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Abstract Infinite distance limits in the moduli space of a quantum gravity theory are characterized by having infinite towers of states becoming light, as dictated by the Distance Conjecture in the Swampland program. These towers imply a drastic breakdown in the perturbative regimes of the effective field theory at a quantum gravity cut-off scale known as the species scale. In this work, we find a universal pattern satisfied in all known infinite distance limits of string theory compactifications, which relates the variation in field space of the mass of the tower and the species scale: ∇ → m m · ∇ → Λ sp Λ sp = 1 d − 2 $$ \frac{\overrightarrow{\nabla}m}{m}\cdotp \frac{\overrightarrow{\nabla}{\Lambda}_{\textrm{sp}}}{\Lambda_{\textrm{sp}}}=\frac{1}{d-2} $$ in d spacetime dimensions. This implies a more precise definition of the Distance conjecture and sharp bounds for the exponential decay rates. We provide plethora of evidence in string theory in diverse dimensions and with different levels of supersymmetry, and identify some sufficient conditions that allow the pattern to hold from a bottom-up perspective.

Abstract We study towers of light particles that appear in infinite-distance limits of moduli spaces of 9-dimensional N $$ \mathcal{N} $$ = 1 string theories, some of which notably feature decompactification limits with running string coupling. The lightest tower in such decompactification limits consists of the non-BPS Kaluza-Klein modes of Type I′ string theory, whose masses depend nontrivially on the moduli of the theory. We work out the moduli-dependence by explicit computation, finding that despite the running decompactification the Distance Conjecture remains satisfied with an exponential decay rate α ≥ 1 / d − 2 $$ \alpha \ge 1/\sqrt{d-2} $$ in accordance with the sharpened Distance Conjecture. The related sharpened Convex Hull Scalar Weak Gravity Conjecture also passes stringent tests. Our results non-trivially test the Emergent String Conjecture, while highlighting the important subtlety that decompactifcation can lead to a running solution rather than to a higher-dimensional vacuum.

Abstract We study whether the universal runaway behaviour of stringy scalar potentials towards infinite field distance limits can produce an accelerated expanding cosmology à la quintessence. We identify a loophole to some proposed bounds that forbid such asymptotic (at parametric control) accelerated expansion in 4d N $$ \mathcal{N} $$ = 1 supergravities, by considering several terms of the potential competing asymptotically. We then analyse concrete string theory examples coming from F-theory flux compactifications on Calabi-Yau fourfolds, extending previous results by going beyond weak string coupling to different infinite distance limits in the complex structure moduli space. We find some potential candidates to yield asymptotic accelerated expansion with a flux potential satisfying γ = ‖ ∇ V ‖ V < 2 $$ \gamma =\frac{\left\Vert \nabla V\right\Vert }{V}

Abstract The most natural expectation away from asymptotic limits in moduli space of supergravity theories is the desert scenario, where there are few states between massless fields and the quantum gravity cutoff. In this paper we initiate a systematic study of these regions deep in the moduli space, and use it to place a bound on the number of massless modes by relating it to the black hole species problem. There exists a consistent sub-Planckian UV cutoff (the species scale) which resolves the black hole species problem without bounding the number of light modes. We reevaluate this in the context of supersymmetric string vacua in the desert region and show that even though heuristically the species scale is compatible with expectations, the BPS states of the actual string vacua lead to a stronger dependence of the cutoff scale on the number of massless modes. We propose that this discrepancy, which can be captured by the “BPS desert conjecture”, resurrects the idea of a uniform bound on the number of light modes as a way to avoid the black hole species problem. This conjecture also implies a stronger form of the Tadpole Conjecture, which leads to an obstruction in stabilizing all moduli semi-classically for large number of moduli in flux compactifications.

Abstract Motivated by principles from the Swampland program, which characterize requirements for a consistent UV completion of quantum gravity, combined with observational data, we are led to a unique corner of the quantum gravity landscape. In particular, using the Distance/Duality conjecture and the smallness of dark energy, we predict the existence of a light tower of states and a unique extra mesoscopic dimension of length l ∼ Λ − 1 4 ∼ 10 − 6 m $$ l\sim {\Lambda}^{-\frac{1}{4}}\sim {10}^{-6}m $$ , with extra massless fermions propagating on it. This automatically leads to a candidate for a tower of sterile neutrinos, and an associated active neutrino mass scale m ν ∼ H 2 Λ − 1 12 M pl − 2 3 $$ {m}_{\nu}\sim {\left\langle H\right\rangle}^2{\Lambda}^{-\frac{1}{12}}{M}_{\textrm{pl}}^{-\frac{2}{3}} $$ . Moreover, assuming the mechanism for stabilization of this dark dimension leads to similar masses for active and sterile neutrinos we are led to the prediction of a Higgs vev H ∼ Λ 1 6 M pl 1 3 $$ \left\langle H\right\rangle \sim {\Lambda}^{\frac{1}{6}}{M}_{\textrm{pl}}^{\frac{1}{3}} $$ . Another prediction of the scenario is a species scale M ̂ ∼ Λ 1 12 M pl 2 3 ∼ 10 9 – 10 10 $$ \hat{M}\sim {\Lambda}^{\frac{1}{12}}{M}_{\textrm{pl}}^{\frac{2}{3}}\sim {10}^9\hbox{--} {10}^{10} $$ GeV, corresponding to the higher-dimensional Planck scale. This energy scale may be related to the resolution of the instability of the Higgs effective potential present at a scale of ~1011 GeV. We also speculate about the interplay between this energy scale and the GZK limit on ultra-high energy cosmic rays.

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.

Abstract We draw attention to a class of generalized global symmetries, which we call “Chern-Weil global symmetries,” that arise ubiquitously in gauge theories. The Noether currents of these Chern-Weil global symmetries are given by wedge products of gauge field strengths, such as F 2 ∧ H 3 and tr( F 2 2 $$ {F}_2^2 $$ ), and their conservation follows from Bianchi identities. As a result, they are not easy to break. However, it is widely believed that exact global symmetries are not allowed in a consistent theory of quantum gravity. As a result, any Chern-Weil global symmetry in a low-energy effective field theory must be either broken or gauged when the theory is coupled to gravity. In this paper, we explore the processes by which Chern-Weil symmetries may be broken or gauged in effective field theory and string theory. We will see that many familiar phenomena in string theory, such as axions, Chern-Simons terms, worldvolume degrees of freedom, and branes ending on or dissolving in other branes, can be interpreted as consequences of the absence of Chern-Weil symmetries in quantum gravity, suggesting that they might be general features of quantum gravity. We further discuss implications of breaking and gauging Chern-Weil symmetries for particle phenomenology and for boundary CFTs of AdS bulk theories. Chern-Weil global symmetries thus offer a unified framework for understanding many familiar aspects of quantum field theory and quantum gravity.

Abstract We formulate a series of conjectures relating the geometry of conformal manifolds to the spectrum of local operators in conformal field theories in d > 2 spacetime dimensions. We focus on conformal manifolds with limiting points at infinite distance with respect to the Zamolodchikov metric. Our central conjecture is that all theories at infinite distance possess an emergent higher-spin symmetry, generated by an infinite tower of currents whose anomalous dimensions vanish exponentially in the distance. Stated geometrically, the diameter of a non-compact conformal manifold must diverge logarithmically in the higher-spin gap. In the holographic context our conjectures are related to the Distance Conjecture in the swampland program. Interpreted gravitationally, they imply that approaching infinite distance in moduli space at fixed AdS radius, a tower of higher-spin fields becomes massless at an exponential rate that is bounded from below in Planck units. We discuss further implications for conformal manifolds of superconformal field theories in three and four dimensions.

Abstract It is widely believed that consistent theories of quantum gravity satisfy two basic kinematic constraints: they are free from any global symmetry, and they contain a complete spectrum of gauge charges. For compact, abelian gauge groups, completeness follows from the absence of a 1-form global symmetry. However, this correspondence breaks down for more general gauge groups, where the breaking of the 1-form symmetry is insufficient to guarantee a complete spectrum. We show that the correspondence may be restored by broadening our notion of symmetry to include non-invertible topological operators, and prove that their absence is sufficient to guarantee a complete spectrum for any compact, possibly disconnected gauge group. In addition, we prove an analogous statement regarding the completeness of twist vortices: codimension-2 objects defined by a discrete holonomy around their worldvolume, such as cosmic strings in four dimensions. We discuss how this correspondence is modified in various, more general contexts, including non-compact gauge groups, Higgsing of gauge theories, and the addition of Chern-Simons terms. Finally, we discuss the implications of our results for the Swampland program, as well as the phenomenological implications of the existence of twist strings.

Abstract We observe a direct relation between the existence of fundamental axionic strings, dubbed EFT strings, and infinite distance limits in 4d N $$ \mathcal{N} $$ = 1 EFTs coupled to gravity. The backreaction of EFT strings can be interpreted as RG flow of their couplings, and allows one to probe different regimes within the field space of the theory. We propose that any 4d EFT infinite distance limit can be realised as an EFT string flow. We show that along such limits the EFT string becomes asymptotically tensionless, and so the EFT eventually breaks down. This provides an upper bound for the maximal field range of an EFT with a finite cut-off, and reproduces the Swampland Distance Conjecture from a bottom-up perspective. Even if there are typically other towers of particles becoming light, we propose that the mass of the leading tower scales as m 2 ∼ T $$ \mathcal{T} $$ w in Planck units, with T $$ \mathcal{T} $$ the EFT string tension and w a positive integer. Our results hold even in the presence of a non-trivial potential, as long as its energy scale remains well below the cut-off. We check both proposals for large classes of 4d N $$ \mathcal{N} $$ = 1 string compactifications, finding that only the values w = 1, 2, 3 are realised.

Genetic tests have led to the discovery of many novel genetic variants related to growth failure, but the clinical significance of some results is not always easy to establish. The aim of this report is to describe both clinical phenotype and genetic characteristics in an adult patient with short stature associated with a homozygous variant in disintegrin and metalloproteinase with thrombospondin motifs type 17 gene (ADAMTS17) combined with a homozygous variant in the GH secretagogue receptor (GHS-R). The index case had severe short stature (SS) (−3.0 SD), small hands and feet, associated with eye disturbances. Genetic tests revealed homozygous compounds for ADAMTS17 responsible for Weill–Marchesani-like syndrome but a homozygous variant in GHS-R was also detected. Dynamic stimulation with an insulin tolerance test showed a normal elevation of GH, while the GH response to macimorelin stimulus was totally flattened. We show the implication of the GHS-R variant and review the molecular mechanisms of both entities. These results allowed us to better interpret the phenotypic spectrum, associated co-morbidities, its implications in dynamic tests, genetic counselling and treatment options not only to the index case but also for her relatives.

Syndromic immunodeficiencies are a heterogeneous group of inborn errors of immunity that can affect the development of non-immune organs and systems. The genetic basis of these immunodeficiencies is highly diverse, ranging from monogenic defects to large chromosomal aberrations. Antibody deficiency is the most prevalent immunological abnormality in patients with syndromic immunodeficiencies caused by chromosomal rearrangements, and usually manifests as a common variable immunodeficiency (CVID)-like phenotype. Here we describe a patient with a complex phenotype, including neurodevelopmental delay, dysmorphic features, malformations, and CVID (hypogammaglobulinemia, reduced pre-switch and switch memory B cells, and impaired vaccine response). Microarray-based comparative genomic hybridization (aCGH) revealed a 13-Mb deletion on chromosome 4q22.2-q24 involving 53 genes, some of which were related to the developmental manifestations in our patient. Although initially none of the affected genes could be linked to his CVID phenotype, subsequent reanalysis identified NFKB1 haploinsufficiency as the cause. This study underscores the value of periodic reanalysis of unsolved genetic studies performed with high-throughput technologies (eg, next-generation sequencing and aCGH). This is important because of the ongoing incorporation of new data establishing the relationship between genes and diseases. In the present case, NFKB1 had not been associated with human disease at the time aCGH was performed. Eight years later, reanalysis of the genes included in the chromosome 4 deletion enabled us to identify NFKB1 haploinsufficiency as the genetic cause of our patient’s CVID. In the future, other genes included in the deletion may be linked to human disease, allowing us to better define the molecular basis of our patient’s complex clinical phenotype.

Abstract Background With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype–phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. Methods We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. Results We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188–221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. Conclusions Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Abstract The Swampland Distance Conjecture (SDC) restricts the geodesic distances that scalars can traverse in effective field theories as they approach points at infinite distance in moduli space. We propose that, when applied to the subset of light fields in effective theories with scalar potentials, the SDC restricts the amount of non-geodesicity allowed for trajectories along valleys of the potential. This is necessary to ensure consistency of the SDC as a valid swampland criterion at any energy scale across the RG flow. We provide a simple description of this effect in moduli space of hyperbolic space type, and products thereof, and obtain critical trajectories which lead to maximum non-geodesicity compatible with the SDC. We recover and generalize these results by expressing the SDC as a new Convex Hull constraint on trajectories, characterizing towers by their scalar charge to mass ratio in analogy to the Scalar Weak Gravity Conjecture. We show that recent results on the asymptotic scalar potential of flux compatifications near infinity in moduli space precisely realize these critical amounts of non-geodesicity. Our results suggest that string theory flux compactifications lead to the most generic potentials allowing for maximum non-geodesicity of the potential valleys while respecting the SDC along them.

Abstract Swampland criteria like the Weak Gravity Conjecture should not only apply to particles, but also to other lower-codimension charged objects in 4d EFTs like strings and membranes. However, the description of the latter is in general subtle due to their large backreaction effects. In the context of 4d N $$ \mathcal{N} $$ = 1 EFTs, we consider 1 2 $$ \frac{1}{2} $$ BPS strings and membranes which are fundamental, in the sense that they cannot be resolved within the EFT regime. We argue that, if interpreted from the EFT viewpoint, the 4d backreaction of these objects translates into a classical RG flow of their couplings. Constraints on the UV charges and tensions get then translated to constraints on the axionic kinetic terms and scalar potential of the EFT. This uncovers new relations among the Swampland Conjectures, which become interconnected by the physical properties of low-codimension objects. In particular, using that string RG flows describe infinite field distance limits, we show that the WGC for strings implies the Swampland Distance Conjecture. Similarly, WGC-saturating membranes generate a scalar potential satisfying the de Sitter Conjecture.

Abstract We analyze the charge-to-mass structure of BPS states in general infinite-distance limits of N $$ \mathcal{N} $$ = 2 compactifications of Type IIB string theory on Calabi-Yau three-folds, and use the results to sharpen the formulation of the Swampland Conjectures in the presence of multiple gauge and scalar fields. We show that the BPS bound coincides with the black hole extremality bound in these infinite distance limits, and that the charge-to-mass vectors of the BPS states lie on degenerate ellipsoids with only two non-degenerate directions, regardless of the number of moduli or gauge fields. We provide the numerical value of the principal radii of the ellipsoid in terms of the classification of the singularity that is being approached. We use these findings to inform the Swampland Distance Conjecture, which states that a tower of states becomes exponentially light along geodesic trajectories towards infinite field distance. We place general bounds on the mass decay rate λ of this tower in terms of the black hole extremality bound, which in our setup implies λ ≥ 1 / 6 $$ \lambda \ge 1/\sqrt{6} $$ . We expect this framework to persist beyond N $$ \mathcal{N} $$ = 2 as long as a gauge coupling becomes small in the infinite field distance limit.

Abstract A bubble of nothing is a spacetime instability where a compact dimension collapses. After nucleation, it expands at the speed of light, leaving “nothing” behind. We argue that the topological and dynamical mechanisms which could protect a compactification against decay to nothing seem to be absent in string compactifications once supersymmetry is broken. The topological obstruction lies in a bordism group and, surprisingly, it can disappear even for a SUSY-compatible spin structure. As a proof of principle, we construct an explicit bubble of nothing for a T 3 with completely periodic (SUSY-compatible) spin structure in an Einstein dilaton Gauss-Bonnet theory, which arises in the low-energy limit of certain heterotic and type II flux compactifications. Without the topological protection, supersymmetric compactifications are purely stabilized by a Coleman-deLuccia mechanism, which relies on a certain local energy condition. This is violated in our example by the nonsupersymmetric GB term. In the presence of fluxes this energy condition gets modified and its violation might be related to the Weak Gravity Conjecture. We expect that our techniques can be used to construct a plethora of new bubbles of nothing in any setup where the low-energy bordism group vanishes, including type II compactifications on CY 3, AdS flux compactifications on 5-manifolds, and M-theory on 7-manifolds. This lends further evidence to the conjecture that any non-supersymmetric vacuum of quantum gravity is ultimately unstable.

Abstract We initiate the systematic study of flux scalar potentials and their vacua by using asymptotic Hodge theory. To begin with, we consider F-theory compactifications on Calabi-Yau fourfolds with four-form flux. We argue that a classification of all scalar potentials can be performed when focusing on regions in the field space in which one or several fields are large and close to a boundary. To exemplify the constraints on such asymptotic flux compactifications, we explicitly determine this classification for situations in which two complex structure moduli are taken to be large. Our classification captures, for example, the weak string coupling limit and the large complex structure limit. We then show that none of these scalar potentials admits de Sitter critical points at parametric control, formulating a new no-go theorem valid beyond weak string coupling. We also check that the recently proposed asymptotic de Sitter conjecture is satisfied near any infinite distance boundary. Extending this strategy further, we generally identify the type of fluxes that induce an infinite series of Anti-de Sitter critical points, thereby generalizing the well-known Type IIA settings. Finally, we argue that also the large field dynamics of any axion in complex structure moduli space is universally constrained. Displacing such an axion by large field values will generally lead to severe backreaction effects destabilizing other directions.

We consider constraints on D-dimensional theories in MD, dSD and AdSD backgrounds in the light of AdS swampland conjectures as applied to their compactification in a circle. In particular we consider the non-SUSY AdS instability conjecture and the AdS distance conjecture. For MD and dSD vacua the results may be summarized by a light fermion conjecture which states that in theories with ΛD≥0 and a positive first non-vanishing supertrace (−1)k+1StrM2k>0, a surplus of light fermions with mass mf≲ΛD1/D must be present. For dSD this is supported by both AdS swampland conjectures. On the contrary, the cases of MD and AdSD can be made consistent with the mild but not the strong version of the AdS Distance conjecture, since the KK tower in the lower d-dim theory will scale as m≲Λdα with α=1/d. The above constraints also suggest that the Standard Model of particle physics would be inconsistent in Minkowski space but consistent in dS if the lightest neutrino is Dirac and lighter than the cosmological constant scale.

Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth disorder caused by germline heterozygous mutations in the DNA methyltransferase DNMT3A. DNMT3A is a critical regulator of hematopoietic stem cell (HSC) differentiation and somatic DNMT3A mutations are frequent in hematologic malignancies and clonal hematopoiesis. Yet, the impact of constitutive DNMT3A mutation on hematopoiesis in TBRS is undefined. In order to establish how constitutive mutation of DNMT3A impacts blood development in TBRS we gathered clinical data and analyzed blood parameters in 18 individuals with TBRS. We also determined the distribution of major peripheral blood cell lineages by flow cytometric analyses. Our analyses revealed non-anemic macrocytosis, a relative decrease in lymphocytes and increase in neutrophils in TBRS individuals compared to unaffected controls. We were able to recapitulate these hematologic phenotypes in multiple murine models of TBRS and identified rare hematological and non-hematological malignancies associated with constitutive Dnmt3a mutation. We further show that loss of DNMT3A in TBRS is associated with an altered DNA methylation landscape in hematopoietic cells affecting regions critical to stem cell function and tumorigenesis. Overall, our data identify key hematopoietic effects driven by DNMT3A mutation with clinical implications for individuals with TBRS and DNMT3A-associated clonal hematopoiesis or malignancies.

Abstract The Swampland Distance Conjecture suggests that an infinite tower of modes becomes exponentially light when approaching a point that is at infinite proper distance in field space. In this paper we investigate this conjecture in the Kähler moduli spaces of Calabi-Yau threefold compactifications and further elucidate the proposal that the infinite tower of states is generated by the discrete symmetries associated to infinite distance points. In the large volume regime the infinite tower of states is generated by the action of the local monodromy matrices and encoded by an orbit of D-brane charges. We express these monodromy matrices in terms of the triple intersection numbers to classify the infinite distance points and construct the associated infinite charge orbits that become massless. We then turn to a detailed study of charge orbits in elliptically fibered Calabi-Yau threefolds. We argue that for these geometries the modular symmetry in the moduli space can be used to transfer the large volume orbits to the small elliptic fiber regime. The resulting orbits can be used in compactifications of M-theory that are dual to F-theory compactifications including an additional circle. In particular, we show that there are always charge orbits satisfying the distance conjecture that correspond to Kaluza-Klein towers along that circle. Integrating out the KK towers yields an infinite distance in the moduli space thereby supporting the idea of emergence in that context.

Abstract The Swampland Distance Conjecture (SDC) constraints the dynamics emerging at infinite distances in field space of any effective field theory consistent with quantum gravity. It provides a relation between the cut-off in energies and the field range which, as we show, in the context of inflation it yields a universal upper bound on the inflaton excursion in terms of the tensor-to-scalar ratio, measured at typical CMB scales. In this note, we investigate the interplay between the SDC and the emergent inflationary physics around infinite distances singularities in string theory, with a special look at its significance for the α-attractor scenario of inflation. We show that the conjecture itself suggests that inflation may arise as an infinite distance phenomenon with the asymptotic kinetic structure typical of α-attractors. Furthermore, we argue that a proper string realisation of these cosmological models in Calabi-Yau manifolds should occur around infinite field distance singularities. However, such constructions typically imply that inflation should not take place in the limit where the inflaton kinetic term develops a pole but rather in the opposite regime. Finally, we study the constraints that the SDC poses on α-attractors and show that they still leave considerable room for compatibility with observations.

Abstract It has been conjectured that in theories consistent with quantum gravity infinite distances in field space coincide with an infinite tower of states becoming massless exponentially fast in the proper field distance. The complex-structure moduli space of Calabi-Yau manifolds is a good testing ground for this conjecture since it is known to encode quantum gravity physics. We study infinite distances in this setting and present new evidence for the above conjecture. Points in moduli space which are at infinite proper distance along any path are characterised by an infinite order monodromy matrix. We utilise the nilpotent orbit theorem to show that for a large class of such points the monodromy matrix generates an infinite orbit within the spectrum of BPS states. We identify an infinite tower of states with this orbit. Further, the theorem gives the local metric on the moduli space which can be used to show that the mass of the states decreases exponentially fast upon approaching the point. We also propose a reason for why infinite distances are related to infinite towers of states. Specifically, we present evidence that the infinite distance itself is an emergent quantum phenomenon induced by integrating out at one-loop the states that become massless. Concretely, we show that the behaviour of the field space metric upon approaching infinite distance can be recovered from integrating out the BPS states. Similarly, at infinite distance the gauge couplings of closed-string Abelian gauge symmetries vanish in a way which can be matched onto integrating out the infinite tower of charged BPS states. This presents evidence towards the idea that also the gauge theory weak-coupling limit can be thought of as emergent.

Abstract It is known that there are AdS vacua obtained from compactifying the SM to 2 or 3 dimensions. The existence of such vacua depends on the value of neutrino masses through the Casimir effect. Using the Weak Gravity Conjecture, it has been recently argued by Ooguri and Vafa that such vacua are incompatible with the SM embedding into a consistent theory of quantum gravity. We study the limits obtained for both the cosmological constant Λ4 and neutrino masses from the absence of such dangerous 3D and 2D SM AdS vacua. One interesting implication is that Λ4 is bounded to be larger than a scale of order m ν 4, as observed experimentally. Interestingly, this is the first argument implying a non-vanishing Λ4 only on the basis of particle physics, with no cosmological input. Conversely, the observed Λ4 implies strong constraints on neutrino masses in the SM and also for some BSM extensions including extra Weyl or Dirac spinors, gravitinos and axions. The upper bounds obtained for neutrino masses imply (for fixed neutrino Yukawa and Λ4) the existence of upper bounds on the EW scale. In the case of massive Majorana neutrinos with a see-saw mechanism associated to a large scale M ≃ 1010 − 14 GeV and Y ν1 ≃ 10−3, one obtains that the EW scale cannot exceed M EW ≲ 102 − 104 GeV. From this point of view, the delicate fine-tuning required to get a small EW scale would be a mirage, since parameters yielding higher EW scales would be in the swampland and would not count as possible consistent theories. This would bring a new perspective into the issue of the EW hierarchy.

Abstract In this paper we study the consistency of generalized global symmetries in theories of quantum gravity, in particular string theory. Such global symmetries arise in theories with (p + 1)-form gauge fields, and for spacetime dimension d ≤ p + 3 there are obstructions to their breaking even by quantum effects of charged objects. In 4d theories with a 2-form gauge field (or with an axion scalar), these fields endow Schwarzschild black holes with quantum hair, a global charge leading to usual trouble with remnants. We describe precise mechanisms, and examples from string compactifications and holographic pairs, in which these problems are evaded by either gauging or breaking the global symmetry, via (suitable versions of) Stuckelberg or 4-form couplings. We argue that even in the absence of such couplings, the generic solution in string theory is the breaking of the global symmetries by cubic Chern-Simons terms involving different antisymmetric tensor fields. We conjecture that any theory with (standard or higher-degree antisymmetric tensor) gauge fields is in the Swampland unless its effective action includes such Chern-Simons terms. This conjecture implies that many familiar theories, like QED (even including the charged particles required by the Weak Gravity Conjecture) or N = 8 $$ \mathcal{N}=8 $$ supergravity in four dimensions, are inconsistent in quantum gravity unless they are completed by these Chern-Simons terms.

Abstract We continue the investigation of F-term axion monodromy inflation in string theory, while seriously taking the issue of moduli stabilization into account. For a number of closed and open string models, we show that they suffer from serious control issues once one is trying to realize trans-Planckian field excursions. More precisely, the flux tuning required to delay the logarithmic scaling of the field distance to a trans-Planckian value cannot be done without leaving the regime where the employed effective supergravity theory is under control. Our findings are consistent with the axionic extension of the Refined Swampland Conjecture, stating that in quantum gravity the effective theory breaks down for a field excursion beyond the Planck scale. Our analysis suggests that models of F-term axion monodromy inflation with a tensor-to-scalar ratio r ≥ O(10−3) cannot be parametrically controlled.

Abstract We clarify the differences between the usual Kaloper-Sorbo description of axion monodromy and the effective axionic potential in terms of Minkowski 4-forms derived in string compactifications. The fact that the metric of the 3-form fields coming from string theory is field dependent (unlike in Kaloper-Sorbo) leads to the backreaction issues recently studied in axion monodromy models within string theory. We reanalyse these problems in terms of the 4-forms focusing on the case in which the non-periodic scalars backreact on the Kahler metric of the inflaton reducing the physical field range. In the closed string sector of Type II Calabi-Yau compactifications with fluxes the metric becomes field dependent precisely when Δϕ ∼ M p , independently of the choice of fluxes. We propose, however, some counter-examples to this universal behaviour by including open string fields.

In the original paper a wrong affiliation has been assigned to author Chongchuo Li during the typesetting.

We study the realization of axion inflation models in the complex structure moduli spaces of Calabi–Yau threefolds and fourfolds. The axions arise close to special points of these moduli spaces that admit discrete monodromy symmetries of infinite order. Examples include the large complex structure point and conifold point, but can be of more general nature. In Type IIB and F-theory compactifications the geometric axions receive a scalar potential from a flux-induced superpotential. We find toy variants of various inflationary potentials including the ones for natural inflation of one or multiple axions, or axion monodromy inflation with polynomial potential. Interesting examples are also given by mirror geometries of torus fibrations with Mordell–Weil group of rank N−1 or an N-section, which admit an axion if N>3.

It has been recently pointed out that high scale inflation, as recently hinted by the BICEP2 results, is consistent with the identification of an inflaton mass mI≃1013 GeV with the SUSY breaking scale in an MSSM with a fine-tuned SM Higgs. This identification leads to a Higgs mass mh≃126 GeV, consistent with LHC measurements. Here we propose that this naturally suggests to identify the inflaton with the heavy MSSM Higgs system. The fact that the extrapolated Higgs coupling λSM≃0 at scales below the Planck scale suggests the Higgs degrees of freedom could be associated with a Wilson line or D-brane position modulus in string theory. The Higgs system then has a shift symmetry and an N=2 structure which guarantees that its potential has an approximate quadratic chaotic inflation form. These moduli in string compactifications, being compact, allow for trans-Planckian inflaton field range analogous to a version of monodromy inflation.

BackgroundWith the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.MethodsWe tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.ResultsWe report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.ConclusionsOverall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Prolyl endopeptidase-like (PREPL) deficiency (MIM#616224) is a rare congenital disorder characterised by neonatal hypotonia and feeding difficulties, growth hormone (GH) deficiency and hypergonadotropic hypogonadism. This syndrome is an autosomal recessive disease resulting from mutations in the PREPL gene (MIM#609557). Herein we report a 7-year-old female patient with biallelic mutations in PREPL (c.1528C>T in one allele and whole gene deletion in the other) with early growth impairment in infancy. GH deficiency was confirmed at 20 months of life. Recombinant GH treatment was introduced with a good response. Her clinical features were similar to those of previously reported cases. The description of new patients with PREPL deficiency syndrome is essential to better delineate the phenotypic and genotypic spectrum of the disease. [ABSTRACT FROM AUTHOR]