1,174 results on '"Thorner P"'
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2. Zeros of $L$-functions in families near the critical line
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Blomer, Valentin and Thorner, Jesse
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Mathematics - Number Theory ,11M41, 11M26, 11F70 - Abstract
We combine the relative trace formula with analytic methods to obtain zero density estimate for $L$-functions in various families of automorphic representations for $\mathrm{GL}(m)$. Applications include strong bounds for the average analytic rank of these $L$-functions at the central point and average equidistribution results for the imaginary parts of the zeros., Comment: 21 pages
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- 2024
3. Methodology for 3D sound synthesis of directional acoustic sources by higher-order ambisonics
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Thorner, Philippe, Bavu, Eric, Doc, Jean-Baptiste, and Langrenne, Christophe
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Physics - Classical Physics - Abstract
This paper presents the 3D soundfield synthesis of the pressure field radiated by directional acoustic sources using both the multimodal method and higher-order ambisonics (HOA). Ambisonics is a technique for encoding and reproducing measured or modeled (virtual) sound pressure field, based on a decomposition of the acoustic field over spherical harmonics. The directional source considered in this work is an acoustic horn excited by a flat piston. The free-field radiation from this horn is first modeled accurately over a wide frequency range using the multimodal method, which requires relatively low computational resources. This radiated pressure field, collected on a dual-layer sphere of virtual sensors distributed over a Lebedev geometry, allows its projection into the ambisonic domain. The pressure field is then synthesized in the laboratory's 3D 5th order HOA spatialization sphere, which consists of fifty-six loudspeakers. This offers the ability of listening to the radiated sound using a higher-order ambisonic synthesis of a 'virtual' source before it is manufactured. To qualitatively evaluate the performance of the proposed procedure, the transfer function of the synthesized horn is measured around the listening point within the spatialization sphere., Comment: Internoise 2024, Aug 2024, Nantes (France), France
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- 2024
4. Zeros of $L$-functions and large partial sums of Dirichlet coefficients
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Kerr, Bryce, Klurman, Oleksiy, and Thorner, Jesse
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Mathematics - Number Theory ,11L40, 11N56, 11F66 - Abstract
Let $L(s,\pi)=\sum_{n=1}^{\infty}\lambda_{\pi}(n)n^{-s}$ be an $L$-function that satisfies a weak form of the generalized Ramanujan conjecture. We prove that large partial sums of $\lambda_{\pi}(n)$ strongly repel the low-lying zeros of $L(s,\pi)$ away from the critical line. Our results extend and quantitatively improve preceding work of Granville and Soundararajan., Comment: 23 pages
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- 2024
5. Remarks on Landau-Siegel zeros
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Basak, Debmalya, Thorner, Jesse, and Zaharescu, Alexandru
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Mathematics - Number Theory - Abstract
For certain families of $L$-functions, we prove that if each $L$-function in the family has only real zeros in a fixed yet arbitrarily small neighborhood of $s=1$, then one may considerably improve upon the known results on Landau-Siegel zeros. Sarnak and the third author proved a similar result under much more restrictive hypotheses., Comment: 7 pages. Referee comments incorporated
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- 2024
6. Exceptional zeros of Rankin-Selberg $L$-functions and joint Sato-Tate distributions
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Thorner, Jesse
- Subjects
Mathematics - Number Theory - Abstract
Let $\chi$ be an idele class character over a number field $F$, and let $\pi,\pi'$ be non-dihedral twist-inequivalent cuspidal automorphic representations of $\mathrm{GL}_2(\mathbb{A}_F)$. We prove the following results. 1. If $m,n\geq 0$ are integers, $m+n\geq 1$, $F$ is totally real, $\chi$ corresponds with a ray class character, and $\pi,\pi'$ correspond with primitive non-CM holomorphic Hilbert cusp forms, then the Rankin-Selberg $L$-function $L(s,\mathrm{Sym}^m(\pi)\times(\mathrm{Sym}^n(\pi')\otimes\chi))$ has a standard zero-free region with no exceptional Landau-Siegel zero. When $m,n\geq 1$ and $m+n\geq 4$, this is new even for $F=\mathbb{Q}$. As an application, we establish the strongest known unconditional effective rates of convergence in the Sato-Tate distribution for $\pi$ and the joint Sato-Tate distribution for $\pi$ and $\pi'$. 2. The Rankin-Selberg $L$-function $L(s,\mathrm{Sym}^2(\pi)\times(\mathrm{Sym}^2 (\pi')\otimes\chi))$ has a standard zero-free region with no exceptional Landau-Siegel zero. Until now, this was only known when $\pi=\pi'$, $\pi$ is self-dual, and $\chi$ is trivial., Comment: 22 pages
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- 2024
7. New variants of arithmetic quantum ergodicity
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Humphries, Peter and Thorner, Jesse
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Mathematics - Number Theory - Abstract
We establish two new variants of arithmetic quantum ergodicity. The first is for self-dual $\mathrm{GL}_2$ Hecke-Maass newforms over $\mathbb{Q}$ as the level and Laplace eigenvalue vary jointly. The second is a nonsplit analogue wherein almost all restrictions of Hilbert (respectively Bianchi) Hecke-Maass cusp forms to the modular surface dissipate as their Laplace eigenvalues grow., Comment: 28 pages. arXiv admin note: substantial text overlap with arXiv:2103.05634
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- 2024
8. A multi-modal single-cell and spatial expression map of metastatic breast cancer biopsies across clinicopathological features
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Klughammer, Johanna, Abravanel, Daniel L., Segerstolpe, Åsa, Blosser, Timothy R., Goltsev, Yury, Cui, Yi, Goodwin, Daniel R., Sinha, Anubhav, Ashenberg, Orr, Slyper, Michal, Vigneau, Sébastien, Jané‐Valbuena, Judit, Alon, Shahar, Caraccio, Chiara, Chen, Judy, Cohen, Ofir, Cullen, Nicole, DelloStritto, Laura K., Dionne, Danielle, Files, Janet, Frangieh, Allison, Helvie, Karla, Hughes, Melissa E., Inga, Stephanie, Kanodia, Abhay, Lako, Ana, MacKichan, Colin, Mages, Simon, Moriel, Noa, Murray, Evan, Napolitano, Sara, Nguyen, Kyleen, Nitzan, Mor, Ortiz, Rebecca, Patel, Miraj, Pfaff, Kathleen L., Porter, Caroline B. M., Rotem, Asaf, Strauss, Sarah, Strasser, Robert, Thorner, Aaron R., Turner, Madison, Wakiro, Isaac, Waldman, Julia, Wu, Jingyi, Gómez Tejeda Zañudo, Jorge, Zhang, Diane, Lin, Nancy U., Tolaney, Sara M., Winer, Eric P., Boyden, Edward S., Chen, Fei, Nolan, Garry P., Rodig, Scott J., Zhuang, Xiaowei, Rozenblatt-Rosen, Orit, Johnson, Bruce E., Regev, Aviv, and Wagle, Nikhil
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- 2024
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9. Bounds for moments of ℓ-torsion in class groups
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Koymans, Peter and Thorner, Jesse
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- 2024
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10. New Variants of Arithmetic Quantum Ergodicity
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Humphries, Peter and Thorner, Jesse
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- 2025
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11. A new zero-free region for Rankin-Selberg $L$-functions
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Harcos, Gergely and Thorner, Jesse
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Mathematics - Number Theory ,Primary 11M41, Secondary 11F66, 11F70 - Abstract
Let $\pi$ and $\pi'$ be cuspidal automorphic representations of $\mathrm{GL}(n)$ and $\mathrm{GL}(n')$ with unitary central characters. We establish a new zero-free region for all $\mathrm{GL}(1)$-twists of the Rankin-Selberg $L$-function $L(s,\pi\times\pi')$, generalizing Siegel's celebrated work on Dirichlet $L$-functions. As an application, we prove the first unconditional Siegel-Walfisz theorem for the Dirichlet coefficients of $-L'(s,\pi\times\pi')/L(s,\pi\times\pi')$. Also, for $n\leq 8$, we extend the region of holomorphy and nonvanishing for the twisted symmetric power $L$-functions $L(s,\pi,\mathrm{Sym}^n\otimes\chi)$ of any cuspidal automorphic representation of $\mathrm{GL}(2)$., Comment: 21 pages, LaTeX2e; v2: updated Section 3 and the Remark below Theorem 1.1; v3: updated Section 1, added Theorem 2.2 and Section 8, added the Remark below the proof of Proposition 4.4; v4: updated the end of Section 1, added Section 4 (part of which was formerly Section 5.2); v5: updated Section 1; v6: updated Section 5
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- 2023
12. An approximate form of Artin’s holomorphy conjecture and non-vanishing of Artin L-functions
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Lemke Oliver, Robert J., Thorner, Jesse, and Zaman, Asif
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- 2024
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13. An explicit version of Bombieri's log-free density estimate and S\'ark\'ozy's theorem for shifted primes
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Thorner, Jesse and Zaman, Asif
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Mathematics - Number Theory - Abstract
We make explicit Bombieri's refinement of Gallagher's log-free "large sieve density estimate near $\sigma = 1$" for Dirichlet $L$-functions. We use this estimate and recent work of Green to prove that if $N\geq 2$ is an integer, $A\subseteq\{1,\ldots,N\}$, and for all primes $p$ no two elements in $A$ differ by $p-1$, then $|A|\ll N^{1-1/10^{18}}$. This strengthens a theorem of S\'ark\"ozy., Comment: 24 pages. v4: Incorporates referee comments
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- 2022
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14. Improving biobehavioral health in younger breast cancer survivors: Pathways to Wellness trial secondary outcomes
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Bower, Julienne E, Partridge, Ann H, Wolff, Antonio C, Cole, Steve W, Irwin, Michael R, Thorner, Elissa D, Joffe, Hadine, Petersen, Laura, Crespi, Catherine M, and Ganz, Patricia A
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Breast Cancer ,Behavioral and Social Science ,Mind and Body ,Cancer ,Rehabilitation ,Clinical Research ,Mental Health ,Women's Health ,Good Health and Well Being ,Female ,Humans ,Middle Aged ,Cancer Survivors ,Breast Neoplasms ,Cognition ,Inflammation ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundThe Pathways to Wellness trial tested the efficacy of 2 interventions for younger breast cancer survivors: mindful awareness practices (MAPs) and survivorship education (SE). This planned secondary analysis examines intervention effects on stress, positive psychological outcomes, and inflammation (Clincaltrials.gov NCT03025139).MethodsWomen diagnosed with breast cancer at or before age 50 years who had completed treatment and had elevated depressive symptoms were randomly assigned to 6 weeks of MAPs, SE, or wait-list control (WLC). Assessments conducted at pre- and postintervention and at 3- and 6-month follow-up measured general stress perceptions, cancer-related intrusive thoughts and worry, positive affect, meaning and peace in life, altruism and empathy, and markers of inflammation. Analyses compared change in outcomes over time in each intervention group relative to WLC using linear mixed models.ResultsA total 247 women were randomly assigned to MAPs (n = 85), SE (n = 81), or WLC (n = 81). MAPs statistically significantly decreased intrusive thoughts and worry at postintervention and 3-month follow-up relative to WLC (P
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- 2023
15. Highly Uniform Prime Number Theorems
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Kaneko, Ikuya and Thorner, Jesse
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Mathematics - Number Theory - Abstract
We prove a highly uniform version of the prime number theorem for a certain class of $L$-functions. The range of $x$ depends polynomially on the analytic conductor, and the error term is expressed in terms of an optimization problem depending explicitly on the available zero-free region. The class contains the Rankin-Selberg $L$-function $L(s,\pi \times \pi')$ associated to cuspidal automorphic representations $\pi$ and $\pi'$ of $\mathrm{GL}_{m}$ and $\mathrm{GL}_{m'}$, respectively. Our main result implies the first uniform prime number theorems for such $L$-functions (with analytic conductor uniformity) in complete generality., Comment: 16 pages. Incorporates referee comments. Theorem 2.6 is improved
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- 2022
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16. A framework for implementing patient-reported outcomes in clinical care: the PROTEUS-practice guide
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Crossnohere, Norah L., Anderson, Nicola, Baumhauer, Judith, Calvert, Melanie, Esparza, Rebecca, Gulbransen, Sandi, Haverman, Lotte, Li, Yuchen, Petersen, Carolyn, Retzer, Ameeta, Sidey-Gibbons, Christopher, Stover, Angela M., Thorner, Elissa, Ursin, Garrett, Velikova, Galina, Walker, Elliott Sparkman, Brundage, Michael, and Snyder, Claire
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- 2024
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17. TOR complex 2 is a master regulator of plasma membrane homeostasis
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Thorner, Jeremy
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Biochemistry and Cell Biology ,Biological Sciences ,Underpinning research ,1.1 Normal biological development and functioning ,Generic health relevance ,Cell Membrane ,Glycerophospholipids ,Homeostasis ,Mechanistic Target of Rapamycin Complex 1 ,Mechanistic Target of Rapamycin Complex 2 ,Membrane Proteins ,Protein Kinases ,Saccharomyces cerevisiae ,Saccharomyces cerevisiae Proteins ,Sphingolipids ,Sterols ,contact sites ,lipids ,membrane proteins ,phosphorylation ,plasma membrane ,protein kinases ,Chemical Sciences ,Medical and Health Sciences ,Biochemistry & Molecular Biology ,Biochemistry and cell biology - Abstract
As first demonstrated in budding yeast (Saccharomyces cerevisiae), all eukaryotic cells contain two, distinct multi-component protein kinase complexes that each harbor the TOR (Target Of Rapamycin) polypeptide as the catalytic subunit. These ensembles, dubbed TORC1 and TORC2, function as universal, centrally important sensors, integrators, and controllers of eukaryotic cell growth and homeostasis. TORC1, activated on the cytosolic surface of the lysosome (or, in yeast, on the cytosolic surface of the vacuole), has emerged as a primary nutrient sensor that promotes cellular biosynthesis and suppresses autophagy. TORC2, located primarily at the plasma membrane, plays a major role in maintaining the proper levels and bilayer distribution of all plasma membrane components (sphingolipids, glycerophospholipids, sterols, and integral membrane proteins). This article surveys what we have learned about signaling via the TORC2 complex, largely through studies conducted in S. cerevisiae. In this yeast, conditions that challenge plasma membrane integrity can, depending on the nature of the stress, stimulate or inhibit TORC2, resulting in, respectively, up-regulation or down-regulation of the phosphorylation and thus the activity of its essential downstream effector the AGC family protein kinase Ypk1. Through the ensuing effect on the efficiency with which Ypk1 phosphorylates multiple substrates that control diverse processes, membrane homeostasis is maintained. Thus, the major focus here is on TORC2, Ypk1, and the multifarious targets of Ypk1 and how the functions of these substrates are regulated by their Ypk1-mediated phosphorylation, with emphasis on recent advances in our understanding of these processes.
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- 2022
18. Effective quantum unique ergodicity for Hecke-Maass newforms and Landau-Siegel zeros
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Thorner, Jesse
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Mathematics - Number Theory - Abstract
We show that Landau-Siegel zeros for Dirichlet $L$-functions do not exist or quantum unique ergodicity for $\mathrm{GL}_2$ Hecke-Maass newforms holds with an effective rate of convergence. This follows from a more general result: Landau-Siegel zeros of Dirichlet $L$-functions repel the zeros of all other automorphic $L$-functions from the line $\mathrm{Re}(s)=1$., Comment: 11 pages
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- 2022
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19. Refinements to the prime number theorem for arithmetic progressions
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Thorner, Jesse and Zaman, Asif
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- 2024
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20. Short-interval sector problems for CM elliptic curves
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Panidapu, Apoorva and Thorner, Jesse
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Mathematics - Number Theory - Abstract
Let $E/\mathbb{Q}$ be an elliptic curve that has complex multiplication (CM) by an imaginary quadratic field $K$. For a prime $p$, there exists $\theta_p \in [0, \pi]$ such that $p+1-\#E(\mathbb{F}_p) = 2\sqrt{p} \cos \theta_p$. Let $x>0$ be large, and let $I\subseteq[0,\pi]$ be a subinterval. We prove that if $\delta>0$ and $\theta>0$ are fixed numbers such that $\delta+\theta<\frac{5}{24}$, $x^{1-\delta}\leq h\leq x$, and $|I|\geq x^{-\theta}$, then \[ \frac{1}{h}\sum_{\substack{x < p \le x+h \\ \theta_p \in I}}\log{p}\sim \frac{1}{2}\mathbf{1}_{\frac{\pi}{2}\in I}+\frac{|I|}{2\pi}, \] where $\mathbf{1}_{\frac{\pi}{2}\in I}$ equals 1 if $\frac{\pi}{2}\in I$ and $0$ otherwise. We also discuss an extension of this result to the distribution of the Fourier coefficients of holomorphic cuspidal CM newforms., Comment: 10 pages, significant revision after referee comments
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- 2021
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21. A Bombieri-Vinogradov theorem for higher rank groups
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Jiang, Yujiao, Lü, Guangshi, Thorner, Jesse, and Wang, Zihao
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Mathematics - Number Theory - Abstract
We establish a result of Bombieri-Vinogradov type for the Dirichlet coefficients at prime ideals of the standard $L$-function associated to a self-dual cuspidal automorphic representation $\pi$ of $\mathrm{GL}_n$ over a number field $F$ which is not a quadratic twist of itself. Our result does not rely on any unproven progress towards the generalized Ramanujan conjecture or the nonexistence of Landau-Siegel zeros. In particular, when $\pi$ is fixed and not equal to a quadratic twist of itself, we prove the first unconditional Siegel-type lower bound for the twisted $L$-values $|L(1,\pi\otimes\chi)|$ in the $\chi$-aspect, where $\chi$ is a primitive quadratic Hecke character over $F$. Our result improves the levels of distribution in other works that relied on these unproven hypotheses. As applications, when $n=2,3,4$, we prove a $\mathrm{GL}_n$ analogue of the Titchmarsh divisor problem and a nontrivial bound for a certain $\mathrm{GL}_n\times\mathrm{GL}_2$ shifted convolution sum., Comment: 40 pages. Added Section 3. Extended discussion of the Siegel zero problem in Section 4
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- 2021
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22. Zeros of Rankin-Selberg $L$-functions in families
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Humphries, Peter and Thorner, Jesse
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Mathematics - Number Theory - Abstract
Let $\mathfrak{F}_n$ be the set of all cuspidal automorphic representations $\pi$ of $\mathrm{GL}_n$ with unitary central character over a number field $F$. We prove the first unconditional zero density estimate for the set $\mathcal{S}=\{L(s,\pi\times\pi')\colon\pi\in\mathfrak{F}_n\}$ of Rankin-Selberg $L$-functions, where $\pi'\in\mathfrak{F}_{n'}$ is fixed. We use this density estimate to establish (i) a hybrid-aspect subconvexity bound at $s=\frac{1}{2}$ for almost all $L(s,\pi\times\pi')\in \mathcal{S}$, (ii) a strong on-average form of effective multiplicity one for almost all $\pi\in\mathfrak{F}_n$, and (iii) a positive level of distribution for $L(s,\pi\times\tilde{\pi})$, in the sense of Bombieri-Vinogradov, for each $\pi\in\mathfrak{F}_n$., Comment: 32 pages. Significant revision based on referee comments
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- 2021
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23. A zero density estimate and fractional imaginary parts of zeros for $\mathrm{GL}_2$ $L$-functions
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Beckwith, Olivia, Liu, Di, Thorner, Jesse, and Zaharescu, Alexandru
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Mathematics - Number Theory - Abstract
We prove an analogue of Selberg's zero density estimate for $\zeta(s)$ that holds for any $\mathrm{GL}_2$ $L$-function. We use this estimate to study the distribution of the vector of fractional parts of $\gamma\mathbf{\alpha}$, where $\mathbf{\alpha}\in\mathbb{R}^n$ is fixed and $\gamma$ varies over the imaginary parts of the nontrivial zeros of a $\mathrm{GL}_2$ $L$-function., Comment: 25 pages
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- 2021
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24. Towards a $\mathrm{GL}_n$ variant of the Hoheisel phenomenon
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Humphries, Peter and Thorner, Jesse
- Subjects
Mathematics - Number Theory - Abstract
Let $\pi$ be a unitary cuspidal automorphic representation of $\mathrm{GL}_n$ over a number field, and let $\tilde{\pi}$ be contragredient to $\pi$. We prove effective upper and lower bounds of the correct order in the short interval prime number theorem for the Rankin-Selberg $L$-function $L(s,\pi\times\tilde{\pi})$, extending the work of Hoheisel and Linnik. Along the way, we prove for the first time that $L(s,\pi\times\widetilde{\pi})$ has an unconditional standard zero-free region apart from a possible Landau-Siegel zero., Comment: 23 pages. Incorporates referee comments
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- 2020
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25. Zeros of $\mathrm{GL}_2$ $L$-functions on the critical line
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Andersen, Nickolas and Thorner, Jesse
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Mathematics - Number Theory - Abstract
We use Levinson's method and the work of Blomer and Harcos on the $\mathrm{GL}_2$ shifted convolution problem to prove that at least 6.96% of the zeros of the L-function of any holomorphic or Maass cusp form lie on the critical line., Comment: 15 pages
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- 2020
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26. Almost all primes satisfy the Atkin-Serre conjecture and are not extremal
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Gafni, Ayla, Thorner, Jesse, and Wong, Peng-Jie
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Mathematics - Number Theory - Abstract
Let $f(z)=\sum_{n=1}^{\infty} a_f(n)e^{2\pi i n z}$ be a non-CM holomorphic cupsidal newform of trivial nebentypus and even integral level $k\geq 2$. Deligne's proof of the Weil conjectures shows that $|a_f(p)|\leq 2p^{\frac{k-1}{2}}$ for all primes $p$. We prove for 100% of primes $p$ that $2p^{\frac{k-1}{2}}\frac{\log\log p}{\sqrt{\log p}}<|a_f(p)|<\lfloor 2p^{\frac{k-1}{2}}\rfloor$. Our proof gives an effective upper bound for the size of the exceptional set. The lower bound shows that the Atkin-Serre conjecture is satisfied for 100% of primes, and the upper bound shows that $|a_f(p)|$ is as large as possible (i.e., $p$ is extremal for $f$) for 0% of primes. Our proofs use the effective form of the Sato-Tate conjecture proved by the second author, which relies on the recent proof of the automorphy of the symmetric powers of $f$ due to Newton and Thorne., Comment: Condition requiring squarefree level is removed. Title change
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- 2020
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27. Targeting Depressive Symptoms in Younger Breast Cancer Survivors: The Pathways to Wellness Randomized Controlled Trial of Mindfulness Meditation and Survivorship Education
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Bower, Julienne E, Partridge, Ann H, Wolff, Antonio C, Thorner, Elissa D, Irwin, Michael R, Joffe, Hadine, Petersen, Laura, Crespi, Catherine M, and Ganz, Patricia A
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Mental Health ,Prevention ,Brain Disorders ,Depression ,Clinical Research ,Breast Cancer ,Cancer ,Women's Health ,Behavioral and Social Science ,Mind and Body ,Rehabilitation ,Clinical Trials and Supportive Activities ,Mental Illness ,Complementary and Integrative Health ,Good Health and Well Being ,Adult ,Breast Neoplasms ,Cancer Survivors ,Case-Control Studies ,Fatigue ,Female ,Follow-Up Studies ,Humans ,Meditation ,Middle Aged ,Mindfulness ,Quality of Life ,Retrospective Studies ,Sleep Initiation and Maintenance Disorders ,Survivorship ,Treatment Outcome ,Young Adult ,Clinical Sciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
PurposeYounger women are at risk for depression and related symptoms following breast cancer. The Pathways to Wellness study, a randomized, multi-institution, three-arm trial, tested the efficacy of two behavioral interventions for younger breast cancer survivors with elevated depressive symptoms: mindful awareness practices (MAPs) and survivorship education (SE) (Clincaltrials.gov identifier: NCT03025139).MethodsWomen diagnosed with breast cancer at or before 50 years of age who had completed treatment and had elevated depressive symptoms were randomly assigned to 6 weeks of MAPs, SE, or wait-list control (WLC). Assessments were conducted preintervention and postintervention and at 3-month and 6-month postintervention follow-ups. Analyses compared each intervention to WLC using linear mixed models. The primary outcome was change in depressive symptoms from preintervention to postintervention on the Center for Epidemiologic Studies-Depression Scale; secondary outcomes included change in fatigue, insomnia, and vasomotor symptoms.ResultsTwo hundred forty-seven women (median age = 46 years) were randomly assigned to MAPs (n = 85), SE (n = 81), or WLC (n = 81). MAPs and SE led to significant decreases in depressive symptoms from preintervention to postintervention relative to WLC (mean change relative to WLC [95% CI]: MAPs, -4.7 [-7.5 to -1.9]; SE, -4.0 [-6.9 to -1.1]), which persisted at 6-month follow-up for MAPs (mean change relative to WLC [95% CI]: MAPs, -3.7 [-6.6 to -0.8]; SE, -2.8 [-5.9 to 0.2]). MAPs, but not SE, also had beneficial effects on fatigue, insomnia, and vasomotor symptoms that persisted at 6-month follow-up (P < .05).ConclusionMindfulness meditation and SE reduced depressive symptoms in younger breast cancer survivors. These interventions can be widely disseminated over virtual platforms and have significant potential benefit for quality of life and overall survivorship in this vulnerable group.
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- 2021
28. Cdc42-Specific GTPase-Activating Protein Rga1 Squelches Crosstalk between the High-Osmolarity Glycerol (HOG) and Mating Pheromone Response MAPK Pathways.
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Patterson, Jesse C, Goupil, Louise S, and Thorner, Jeremy
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cell regulation ,protein phosphorylation ,reporters ,signal insulation ,single-cell analysis ,transcriptional ,1.1 Normal biological development and functioning ,Generic health relevance ,Biochemistry and Cell Biology - Abstract
Eukaryotes utilize distinct mitogen/messenger-activated protein kinase (MAPK) pathways to evoke appropriate responses when confronted with different stimuli. In yeast, hyperosmotic stress activates MAPK Hog1, whereas mating pheromones activate MAPK Fus3 (and MAPK Kss1). Because these pathways share several upstream components, including the small guanosine-5'-triphosphate phosphohydrolase (GTPase) cell-division-cycle-42 (Cdc42), mechanisms must exist to prevent inadvertent cross-pathway activation. Hog1 activity is required to prevent crosstalk to Fus3 and Kss1. To identify other factors required to maintain signaling fidelity during hypertonic stress, we devised an unbiased genetic selection for mutants unable to prevent such crosstalk even when active Hog1 is present. We repeatedly isolated truncated alleles of RGA1, a Cdc42-specific GTPase-activating protein (GAP), each lacking its C-terminal catalytic domain, that permit activation of the mating MAPKs under hyperosmotic conditions despite Hog1 being present. We show that Rga1 down-regulates Cdc42 within the high-osmolarity glycerol (HOG) pathway, but not the mating pathway. Because induction of mating pathway output via crosstalk from the HOG pathway takes significantly longer than induction of HOG pathway output, our findings suggest that, under normal conditions, Rga1 contributes to signal insulation by limiting availability of the GTP-bound Cdc42 pool generated by hypertonic stress. Thus, Rga1 action contributes to squelching crosstalk by imposing a type of "kinetic proofreading". Although Rga1 is a Hog1 substrate in vitro, we eliminated the possibility that its direct Hog1-mediated phosphorylation is necessary for its function in vivo. Instead, we found first that, like its paralog Rga2, Rga1 is subject to inhibitory phosphorylation by the S. cerevisiae cyclin-dependent protein kinase 1 (Cdk1) ortholog Cdc28 and that hyperosmotic shock stimulates its dephosphorylation and thus Rga1 activation. Second, we found that Hog1 promotes Rga1 activation by blocking its Cdk1-mediated phosphorylation, thereby allowing its phosphoprotein phosphatase 2A (PP2A)-mediated dephosphorylation. These findings shed light on why Hog1 activity is required to prevent crosstalk from the HOG pathway to the mating pheromone response pathway.
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- 2021
29. Phosphorylation of mRNA-Binding Proteins Puf1 and Puf2 by TORC2-Activated Protein Kinase Ypk1 Alleviates Their Repressive Effects.
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Galez, Henri A, Roelants, Françoise M, Palm, Sarah M, Reynaud, Kendra K, Ingolia, Nicholas T, and Thorner, Jeremy
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Pumilio family RNA-binding proteins ,Saccharomyces cerevisiae ,cell signaling ,plasma membrane homeostasis ,Chemical Engineering ,Civil Engineering ,Environmental Engineering - Abstract
Members of the Puf family of RNA-binding proteins typically associate via their Pumilio homology domain with specific short motifs in the 3'-UTR of an mRNA and thereby influence the stability, localization and/or efficiency of translation of the bound transcript. In our prior unbiased proteome-wide screen for targets of the TORC2-stimulated protein kinase Ypk1, we identified the paralogs Puf1/Jsn1 and Puf2 as high-confidence substrates. Earlier work by others had demonstrated that Puf1 and Puf2 exhibit a marked preference for interaction with mRNAs encoding plasma membrane-associated proteins, consistent with our previous studies documenting that a primary physiological role of TORC2-Ypk1 signaling is maintenance of plasma membrane homeostasis. Here, we show, first, that both Puf1 and Puf2 are authentic Ypk1 substrates both in vitro and in vivo. Fluorescently tagged Puf1 localizes constitutively in cortical puncta closely apposed to the plasma membrane, whereas Puf2 does so in the absence of its Ypk1 phosphorylation, but is dispersed in the cytosol when phosphorylated. We further demonstrate that Ypk1-mediated phosphorylation of Puf1 and Puf2 upregulates production of the protein products of the transcripts to which they bind, with a concomitant increase in the level of the cognate mRNAs. Thus, Ypk1 phosphorylation relieves Puf1- and Puf2-mediated post-transcriptional repression mainly by counteracting their negative effect on transcript stability. Using a heterologous protein-RNA tethering and fluorescent protein reporter assay, the consequence of Ypk1 phosphorylation in vivo was recapitulated for full-length Puf1 and even for N-terminal fragments (residues 1-340 and 143-295) corresponding to the region upstream of its dimerization domain (an RNA-recognition motif fold) encompassing its two Ypk1 phosphorylation sites (both also conserved in Puf2). This latter result suggests that alleviation of Puf1-imposed transcript destabilization does not obligatorily require dissociation of Ypk1-phosphorylated Puf1 from a transcript. Our findings add new insight about how the TORC2-Ypk1 signaling axis regulates the content of plasma membrane-associated proteins to promote maintenance of the integrity of the cell envelope.
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- 2021
30. Screening for Depression in Younger Breast Cancer Survivors: Outcomes From Use of the 9-item Patient Health Questionnaire.
- Author
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Ganz, Patricia A, Bower, Julienne E, Partridge, Ann H, Wolff, Antonio C, Thorner, Elissa D, Joffe, Hadine, Irwin, Michael R, Petersen, Laura, and Crespi, Catherine M
- Abstract
BackgroundMajor cancer organizations recommend depression screening in patients and survivors. The 9-item Patient Health Questionnaire (PHQ-9) is often suggested, with limited information about its use.MethodsEnrollment data collected from younger breast cancer survivors participating in a behavioral intervention trial were used to examine the relationship between PHQ-9 scores (range = 0-27), patient characteristics, and responses to standardized psychosocial assessment tools. Major depressive disorder criterion was met if responses to the first 2 PHQ-9 items (range = 0-6) were 3 or greater. The sample was categorized by total PHQ-9 scores: less than 5 (minimal depressive symptoms), 5-9 (mild to moderate depressive symptoms), and 10 or greater (moderate to severe depression). PHQ-9 category associations with medical, demographic, psychosocial, and behavioral characteristics were examined using analysis of variance for continuous variables and χ2 tests for categorical variables.ResultsA total of 231 women met the study prescreening eligibility criterion of mild depressive symptoms and enrolled in the study. On average, they were 45.2 years old and 2.6 years since diagnosis. At enrollment, 22.1% met the screening criterion for possible major depressive disorder; among those with PHQ-9 scores of 10 or greater, 58.3% met this criterion. Anxiety, fatigue, insomnia, and intrusive thoughts about cancer were frequent and were associated with depressive symptom severity (all P < .001). In contrast, neither demographic nor cancer treatment characteristics were associated with depressive symptoms.ConclusionsDepressive symptoms in this selected sample of younger breast cancer survivors were independent of demographic characteristics or cancer treatment history, suggesting that depression screening is necessary to detect uncontrolled depressive symptoms.
- Published
- 2021
31. Screening for Depression in Younger Breast Cancer Survivors: Outcomes from Use of the Patient Health Questionnaire-9 (PHQ-9)
- Author
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Ganz, Patricia A, Bower, Julienne E, Partridge, Ann H, Wolff, Antonio C, Thorner, Elissa D, Joffe, Hadine, Irwin, Michael R, Petersen, Laura, and Crespi, Catherine M
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Mental Illness ,Mental Health ,Depression ,Cancer ,Breast Cancer ,Women's Health ,Behavioral and Social Science ,Brain Disorders ,Clinical Research ,7.3 Management and decision making ,Mental health ,Good Health and Well Being ,Analysis of Variance ,Anxiety ,Breast Neoplasms ,Cancer Survivors ,Chi-Square Distribution ,Depressive Disorder ,Major ,Fatigue ,Female ,Humans ,Middle Aged ,Patient Health Questionnaire ,Sleep Initiation and Maintenance Disorders ,Symptom Assessment ,Thinking ,Oncology and carcinogenesis - Abstract
BackgroundMajor cancer organizations recommend depression screening in patients and survivors. The 9-item Patient Health Questionnaire (PHQ-9) is often suggested, with limited information about its use.MethodsEnrollment data collected from younger breast cancer survivors participating in a behavioral intervention trial were used to examine the relationship between PHQ-9 scores (range = 0-27), patient characteristics, and responses to standardized psychosocial assessment tools. Major depressive disorder criterion was met if responses to the first 2 PHQ-9 items (range = 0-6) were 3 or greater. The sample was categorized by total PHQ-9 scores: less than 5 (minimal depressive symptoms), 5-9 (mild to moderate depressive symptoms), and 10 or greater (moderate to severe depression). PHQ-9 category associations with medical, demographic, psychosocial, and behavioral characteristics were examined using analysis of variance for continuous variables and χ2 tests for categorical variables.ResultsA total of 231 women met the study prescreening eligibility criterion of mild depressive symptoms and enrolled in the study. On average, they were 45.2 years old and 2.6 years since diagnosis. At enrollment, 22.1% met the screening criterion for possible major depressive disorder; among those with PHQ-9 scores of 10 or greater, 58.3% met this criterion. Anxiety, fatigue, insomnia, and intrusive thoughts about cancer were frequent and were associated with depressive symptom severity (all P < .001). In contrast, neither demographic nor cancer treatment characteristics were associated with depressive symptoms.ConclusionsDepressive symptoms in this selected sample of younger breast cancer survivors were independent of demographic characteristics or cancer treatment history, suggesting that depression screening is necessary to detect uncontrolled depressive symptoms.
- Published
- 2021
32. Effective forms of the Sato--Tate conjecture
- Author
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Thorner, Jesse
- Subjects
Mathematics - Number Theory - Abstract
We prove effective forms of the Sato-Tate conjecture for holomorphic cuspidal newforms which improve on the author's previous work (solo and joint with Lemke Oliver). We also prove an effective form of the joint Sato-Tate distribution for two twist-inequivalent newforms. Our results are unconditional because of recent work of Newton and Thorne., Comment: 19 pages. The condition that the level be squarefree is removed
- Published
- 2020
- Full Text
- View/download PDF
33. Jensen Polynomials for the Riemann Xi Function
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Griffin, Michael, Ono, Ken, Rolen, Larry, Thorner, Jesse, Tripp, Zachary, and Wagner, Ian
- Subjects
Mathematics - Number Theory - Abstract
We investigate Riemann's xi function $\xi(s):=\frac{1}{2}s(s-1)\pi^{-\frac{s}{2}}\Gamma(\frac{s}{2})\zeta(s)$ (here $\zeta(s)$ is the Riemann zeta function). The Riemann Hypothesis (RH) asserts that if $\xi(s)=0$, then $\mathrm{Re}(s)=\frac{1}{2}$. P\'olya proved that RH is equivalent to the hyperbolicity of the Jensen polynomials $J^{d,n}(X)$ constructed from certain Taylor coefficients of $\xi(s)$. For each $d\geq 1$, recent work proves that $J^{d,n}(X)$ is hyperbolic for sufficiently large $n$. Here we make this result effective. Moreover, we show how the low-lying zeros of the derivatives $\xi^{(n)}(s)$ influence the hyperbolicity of $J^{d,n}(X)$., Comment: 13 pages. This revision represents a major revision of the previous version. The exposition has been improved and many clarifications have been added. Moreover, Theorem 1.1 has been improved
- Published
- 2019
- Full Text
- View/download PDF
34. A zero density estimate for Dedekind zeta functions
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Thorner, Jesse and Zaman, Asif
- Subjects
Mathematics - Number Theory - Abstract
Given a nontrivial finite group $G$, we prove the first zero density estimate for families of Dedekind zeta functions associated to Galois extensions $K/\mathbb{Q}$ with $\mathrm{Gal}(K/\mathbb{Q})\cong G$ that does not rely on unproven progress towards the strong form of Artin's conjecture. We use this to remove the hypothesis of the strong Artin conjecture from the work of Pierce, Turnage-Butterbaugh, and Wood on the average error in the Chebotarev density theorem and $\ell$-torsion in ideal class groups., Comment: Considerably streamlined, small refinements to Theorems 1.1 and 1.2. 14 pages
- Published
- 2019
- Full Text
- View/download PDF
35. The Explicit Sato-Tate Conjecture For Primes In Arithmetic Progressions
- Author
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Hammonds, Trajan, Kothari, Casimir, Luntzlara, Noah, Miller, Steven J., Thorner, Jesse, and Wieman, Hunter
- Subjects
Mathematics - Number Theory ,11F30, 11M41, 11N13 - Abstract
Let $\tau(n)$ be Ramanujan's tau function, defined by the discriminant modular form \[ \Delta(z) = q\prod_{j=1}^{\infty}(1-q^{j})^{24}\ =\ \sum_{n=1}^{\infty}\tau(n) q^n \,,q=e^{2\pi i z} \] (this is the unique holomorphic normalized cuspidal newform of weight 12 and level 1). Lehmer's conjecture asserts that $\tau(n)\neq 0$ for all $n\geq 1$; since $\tau(n)$ is multiplicative, it suffices to study primes $p$ for which $\tau(p)$ might possibly be zero. Assuming standard conjectures for the twisted symmetric power $L$-functions associated to $\tau$ (including GRH), we prove that if $x\geq 10^{50}$, then \[ \#\{x < p\leq 2x: \tau(p) = 0\} \leq 1.22 \times 10^{-5} \frac{x^{3/4}}{\sqrt{\log x}},\] a substantial improvement on the implied constant in previous work. To achieve this, under the same hypotheses, we prove an explicit version of the Sato-Tate conjecture for primes in arithmetic progressions., Comment: 16 pages, fixed typographical errors and minor computational details. To be published in the International Journal of Number Theory
- Published
- 2019
- Full Text
- View/download PDF
36. An unconditional $\mathrm{GL}(n)$ large sieve
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Thorner, Jesse and Zaman, Asif
- Subjects
Mathematics - Number Theory - Abstract
Let $\mathfrak{F}_n$ be the set of all cuspidal automorphic representations $\pi$ of $\mathrm{GL}_n$ over a number field with unitary central character. We prove two unconditional large sieve inequalities for the Hecke eigenvalues of $\pi\in\mathfrak{F}_n$, one on the integers and one on the primes. The second leads to the first unconditional zero density estimate for the family of $L$-functions $L(s,\pi)$ associated to $\pi\in\mathfrak{F}_n$, which we make log-free. As an application of the zero density estimate, we prove a hybrid subconvexity bound for $L(\frac{1}{2},\pi)$ for a density one subset of $\pi\in\mathfrak{F}_n$., Comment: 17 pages. Incorporates referee comments
- Published
- 2019
- Full Text
- View/download PDF
37. TORC2-Dependent Ypk1-Mediated Phosphorylation of Lam2/Ltc4 Disrupts Its Association with the β-Propeller Protein Laf1 at Endoplasmic Reticulum-Plasma Membrane Contact Sites in the Yeast Saccharomyces cerevisiae.
- Author
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Topolska, Magdalena, Roelants, Françoise M, Si, Edward P, and Thorner, Jeremy
- Subjects
ergosterol ,homeostasis ,membrane contact sites ,protein kinases ,regulation ,Biochemistry and Cell Biology - Abstract
Membrane-tethered sterol-binding Lam/Ltc proteins localize at junctions between the endoplasmic reticulum (ER) membrane and other organelles. Two of the six family members-Lam2/Ltc4 (initially Ysp2) and paralog Lam4/Ltc3-localize to ER-plasma membrane (PM) contact sites (CSs) and mediate retrograde ergosterol transport from the PM to the ER. Our prior work demonstrated that Lam2 and Lam4 are substrates of TORC2-regulated protein kinase Ypk1, that Ypk1-mediated phosphorylation inhibits their function in retrograde sterol transport, and that PM sterol retention bolsters cell survival under stressful conditions. At ER-PM CSs, Lam2 and Lam4 associate with Laf1/Ymr102c and Dgr2/Ykl121w (paralogous WD40 repeat-containing proteins) that reportedly bind sterol. Using fluorescent tags, we found that Lam2 and Lam4 remain at ER-PM CSs when Laf1 and Dgr2 are absent, whereas neither Laf1 nor Dgr2 remain at ER-PM CSs when Lam2 and Lam4 are absent. Loss of Laf1 (but not Dgr2) impedes retrograde ergosterol transport, and a laf1∆ mutation does not exacerbate the transport defect of lam2∆ lam4∆ cells, indicating a shared function. Lam2 and Lam4 bind Laf1 and Dgr2 in vitro in a pull-down assay, and the PH domain in Lam2 hinders its interaction with Laf1. Lam2 phosphorylated by Ypk1, and Lam2 with phosphomimetic (Glu) replacements at its Ypk1 sites, exhibited a marked reduction in Laf1 binding. Thus, phosphorylation prevents Lam2 interaction with Laf1 at ER-PM CSs, providing a mechanism by which Ypk1 action inhibits retrograde sterol transport.
- Published
- 2020
38. Editorial overview 'Network news: Reporting from the frontlines of cell signaling'.
- Author
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Ablasser, Andrea and Thorner, Jeremy
- Subjects
Cell regulation ,Intercellular communication ,Signal transduction ,Signaling mechanisms ,Developmental Biology ,Biochemistry and Cell Biology - Published
- 2020
39. Adverse prognostic impact of the loss of STAG2 protein expression in patients with newly diagnosed localised Ewing sarcoma: A report from the Children’s Oncology Group
- Author
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Shulman, David S., Chen, Sonja, Hall, David, Nag, Anwesha, Thorner, Aaron R., Lessnick, Stephen L., Stegmaier, Kimberly, Janeway, Katherine A., DuBois, Steven G., Krailo, Mark D., Barkauskas, Donald A., Church, Alanna J., and Crompton, Brian D.
- Published
- 2022
- Full Text
- View/download PDF
40. Factors associated with worsening sexual function during adjuvant endocrine therapy in a prospective clinic-based cohort of women with early-stage breast cancer
- Author
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Verma, Neha, Blackford, Amanda L., Thorner, Elissa, Lehman, Jennifer, Snyder, Claire, Stearns, Vered, and Smith, Karen Lisa
- Published
- 2022
- Full Text
- View/download PDF
41. Phosphorylation by the stress-activated MAPK Slt2 down-regulates the yeast TOR complex 2
- Author
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Leskoske, Kristin L., Roelants, Françoise M., Emmerstorfer-Augustin, Anita, Augustin, Christoph M., Si, Edward P., Hill, Jennifer M., and Thorner, Jeremy
- Subjects
Quantitative Biology - Cell Behavior - Abstract
Saccharomyces cerevisiae target of rapamycin (TOR) complex 2 (TORC2) is an essential regulator of plasma membrane lipid and protein homeostasis. How TORC2 activity is modulated in response to changes in the status of the cell envelope is unclear. Here we document that TORC2 subunit Avo2 is a direct target of Slt2, the mitogen-activated protein kinase (MAPK) of the cell wall integrity pathway. Activation of Slt2 by overexpression of a constitutively active allele of an upstream Slt2 activator (Pkc1) or by auxin-induced degradation of a negative Slt2 regulator (Sln1) caused hyperphosphorylation of Avo2 at its MAPK phosphoacceptor sites in a Slt2-dependent manner and diminished TORC2-mediated phosphorylation of its major downstream effector, protein kinase Ypk1. Deletion of Avo2 or expression of a phosphomimetic Avo2 allele rendered cells sensitive to two stresses (myriocin treatment and elevated exogenous acetic acid) that the cell requires Ypk1 activation by TORC2 to survive. Thus, Avo2 is necessary for optimal TORC2 activity, and Slt2-mediated phosphorylation of Avo2 down-regulates TORC2 signaling. Compared with wild-type Avo2, phosphomimetic Avo2 shows significant displacement from the plasma membrane, suggesting that Slt2 inhibits TORC2 by promoting Avo2 dissociation. Our findings are the first demonstration that TORC2 function is regulated by MAPK-mediated phosphorylation., Comment: This work was supported by National Institutes of Health (NIH) Predoctoral Traineeship GM07232 and a University of California at Berkeley MacArthur and Lakhan-Pal Graduate Fellowship to K.L.L., Erwin Schroedinger Fellowship J3787-B21 from the Austrian Science Fund to AE-A, Marie Sklodowska-Curie Action H2020-MSCA-IF-2016 InsiliCardio, GA 75083 to CMA, and NIH R01 research grant GM21841 to JT
- Published
- 2019
- Full Text
- View/download PDF
42. Tracking yeast pheromone receptor Ste2 endocytosis using fluorogen-activating protein tagging
- Author
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Emmerstorfer-Augustin, Anita, Augustin, Christoph M., Shams, Shadi, and Thorner, Jeremy
- Subjects
Quantitative Biology - Cell Behavior - Abstract
To observe internalization of the yeast pheromone receptor Ste2 by fluorescence microscopy in live cells in real time, we visualized only those molecules present at the cell surface at the time of agonist engagement (rather than the total cellular pool) by tagging this receptor at its N-terminus with an exocellular fluorogen-activating protein (FAP). A FAP is a single-chain antibody engineered to bind tightly a nonfluorescent, cell-impermeable dye (fluorogen), thereby generating a fluorescent complex. The utility of FAP tagging to study trafficking of integral membrane proteins in yeast, which possesses a cell wall, had not been examined previously. A diverse set of signal peptides and propeptide sequences were explored to maximize expression. Maintenance of the optimal FAP-Ste2 chimera intact required deletion of two, paralogous, glycosylphosphatidylinositol (GPI)-anchored extracellular aspartyl proteases (Yps1 and Mkc7). FAP-Ste2 exhibited a much brighter and distinct plasma membrane signal than Ste2-GFP or Ste2-mCherry yet behaved quite similarly. Using FAP-Ste2, new information was obtained about the mechanism of its internalization, including novel insights about the roles of the cargo-selective endocytic adaptors Ldb19/Art1, Rod1/Art4, and Rog3/Art7., Comment: This work was supported by Erwin Schroedinger Fellowship J3787-B21 from the Austrian Science Fund and by National Institutes of Health (NIH) R01 Research Grant GM21841. Additionally, this project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Action H2020-MSCA-IF-2016 InsiliCardio, GA No. 750835
- Published
- 2019
- Full Text
- View/download PDF
43. Zeros of Rankin-Selberg $L$-functions at the edge of the critical strip
- Author
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Brumley, Farrell, Thorner, Jesse, and Zaman, Asif
- Subjects
Mathematics - Number Theory - Abstract
Let $\pi$ and $\pi_0$ be unitary cuspidal automorphic representations. We prove log-free zero density estimates for Rankin-Selberg $L$-functions of the form $L(s,\pi\times\pi_0)$, where $\pi$ varies in a given family and $\pi_0$ is fixed. These estimates are unconditional in many cases of interest; they hold in full generality assuming an average form of the generalized Ramanujan conjecture. We consider applications of these estimates related to mass equidistribution for Hecke-Maass forms, the rarity of Landau-Siegel zeros of Rankin-Selberg $L$-functions, the Chebotarev density theorem, and $\ell$-torsion in class groups of number fields., Comment: 53 pages. Farrell Brumley added as coauthor. Added two appendices, one of which is authored by Colin Bushnell and Guy Henniart. Theorem 1.3 added, leads to cleaner versions of Theorems 1.2 and 1.4
- Published
- 2018
- Full Text
- View/download PDF
44. Weak subconvexity without a Ramanujan hypothesis
- Author
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Soundararajan, Kannan and Thorner, Jesse
- Subjects
Mathematics - Number Theory - Abstract
We describe a new method to obtain weak subconvexity bounds for $L$-functions with mild hypotheses on the size of the Dirichlet coefficients. We verify these hypotheses for all automorphic $L$-functions and (with mild restrictions) the Rankin-Selberg $L$-functions attached to two automorphic representations. The proof relies on a new unconditional log-free zero density estimate for Rankin-Selberg $L$-functions., Comment: 25 pages. Appendix by Farrell Brumley. Referee comments incorporated
- Published
- 2018
- Full Text
- View/download PDF
45. A unified and improved Chebotarev density theorem
- Author
-
Thorner, Jesse and Zaman, Asif
- Subjects
Mathematics - Number Theory ,11R44 - Abstract
We establish an unconditional effective Chebotarev density theorem that improves uniformly over the well-known result of Lagarias and Odlyzko. As a consequence, we give a new asymptotic form of the Chebotarev density theorem that can count much smaller primes with arbitrary log-power savings, even in the case where a Landau-Siegel zero is present. Our main theorem interpolates the strongest unconditional upper bound for the least prime ideal with a given Artin symbol as well as the Chebotarev analogue of the Brun-Titchmarsh theorem proved by the authors. We also present a new application of our main result that exhibits considerable gains over earlier versions of the Chebotarev density theorem. If $f$ is a positive definite primitive binary quadratic form then we count lattice points $(u,v) \in \mathbb{Z}^2$ such that $f(u,v)$ is prime and $u, v$ have no prime factors $\leq z$ with uniformity in $z$ and the discriminant of $f$., Comment: 26 pages; v3 intro revised and application added in Sections 6 and 7; typos corrected
- Published
- 2018
- Full Text
- View/download PDF
46. Turning it inside out: The organization of human septin heterooligomers.
- Author
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McMurray, Michael and Thorner, Jeremy
- Subjects
X-ray crystallography ,cytoskeleton ,electron microscopy ,oligomerization ,polymerization ,protein structure ,septins ,Crystallography ,X-Ray ,Cytoskeleton ,Humans ,Phylogeny ,Septins - Abstract
Septin family proteins are quite similar to each other both within and between eukaryotic species. Typically, multiple discrete septins co-assemble into linear heterooligomers (usually hexameric or octameric rods) with a variety of cellular functions. We know little about how incorporation of different septins confers different properties to such complexes. This issue is especially acute in human cells where 13 separate septin gene products (often produced in multiple forms arising from alternative start codons and differential splicing) are expressed in a tissue-specific manner. Based on sequence alignments and phylogenetic criteria, human septins fall into four distinct groups predictive of their interactions, that is, members of the same group appear to occupy the same position within oligomeric septin protomers, which are palindromic (have twofold rotational symmetry about a central homodimeric pair). Many such protomers are capable of end-to-end polymerization, generating filaments. Over a decade ago, a study using X-ray crystallography and single-particle electron microscopy deduced the arrangement within recombinant heterohexamers comprising representatives of three human septin groups-SEPT2, SEPT6, and SEPT7. This model greatly influenced subsequent studies of human and other septin complexes, including how incorporating a septin from a fourth group forms heterooctamers, as first observed in budding yeast. Two recent studies, including one in this issue of Cytoskeleton, provide clear evidence that, in fact, the organization of subunits within human septin heterohexamers and heterooctamers is inverted relative to the original model. These findings are discussed here in a broader context, including possible causes for the initial confusion.
- Published
- 2019
47. Analysis of the roles of phosphatidylinositol-4,5-bisphosphate and individual subunits in assembly, localization, and function of Saccharomyces cerevisiae target of rapamycin complex 2
- Author
-
Marshall, Maria Nieves Martinez, Emmerstorfer-Augustin, Anita, Leskoske, Kristin L, Zhang, Lydia H, Li, Biyun, and Thorner, Jeremy
- Subjects
Underpinning research ,1.1 Normal biological development and functioning ,Generic health relevance ,Armadillo Domain Proteins ,Carrier Proteins ,Cell Membrane ,Mechanistic Target of Rapamycin Complex 2 ,Phosphatidylinositol 4 ,5-Diphosphate ,Protein Domains ,Protein Subunits ,Saccharomyces cerevisiae ,Saccharomyces cerevisiae Proteins ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Eukaryotic cell survival requires maintenance of plasma membrane (PM) homeostasis in response to environmental insults and changes in lipid metabolism. In yeast, a key regulator of PM homeostasis is target of rapamycin (TOR) complex 2 (TORC2), a multiprotein complex containing the evolutionarily conserved TOR protein kinase isoform Tor2. PM localization is essential for TORC2 function. One core TORC2 subunit (Avo1) and two TORC2--associated regulators (Slm1 and Slm2) contain pleckstrin homology (PH) domains that exhibit specificity for binding phosphatidylinositol-4,5-bisphosphate (PtdIns4,5P2). To investigate the roles of PtdIns4,5P2 and constituent subunits of TORC2, we used auxin-inducible degradation to systematically eliminate these factors and then examined localization, association, and function of the remaining TORC2 components. We found that PtdIns4,5P2 depletion significantly reduced TORC2 activity, yet did not prevent PM localization or disassembly of TORC2. Moreover, truncated Avo1 (lacking its C-terminal PH domain) was still recruited to the PM and supported growth. Even when all three PH-containing proteins were absent, the remaining TORC2 subunits were PM-bound. Revealingly, Avo3 localized to the PM independent of both Avo1 and Tor2, whereas both Tor2 and Avo1 required Avo3 for their PM anchoring. Our findings provide new mechanistic information about TORC2 and pinpoint Avo3 as pivotal for TORC2 PM localization and assembly in vivo.
- Published
- 2019
48. Analysis of the roles of phosphatidylinositol-4,5-bisphosphate and individual subunits in assembly, localization, and function of Saccharomyces cerevisiae target of rapamycin complex 2.
- Author
-
Martinez Marshall, Maria Nieves, Emmerstorfer-Augustin, Anita, Leskoske, Kristin L, Zhang, Lydia H, Li, Biyun, and Thorner, Jeremy
- Subjects
Cell Membrane ,Saccharomyces cerevisiae ,Phosphatidylinositol 4 ,5-Diphosphate ,Carrier Proteins ,Saccharomyces cerevisiae Proteins ,Protein Subunits ,Armadillo Domain Proteins ,Protein Domains ,Mechanistic Target of Rapamycin Complex 2 ,Phosphatidylinositol 4 ,5-Diphosphate ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Eukaryotic cell survival requires maintenance of plasma membrane (PM) homeostasis in response to environmental insults and changes in lipid metabolism. In yeast, a key regulator of PM homeostasis is target of rapamycin (TOR) complex 2 (TORC2), a multiprotein complex containing the evolutionarily conserved TOR protein kinase isoform Tor2. PM localization is essential for TORC2 function. One core TORC2 subunit (Avo1) and two TORC2--associated regulators (Slm1 and Slm2) contain pleckstrin homology (PH) domains that exhibit specificity for binding phosphatidylinositol-4,5-bisphosphate (PtdIns4,5P2). To investigate the roles of PtdIns4,5P2 and constituent subunits of TORC2, we used auxin-inducible degradation to systematically eliminate these factors and then examined localization, association, and function of the remaining TORC2 components. We found that PtdIns4,5P2 depletion significantly reduced TORC2 activity, yet did not prevent PM localization or disassembly of TORC2. Moreover, truncated Avo1 (lacking its C-terminal PH domain) was still recruited to the PM and supported growth. Even when all three PH-containing proteins were absent, the remaining TORC2 subunits were PM-bound. Revealingly, Avo3 localized to the PM independent of both Avo1 and Tor2, whereas both Tor2 and Avo1 required Avo3 for their PM anchoring. Our findings provide new mechanistic information about TORC2 and pinpoint Avo3 as pivotal for TORC2 PM localization and assembly in vivo.
- Published
- 2019
49. Regulation of TORC2 function and localization by Rab5 GTPases in Saccharomyces cerevisiae
- Author
-
Locke, Melissa N and Thorner, Jeremy
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Genetics ,Underpinning research ,1.1 Normal biological development and functioning ,Generic health relevance ,Glycogen Synthase Kinase 3 ,Guanine Nucleotide Exchange Factors ,Humans ,Mechanistic Target of Rapamycin Complex 2 ,Models ,Molecular ,Saccharomyces cerevisiae ,Saccharomyces cerevisiae Proteins ,Signal Transduction ,Up-Regulation ,rab5 GTP-Binding Proteins ,Growth control ,protein kinase ,phosphorylation ,plasma membrane ,endocytosis ,guanine nucleotide ,mutants ,Developmental Biology ,Biochemistry and cell biology - Abstract
The evolutionarily conserved Target of Rapamycin (TOR) complex-2 (TORC2) is an essential regulator of plasma membrane homeostasis in budding yeast (Saccharomyces cerevisiae). In this yeast, TORC2 phosphorylates and activates the effector protein kinase Ypk1 and its paralog Ypk2. These protein kinases, in turn, carry out all the crucial functions of TORC2 by phosphorylating and thereby controlling the activity of at least a dozen downstream substrates. A previously uncharacterized interplay between the Rab5 GTPases and TORC2 signaling was uncovered through analysis of a newly suspected Ypk1 target. Muk1, one of two guanine nucleotide exchange factors for the Rab5 GTPases, was found to be a physiologically relevant Ypk1 substrate; and, genetic analysis indicates that Ypk1-mediated phosphorylation activates the guanine nucleotide exchange activity of Muk1. Second, it was demonstrated both in vivo and in vitro that the GTP-bound state of the Rab5 GTPase Vps21/Ypt51 physically associates with TORC2 and acts as a direct positive effector required for full TORC2 activity. These interrelationships provide a self-reinforcing control circuit for sustained up-regulation of TORC2-Ypk1 signaling. In this overview, we summarize the experimental basis of these findings, their implications, and speculate as to the molecular basis for Rab5-mediated TORC2 activation.
- Published
- 2019
50. Correction: Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children’s Oncology Group
- Author
-
Shulman, David S, Klega, Kelly, Imamovic-Tuco, Alma, Clapp, Andrea, Nag, Anwesha, Thorner, Aaron R, Van Allen, Eliezer, Ha, Gavin, Lessnick, Stephen L, Gorlick, Richard, Janeway, Katherine A, Leavey, Patrick J, Mascarenhas, Leo, London, Wendy B, Vo, Kieuhoa T, Stegmaier, Kimberly, Hall, David, Krailo, Mark D, Barkauskas, Donald A, DuBois, Steven G, and Crompton, Brian D
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Pediatric ,Rare Diseases ,Pediatric Cancer ,Pediatric Research Initiative ,Clinical Research ,Cancer ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
The authors have noticed that the final paragraph of the Results section contains errors in the number of patients involved. The correct number of patients is included in the text below. These errors do not affect the Figure referenced.In osteosarcoma, we focused on 8q gain as a specific biological feature of interest. Among the 41 patients with detectable ctDNA in the osteosarcoma cohort, 8q gain was detected in 73.2% (30/41). The 3-year EFS for patients with 8q gain (n = 30) in ctDNA was 60.0% (95% CI 40.5-75.0) compared to 80.8 (95% CI 42.4-94.9) in patients without 8q gain (n = 11) in ctDNA (p = 0.18; Fig. 3).
- Published
- 2019
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