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Background/Goal/Aim The tetracenomycins are aromatic anticancer polyketides that inhibit peptide translation via binding to the large ribosomal subunit. Here, we expressed the elloramycin biosynthetic gene cluster in the heterologous host Streptomyces coelicolor M1146 to facilitate the downstream production of tetracenomycin analogs. Main Methods and Major Results We developed a BioBricks® genetic toolbox of genetic parts for substrate precursor engineering in S. coelicolor M1146::cos16F4iE. We cloned a series of integrating vectors based on the VWB, TG1, and SV1 integrase systems to interrogate gene expression in the chromosome. We genetically engineered three separate genetic constructs to modulate tetracenomycin biosynthesis: 1) the vhb hemoglobin from obligate aerobe Vitreoscilla stercoraria to improve oxygen utilization; (2) the accA2BE acetyl-CoA carboxylase to enhance condensation of malonyl-CoA; (3) lastly, the sco6196 acyltransferase, which is a “metabolic regulatory switch” responsible for mobilizing triacylglycerols to β-oxidation machinery for acetyl-CoA. In addition, we engineered the tcmO 8-O-methyltransferase and newly identified tcmD 12-O-methyltransferase from Amycolatopsis sp. A23 to generate tetracenomycins C and X. We also co-expressed the tcmO methyltransferase with oxygenase urdE to generate the analog 6-hydroxy-tetracenomycin C. Conclusions and Implications Altogether, this system is compatible with the BioBricks® [RFC 10] cloning standard for the co-expression of multiple gene sets for metabolic engineering of Streptomyces coelicolor M1146::cos16F4iE. This production platform improves access to potent analogs, such as tetracenomycin X, and sets the stage for the production of new tetracenomycins via combinatorial biosynthesis. This article is protected by copyright. All rights reserved 

Abstract Skeletal muscle is a tissue that is directly involved in the progression and persistence of type 2 diabetes (T2D), a disease that is becoming increasingly common. Gaining better insight into the mechanisms that are affecting skeletal muscle dysfunction in the context of T2D has the potential to lead to novel treatments for a large number of patients. Through its ability to emulate skeletal muscle architecture while also incorporating aspects of disease, tissue-engineered skeletal muscle (TE-SkM) has the potential to provide a means for rapid high-throughput discovery of therapies to treat skeletal muscle dysfunction, to include that which occurs with T2D. Muscle precursor cells isolated from lean or obese male Zucker diabetic fatty rats were used to generate TE-SkM constructs. Some constructs were treated with adipogenic induction media to accentuate the presence of adipocytes that is a characteristic feature of T2D skeletal muscle. The maturity (compaction and creatine kinase activity), mechanical integrity (Young's modulus), organization (myotube orientation), and metabolic capacity (insulin-stimulated glucose uptake) were all reduced by diabetes. Treating constructs with adipogenic induction media increased the quantity of lipid within the diabetic TE-SkM constructs, and caused changes in construct compaction, cell orientation, and insulin-stimulated glucose uptake in both lean and diabetic samples. Collectively, the findings herein suggest that the recapitulation of structural and metabolic aspects of T2D can be accomplished by engineering skeletal muscle in vitro. Impact Statement The tissue engineering of skeletal muscle to model disease and injury has great promise to provide a tool to develop and/or improve therapeutic approaches for improved health care. A tissue-engineered skeletal muscle model of one of the most common and debilitating diseases, type 2 diabetes, has been developed in vitro as evidenced by the structural and metabolic alterations that are consistent with the disease phenotype in vivo. 

A first search for beyond the standard model physics in jet multiplicity patterns of multilepton events is presented, using a data sample corresponding to an integrated luminosity of $138{\mathrm{fb}}^{-1}$of 13 TeV proton-proton collisions recorded by the CMS detector at the LHC. The search uses observed jet multiplicity distributions in one-, two-, and four-lepton events to explore possible enhancements in jet production rate in three-lepton events with and without bottom quarks. The data are found to be consistent with the standard model expectation. The results are interpreted in terms of supersymmetric production of electroweak chargino-neutralino superpartners with cascade decays terminating in prompt hadronic $R$-parity violating interactions. 

A search for the rare decay $D^0\to {\mu }^{+}{\mu }^{-}$is reported using proton-proton collision events at $\sqrt{s}=13.6\mathrm{TeV}$collected by the CMS detector in 2022–2023, corresponding to an integrated luminosity of $64.5{\mathrm{fb}}^{-1}$. This is the first analysis to use a newly developed inclusive dimuon trigger, expanding the scope of the CMS flavor physics program. The search uses $D^0$mesons obtained from $D^{*+}\to D^0{\pi }^{+}$decays. No significant excess is observed. A limit on the branching fraction of $\mathcal{B}(D^0\to {\mu }^{+}{\mu }^{-})<2.4\times {10}^{-9}$at 95% confidence level is set. This is the most stringent upper limit set on any flavor changing neutral current decay in the charm sector. 

A<sc>bstract</sc> A search for a heavy pseudoscalar Higgs boson, A, decaying to a 125 GeV Higgs boson h and a Z boson is presented. The h boson is identified via its decay to a pair of tau leptons, while the Z boson is identified via its decay to a pair of electrons or muons. The search targets the production of the A boson via the gluon-gluon fusion process, gg → A, and in association with bottom quarks,$$\text{b}\overline{\text{b}}\text{A }$$. The analysis uses a data sample corresponding to an integrated luminosity of 138 fb⁻¹collected with the CMS detector at the CERN LHC in proton-proton collisions at a centre-of-mass energy of$$\sqrt{s}=13$$TeV. Constraints are set on the product of the cross sections of the A production mechanisms and the A → Zh decay branching fraction. The observed (expected) upper limit at 95% confidence level ranges from 0.049 (0.060) pb to 1.02 (0.79) pb for the gg → A process and from 0.053 (0.059) pb to 0.79 (0.61) pb for the$$\text{b}\overline{\text{b}}\text{A }$$process in the probed range of the A boson mass,m_A, from 225 GeV to 1 TeV. The results of the search are used to constrain parameters within the$${\text{M}}_{\text{h},\text{EFT}}^{125}$$benchmark scenario of the minimal supersymmetric extension of the standard model. Values of tanβbelow 2.2 are excluded in this scenario at 95% confidence level for allm_Avalues in the range from 225 to 350 GeV.