through Regulation of Jak/Stat Pathway and Ameliorates Collagen-Induced Arthritis in Rats [Inflammation, Immunopharmacology, and Asthma]

Cinnamaldehyde (Cin), a bioactive cinnamon essential oil from traditional Chinese medicine herb Cinnamomum cassia, has been reported to have multipharmacological activities including anti-inflammation. However, its role and molecular mechanism of anti-inflammatory activity in musculoskeletal tissues remains unclear. Here, we first investigated the effects and molecular mechanisms of Cin in human synoviocyte cells. Then in vivo therapeutic effect of Cin on collagen-induced arthritis (CIA) also studied. Cell Counting Kit ‎CCK-8 assay was performed to evaluate the cell cytotoxicity. Proinflammatory cytokine expression was evaluated using quantitative polymerase chain reaction and ELISA. Protein expression was measured by western blotting. The in vivo effect of Cin (75 mg/kg per day) was evaluated in rats with CIA by gavage administration. Disease progression was assessed by clinical scoring, radiographic, and histologic examinations. Cin significantly inhibited interleukin (IL)-1β–induced IL-6, IL-8, and tumor necrosis factor-α release from human synoviocyte cells. The molecular analysis revealed that Cin impaired IL-6–induced activation of Janus kinase 2 (JAK2), signal transducer and activator of transcription 1 (STAT1), and STAT3 signaling pathway by inhibiting the phosphorylation of JAK2, STAT1, and STAT3, without affecting NF-B pathway. Cin reduced collagen-induced swollen paw volume of arthritic rats. The anti-inflammation effects of Cin were associated with decreased severity of arthritis, joint swelling, and reduced bone erosion and destruction. Furthermore, serum IL-6 level was decreased when Cin administered therapeutically to CIA rats. Cin suppresses IL-1β–induced inflammation in synoviocytes through the JAK/STAT pathway and alleviated collagen-induced arthritis in rats. These data indicated that Cin might be a potential traditional Chinese medicine–derived, disease-modifying, antirheumatic herbal drug.

SIGNIFICANCE STATEMENT

In this study, we found that cinnamaldehyde (Cin) suppressed proinflammatory cytokines secretion in rheumatology arthritis synoviocyte cells by Janus kinase/signal transducer and activator of transcription pathway. The in vivo results showed that Cin ameliorated collagen-induced arthritis in rats. These findings indicate that Cin is a potential traditional Chinese medicine–derived, disease-modifying, antirheumatic herbal drug.




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Distinct Regulation of {sigma}1 Receptor Multimerization by Its Agonists and Antagonists in Transfected Cells and Rat Liver Membranes [Cellular and Molecular]

Extensive studies have shown that the 1 receptor (1R) interacts with and modulates the activity of multiple proteins with important biological functions. Recent crystal structures of 1R as a homotrimer differ from a dimer-tetramer model postulated earlier. It remains inconclusive whether ligand binding regulates 1R oligomerization. Here, novel nondenaturing gel methods and mutational analysis were used to examine 1R oligomerization. In transfected cells, 1R exhibited as multimers, dimers, and monomers. Overall, 1R agonists decreased, whereas 1R antagonists increased 1R multimers, suggesting that agonists and antagonists differentially affect the stability of 1R multimers. Endogenous 1R in rat liver membranes also showed similar regulation of oligomerization as in cells. Mutations at key residues lining the trimerization interface (Arg119, Asp195, Phe191, Trp136, and Gly91) abolished multimerization without disrupting dimerization. Intriguingly, truncation of the N terminus reduced 1R to apparent monomer. These results demonstrate that multiple domains play crucial roles in coordinating high-order quaternary organization of 1R. The E102Q 1R mutant implicated in juvenile amyotrophic lateral sclerosis formed dimers only, suggesting that dysregulation of 1R multimeric assembly may impair its function. Interestingly, oligomerization of 1R was pH-dependent and correlated with changes in [3H](+)-pentazocine binding affinity and Bmax. Combined with mutational analysis, it is reasoned that 1R multimers possess high-affinity and high-capacity [3H](+)-pentazocine binding, whereas monomers likely lack binding. These results suggest that 1R may exist in interconvertible oligomeric states in a dynamic equilibrium. Further exploration of ligand-regulated 1R multimerization may provide novel approaches to modulate the function of 1R and its interacting proteins.

SIGNIFICANCE STATEMENT

The 1 receptor (1R) modulates the activities of various partner proteins. Recently, crystal structures of 1R were elucidated as homotrimers. This study used novel nondenaturing gel methods to examine 1R oligomerization in transfected cells and rat liver membranes. Overall, agonist binding decreased, whereas antagonist binding increased 1R multimers, which comprised trimers and larger units. 1R multimers were shown to bind [3H](+)-pentazocine with high affinity and high capacity. Furthermore, mutational analysis revealed a crucial role of its N-terminal domain in 1R multimerization.




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Monocarboxylate Transporters (SLC16): Function, Regulation, and Role in Health and Disease [Review Articles]

The solute carrier family 16 (SLC16) is comprised of 14 members of the monocarboxylate transporter (MCT) family that play an essential role in the transport of important cell nutrients and for cellular metabolism and pH regulation. MCTs 1–4 have been extensively studied and are involved in the proton-dependent transport of L-lactate, pyruvate, short-chain fatty acids, and monocarboxylate drugs in a wide variety of tissues. MCTs 1 and 4 are overexpressed in a number of cancers, and current investigations have focused on transporter inhibition as a novel therapeutic strategy in cancers. MCT1 has also been used in strategies aimed at enhancing drug absorption due to its high expression in the intestine. Other MCT isoforms are less well characterized, but ongoing studies indicate that MCT6 transports xenobiotics such as bumetanide, nateglinide, and probenecid, whereas MCT7 has been characterized as a transporter of ketone bodies. MCT8 and MCT10 transport thyroid hormones, and recently, MCT9 has been characterized as a carnitine efflux transporter and MCT12 as a creatine transporter. Expressed at the blood brain barrier, MCT8 mutations have been associated with an X-linked intellectual disability, known as Allan-Herndon-Dudley syndrome. Many MCT isoforms are associated with hormone, lipid, and glucose homeostasis, and recent research has focused on their potential roles in disease, with MCTs representing promising novel therapeutic targets. This review will provide a summary of the current literature focusing on the characterization, function, and regulation of the MCT family isoforms and on their roles in drug disposition and in health and disease.

Significance Statement

The 14-member solute carrier family 16 of monocarboxylate transporters (MCTs) plays a fundamental role in maintaining intracellular concentrations of a broad range of important endogenous molecules in health and disease. MCTs 1, 2, and 4 (L-lactate transporters) are overexpressed in cancers and represent a novel therapeutic target in cancer. Recent studies have highlighted the importance of MCTs in glucose, lipid, and hormone homeostasis, including MCT8 in thyroid hormone brain uptake, MCT12 in carnitine transport, and MCT11 in type 2 diabetes.




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Developmental regulation of cell type-specific transcription by novel promoter-proximal sequence elements [Research Papers]

Cell type-specific transcriptional programs that drive differentiation of specialized cell types are key players in development and tissue regeneration. One of the most dramatic changes in the transcription program in Drosophila occurs with the transition from proliferating spermatogonia to differentiating spermatocytes, with >3000 genes either newly expressed or expressed from new alternative promoters in spermatocytes. Here we show that opening of these promoters from their closed state in precursor cells requires function of the spermatocyte-specific tMAC complex, localized at the promoters. The spermatocyte-specific promoters lack the previously identified canonical core promoter elements except for the Inr. Instead, these promoters are enriched for the binding site for the TALE-class homeodomain transcription factors Achi/Vis and for a motif originally identified under tMAC ChIP-seq peaks. The tMAC motif resembles part of the previously identified 14-bp β2UE1 element critical for spermatocyte-specific expression. Analysis of downstream sequences relative to transcription start site usage suggested that ACA and CNAAATT motifs at specific positions can help promote efficient transcription initiation. Our results reveal how promoter-proximal sequence elements that recruit and are acted upon by cell type-specific chromatin binding complexes help establish a robust, cell type-specific transcription program for terminal differentiation.




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Positive autofeedback regulation of Ptf1a transcription generates the levels of PTF1A required to generate itch circuit neurons [Research Papers]

Peripheral somatosensory input is modulated in the dorsal spinal cord by a network of excitatory and inhibitory interneurons. PTF1A is a transcription factor essential in dorsal neural tube progenitors for specification of these inhibitory neurons. Thus, mechanisms regulating Ptf1a expression are key for generating neuronal circuits underlying somatosensory behaviors. Mutations targeted to distinct cis-regulatory elements for Ptf1a in mice, tested the in vivo contribution of each element individually and in combination. Mutations in an autoregulatory enhancer resulted in reduced levels of PTF1A, and reduced numbers of specific dorsal spinal cord inhibitory neurons, particularly those expressing Pdyn and Gal. Although these mutants survive postnatally, at ~3–5 wk they elicit a severe scratching phenotype. Behaviorally, the mutants have increased sensitivity to itch, but acute sensitivity to other sensory stimuli such as mechanical or thermal pain is unaffected. We demonstrate a requirement for positive transcriptional autoregulatory feedback to attain the level of the neuronal specification factor PTF1A necessary for generating correctly balanced neuronal circuits.




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Posttranscriptional Regulation of tnaA by Protein-RNA Interaction Mediated by Ribosomal Protein L4 in Escherichia coli [Article]

Escherichia coli ribosomal protein (r-protein) L4 has extraribosomal biological functions. Previously, we described L4 as inhibiting RNase E activity through protein-protein interactions. Here, we report that from stabilized transcripts regulated by L4-RNase E, mRNA levels of tnaA (encoding tryptophanase from the tnaCAB operon) increased upon ectopic L4 expression, whereas TnaA protein levels decreased. However, at nonpermissive temperatures (to inactivate RNase E), tnaA mRNA and protein levels both increased in an rne temperature-sensitive [rne(Ts)] mutant strain. Thus, L4 protein fine-tunes TnaA protein levels independently of its inhibition of RNase E. We demonstrate that ectopically expressed L4 binds with transcribed spacer RNA between tnaC and tnaA and downregulates TnaA translation. We found that deletion of the 5' or 3' half of the spacer compared to the wild type resulted in a similar reduction in TnaA translation in the presence of L4. In vitro binding of L4 to the tnaC-tnaA transcribed spacer RNA results in changes to its secondary structure. We reveal that during early stationary-phase bacterial growth, steady-state levels of tnaA mRNA increased but TnaA protein levels decreased. We further confirm that endogenous L4 binds to tnaC-tnaA transcribed spacer RNA in cells at early stationary phase. Our results reveal the novel function of L4 in fine-tuning TnaA protein levels during cell growth and demonstrate that r-protein L4 acts as a translation regulator outside the ribosome and its own operon.

IMPORTANCE Some ribosomal proteins have extraribosomal functions in addition to ribosome translation function. The extraribosomal functions of several r-proteins control operon expression by binding to own-operon transcripts. Previously, we discovered a posttranscriptional, RNase E-dependent regulatory role for r-protein L4 in the stabilization of stress-responsive transcripts. Here, we found an additional extraribosomal function for L4 in regulating the tna operon by L4-intergenic spacer mRNA interactions. L4 binds to the transcribed spacer RNA between tnaC and tnaA and alters the structural conformation of the spacer RNA, thereby reducing the translation of TnaA. Our study establishes a previously unknown L4-mediated mechanism for regulating gene expression, suggesting that bacterial cells have multiple strategies for controlling levels of tryptophanase in response to varied cell growth conditions.




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CXCR4 upregulation is an indicator of sensitivity to B-cell receptor/PI3K blockade and a potential resistance mechanism in B-cell receptor-dependent diffuse large B-cell lymphomas

B-cell receptor (BCR) signaling pathway components represent promising treatment targets in multiple B-cell malignancies including diffuse large B-cell lymphoma (DLBCL). In in vitro and in vivo model systems, a subset of DLBCLs depend upon BCR survival signals and respond to proximal BCR/phosphoinositide 3 kinase (PI3K) blockade. However, single-agent BCR pathway inhibitors have had more limited activity in patients with DLBCL, underscoring the need for indicators of sensitivity to BCR blockade and insights into potential resistance mechanisms. Here, we report highly significant transcriptional upregulation of C-X-C chemokine receptor 4 (CXCR4) in BCR-dependent DLBCL cell lines and primary tumors following chemical spleen tyrosine kinase (SYK) inhibition, molecular SYK depletion or chemical PI3K blockade. SYK or PI3K inhibition also selectively upregulated cell surface CXCR4 protein expression in BCR-dependent DLBCLs. CXCR4 expression was directly modulated by fork-head box O1 via the PI3K/protein kinase B/forkhead box O1 signaling axis. Following chemical SYK inhibition, all BCR-dependent DLBCLs exhibited significantly increased stromal cell-derived factor-1α (SDF-1α) induced chemotaxis, consistent with the role of CXCR4 signaling in B-cell migration. Select PI3K isoform inhibitors also augmented SDF-1α induced chemotaxis. These data define CXCR4 upregulation as an indicator of sensitivity to BCR/PI3K blockade and identify CXCR4 signaling as a potential resistance mechanism in BCR-dependent DLBCLs.




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Bone marrow niche dysregulation in myeloproliferative neoplasms

The bone marrow niche is a complex and dynamic structure composed of a multitude of cell types which functionally create an interactive network facilitating hematopoietic stem cell development and maintenance. Its specific role in the pathogenesis, response to therapy, and transformation of myeloproliferative neoplasms has only recently been explored. Niche functionality is likely affected not only by the genomic background of the myeloproliferative neoplasm-associated mutated hematopoietic stem cells, but also by disease-associated ‘chronic inflammation’, and subsequent adaptive and innate immune responses. ‘Cross-talk’ between mutated hematopoietic stem cells and multiple niche components may contribute to propagating disease progression and mediating drug resistance. In this timely article, we will review current knowledge surrounding the deregulated bone marrow niche in myeloproliferative neoplasms and suggest how this may be targeted, either directly or indirectly, potentially influencing therapeutic choices both now and in the future.




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Coupled regulations of enzymatic activity and structure formation of aldehyde dehydrogenase Ald4p [RESEARCH ARTICLE]

Chalongrat Noree and Naraporn Sirinonthanawech

Previously, we have developed an extramitochondrial assembly system, where mitochondrial targeting signal (MTS) can be removed from a given mitochondrial enzyme, which could be used to characterize the regulatory factors involved in enzyme assembly/disassembly in vivo. Here, we demonstrate that addition of exogenous acetaldehyde can quickly induce the supramolecular assembly of MTS-deleted aldehyde dehydrogenase Ald4p in yeast cytoplasm. Also, by using PCR-based modification of the yeast genome, cytoplasmically targeted Ald4p cannot polymerize into long filaments when key functional amino acid residues are substituted, as shown by N192D, S269A, E290K and C324A mutations. This study has confirmed that extramitochondrial assembly could be a powerful external system for studying mitochondrial enzyme assembly, and its regulatory factors outside the mitochondria. In addition, we propose that mitochondrial enzyme assembly/disassembly is coupled to the regulation of a given mitochondrial enzyme activity.




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Noncoding Variants Connect Enhancer Dysregulation with Nuclear Receptor Signaling in Hematopoietic Malignancies [Research Articles]

Mutations in protein-coding genes are well established as the basis for human cancer, yet how alterations within noncoding genome, a substantial fraction of which contain cis-regulatory elements (CRE), contribute to cancer pathophysiology remains elusive. Here, we developed an integrative approach to systematically identify and characterize noncoding regulatory variants with functional consequences in human hematopoietic malignancies. Combining targeted resequencing of hematopoietic lineage–associated CREs and mutation discovery, we uncovered 1,836 recurrently mutated CREs containing leukemia-associated noncoding variants. By enhanced CRISPR/dCas9–based CRE perturbation screening and functional analyses, we identified 218 variant-associated oncogenic or tumor-suppressive CREs in human leukemia. Noncoding variants at KRAS and PER2 enhancers reside in proximity to nuclear receptor (NR) binding regions and modulate transcriptional activities in response to NR signaling in leukemia cells. NR binding sites frequently colocalize with noncoding variants across cancer types. Hence, recurrent noncoding variants connect enhancer dysregulation with nuclear receptor signaling in hematopoietic malignancies.

Significance:

We describe an integrative approach to identify noncoding variants in human leukemia, and reveal cohorts of variant-associated oncogenic and tumor-suppressive cis-regulatory elements including KRAS and PER2 enhancers. Our findings support a model in which noncoding regulatory variants connect enhancer dysregulation with nuclear receptor signaling to modulate gene programs in hematopoietic malignancies.

See related commentary by van Galen, p. 646.

This article is highlighted in the In This Issue feature, p. 627




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Maternal Epigenetic Regulation Contributes to Prevention of Estrogen Receptor-negative Mammary Cancer with Broccoli Sprout Consumption

Cruciferous vegetables have been of special interest due to the rich presence of bioactive compounds such as sulforaphane which show promising potential on cancer prevention and therapy as an epigenetic dietary strategy. Abnormal epigenetic alteration as one of the primary contributors to tumor development is closely related to breast cancer initiation and progression. In the present study, we investigated the effect of dietary broccoli sprouts (BSp), a common cruciferous vegetable, on prevention of estrogen receptor (ER)-negative mammary tumors at three different temporal exposure windows using a spontaneous breast cancer mouse model. Our findings indicate that maternal BSp treatment exhibited profound inhibitory and preventive effects on mammary cancer formation in the nontreated mouse offspring. The BSp diet administered to adult mice also showed suppressive effects on mammary cancer but was not as profound as the maternal BSp preventive effects. Moreover, such protective effects were linked with differentially expressed tumor- and epigenetic-related genes, as well as altered global histone acetylation, DNA methylation, and DNA hydroxymethylation levels. We also found that the expression changes of tumor-related genes were associated with the levels of histone methylation of H3K4 and H3K9 in the gene promoter regions. In addition, BSp-enriched sulforaphane was shown to increase protein expression of tumor suppressor genes such as p16 and p53 and inhibit the protein levels of Bmi1, DNA methyltransferases, and histone deacetylases in ERα-negative breast cancer cell lines. Collectively, these results suggest that maternal exposure to key phytochemicals may contribute to ER-negative mammary tumor prevention in their offspring through epigenetic regulations.




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MEF2c-Dependent Downregulation of Myocilin Mediates Cancer-Induced Muscle Wasting and Associates with Cachexia in Patients with Cancer

Skeletal muscle wasting is a devastating consequence of cancer that contributes to increased complications and poor survival, but is not well understood at the molecular level. Herein, we investigated the role of Myocilin (Myoc), a skeletal muscle hypertrophy-promoting protein that we showed is downregulated in multiple mouse models of cancer cachexia. Loss of Myoc alone was sufficient to induce phenotypes identified in mouse models of cancer cachexia, including muscle fiber atrophy, sarcolemmal fragility, and impaired muscle regeneration. By 18 months of age, mice deficient in Myoc showed significant skeletal muscle remodeling, characterized by increased fat and collagen deposition compared with wild-type mice, thus also supporting Myoc as a regulator of muscle quality. In cancer cachexia models, maintaining skeletal muscle expression of Myoc significantly attenuated muscle loss, while mice lacking Myoc showed enhanced muscle wasting. Furthermore, we identified the myocyte enhancer factor 2 C (MEF2C) transcription factor as a key upstream activator of Myoc whose gain of function significantly deterred cancer-induced muscle wasting and dysfunction in a preclinical model of pancreatic ductal adenocarcinoma (PDAC). Finally, compared with noncancer control patients, MYOC was significantly reduced in skeletal muscle of patients with PDAC defined as cachectic and correlated with MEF2c. These data therefore identify disruptions in MEF2c-dependent transcription of Myoc as a novel mechanism of cancer-associated muscle wasting that is similarly disrupted in muscle of patients with cachectic cancer.Significance:This work identifies a novel transcriptional mechanism that mediates skeletal muscle wasting in murine models of cancer cachexia that is disrupted in skeletal muscle of patients with cancer exhibiting cachexia.




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[PERSPECTIVES] Regulating Preimplantation Genetic Testing across the World: A Comparison of International Policy and Ethical Perspectives

Preimplantation genetic testing (PGT) is a reproductive technology that, in the course of in vitro fertilization (IVF), allows prospective parents to select their future offspring based on genetic characteristics. PGT could be seen as an exercise of reproductive liberty, thus potentially raising significant socioethical and legal controversy. In this review, we examine—from a comparative perspective—variations in policy approaches to the regulation of PGT. We draw on a sample of 19 countries (Australia, Austria, Belgium, Brazil, Canada, China, France, Germany, India, Israel, Italy, Japan, Mexico, Netherlands, Singapore, South Korea, Switzerland, United Kingdom, and the United States) to provide a global landscape of the spectrum of policy and legislative approaches (e.g., restrictive to permissive, public vs. private models). We also explore central socioethical and policy issues and contentious applications, including permissibility criteria (e.g., medical necessity), nonmedical sex selection, and reproductive tourism. Finally, we further outline genetic counseling requirements across policy approaches.




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A Path Towards Reasonable Autonomous Weapons Regulation

Experts representing a diversity of views on autonomous weapons systems collaborate on a realistic policy roadmap



  • robotics
  • robotics/artificial-intelligence

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Evidence Builds Linking Anticoagulation to COVID-19 Survival - Medscape

  1. Evidence Builds Linking Anticoagulation to COVID-19 Survival  Medscape
  2. Blood thinners may boost survival rates of Covid-infected patients: Study  ETHealthworld.com
  3. Coronavirus blood-clot mystery intensifies  Nature.com
  4. Coronavirus: Blood thinners could boost survival chances of patients  The Independent
  5. Blood thinners may help COVID-19 patients  ABC27
  6. View Full coverage on Google News




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New regulations to protect killer whales ask fishermen to stop fishing near whales year round

For the second year in a row, the Government of Canada is enacting restrictions to help protect the southern resident killer whale population.



  • News/Canada/British Columbia

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'No way food safety not compromised': US regulation rollbacks during Covid-19 criticised

Major pork plant closed after hundreds of workers contract coronavirus, while speeding up of poultry production lines raises concerns over standards

The US government is accelerating controversial regulatory rollbacks to speed up production at meat plants, as companies express growing alarm at the impact of Covid-19 on their operations.

Last week Smithfield shut down one of the largest pork plants in the country after hundreds of employees contracted the coronavirus. The plant in South Dakota – whose output represents 4–5% of US pork production – is reported to be the largest single-source coronavirus hotspot in the US, with more than 600 cases. In response, the company said it was “critical” for the meat industry to “continue to operate unabated”.

Now it has emerged that as a wave of plants announce closures, US meat plants are being granted permission to increase the speed of their production lines. This comes despite warnings that the waivers for higher speeds on slaughter and processing lines will compromise food safety.

Continue reading...




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Australia pushing for new regulations on wildlife markets to prevent future pandemics

Australia's Chief Veterinary Officer is urging international counterparts to support the formation of new regulations and standards for wildlife markets in the wake of the coronavirus outbreak.




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TTB Finalizes Portions of Modernization of Advertising and Labeling Regulations for Wine, Distilled Spirits, and Malt Beverages Rule

#TTB just made changes to modernize the way that #wine, #distilledspirits, and #maltbeverages are labeled and advertised. KKB associate Dan Logan and partner Dan Dwyer highlight some of the key changes (and proposals that were rejected).

The post TTB Finalizes Portions of Modernization of Advertising and Labeling Regulations for Wine, Distilled Spirits, and Malt Beverages Rule appeared first on Kleinfeld Kaplan & Becker LLP.




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ACRO testifies before IRS and Treasury Department on proposed Base Erosion and Anti-Abuse Tax (BEAT) regulation

On Monday, March 25, 2019 ACRO provided testimony at a public hearing held by the Internal Revenue Service (IRS) and Treasury Department...




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Boston-Based Bus Company Agrees to $650,000 Penalty for Violating the Clean Air Act and Anti-Idling Regulations

Paul Revere Transportation LLC, a bus company based in Boston, has agreed to pay a $650,000 civil penalty after being found liable by a jury in June for violating federal and state clean air laws for idling their buses for extended periods of time. The company was found liable on June 8, 2009, after a six-day trial in U.S. District Court in Boston, for 234 separate violations of the Clean Air Act and a Massachusetts anti-idling regulation.



  • OPA Press Releases

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Department of Justice Announces Plans to Prepare New ADA Regulations

The Justice Department publishes four new Americans with Disabilities Act (ADA) proposals addressing the accessibility of websites, the provision of captioning and video description in movies shown in theaters, accessible equipment and furniture, and the ability of 9-1-1 centers to take text and video calls from individuals with disabilities.



  • OPA Press Releases

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Department of Justice Announces Public Hearings on Proposed Revisions to ADA Regulations

The Department of Justice has scheduled three public hearings on its regulatory proposals concerning the Americans with Disabilities Act (ADA).



  • OPA Press Releases

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Special Master Sheila L. Birnbaum Announces Draft Regulations to Govern 9/11 Victim Compensation Fund

One month after assuming the position, September 11th Victim Compensa­tion Fund (VCF) Special Master Sheila L. Birnbaum today published draft regulations to govern the VCF, and asked the public to give her feedback on the proposals before victims can begin submitting claims to the fund later this year.



  • OPA Press Releases

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Remarks as Prepared for Delivery by Assistant Attorney General Lanny A. Breuer at Public Hearing on Potential Regulation to Strengthen Anti-Money Laundering Safeguards

"This rulemaking presents an important opportunity to close a gap in our financial regulations that makes it easier for criminals to move illicit proceeds through the United States financial system," said Assistant Attorney General Breuer.




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Court Rejects Banking Associations’ Challenge to Regulations Addressing Offshore Tax Avoidance

Today the District Court in the District of Columbia dismissed a challenge filed by the Florida Bankers Association and Texas Bankers Association challenging 2012 amendments to the Department of the Treasury’s interest-reporting regulations.



  • OPA Press Releases

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Justice Department Announces Proposed Amendment to Americans with Disabilities Act Regulations to Expand Access to Movie Theaters for Individuals with Hearing and Vision Disabilities

The Justice Department announced today that Attorney General Eric Holder has signed a Notice of Proposed Rulemaking (NPRM) to amend the Title III regulation for the Americans with Disabilities Act (ADA) to require movie theaters to provide closed movie captioning and audio description in order to give persons with hearing and vision disabilities access to movies



  • OPA Press Releases

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Pew Calls On DEA to Expedite Addiction Treatment Regulation

Pew’s substance use prevention and treatment initiative sent a letter to the Drug Enforcement Administration (DEA) on April 27 encouraging the agency to expedite a final rule that will help opioid treatment programs (OTPs)—federally regulated facilities where patients take medications for opioid use disorder under the supervision of medical staff and receive counseling and other care services—...




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Cannabidiol (CBD) and FDA—Regulating a New Market

Potential brain health benefits of cannabidiol (CBD) can make it an attractive ingredient for supplement brands, but federal regulations and FDA action may hinder product success in the market.




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Igniting autophagy through the regulation of phase separation




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Homeostasis and regulation of autoreactive B cells




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YTHDF2 promotes the liver cancer stem cell phenotype and cancer metastasis by regulating OCT4 expression via m6A RNA methylation




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Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction




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The regulation and functions of DNA and RNA G-quadruplexes




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Regulating Insurance After the Crisis

EXECUTIVE SUMMARY

Despite a long-standing policy debate, insurance remains the only major financial industry not to be regulated at the federal level, a tradition dating from the 19th century. However, recent financial turmoil has fundamentally changed the terms of this important discussion.

Many contend that as opposed to as many 51 separate regulators, a single federal insurance regulator would: allow insurers to pass substantial savings on to their consumers; preempt market distorting state regulation of rates; attract the expert talent needed to supervise the increasingly complex industry products; improve competition between insurers and non-insurance financial institutions for insurance-like products; better position insurers to compete globally and; make national policy with respect to insurer solvency.
 
However, state insurance regulators and some smaller insurers and insurance agents favor the current system, arguing that: they alone have the interest, expertise, and accessibility to consumers to handle best consumer complaints; insurance rates must be subject to oversight if not outright control to protect consumers; and state regulators have moved aggressively in recent years to improve their solvency regulation.

After weighing these arguments, I conclude in this essay that insurers and agents operating in multiple states should have the option to operate under a more streamlined regulatory system, and in particular to choose between being chartered and thus regulated by individual state regulators, or by a new federal insurance regulator. Congress has considered but not yet enacted legislation establishing this “optional federal charter” system, analogous (although not identical) to the regulatory system that has long governed the U.S. banking industry.

Further, the recent financial crisis and associated bailout of AIG make it is clear that, in addition to the optional federal charter, the government should require federal solvency and consumer protection regulation of the largest insurers that are deemed to be “systemically important financial institutions.” Clearly, if the federal government is potentially needed as a source of debt or equity funds for certain insurers, there is a strong case for having the federal authorities actively oversee the financial safety and soundness of at least those firms that may benefit from federal, and thus national taxpayer, assistance.

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gulati

Regulating Systemic Risk

EXECUTIVE SUMMARY

The ongoing financial crisis that began in 2007 has revealed a fundamental weakness in our financial regulatory system: the absence of a regulator charged with overseeing and preventing “systemic risk,” or the risks to the health of the entire financial system posed by the failure of one or more “systemically important financial institutions” (SIFIs).

On March 26, the Treasury Department released the first part of its plan to fix the financial system, which concentrates on reducing systemic risk. The Treasury’s suggestions, if enacted into law, would go a long a way toward achieving this objective. One of the central elements in the plan is to establish a systemic risk regulator. Treasury did not identify which agency or agencies should assume this job. I address this issue, among others, in this essay on systemic risk.

Ideally, all federal financial regulatory activities should be consolidated in two agencies, a financial solvency regulator and a federal consumer protection regulator, with systemic risk responsibilities being assigned to the solvency regulator. As a second-best option, clear systemic risk oversight authority should be assigned to the Fed. Either of these options is superior to creating a new agency or regulating systemic risk through a “college” of existing financial regulators.

The systemic risk regulator (SRR) should supervise all SIFIs, although the nature and details of this supervision should take account of the differences in types of such institutions (banks, large insurers, hedge funds, private equity funds, and financial conglomerates). The SRR should also regularly analyze and report to Congress on the systemic risks confronting the financial system.

There are legitimate concerns about vesting such large responsibilities with any financial regulator. But as long as there are financial institutions whose failure could lead to calamitous financial and economic consequences, and thus invite all-but-certain federal rescue efforts if the threat of failure is real, then some arm of the federal government must oversee systemic risk and do the best it can to make that oversight work.

While the United States should continue to cooperate with governments of other countries in reforming financial systems, notably through the G-20 process, policymakers here should not wait for international agreements to be in place before putting our own financial house in order.

Read the full paper » (pdf)

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gulati

‘Essential’ cannabis businesses: Strategies for regulation in a time of widespread crisis

Most state governors and cannabis regulators were underprepared for the COVID-19 pandemic, a crisis is affecting every economic sector. But because the legal cannabis industry is relatively new in most places and still evolving everywhere, the challenges are even greater. What’s more, there is no history that could help us understand how the industry will endure the current economic situation. And so, in many…

       




gulati

Six COVID-related deregulations to watch

The Trump administration has undertaken a series of deregulatory measures to address various challenges of the COVID-19 pandemic. The Brookings’ Center on Regulation and Markets is actively tracking these actions alongside the administration’s broader deregulatory agenda. We asked scholars from the Brookings Economic Studies Program for their thoughts on some of the most impactful COVID-related deregulations to date. What do these rules entail, and how do the measures,…

      




gulati

Tracking deregulation in the Trump era

The Trump administration has major deregulatory ambitions. But how much deregulation is actually happening? This tracker helps you monitor a selection of delayed, repealed, and new rules, notable guidance and policy revocations, and important court battles across eight major categories, including environmental, health, labor, and more. For a more thorough explanation of the tracker, including…

       




gulati

Six COVID-related deregulations to watch

The Trump administration has undertaken a series of deregulatory measures to address various challenges of the COVID-19 pandemic. The Brookings’ Center on Regulation and Markets is actively tracking these actions alongside the administration’s broader deregulatory agenda. We asked scholars from the Brookings Economic Studies Program for their thoughts on some of the most impactful COVID-related deregulations to date. What do these rules entail, and how do the measures,…

       




gulati

Updating communications law and regulations for the mobile era


Event Information

March 24, 2015
10:00 AM - 11:00 AM EDT

Saul Room/Zilkha Lounge
Brookings Institution
1775 Massachusetts Avenue NW
Washington, DC 20036

Register for the Event

The last time policymakers substantially reviewed federal communications policy, it was the early 1990s. At that time, the Internet was only beginning to reveal itself to be the dynamic technology seen today. Mobile devices and services, such as 100 megabit broadband, smartphones, applications, social networks, tablets, and digital streaming, were barely imagined, let alone factored into policy discussions. As the recent debate around net neutrality highlights, policymakers today can be hamstrung in efforts to fit today's communications technologies and services into last century's communications law. Given that most major communications laws are out of step with today’s advanced mobile capabilities, what shape would smart, updated legislation and regulatory changes take? What are the major changes to U.S. communications law that most need to be addressed and implemented?

On March 24, the Center for Technology Innovation at Brookings hosted a conversation with Craig Silliman, general counsel and executive vice president for public policy at Verizon, to examine what 21st century communications polices might look like.

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gulati

Campaign finance regulation in Latin America


The use of economic resources to support election campaigns is an essential ingredient of democratic competition. Often viewed as a malady of democracy, campaign finance is actually part of the normal workings of democratic life. However, it is indisputable that money is capable of inflicting significant distortions on politics and policymaking. When there is a failure to regulate money in the political process or existing regulation is ineffectual, the legitimacy of democratic processes can be jeopardized.

These concerns are particularly relevant to Latin America, a region plagued by a highly unequal income distribution, and where organized crime has a major presence, transacts billions of dollars each year in illicit business, and has the potential to corrupt democratic institutions. In this policy brief, Kevin Casas-Zamora and Daniel Zovatto offer practical guidance for making campaign finance regulation feasible and increasing its likelihood of success. In undertaking reform, countries should prioritize the most urgently needed changes with the broadest political consensus. Proposals for reform include:

• Establish greater control over private funding of parties and election campaigns;

• Create a public subsidy system to ensure fair access for parties and candidates to adequate funding to finance both regular day-to-day operations and election campaigns;

• Adopt mechanisms to keep campaign spending from skyrocketing;

• Craft party and candidate reporting systems to increase accountability, transparency, and disclosure; and

• Establish a graduated and credible system of sanctions for the chief financial officers of political parties in the event of violations of the rules in force.

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Image Source: © STRINGER Mexico / Reuters
      
 
 




gulati

Campaign finance regulation in Latin America


The use of economic resources to support election campaigns is an essential ingredient of democratic competition. Often viewed as a malady of democracy, campaign finance is actually part of the normal workings of democratic life. However, it is indisputable that money is capable of inflicting significant distortions on politics and policymaking. When there is a failure to regulate money in the political process or existing regulation is ineffectual, the legitimacy of democratic processes can be jeopardized.

These concerns are particularly relevant to Latin America, a region plagued by a highly unequal income distribution, and where organized crime has a major presence, transacts billions of dollars each year in illicit business, and has the potential to corrupt democratic institutions. In this policy brief, Kevin Casas-Zamora and Daniel Zovatto offer practical guidance for making campaign finance regulation feasible and increasing its likelihood of success. In undertaking reform, countries should prioritize the most urgently needed changes with the broadest political consensus. Proposals for reform include:

• Establish greater control over private funding of parties and election campaigns;

• Create a public subsidy system to ensure fair access for parties and candidates to adequate funding to finance both regular day-to-day operations and election campaigns;

• Adopt mechanisms to keep campaign spending from skyrocketing;

• Craft party and candidate reporting systems to increase accountability, transparency, and disclosure; and

• Establish a graduated and credible system of sanctions for the chief financial officers of political parties in the event of violations of the rules in force.

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Image Source: © STRINGER Mexico / Reuters
     
 
 




gulati

Cuba moves backwards: New regulations likely to impede private sector growth

In a leap backwards, the Cuban government has published a massive compendium of tough new regulations governing the island’s struggling private enterprises. The new regulations—the first major policy pronouncement during the administration of President Miguel Díaz-Canel—appear more focused on controlling and restricting the emerging private sector than on stimulating investment and job creation, more concerned…

       




gulati

‘Essential’ cannabis businesses: Strategies for regulation in a time of widespread crisis

Most state governors and cannabis regulators were underprepared for the COVID-19 pandemic, a crisis is affecting every economic sector. But because the legal cannabis industry is relatively new in most places and still evolving everywhere, the challenges are even greater. What’s more, there is no history that could help us understand how the industry will endure the current economic situation. And so, in many…

       




gulati

New Regulations Enhance Savers’ Retirement Security


Americans who use defined contribution retirement savings plans (for example, 401(k) or 403(b) plans) or Individual Retirement Accounts will see their retirement security enhanced by two recently announced regulatory initiatives. The first is a series of Treasury Department/IRS proposed regulations that such individuals to use annuity-like guaranteed lifetime income products. The second is a final Department of Labor rule requiring complete fee disclosure to employers sponsoring retirement saving plans. Together, the two initiatives will give current retirement savers and future retirees more flexibility in structuring their retirement incomes, while making it possible to avoid excessive or hidden fees.

Four Treasury/IRS proposals, which were developed under the leadership of our former RSP colleague Mark Iwry, deal with several of the most pressing issues faced by employers and savers that currently reduce the use of annuities. The first proposal would reduce barriers to giving retiring savers the option of annuitizing part of their account balances. Currently, people need to annuitize either the entire balance or none at all. People are naturally wary of annuitizing the entire amount because it leaves them with little in the way of a cash cushion for emergencies. By choosing to annuitize part of the balance, people can retain a lump sum for emergency or other purposes.

A second proposal would remove a technical impediment to using longevity annuities, an annuity that is typically purchased close to retirement but does not begin to pay benefit until the retiree reaches age 85 or a similar age. Longevity annuities enable retirees to manage their money for a set period of time, secure in the knowledge that the longevity annuity will provide income after that, should they live longer than expected.

The third proposal would allow an individual to begin to partially annuitize their savings well before retirement. Starting to annuitize early by buying small pieces of an annuity over twenty or so years allows the saver to avoid having to make a “once and for all” decision and allows the savers to spread out the interest rate risk over time. This option had been subject to a requirement that the saver get a notarized statement from his or her spouse (if any) concerning whether the annuity covers just the saver or both the saver and his or her spouse. The proposal allows this to be handled by the issuing insurer when payments would begin rather than when purchases begin.

The fourth proposal would apply to relatively rare case where the employer has both a retirement savings plan and a traditional defined benefit pension, and would allow an employee to buy a low-cost annuity through the employer’s DB pension.

These four regulatory changes are positive developments. The changes announced today eliminate unintentional barriers to the use of lifetime income products without dictating how individuals should use them. Some may choose to partially annuitize at retirement, some to use longevity annuities to protect them in later years, and some to begin to buy annuities well before retirement. Whatever the choice, the proposals open up new options to future retirees, and should encourage even more market innovations.

At about the same time, the Department of Labor released final regulations requiring providers to disclose all direct and indirect fees to the employer sponsoring a 401(k) plan. The regulations will add needed transparency on fees that will enable increased competition to produce better results for employers and employees.

Despite removing a required template of charges, the new regulations nevertheless give employers a complete and accurate picture of all charges they have to pay, including indirect fees paid by the provider to others. Currently, many indirect fees are not disclosed even though they may reduce the earnings of participants. Endorsed by industry and consumer groups, the disclosures will enable employers who use this information properly to meet their fiduciary responsibility to choose a responsible fee level. What is even more important, the full disclosure will enable employers to structure their 401(k) plan so that individual savers can get the best returns possible, and not be subject to unreasonable fees.

While much more remains to be done to improve retirement savings plan, the steps taken by the proposed Treasury/IRS regulations and the Department of Labor’s final regulations will help savers to improve retirement security.

Image Source: © Rebecca Cook / Reuters
     
 
 




gulati

‘Essential’ cannabis businesses: Strategies for regulation in a time of widespread crisis

Most state governors and cannabis regulators were underprepared for the COVID-19 pandemic, a crisis is affecting every economic sector. But because the legal cannabis industry is relatively new in most places and still evolving everywhere, the challenges are even greater. What’s more, there is no history that could help us understand how the industry will endure the current economic situation. And so, in many…