Canonical Counterpart Research Articles

Rank-Reduced Equation-of-Motion Coupled Cluster Triples: an Accurate and Affordable Way of Calculating Electronic Excitation Energies.

In the present work, we report an implementation of the rank-reduced equation-of-motion coupled cluster method with approximate triple excitations (RR-EOM-CC3). The proposed variant relies on tensor decomposition techniques in order to alleviate the high cost of computing and manipulating the triply excited amplitudes. In the RR-EOM-CC3 method, both ground-state and excited-state triple-excitation amplitudes are compressed according to the Tucker-3 format. This enables factorization of the working equations such that the formal scaling of the method is reduced to N6, where N is the system size. An additional advantage of our method is the fact that the accuracy can be strictly controlled by proper choice of two parameters defining sizes of triple-excitation subspaces in the Tucker decomposition for the ground and excited states. Optimal strategies of selecting these parameters are discussed. The developed method has been tested in a series of calculations of electronic excitation energies and compared to its canonical EOM-CC3 counterpart. Errors several times smaller than the inherent error of the canonical EOM-CC3 method (in comparison to FCI) are straightforward to achieve. This conclusion holds both for valence states dominated by single excitations and for states with pronounced doubly excited character. Taking advantage of the decreased scaling, we demonstrate substantial computational costs reductions (in comparison with the canonical EOM-CC3) in the case of two large molecules - l-proline and heptazine. This illustrates the usefulness of the RR-EOM-CC3 method for accurate determination of excitation energies of large molecules.

Nucleotide alterations in the HLA-C class I gene can cause aberrant splicing and marked changes in RNA levels in a polymorphic context-dependent manner.

Polymorphisms of HLA genes, which play a crucial role in presenting peptides with diverse sequences in their peptide-binding pockets, are also thought to affect HLA gene expression, as many studies have reported associations between HLA gene polymorphisms and their expression levels. In this study, we devised an ectopic expression assay for the HLA class I genes in the context of the entire gene, and used the assay to show that the HLA-C*03:03:01 and C*04:01:01 polymorphic differences observed in association studies indeed cause different levels of RNA expression. Subsequently, we investigated the C*03:23N null allele, which was previously noted for its reduced expression, attributed to an alternate exon 3 3' splice site generated by G/A polymorphism at position 781 within the exon 3. We conducted a thorough analysis of the splicing patterns of C*03:23N, and revealed multiple aberrant splicing, including the exon 3 alternative splicing, which overshadowed its canonical counterpart. After confirming a significant reduction in RNA levels caused by the G781A alteration in our ectopic assay, we probed the function of the G-rich sequence preceding the canonical exon 3 3' splice site. Substituting the G-rich sequence with a typical pyrimidine-rich 3' splice site sequence on C*03:23N resulted in a marked elevation in RNA levels, likely due to the enhanced preference for the canonical exon 3 3' splice site over the alternate site. However, the same substitution led to a reduction in RNA levels for C*03:03:01. These findings suggested the dual roles of the G-rich sequence in RNA expression, and furthermore, underscore the importance of studying polymorphism effects within the framework of the entire gene, extending beyond conventional mini-gene reporter assays.

Linking Phosphoinositides to Proteins: A Novel Signaling Pipeline

Phosphoinositide (PIPn) signaling plays pivotal roles in myriad biological processes and is altered in many diseases including cancer. Canonical PIPn signaling involves membrane-associated PIPn lipid second messengers that modulate protein recruitment and activity at membrane focal points. In the nucleus, PIPn signaling operates separately from membranous compartments defining the paradigm of non-canonical PIPn signaling. However, the mechanisms by which this non-membranous nuclear PIPn pool is established and mediates stress signaling is poorly understood. The recent discovery of a p53-signalosome by Chen et al. (Nature Cell Biology 2022) represents a new PIPn signaling axis that operates independently from membrane structures where PIPns are dynamically linked to nuclear p53 and modified by PIPn kinases and phosphatases, allowing the activation of a nuclear PI 3-kinase/Akt pathway that is entirely distinct from the canonical membrane-localized pathway. Here, we will discuss emerging insights about the non-canonical PIPn pathway, which links PIPns to a growing number of cellular targets and highlight the similarities/differences with its canonical counterpart. We will also discuss potential therapeutic targets in this non-canonical PIPn pathway, which is likely to be deregulated in many diseases.

Intralingual translation, cultural accessibility and the ethics of translation: The Volxbibel as a case study

This article deals with the ethics of intralingual translation and cultural accessibility. Based on the analysis of five characteristic text examples of the Volxbibel, a German intralingual translation of the Bible which makes excessive use of local adaptive strategies and whose central aim is to make the Scriptures accessible to youngsters, it will be shown that cultural accessibility can only be achieved if the ethical dimension of semiotic translational transfer is taken duly into account. Methodologically, the analysis will be based on a contrastive pragmatic analysis of the Volxbibel and its canonical counterpart, the Lutherbibel. The results of the analysis reveal that ethically grounded intralingual translation can only be achieved when transfer actions are oriented, not only towards the translational skopos and the target-text, but, at the same time, respect the source-text author’s intention(s) and the source-text’s ideological and socio-cultural background. Finally, on the grounds of these results, a slight adjustment of Zethsen’s and Hill-Madsen’s criterial definition of translation is proposed, by explicitly integrating therein the ethical dimension. This would contribute to a more precise delineation of both intralingual and interlingual translation.

Abstract 3959: Novel spliced isoform of the proteasome subunit ADRM1/Rpn13 promotes hepatocellular carcinoma (HCC) development through selective degradation of tumor suppressor p53

Abstract The Ubiquitin-Proteasome System (UPS) is the major pathway in eukaryotic cells that regulates intracellular protein degradation and turnover. Cumulative evidence has suggested that defects in the UPS machinery are involved in the pathogenesis of human diseases, including cancer. The proteasome-associated polyubiquitin receptor ADRM1 (also known as Rpn13) orchestrates the process of substrate recruitment with deubiquitination in the proteasome through its N-terminal ubiquitin-binding domain and C-terminal activation of deubiquitinating enzyme. Using long-read SMRT-seq to profile the RNA splicing landscape in hepatocellular carcinoma (HCC), we previously reported on an unannotated alternative spliced variant of ADRM1 in human hepatocellular carcinoma (HCC) (Hepatology 2019). This novel isoform exhibits an exon 9 skipping (ADRM1-ΔEx9) that resulted in an altered C-terminus of the protein. In this study, we undertook further investigations to characterize the detailed functional effects of ADRM1-ΔEx9 in HCC biology and the underlying mechanism. Initial study by junction-specific Taqman PCR assay showed that ADRM1-ΔEx9 is more frequently upregulated in HCC tumors than the canonical full-length counterpart (ADRM1-FL). There is an interchange between the two isoforms as tumor develops which underscores an isoform-switch in favor of HCC development. Indeed, our result showed that ADRM1-ΔEx9, but not ADRM1-FL, correlated significantly with inferior patient survival. Functionally, ADRM1-ΔEx9 knockdown profoundly suppressed proliferation by inducing spontaneous apoptosis in HCC cell lines and patient-derived HCC organoids. The corresponding effects were less apparent from ADRM1-FL knockdown. Consistently, overexpression of ADRM1-ΔEx9 in normal human liver organoids promoted pre-malignant features alongside increased in-vitro propagation time. Ubiquitin Proteome profiling revealed that ADRM1-ΔEx9 led to a reduced expression of the pivotal tumor suppressor p53. A parallel transcriptome also substantiated that ADRM1-ΔEx9 modulated genes involved in the p53 and apoptosis pathways. Collectively, our study demonstrated that the non-canonical spliced isoform ADRM1-ΔEx9 confers growth and pro-survival advantages in HCC through mediating selective degradation of tumor suppressor p53 protein. Citation Format: Yanmei Sun, Mingjing Xu, Ho Lee Wan, Alissa M. Wong, Kelvin K. Ng, Nathalie Wong. Novel spliced isoform of the proteasome subunit ADRM1/Rpn13 promotes hepatocellular carcinoma (HCC) development through selective degradation of tumor suppressor p53. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3959.

The Daughter of Doctor Moreau by Silvia Moreno-Garcia

Reviewed by: The Daughter of Doctor Moreau by Silvia Moreno-Garcia Suzanne Manizza Roszak SILVIA MORENO-GARCIA The Daughter of Doctor Moreau New York. Del Rey. 2022. 320 pages. SILVIA MORENO-GARCIA is known for an intersectional feminist approach to genre fiction that resists intertwining currents of sexism, white supremacy, and colonial and neocolonial power. With the 2020 publication of Mexican Gothic, her sixth novel but the first to appear on the New York Times best-seller list, the work that Moreno-Garcia had long been doing finally became a matter of public knowledge. Two years later came The Daughter of Doctor Moreau, an aesthetically rich and politically significant retelling of H. G. Wells's 1896 novel that would transplant Wells's original premise to the late nineteenth-century Yucatán. Rendered in gorgeous prose that maintains its allegiances to the often-maligned world of commercial fiction, Moreno-Garcia's narrative features a young woman protagonist named Carlota, the eponymous daughter determined to defend herself and her world from encroaching danger. Described by its author as "loosely inspired" by Wells's Doctor Moreau, the retelling makes pointed interventions that disrupt the legacy of its canonical counterpart. The novel's alternating close-third points of view are two alternatives to the first-person narration of Wells's earlier text, which privileges an outsider's expressions of revulsion at what it terms "grotesque" in the identities of Moreau's "Beast People." In Moreno-Garcia's reinvention, the real grotesqueries are expressions of white Eurocentric power: most obviously the French-born Moreau's horrific experimentation on animals and in some cases on women of color, but also the callous responses of "European-descended" Mexican characters to the plight of Moreau's victims, their viciously racist attitudes toward the novel's Indigenous Maya community against the backdrop of the Caste War of Yucatán, and even the pale gothic visuality of whiteness, which the narrative imbues with its own visceral horror. Giving voice to Carlota's perspective in particular allows Moreno-Garcia to reject the imperative that subaltern figures like Wells's puma-woman can only be gazed on distantly in their suffering and their revenge. Moreno-Garcia has been candid in speaking out about the specter of white supremacy in her life and the lives of her loved ones. In 2019, then the author of novels including Signal to Noise and The Beautiful Ones, she took aim at the pattern of discrimination against writers of color within the Canadian publishing industry: "There was nobody here who wanted to represent me," she commented. Moreno-Garcia's experience of being "treated worse than white writers—ignored or not [End Page 77] given the resources to succeed" represents an extension of the same persistently pathological system that The Daughter of Doctor Moreau invokes and resists. Likewise, the novel is insistent in refusing the racist logic that led others to tell Moreno-Garcia's mother that she "was ugly due to her dark skin and Indigenous heritage." The claims of "upper-crust Mexicans" to "a pure, white ascendancy" are pointedly problematized, with special attention to the stigmatization of non-white-presenting womanhood within a social apparatus that fetishizes the "girls of milk and honey" who are Carlota's opposites. Just as it plays with and against Wells's vision, however, Moreno-Garcia's novel adopts an ingenious speculative approach that will not be confined by the bleakness it reflects. By the close of The Daughter of Doctor Moreau, the eponymous heroine has come into her own, claiming forms of agency that, as the book itself underlines, are virtually unheard of for "dreadfully young" unmarried women in Carlota's fin de siècle universe. As Doctor Moreau's daughter uses these resources to enact change on a larger scale, we begin to see that the most exhilarating strength of Moreno-Garcia's method is its fierce embrace of possibility. The Daughter of Doctor Moreau is important because of what it refuses to look away from—but also because of the joy, the beauty, and the victories it allows us to experience and imagine. Suzanne Manizza Roszak University of Groningen Copyright © 2023 World Literature Today and the Board of...

Single sidewall cooling modulation on Rayleigh–Bénard convection

We experimentally explored the effect of single-sidewall cooling on Rayleigh–Bénard (RB) convection. Canonical RB was also studied to aid insight. The scenarios shared tank dimensions and bottom and top wall temperatures; the single sidewall cooling had the top wall temperature. Turbulence was explored at two canonical Rayleigh numbers, $Ra=1.6\times 10^{10}$ and $Ra=2\times 10^9$ under Prandtl number $Pr=5.4$ . Particle image velocimetry described vertical planes parallel and perpendicular to the sidewall cooling. The two $Ra$ scenarios reveal pronounced changes in the flow structure and large-scale circulation (LSC) due to the sidewall cooling. The density gradient induced by the sidewall cooling led to asymmetric descending and ascending flows and irregular LSC. Flow statistics departed from the canonical case, exhibiting lower buoyancy effects, represented by an effective Rayleigh number with effective height dependent on the distance from the lateral cooling. Velocity spectra show two scalings, $\varPhi \propto f^{-5/3}$ Kolmogorov (KO41) and $\varPhi \propto f^{-11/5}$ Bolgiano (BO59) in the larger $Ra$ ; the latter was not present in the smaller set-up. The BO59 scaling with sidewall cooling appears at higher frequencies than its canonical counterpart, suggesting weaker buoyancy effects. The LSC core motions allowed us to identify a characteristic time scale of the order of vortex turnover time associated with distinct vortex modes. The velocity spectra of the vortex core oscillation along its principal axis showed a scaling of $\varPhi _c \propto f^{-5/3}$ for the single sidewall cooling, which was dominant closer there. It did not occur in the canonical case, evidencing the modulation of LSC oscillation on the flow.

The Production of the Book of Mormon in Light of a Tibetan Buddhist Parallel

The Production of the Book of Mormon in Light of a Tibetan Buddhist Parallel

Stress in DNA Gridiron Facilitates the Formation of Two-Dimensional Crystalline Structures.

Programmable DNA nanotechnology has generated some of the most intricate self-assembled nanostructures and has been employed in a growing number of applications, including functional nanomaterials, nanofabrication, biophysics, photonics, molecular machines, and drug delivery. An important design rule for DNA nanostructures is to minimize the mechanical stress to reduce the potential energy in these nanostructures whenever it is possible. This work revisits the DNA gridiron design consisting of Holliday junctions and compares the self-assembly of the canonical DNA gridiron with a new design of DNA gridiron, which has a higher degree of mechanical stress because of the interweaving of DNA helices. While the interweaving DNA gridiron indeed exhibits lower yield, compared to its canonical counterpart of a similar size, we discover that the mechanical stress within the interweaving gridiron can promote the formation of the two-dimensional crystalline lattice instead of nanotubes. Furthermore, tuning the design of interweaving gridiron leads to the change of overall crystal size and regularity of geometry. Interweaving DNA double helices represents a new design strategy in the self-assembly of DNA nanostructures. Furthermore, the discovery of the new role of mechanical stress in the self-assembly of DNA nanostructures provides useful knowledge to DNA nanotechnology practitioners: a more balanced view regarding mechanical stress can be considered when designing future DNA nanostructures.

Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental Pancreatitis.

BackgroundAutophagosome, the central organelle in autophagy process, can assemble via canonical pathway mediated by LC3-II, the lipidated form of autophagy-related protein LC3/ATG8, or noncanonical pathway mediated by the small GTPase Rab9. Canonical autophagy is essential for exocrine pancreas homeostasis, and its disordering initiates and drives pancreatitis. The involvement of noncanonical autophagy has not been explored. We examine the role of Rab9 in pancreatic autophagy and pancreatitis severity.MethodsWe measured the effect of Rab9 on parameters of autophagy and pancreatitis responses using transgenic mice overexpressing Rab9 (Rab9TG) and adenoviral transduction of acinar cells. Effect of canonical autophagy on Rab9 was assessed in ATG5-deficient acinar cells.ResultsPancreatic levels of Rab9 and its membrane-bound (active) form decreased in rodent pancreatitis models and in human disease. Rab9 overexpression stimulated noncanonical and inhibited canonical/LC3-mediated autophagosome formation in acinar cells through up-regulation of ATG4B, the cysteine protease that delipidates LC3-II. Conversely, ATG5 deficiency caused Rab9 increase in acinar cells. Inhibition of canonical autophagy in Rab9TG pancreas was associated with accumulation of Rab9-positive vacuoles containing markers of mitochondria, protein aggregates, and trans-Golgi. The shift to the noncanonical pathway caused pancreatitis-like damage in acinar cells and aggravated experimental pancreatitis.ConclusionsThe results show that Rab9 regulates pancreatic autophagy and indicate a mutually antagonistic relationship between the canonical/LC3-mediated and noncanonical/Rab9-mediated autophagy pathways in pancreatitis. Noncanonical autophagy fails to substitute for its canonical counterpart in protecting against pancreatitis. Thus, Rab9 decrease in experimental and human pancreatitis is a protective response to sustain canonical autophagy and alleviate disease severity.

Accuracy of DLPNO-CCSD(T): Effect of Basis Set and System Size.

The DLPNO-CCSD(T) method is designed to study large molecular systems at significantly reduced cost relative to its canonical counterpart. However, the error in this approach is also size-extensive and relies on cancellation of errors for the calculation of relative energies. This work provides a direct comparison of canonical CCSD(T) and TightPNO DLPNO-CCSD(T) calculations of reaction energies and barriers of a broad range of chemical reactions. The dataset includes acidities, anion binding affinities, enolization, Diels-Alder, nucleophilic substitution, and atom transfer reactions and complements existing theoretical datasets in terms of system size as well as new reaction types (e.g., anion binding affinities and chlorine atom transfer reactions). The performance of DLPNO-CCSD(T) was further examined with respect to systematic variation of basis set and system size and amounts of nonbonded interaction present in the system. The errors in the DLPNO-CCSD(T) were found to be relatively insensitive to the choice of basis set for small systems but increase monotonically with system size. Additionally, calculations of barriers appear to be more challenging than reaction energies with errors exceeding 5 kJ mol-1 for many Diels-Alder reactions. Further tests on three realistic organic reactions reveal the impact of the DLPNO approximation in calculating absolute and relative barriers that are important for predictions such as stereoselectivity.

CENP-A Nucleosome is a Sensitive Allosteric Scaffold for DNA and Chromatin Factors

Centromeric loci of chromosomes are defined by nucleosomes containing the histone H3 variant CENP-A, which bind their DNA termini more permissively than their canonical counterpart, a feature that is critical for the mitotic fidelity. A recent cryo-EM study demonstrated that the DNA termini of CENP-A nucleosomes, reconstituted with the Widom 601 DNA sequence, are asymmetrically flexible, meaning one terminus is more clearly resolved than the other. However, an earlier work claimed that both ends could be resolved in the presence of two stabilizing single chain variable fragment (scFv) antibodies per nucleosome, and thus are likely permanently bound to the histone octamer. This suggests that the binding of scFv antibodies to the histone octamer surface would be associated with CENP-A nucleosome conformational changes, including stable binding of the DNA termini. Here, we present computational evidence that allows to explain at atomistic level the structural rearrangements of CENP-A nucleosomes resulting from the antibody binding. The antibodies, while they only bind the octamer façades, are capable of altering the dynamics of the nucleosomal core, and indirectly also the surrounding DNA. This effect has more drastic implications for the structure and the dynamics of the CENP-A nucleosome in comparison to its canonical counterpart. Furthermore, we find evidence that the antibodies bind the left and the right octamer façades at different affinities, another manifestation of the DNA sequence. We speculate that the cells could use induction of similar allosteric effects to control centromere function.

Seasonal Forecast of South China Sea Summer Monsoon Onset Disturbed by Cold Tongue La Niña in the Past Decade

It has been suggested that a warm (cold) ENSO event in winter is mostly followed by a late (early) onset of the South China Sea (SCS) summer monsoon (SCSSM) in spring. Our results show this positive relationship, which is mainly determined by their phase correlation, has been broken under recent rapid global warming since 2011, due to the disturbance of cold tongue (CT) La Nina events. Different from its canonical counterpart, a CT La Nina event is characterized by surface meridional wind divergences in the central-eastern equatorial Pacific, which can delay the SCSSM onset by enhanced convections in the warming Indian Ocean and the western subtropical Pacific. Owing to the increased Indian-western Pacific warming and the prevalent CT La Nina events, empirical seasonal forecasting of SCSSM onset based on ENSO may be challenged in the future.

Extrapolation to the Limit of a Complete Pair Natural Orbital Space in Local Coupled-Cluster Calculations.

The domain-based local pair natural orbital (PNO) coupled-cluster DLPNO-CCSD(T) method allows one to perform single point energy calculations for systems with hundreds of atoms while retaining essentially the accuracy of its canonical counterpart, with errors that are typically smaller than 1 kcal/mol for relative energies. Crucial to the accuracy and efficiency of the method is a proper definition of the virtual space in which the coupled-cluster equations are solved, which is spanned by a highly compact set of pair natural orbitals (PNOs) that are specific for each electron pair. The dimension of the PNO space is controlled by the TCutPNO threshold: only PNOs with an occupation number greater than TCutPNO are included in the correlation space of a given electron pair, whilst the remaining PNOs are discarded. To keep the error of the method small, a conservative TCutPNO value is used in standard DLPNO-CCSD(T) calculations. This often leads to unnecessarily large PNO spaces, which limits the efficiency of the method. Herein, we introduce a new computational strategy to approach the complete PNO space limit (for a given basis set) that consists in extrapolating the results obtained with different TCutPNO values. The method is validated on the GMTKN55 set using canonical CCSD(T) data as the reference. Our results demonstrate that a simple two-point extrapolation scheme can be used to significantly increase the efficiency and accuracy of DLPNO-CCSD(T) calculations, thus extending the range of applicability of the technique.

Abstract 2543: Concurrent profiling of canonical and modified miRNAomes from TCGA and TARGET cohorts leads to enhanced resolution in cancer

Abstract MicroRNAs (miRs), a class of regulatory single-stranded small non-coding RNAs, are frequently deregulated in cancer and have been proposed as diagnostic and prognostic biomarkers in this fatal disease. Recent improvements in high-throughput sequencing (HTS) technologies have allowed the discovery of post-transcriptional modification phenomena involving miRs (e.g., isomiRs, A-to-I editing sites) able to alter the miR canonical sequence and thus their function. However, albeit earlier studies have proposed the exploitation of modified miRs as potential cancer biomarkers, their comprehensive and concurrent profiling, in cancer, still lacks. In light of this, we have applied the miRge2 pipeline (PubmedID:30153801) to more than 12K samples across 38 different cancer types from TCGA and TARGET, aiming at profiling the expression of all detectable canonical and modified miR isoforms in cancer. We identified over 29K unique miR isoforms (21 novel ones) expressed in at least one tumor type, whereby about 85% contains at least one modification (e.g., SNPs, RNA editing). According to our results, taking into account both canonical and modified miR isoforms throughout the analysis leads to an increase of about 20-fold in the identification of potential diagnostic and prognostic miRs with respect to conventional methods, which exclusively consider canonical miRs (miRBase v22). Then, leveraging on an independent cohort of 38 colorectal cancers and 21 adjacent healthy tissues (EGAS00001001127), we found that ~600 significantly deregulated miR isoforms were in common with the ones derived from the TCGA COAD dataset. Focusing on two miR isoforms, the canonical miR-151a-3p and its isoform (miR-151a-3p_-2|-2) with two left-shifted residues in both 5' and 3' end, which we found to be up-regulated in both cohorts, we performed a target prediction coupled with a miR/protein anti-correlation analysis. Interestingly, we found that the two miRs have a distinct set of targets. Finally, employing an Ingenuity(R) Pathway Analysis on their predicted targets, we observed that miR-151a-3p_-2|-2, in contrast to the canonical counterpart, is significantly involved in oncogenic pathways, such as PAK and CXCR4 signaling. This suggests that the final tumor phenotype could be substantially affected by modified miR isoforms. Here, we present one of the most in-depth and extensive miRNome profiling in cancer performed to date, revealing one magnitude of novel potential diagnostic and prognostic cancer biomarkers and enlightening the contribution of miR isoforms to the wider miRNome in cancer pathogenesis. Citation Format: Rosario Distefano, Luisa Tomasello, Gioacchino P. Marceca, Marina Bagnoli, Alessandro Lagana', Mario Acunzo, Chi Song, Pierluigi Gasparini, Giovanni Nigita, Carlo M. Croce. Concurrent profiling of canonical and modified miRNAomes from TCGA and TARGET cohorts leads to enhanced resolution in cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2543.

A multireference coupled-electron pair approximation combined with complete-active space perturbation theory in local pair-natural orbital framework.

The Complete-Active Space Second-order Perturbation Theory (CASPT2) has been one of the most widely-used methods for reliably calculating electronic structures of multireference systems. Because of its lowest level treatment of dynamic correlation, it has a high computational feasibility; however, its accuracy in some cases falls short of needs. Here, as a simple yet higher-order alternative, we introduce a hybrid theory of the CASPT2 and a multireference variant of the Coupled-Electron Pair Approximation (CEPA), which is a class of high level correlation theory. A central feature of our theory (CEPT2) is to use the two underlying theories for describing different divisions of correlation components based on the full internal contraction framework. The external components, which usually give a major contribution to the dynamic correlation, are intensively described using the CEPA Ansatz, while the rests are treated at the CASPT2 level. Furthermore, to drastically reduce the computational demands, we have incorporated the pair-natural orbital (PNO) method into our multireference implementations. This development, thus, requires highly complex derivations and coding, while it has been largely facilitated with an automatic expression and code generation technique. To highlight the accuracy of the CEPT2 approach and to assess the errors caused by the PNO truncation, benchmark calculations are shown on small- to medium-size molecules, illustrating the high accuracy of the present CEPT2 model. By tightening the truncation thresholds, the PNO-CEPT2 energy converges toward the canonical counterpart and is more accurate than that of PNO-CASPT2 as long as the same truncation thresholds are used.

Abstract P4-08-02: The human intermediate prolactin receptor is a breast cancer oncogene

Abstract Epidemiological, cellular, and genetic analyses indicate the hormone prolactin (PRL) and its cognate receptor in humans (hPRLr) are significantly involved in breast cancer pathogenesis. Recent evidence demonstrated that a truncated mouse PRLr (mPRLrT) is oncogenic when expressed alongside its canonical long form counterpart (mPRLrL). mPRLrT shares significant sequence homology with a naturally-occurring and widely-expressed hPRLr splice variant, the intermediate hPRLr (hPRLrI). To confirm the oncogenic potential of hPRLrI, isoform-specific hPRLrI knock-down (KD) was performed in breast cancer cell line MCF7. hPRLrI KD resulted in a significant decrease in proliferation, migration, and anchorage-independent growth. Next, given the similarity between mPRLrT and hPRLrI, we hypothesized hPRLrI may also be sufficient to induce transformation, when expressed alongside wild-type long hPRLr (hPRLrL). Like the mPRLrT, hPRLrI co-expression with hPRLrL in the immortalized but not transformed human breast cell line MCF10A resulted in a significant increase in proliferation, migration, and anchorage-independent growth. These results were not observed following overexpression of either isoform alone, demonstrating that hPRLrL/I co-expression is necessary to induce transformation of normal mammary epithelia. To test our hypothesis in vivo, we established MCF10A xenografts using female NOD scid gamma (NSG) mice. Following intraductal injection, we observed rapid tumor growth in the hPRLrL/I co-expression cohort, significantly over that of the cohorts harboring either isoform alone. To determine mechanisms of transformation, we examined both differential protein stability and altered signaling events. In analyzing receptor degradation, a cycloheximide assay revealed hPRLrL stability is increased when heterodimerized with hPRLrI. hPRLrL turnover has been reported to be impaired in human breast cancer, indicating this phenomenon may be involved in the observed hPRLrI-mediated transformation. In regards to differential signaling, we examined the Jak2/Stat5a pathway. Jak2 is a promiscuous kinase whose significant oncogenic actions are well-characterized, while Stat5a is a transcription factor whose activities are critical in attenuating the actions of Jak2. Following PRL stimulation, it was observed that hPRLrL/I co-expression induced approximately two-fold greater Jak2-Y1007/1008 phosphorylation (pJak2) compared to that induced by hPRLrL expression alone. Further, it was observed that hPRLrL/I co-expression induced ten-fold less Stat5a-Y694 phosphorylation (pY-Stat5a) than hPRLrL expression alone. These data indicate unchecked pJak2 activity may also be a contributing mechanism in the observed transformation. Overall, these results demonstrate that hPRLrI, alongside hPRLrL, is sufficient for transformation of normal breast tissue. Citation Format: Jacqueline M Grible, Shannon E Hedrick, Charles V Clevenger. The human intermediate prolactin receptor is a breast cancer oncogene [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-08-02.

Multipartite Entanglement Structure in the Eigenstate Thermalization Hypothesis.

We study the quantum Fisher information (QFI) and, thus, the multipartite entanglement structure of thermal pure states in the context of the eigenstate thermalization hypothesis (ETH). In both the canonical ensemble and the ETH, the quantum Fisher information may be explicitly calculated from the response functions. In the case of the ETH, we find that the expression of the QFI bounds the corresponding canonical expression from above. This implies that although average values and fluctuations of local observables are indistinguishable from their canonical counterpart, the entanglement structure of the state is starkly different; with the difference amplified, e.g., in the proximity of a thermal phase transition. We also provide a state-of-the-art numerical example of a situation where the quantum Fisher information in a quantum many-body system is extensive while the corresponding quantity in the canonical ensemble vanishes. Our findings have direct relevance for the entanglement structure in the asymptotic states of quenched many-body dynamics.

Ensemble inequivalence in the Blume-Emery-Griffiths model near a fourth-order critical point.

The canonical phase diagram of the Blume-Emery-Griffiths model with infinite-range interactions is known to exhibit a fourth-order critical point at some negative value of the biquadratic interaction K<0. Here we study the microcanonical phase diagram of this model for K<0, extending previous studies which were restricted to positive K. A fourth-order critical point is found to exist at coupling parameters which are different from those of the canonical ensemble. The microcanonical phase diagram of the model close to the fourth-order critical point is studied in detail revealing some distinct features from the canonical counterpart.

A general LC-MS-based RNA sequencing method for direct analysis of multiple-base modifications in RNA mixtures.

A complete understanding of the structural and functional potential of RNA requires understanding of chemical modifications and non-canonical bases; this in turn requires advances in current sequencing methods to be able to sequence not only canonical ribonucleotides, but at the same time directly sequence these non-standard moieties. Here, we present the first direct and modification type-independent RNA sequencing method via introduction of a 2-dimensional hydrophobic end-labeling strategy into traditional mass spectrometry-based sequencing (2D HELS MS Seq) to allow de novo sequencing of RNA mixtures and enhance sample usage efficiency. Our method can directly read out the complete sequence, while identifying, locating, and quantifying base modifications accurately in both single and mixed RNA samples containing multiple different modifications at single-base resolution. Our method can also quantify stoichiometry/percentage of modified RNA versus its canonical counterpart RNA, simulating a real biological sample where modifications exist but may not be 100% at a particular site in the RNA. This method is a critical step towards fully sequencing real complex cellular RNA samples of any type and containing any modification type and can also be used in the quality control of modified therapeutic RNAs.