On a theory of the bb-function in positive characteristic

We present a theory of the $b$-function (or Bernstein-Sato polynomial) in positive characteristic. Let $f$ be a non-constant polynomial with coefficients in a perfect field $k$ of characteristic $p>0.$ Its $b$-function $b_f$ is defined to be an ideal of the algebra of continuous $k$-valued functions on $\mathbb{Z}_p.$ The zero-locus of the $b$-function is thus naturally interpreted as a subset of $\mathbb{Z}_p,$ which we call the set of roots of $b_f.$ We prove that $b_f$ has finitely many roots and that they are negative rational numbers. Our construction builds on an earlier work of Musta\c{t}\u{a} and is in terms of $D$-modules, where $D$ is the ring of Grothendieck differential operators. We use the Frobenius to obtain finiteness properties of $b_f$ and relate it to the test ideals of $f.$Comment: Final versio

On D-modules related to the b-function and Hamiltonian flow

Let f be a quasi-homogeneous polynomial with an isolated singularity. We compute the length of the D-modules $Df^c/Df^{c+1}$ generated by complex powers of f in terms of the Hodge filtration on the top cohomology of the Milnor fiber. For 1/f we obtain one more than the reduced genus of the singularity. We conjecture that this holds without the quasi-homogeneous assumption. We also deduce that the aforementioned quotient is nonzero when c is a root of the b-function of f (which Saito recently showed fails to hold in the inhomogeneous case). We obtain these results by comparing these D-modules to those defined by Etingof and the second author which represent invariants under Hamiltonian flow.Comment: 15 pages, final version. All comments welcom

Feynman integral relations from parametric annihilators

We study shift relations between Feynman integrals via the Mellin transform through parametric annihilation operators. These contain the momentum space IBP relations, which are well-known in the physics literature. Applying a result of Loeser and Sabbah, we conclude that the number of master integrals is computed by the Euler characteristic of the Lee-Pomeransky polynomial. We illustrate techniques to compute this Euler characteristic in various examples and compare it with numbers of master integrals obtained in previous works.Comment: v2: new section 3.1 added, several misprints corrected and additional remark

Bernstein-Sato theory modulo pmp^m

For fixed prime integer $p > 0$ we develop a notion of Bernstein-Sato polynomial for polynomials with $\mathbb{Z} / p^m$-coefficients, compatible with existing theory in the case $m = 1$. We show that the ``roots" of such polynomials are rational and we show that the negative roots agree with those of the mod-$p$ reduction. We give examples to show that, surprisingly, roots may be positive in this context. Moreover, our construction allows us to define a notion of ``strength" for roots by measuring $p$-torsion, and we show that ``strong" roots give rise to roots in characteristic zero through mod-$p$ reduction.Comment: Comments welcom

Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy

Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies

On the pp-supports of a holonomic D\mathcal{D}-module

For a smooth variety $Y$ over a perfect field of positive characteristic, the sheaf $D_Y$ of crystalline differential operators on $Y$ (also called the sheaf of $PD$-differential operators) is known to be an Azumaya algebra over $T^*_{Y'},$ the cotangent space of the Frobenius twist $Y'$ of $Y.$ Thus to a sheaf of modules $M$ over $D_Y$ one can assign a closed subvariety of $T^*_{Y'},$ called the $p$-support, namely the support of $M$ seen as a sheaf on $T^*_{Y'}.$ We study here the family of $p$-supports assigned to the reductions modulo primes $p$ of a holonomic $\mathcal{D}$-module. We prove that the Azumaya algebra of differential operators splits on the regular locus of the $p$-support and that the $p$-support is a Lagrangian subvariety of the cotangent space, for $p$ large enough. The latter was conjectured by Kontsevich. Our approach also provides a new proof of the involutivity of the singular support of a holonomic $\mathcal{D}$-module, by reduction modulo $p.$Comment: The article has been rewritten with much improved exposition as well as some additional results, e.g. Corollary 6.3.1. This is the final version, accepted for publication in Inventiones Mathematica

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field