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Supplementary Figure 4. Effect of KAT6B shRNA-mediated depletion in the growth rate according to the XTT assay

Supplementary Figure 1. KAT6B copy number and DNA methylation status in SCLC cell lines

Supplementary Figure 7. Effect of twenty-eight histone deacetylase inhibitors and two classical drugs in SCLC chemotherapy, such as cisplatin and etoposide, in the IC50 values of KAT6B shRNA-transfected vs scramble shRNA-transfected NCI-N417 cells.

Supplementary Table 1. List of antibodies and primer sets used in the study.

Supplementary Table 3. The twenty-eight HDAC inhibitors used in the study and their specificity

Supplementary Figure 3. Expression of KAT6B isoforms in SCLC cell lines.

Supplementary Table 2. Genes that significantly change expression upon KAT6B depletion. Normalized intensities from the array in each sample and log Fold Changes from the analysis are depicted.

Supplementary Figure 6. Immunohistochemistry studies for KAT6B and acetylated K23-H3 staining according to KAT6B deletion status

Supplementary Figure 8. Effect of KAT6B shRNA-mediated depletion in ATM expression and H2AX phosphorylation

Supplementary Figure 2. Copy number and expression levels of six KATs in SCLC cell lines

Isospin-breaking corrections to the hadron vacuum polarization component of the anomalous magnetic moment of the muon are needed to ensure the theoretical precision of $g_\mu -2$ is below the experimental precision. We describe the status of our work calculating, using lattice QCD, the QED correction to the light and strange connected hadronic vacuum polarization in a Dashen scheme. We report results using physical $N_f=2+1+1$ HISQ ensembles at three lattice spacings and three heavier-than-light valence quark masses., Comment: 9 pages, 4 figures, to be published in Proceedings of Science, contribution to the 39th International Symposium on Lattice Field Theory, LATTICE2022, Bonn, Germany

We present lattice-QCD calculations of the hadronic form factors for the semileptonic decays $D\to\pi\ell\nu$, $D\to K\ell\nu$, and $D_s\to K\ell\nu$. Our calculation uses the highly improved staggered quark (HISQ) action for all valence and sea quarks and includes $N_f=2+1+1$ MILC ensembles with lattice spacings ranging from $a\approx0.12$ fm down to $0.042$ fm. At most lattice spacings, an ensemble with physical-mass light quarks is included. The HISQ action allows all the quarks to be treated with the same relativistic light-quark action, allowing for nonperturbative renormalization using partial conservation of the vector current. We combine our results with experimental measurements of the differential decay rates to determine $|V_{cd}|^{D\to\pi}=0.2238(11)^{\rm Expt}(15)^{\rm QCD}(04)^{\rm EW}(02)^{\rm SIB}[22]^{\rm QED}$ and $|V_{cs}|^{D\to K}=0.9589(23)^{\rm Expt}(40)^{\rm QCD}(15)^{\rm EW}(05)^{\rm SIB}[95]^{\rm QED}$ This result for $|V_{cd}|$ is the most precise to date, with a lattice-QCD error that is, for the first time for the semileptonic extraction, at the same level as the experimental error. Using recent measurements from BES III, we also give the first-ever determination of $|V_{cd}|^{D_s\to K}=0.258(15)^{\rm Expt}(01)^{\rm QCD}[03]^{\rm QED}$ from $D_s\to K \ell\nu$. Our results also furnish new Standard Model calculations of the lepton flavor universality ratios $R^{D\to\pi}=0.98671(17)^{\rm QCD}[500]^{\rm QED}$, $R^{D\to K}=0.97606(16)^{\rm QCD}[500]^{\rm QED}$, and $R^{D_s\to K}=0.98099(10)^{\rm QCD}[500]^{\rm QED}$, which are consistent within $2\sigma$ with experimental measurements. Our extractions of $|V_{cd}|$ and $|V_{cs}|$, when combined with a value for $|V_{cb}|$, provide the most precise test of second-row CKM unitarity, finding agreement with unitarity at the level of one standard deviation., Comment: 92 pages, V2 matches version accepted for publication in PRD. Expanded supplementary material for reconstructing our final results. An implementation of nonlinear shrinkage is also included

UV radiation is one of the main contributors to skin photoaging by promoting the accumulation of cellular senescence, which in turn induces a proinflammatory and tissue-degrading state that favors skin aging. The members of the sirtuin family of NAD + -dependent enzymes play an anti-senescence role and their activation suggests a promising approach for preventing UV-induced senescence in the treatment of skin aging. A two-step screening designed to identify compounds able to protect cells from UV-induced senescence through sirtuin activation identified shikimic acid (SA), a metabolic intermediate in many organisms, as a bona-fide candidate. The protective effects of SA against senescence were dependent on specific activation of SIRT1 as the effect was abrogated by the SIRT1 inhibitor EX-527. Upon UV irradiation SA induced S-phase accumulation and a decrease in p16 INK4A expression but did not protect against DNA damage or increased polyploidies. In contrast, SA reverted misfolded protein accumulation upon senescence, an effect that was abrogated by EX-527. Consistently, SA induced an increase in the levels of the chaperone BiP, resulting in a downregulation of unfolded protein response (UPR) signaling and UPR-dependent autophagy, avoiding their abnormal hyperactivation during senescence. SA did not directly activate SIRT1 in vitro, suggesting that SIRT1 is a downstream effector of SA signaling specifically in the response to cellular senescence. Our study not only uncovers a shikimic acid/SIRT1 signaling pathway that prevents cellular senescence, but also reinforces the role of sirtuins as key regulators of cell proteostasis.

Transmission of genetic material through high-quality gametes to progeny requires accurate homologous chromosome recombination and segregation during meiosis. A failure to accomplish these processes can have major consequences in reproductive health, including infertility, and development disorders in offspring. Sirtuins, a family of NAD+ -dependent protein deacetylases and ADP-ribosyltransferases, play key roles in genome maintenance, metabolism, and aging. In recent years, Sirtuins have emerged as regulators of several reproductive processes and interventions aiming to target Sirtuin activity are of great interest in the reproductive biology field. Sirtuins are pivotal to protect germ cells against oxidative stress, a major determinant influencing ovarian aging and the quality of gametes. Sirtuins also safeguard the integrity of the genome through epigenetic programs required for regulating gene repression, DNA repair, and chromosome segregation, among others. Although these functions are relatively well characterized in many somatic tissues, how they contribute to reproductive functions is not well understood. This review summarizes our current knowledge on the role of Sirtuins in female reproductive systems and discusses the underlying molecular pathways. In addition, we highlight the importance of Sirtuins as antiaging factors in the ovary and summarize current preclinical efforts to identify treatments to extend female reproductive longevity.

Adaptation to different forms of environmental stress is crucial for maintaining essential cellular functions and survival. The nucleolus plays a decisive role as a signaling hub for coordinating cellular responses to various extrinsic and intrinsic cues. p53 levels are normally kept low in unstressed cells, mainly due to E3 ubiquitin ligase MDM2-mediated degradation. Under stress, nucleophosmin (NPM) relocates from the nucleolus to the nucleoplasm and binds MDM2, thereby preventing degradation of p53 and allowing cell-cycle arrest and DNA repair. Here, we demonstrate that the mammalian sirtuin SIRT7 is an essential component for the regulation of p53 stability during stress responses induced by ultraviolet (UV) irradiation. The catalytic activity of SIRT7 is substantially increased upon UV irradiation through ataxia telangiectasia mutated and Rad3 related (ATR)-mediated phosphorylation, which promotes efficient deacetylation of the SIRT7 target NPM. Deacetylation is required for stress-dependent relocation of NPM into the nucleoplasm and MDM2 binding, thereby preventing ubiquitination and degradation of p53. In the absence of SIRT7, stress-dependent stabilization of p53 is abrogated, both in vitro and in vivo, impairing cellular stress responses. The study uncovers an essential SIRT7-dependent mechanism for stabilization of the tumor suppressor p53 in response to genotoxic stress.

Sirtuins play an important role in the regulation of hematopoiesis, as they do in other tissues. Consequently, their deregulation causes immune-related pathologies such as leukemia and chronic inflammation. Sirtuins participate in these processes at different levels, most of which are related to previously known functions such as the protection of genome integrity, control of apoptosis, metabolic homeostasis, and pluripotency. Our current knowledge is still limited, but five ways what we do know strongly suggests that sirtuins are crucial for hematopoietic homeostasis and have considerable therapeutic potential for treating this group of pathologies.

A key challenge for clinical application of induced pluripotent stem cells (iPSC) to accurately model and treat human pathologies depends on developing a method to generate genetically stable cells to reduce long-term risks of cell transplant therapy. Here, we hypothesized that CYCLIN D1 repairs DNA by highly efficient homologous recombination (HR) during reprogramming to iPSC that reduces genetic instability and threat of neoplastic growth. We adopted a synthetic mRNA transfection method using clinically compatible conditions with CYCLIN D1 plus base factors (OCT3/4, SOX2, KLF4, LIN28) and compared with methods that use C-MYC. We demonstrate that CYCLIN D1 made iPSC have (a) lower multitelomeric signal, (b) reduced double-strand DNA breaks, (c) correct nuclear localization of RAD51 protein expression, and (d) reduced SNP changes per chromosome, compared with the classical reprogramming method using C-MYC. CYCLIN D1 iPSC have reduced teratoma Ki67 cell growth kinetics and derived neural stem cells successfully engraft in a hostile spinal cord injury (SCI) microenvironment with efficient survival, differentiation. We demonstrate that CYCLIN D1 promotes double-stranded DNA damage repair predominantly through HR during cell reprogramming to efficiently produce iPSC. CYCLIN D1 reduces general cell stress associated with significantly lower SIRT1 gene expression and can rescue Sirt1 null mouse cell reprogramming. In conclusion, we show synthetic mRNA transfection of CYCLIN D1 repairs DNA during reprogramming resulting in significantly improved genetically stable footprint in human iPSC, enabling a new cell reprogramming method for more accurate and reliable generation of human iPSC for disease modeling and future clinical applications. © AlphaMed Press 2021 A key challenge for clinical application of induced pluripotent stem cells (iPSC) to accurately model and treat human pathologies lies in developing a method for their generation that are genetically stable to reduce long-term risks of cell transplant therapy. The authors show synthetic mRNA transfection of CYCLIN D1 repairs DNA during reprogramming resulting in significantly improved genetically stable footprint in human iPSC, enabling more accurate and reliable generation of human iPSC for disease modeling and future clinical applications.

We present a calculation of the scalar, vector and tensor pion and kaon form factors using one ensemble of two degenerate light, a strange and a charm quark ($N_f=2+1+1$) of maximally twisted mass fermions with clover improvement. The quark masses are chosen so that they produce a pion mass of about 265 MeV, and a kaon mass of 530 MeV. The lattice spacing of the ensemble is 0.093 fm and the lattice has a spatial extent of 3 fm. We use a rest frame, as well as a boosted frame to obtain the form factors for a wider and denser set of four-vector momentum transfer squared, $Q^2$. To assess and eliminate excited-states contamination, we analyze several values of the source-sink time separation within the range of 1.12 - 2.23 fm (1.12 - 1.67 fm) for the rest (boosted) frame. The $Q^2$ dependence of the form factors is parametrized using a monopole fit, which leads to the extraction of the corresponding radius, and the tensor anomalous magnetic moment for the tensor form factor. The results for these parametrizations are compared for the pion and kaon to assess the level of the SU(3) flavor symmetry breaking., Comment: 10 pages, 6 figures, Proceedings of the 38th Annual International Symposium on Lattice Field Theory - LATTICE2021

We present an update on the ongoing calculations by the Fermilab Lattice, HPQCD, and MILC Collaboration of the leading-order (in electromagnetism) hadronic vacuum polarization contribution to the anomalous magnetic moment of the muon. Our project employs ensembles with four flavors of highly improved staggered fermions, physical light-quark masses, and four lattice spacings ranging from $a \approx 0.06$ to 0.15 fm for most of the results thus far.