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Since the first recorded case of the SARS-CoV-2, it has acquired several mutations in its genome while spreading throughout the globe. In this study, we investigated the significance of these mutations by analyzing the host miRNA binding and virus's internal ribosome entry site (IRES). Strikingly, we observed that due to the acquired mutations, five host miRNAs which lost their affinity for targeting the viral genome, and another five can target the mutated viral genome. Moreover, functional enrichment analysis suggests that targets of both of these miRNAs might be involved in various host immune signaling pathways. Remarkably, we detected that three particular mutations in the IRES can disrupt its secondary structure which can further make the virus less functional. These results could be valuable in exploring the functional importance of the mutations of SARS-CoV-2 and could provide novel insights into the differences observed different parts of the world.

Heart muscle maintains blood circulation, while skeletal muscle powers skeletal movement. Despite having similar myofibrilar sarcomeric structures, these striated muscles differentially express specific sarcomere components to meet their distinct contractile requirements. The mechanism responsible is still unclear. We show here that preservation of the identity of the two striated muscle types depends on epigenetic repression of the alternate lineage gene program by the chromatin remodeling complex Chd4/NuRD. Loss of Chd4 in the heart triggers aberrant expression of the skeletal muscle program, causing severe cardiomyopathy and sudden death. Conversely, genetic depletion of Chd4 in skeletal muscle causes inappropriate expression of cardiac genes and myopathy. In both striated tissues, mitochondrial function was also dependent on the Chd4/NuRD complex. We conclude that an epigenetic mechanism controls cardiac and skeletal muscle structural and metabolic identities and that loss of this regulation leads to hybrid striated muscle tissues incompatible with life. We thank Drs. Richard Harvey (University of Sydney, Australia) and Michael Schneider (Imperial College, London, UK) for providing Nkx2.5cre/+ and α-MHCcre/+ transgenic lines, respectively, Dr. S. Bartlett for English editing, and Gemma Benito and Ana Guío for technical assistance. J.M.R. is supported by the Spanish Ministry of Economy and Competitiveness (Ministerio de Economía y Competitividad; SAF 2012 34296 and SAF 2015 63633-R), the Spanish Ministry of Health (Ministerio de Sanidad y Consumo) Red de Investigación Cardiovascular (RIC; grant RD06/0042/0022), and the Fundación La Marató TV3 (264/C/2012). The RIC also supports J.L.P. (RD12/0042/0005) and L.J.J.-B. (RD12/0042/0056). RIC grants are partially funded by FEDER funds. P.M.-C., J.A.E., and J.L.P. are supported by SAF2012-38547, SAF2015-67369-R, SAF2012-1207, and SAF2013-45543-R, respectively. E.P. and P.M.-C. were also supported by SAF2015-67369-R. NGS experiments were performed at the CNIC Genomics Unit. IF of adult hearts was performed at the Advanced Fluorescence Microscopy Unit of (IBMB-CSIC) Barcelona. The CNIC is supported by the Spanish Ministry of Economy and Competitiveness and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). R.A.-P. was supported by a Ramón y Cajal grant and is a holder of a Marie Curie grant (RA-P:UEO/MCA1108). M.Z. was a holder of a Marie Curie Outgoing International Fellowship (MOIF-CT-2006-039327), and P.G.A. was supported by a Ramón y Cajal grant from the Spanish Ministry of Education, Science and Sport.

The constitutively-expressed cyclooxygenase 1 (COX-1) and the inducible COX-2 are both involved in the conversion of arachidonic acid (AA) to prostaglandins (PGs). However, the functional roles of COX-1 at the cellular level remain unclear. We hypothesized that by comparing differential gene expression and eicosanoid metabolism in lung fibroblasts from wild-type (WT) mice and COX-2(-/-) or COX-1(-/-) mice may help address the functional roles of COX-1 in inflammation and other cellular functions. Compared to WT, the number of specifically-induced transcripts were altered descendingly as follows: COX-2(-/-)COX-1(-/-)WT+IL-1β. COX-1(-/-) or COX-2(-/-) cells shared about 50% of the induced transcripts with WT cells treated with IL-1β, respectively. An interactive "anti-inflammatory, proinflammatory, and redox-activated" signature in the protein-protein interactome map was observed in COX-2(-/-) cells. The augmented COX-1 mRNA (in COX-2(-/-) cells) was associated with the upregulation of mRNAs for glutathione S-transferase (GST), superoxide dismutase (SOD), NAD(P)H dehydrogenase quinone 1 (NQO1), aryl hydrocarbon receptor (AhR), peroxiredoxin, phospholipase, prostacyclin synthase, and prostaglandin E synthase, resulting in a significant increase in the levels of PGE2, PGD2, leukotriene B4 (LTB4), PGF1α, thromboxane B2 (TXB2), and PGF2α. The COX-1 plays a dominant role in shifting AA toward the LTB4 pathway and anti-inflammatory activities. Compared to WT, the upregulated COX-1 mRNA in COX-2(-/-) cells generated an "eicosanoid storm". The genomic characteristics of COX-2(-/-) is similar to that of proinflammatory cells as observed in IL-1β induced WT cells. COX-1(-/-) and COX-2(-/-) cells exhibited compensation of various eicosanoids at the genomic and metabolic levels.

DYRK1A is a dosage-sensitive protein kinase that fulfills key roles during development and in tissue homeostasis, and its dysregulation results in human pathologies. DYRK1A is present in both the nucleus and cytoplasm of mammalian cells, although its nuclear function remains unclear. Genome-wide analysis of DYRK1A-associated loci reveals that the kinase is recruited preferentially to promoters of genes actively transcribed by RNA polymerase II (RNAPII), which are functionally associated with translation, RNA processing, and cell cycle. DYRK1A-bound promoter sequences are highly enriched in a conserved palindromic motif, which is necessary to drive DYRK1A-dependent transcriptional activation. DYRK1A phosphorylates the C-terminal domain (CTD) of RNAPII at Ser2 and Ser5. Depletion of DYRK1A results in reduced association of RNAPII at the target promoters as well as hypophosphorylation of the RNAPII CTD along the target gene bodies. These results are consistent with DYRK1A being a transcriptional regulator by acting as a CTD kinase. This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO: BFU2010-15347, BFU2013-44513 to S.d.l.L., SAF2012-36199 to N.L.-B., and ‘Centro de Excelencia Severo Ochoa 2013-2017’-SEV-2012-0208) and the Secretariat of Universities and Research-Government of Catalonia (2014SGR674 to S.d.l.L.). C.D.V. and E.S. were FPI predoctoral fellows financed by MINECO (BES2008-002751 and BES2005-10136)

SUMMARY The importance of the retinoblastoma tumor suppressor protein pRB in cell cycle control is well established. However, less is known about its role in differentiation during animal development. Here, we investigated the role of Rbf, the Drosophila pRB homolog, in adult skeletal muscles. We found that the depletion of Rbf severely reduced muscle growth and altered myofibrillogenesis but only minimally affected myoblast proliferation. We identified an Rbf-dependent transcriptional program in late muscle development that is distinct from the canonical role of Rbf in cell cycle control. Unexpectedly, Rbf acts as a transcriptional activator of the myogenic and metabolic genes in the growing muscles. The genomic regions bound by Rbf contained the binding sites of several factors that genetically interacted with Rbf by modulating Rbf-dependent phenotype. Thus, our results reveal a distinctive role for Rbf as a direct activator of the myogenic transcriptional program that drives late muscle differentiation., Graphical Abstract, In Brief Inactivation of the tumor suppressor RB, an obligatory step in most cancers, results in unrestrained cell cycle progression. Zappia et al. show that Rbf, the RB Drosophila ortholog, directly activates the metabolic program that accompanies muscle development. This work expands the understanding of the plethora of Rbf functions.

SummaryE2F/DP transcription factors regulate cell proliferation and apoptosis. Here, we investigated the mechanism of the resistance of Drosophila dDP mutants to irradiation-induced apoptosis. Contrary to the prevailing view, this is not due to an inability to induce the apoptotic transcriptional program, because we show that this program is induced; rather, this is due to a mitochondrial dysfunction of dDP mutants. We attribute this defect to E2F/DP-dependent control of expression of mitochondria-associated genes. Genetic attenuation of several of these E2F/DP targets mimics the dDP mutant mitochondrial phenotype and protects against irradiation-induced apoptosis. Significantly, the role of E2F/DP in the regulation of mitochondrial function is conserved between flies and humans. Thus, our results uncover a role of E2F/DP in the regulation of mitochondrial function and demonstrate that this aspect of E2F regulation is critical for the normal induction of apoptosis in response to irradiation.

Carcass quality of JamunapariBlack Bengal (JBB), Black Bengal selected for growth (SBB) and random-bred (RBB) wethers of 1 year of age was studied. There was no significant difference between JBB and SBB in pre-slaughter traits and carcass characteristics, except height at wither and dressing percentage which were significantly higher in JBB than in SBB, and muscle fiber diameter which was significantly smaller in JBB than in SBB. Performance of RBB was significantly lower than JBB and SBB. When hot carcass, non-carcass, variety meat, prime cuts, fat deposition and total saleable portion were expressed as % of empty live weight and compared among genetic groups, JBB ranked first. Selection for rapid growth rate within Black Bengal goat increased its live weight and improved meat production. Increased live weight showed a positive relationship with increased fat deposition. Relationships between ‘eye muscle’ area and hot carcass yield, empty live weight and gut fat and perinephric fat and gut fat were positive and significant. # 2000 Elsevier Science B.V. All rights reserved.

Growth performance potential of 892 Black Bengal kids was studied in four different locations across Bangladesh. Birth weight of kids for Mymensingh (1), Trisal (2) and Tangail Regions (3) were similar (1.01 kg) with significantly lower birth weight in Rangpur (4) (0.88 kg). The effect of birth type and sex was significant with higher weights for single (1.03 kg) and male kids (1.03 kg). Monthly weights of kids followed the same pattern as birth weight. Monthly weights of kids in Regions 1, 2 and 3 were similar with significantly lower weight for Region 4. Birth type and sex affected monthly weights in different periods where single and male kids had significantly higher weights for all periods. Average daily gains had the same trend as body weights of kids in different periods and lowest in triplet and female kids in Region 4. Results revealed that growth performance of Black Bengal kids is lower than previously reported, which might be caused by inappropriate management and inadequate feed availability around the year.

Survivability of Black Bengal kids produced in four different locations of Bangladesh was studied. Records on 892 kids born over a period from 1987 to 1991 were included. Data were analysed considering the fixed effects as region, parity, birth type, sex, season and year. Overall survival rates during birth -1, 1–2, 2–3 and birth -3 months of age were 84.4 ± 1.9, 91.3 ± 1.6, 95.9 ± 1.1 and 71.7 ± 2.4%, respectively. Regional effect on birth weight was significant (P < 0.05) for the period from birth to 3 months having highest survival rate in Region 1 (76.9 ± 1.4) and lowest for Region 4 (61.1 ± 5.5). Effect of parity was insignificant but survivability increased gradually with the increase in parity number having the highest survival rate in the 5th parity. Birth weight of kids and milk yield of dams had a relationship with survivability during the pre-weaning period. It was evident that survivability of kids increased with the increase of birth weight of kids and milk yield of dams. Season had a significant effect (P < 0.01) on survival rates of kids, with the highest survivability in the rainy season and the lowest in summer. Type of birth had no significant effect on survival rates but single kids always had a higher survival rate than twins and triplets. Effect of sex was significant (P < 0.01) for birth -1 and birth -3 months of age, male kids having a higher survival rate than females. Year had a significant effect (P < 0.01) on survival and increased gradually with advancing months. Lower birth weights, dams with insufficient milk and lack of husbandry knowledge were considered the main factors responsible for higher kid mortality.